1 PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 2 PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 3 Editor-in-chief Dr. Sanjeev Acharya Chairman & Editor Mr. Rajesh Vagh Advisory Members Dr. Amit Kumar Das Dr. N. Udupa Dr. Mrs.Sanju Nanda Dr. Jaiprakash Dr. Ambikanandan Misra Editorial Members Dr. Sameer Sapra Dr. Saurabh Dahiya Mr. Sachin Kushare Dr. Dhrubo Jyoti Sen Dr. Raaz K Maheshwari Mr. Prashant L Pingale Dr. Shiv Om Pratap Dr. Amit Gangwal Mr. Uday Venkat M Mr. B. Raj Kumar Mr. Prabodh Sapkale Dr. Bhavesh Nayak Dr. Shalini Sharma Dr. Samir Shah Asst Editor GSN Koteshwara Rao As healthcare professionals, we are always concerned about the future therapies. We keen to know about new developments, researches and scrutinize the small-small points which will increase our knowledge. It is not wrong to say, stem cell era when lot of development is going on in same area and government is also announced newer guidelines for stem cell research. There is lots of expectation from this new research area. Though stem cell is not something new but in recent decades huge number of research is being performed in area of stem cells. There are newer menstrual blood, as researchers said that, is found to be the most potent source of stem cells so far. Discovering curative power of stem cells has been a revolutionary breakthrough in the field of surgery and medicine till date, which has actually given many the precious gift of life. Due to their simplicity of collection and isolation, Menstrual Stem Cells would be a great impending basis of multipotent cells if they also showed these properties. This issue is giving information on surfactants versatility in food industry, reviews on Fast Dissolving Tablet, African Anti-Malarial Herbal Plants, microemulsion, Floating Drug Delivery System, Effect of Diabetes on Vascular Endothelium, Ethnopharmacological Potential of Ricinus Communis, chemical and biological activity of Trifolium Pretense, Nutritional Value of Dry Fruits, Benzimidazole Derivatives, Von Hippel-Lindau (VHL) Syndrome, Medicinal value of carom seeds and research on Medication Safety in Children. On behalf of our editorial team, I sincerely thank all authors for sharing their views and research with us. Hope we will receive similar support in future also. - Rajesh Vagh Views and opinions expressed in this publication are not necessarily those of publishers. While every effort has been made to ensure accuracy of the information published in this issue, PharmaTutor or any of its associates can not take any responsibility for any errors or omissions. No part of this publication may be reproduced or transmitted in any form, without the prior permission in writing from publisher. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 4 CONTENT Editorial Article ●Astounding Tea: A Plunge of Dynamism and Vivacity (Raaz Maheshwari, India)……………………………………………………………………………………………………………………………………… Review & Research Articles ● Menstrual Blood-Embracing Scenario of Futuristic Regenerative Medicine (Languluri Reddenna et al, India)……… (Rakesh K. Sharma, India) ……………………………………………….. ● A Review: Formulation of Fast Dissolving Tablet (Patel Zinkal K, India) ……………………………………………………………... ● African Herbal Plants used as Anti-Malarial Agents - A Review (Enegide Chinedu, Nigeria) ……………………………….. 47 ● Futuristic Drug Delivery System Microemulsions: A Review (Shingitha K.P, India) .………………………………………….... ● Review: An Overview on Floating Drug Delivery System (Hemant Maheta et al, India) ..……………………………………. ● A Review: Effect of Diabetes on Vascular Endothelium (Yogesh K. Patil, India) ...………………………………………………. ● A Review on Ethnopharmacological Potential of Ricinus Communis Linn.(KM Preeti et al, India) ...…………………… ● Biotechnology for a Better World (Nirav.R. Soni, India) …………………………………………………………………………………….. 86 ● A review on chemical and biological activity of Trifolium Pretense (Neeta Chaudhary et al, India) ………………….… ● Nutritional Value of Dry Fruits and their Vital Significance - A Review (Pooja Dhiman et al, India)…………………… ● Benzimidazole Derivatives and Its Biological Importance: A Review (Vishwanadham Yerragunta et al, India)….. 109 ● Von Hippel-Lindau (VHL) Syndrome: A Critical Insight (Tapan Behl et al, I dia …………….…………………………………. 114 ● Medicinal value of carom seeds – An overview (Pooja Dhiman et al, India) …………..………………………………………… ● Medication Safety in Children(Languluri Reddenna et al, India) …………………………………………………………………….… 124 ● Surfactants: Basics and Versatility in Food Industries Awareness Articles ● Challenging role of Pharmacist in Health Care The Future Prospects (Nishant Verma, India) ……………………...….. 134 Conferences & Events PHARMA INDUSTRY-INSTITUTE INTERACTION SUMMIT …………………………………………………………………….………………. 41 NATIONAL SEMINAR ON EMPOWERMENT OF WOMEN …………………………………………………………………….………………. WORKSHOP IN ASSOCIATION WITH INCLINITION ON AT P. WADHWANI COLLEGE OF PHARMACY ….………………… NATIONAL CONFERENCE AT BHAGWAN MAHAVIR MEDICAL RESEARCH CENTRE ……………………………….……………… ONE DAY NATIONAL SEMINAR ON DRUG DISCOVERY AND DEVELOPMENT IN ITM UNIVERSITY ……….……………….. NIPiCON 2014 postevent report …………………………………………………………………….………………………………………………….. READER’S CORNER LOWER-INTENSITY STATIN COMBINATION THERAPY PHARMA FACTS CLINICAL NOTES NEWS CORNER PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 30 53 108 137 5 Editorial Article Astounding Tea: A Plunge of Dynamism and Vivacity Raaz Maheshwari,* Department of Chemistry, SBRM Govt PG College, Nagaur, Rajasthan, India *rkmgreenchem.jaipur@gmail.com There are over 3000 varieties of tea, not including botanicals and fruit infusions. To be a tea, it must come from the camellia sinensis plant. There are several varieties of this plant, producing many types of teas. Types depend on the manufacturing and crafting of the leaf. The flavor profiles and quality change year to year, like wine, and is influenced by soil, temperature, rainfall, elevation and other elements in nature. Even the botanicals growing nearby can affect the flavors of the tea. The media has exhaustively publicized the numerous ways drinking tea is good for you: from fighting certain cancers, to decreasing the risk of heart disease and Alzheimer's disease, to controlling cholesterol and even reducing tooth decay! Although most people are aware of tea's health benefits, they are not aware of which teas are the most beneficial. So, from a health perspective, are all teas created equal? Tea is an aromatic beverage commonly prepared by pouring boiling hot water over cured leaves of the Camellia sinensis plant. The term also refers to the plant itself. After water, tea is the most widely consumed beverage in the world. It has a cooling, slightly bitter, astringent flavour which many people enjoy. Consumption of tea (especially green) is beneficial to health and longevity given its antioxidant, flavanols, flavonoids, polyphenols, and catechins content. Tea catechins have known anti-inflammatory and neuroprotective activities, help to regulate food intake, and have an affinity for cannabinoid receptors, which may suppress pain and nausea, and provide calming effects. Consumption of green tea is associated with a lower risk of diseases that cause functional disa ilit , su h as st oke, og iti e i pai e t, a d osteopo osis i the elde l . Tea contains L-theanine, and its consumption is strongly associated with a calm but alert and fo used, elati el p odu ti e α - wave dominant), mental state in humans. This mental state is also common to meditative practice. In this article some health benefits of consuming variety of tea is delineated precisely. What are the purported health benefits of consuming tea? Before we begin, note that here we are talking about tea from the tea plant, Camellia sinensis, and not herbal teas, which are really derived from the flowers, leaves, seeds, bark, or roots of certain plants but contain no actual "real" tea (herbal teas do have purported health benefits, but they are beyond the scope of this bite) . Teas can generally be divided into categories based on how they are processed. There are at least six different types of tea: white, yellow, green, oolong (or wulong), black (called red tea in China), and post-fermented tea (or black tea for the Chinese) of which the most commonly found on the market are white, green, oolong, and black. Some varieties, such as traditional PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 6 oolong tea and Pu-erh tea, a post-fermented tea, can be used medicinally. After picking, the leaves of C. sinensis soon begin to wilt and oxidize, unless they are immediately dried. The leaves turn progressively darker as their chlorophyll breaks down and tannins are released. This enzymatic oxidation process, known as fermentation in the tea industry, is caused by the plant's intracellular enzymes and causes the tea to darken. In tea processing, the darkening is stopped at a predetermined stage by heating, which deactivates the enzymes responsible. In the production of black teas, the halting of oxidization by heating is carried out simultaneously with drying. Without careful moisture and temperature control during manufacture and packaging, the tea may become unfit for consumption, due to the growth of undesired molds and bacteria. At minimum, it may alter the taste and make it undesirable. The following table shows the amount of tea production (in tons) by leading countries in recent years. Data are generated by the Food and Agriculture Organization (FAO) of the United Nations as of February 2012. To get the most out of Tea, Studies have shown that tea may promote good health in the following ways: *Heart Health: The polyphenols (antioxidants) found in tea are very effective in preventing cholesterol from oxidizing and damaging blood vessels. Green tea has been shown to improve the health of the delicate cells lining the blood vessels, which helps lower one's risk of heart disease. *Cancer Prevention: The polyphenols (catechins in particular) in tea may help prevent or decrease the growth and spread of certain cancers. They scavenge oxidants before cell injuries occur, reduce the incidence and size of chemically induced tumors, and inhibit the growth of tumor cells. In studies of liver, skin, and stomach cancer, chemically induced tumors were shown to decrease in size in mice that were fed green and black tea1. *Skin Protector: Not only has tea been shown to be effective in decreasing cancer risk when consumed orally, but it may also be beneficial when applied superficially to the skin. Some research has shown that when green tea is applied to sunburned skin it decreases the development of cancerous skin tumors. This evidence has led many cosmetics companies to start adding green tea to their skin care products. *Alzheimer's Disease Arsenal: Both green and black teas have been shown to hinder the activity of two enzymes in the brain associated with Alzheimer's disease. Although tea consumption cannot cure Alzheimer's, it may be another part of the puzzle in treating or slowing down the development of the disease. *Good for Teeth: Compounds in tea protect teeth by increasing the acid resistance of tooth enamel and acting as antibiotics that kill off dangerous, decay-promoting bacteria. Which tea varieties provide the above health benefits? All "real" teas, which include green, black, and oolong tea varieties, are beneficial to your health. As mentioned above, these teas are all derived from the same tea plant, Camellia sinensis, and contain numerous healthful compounds including polyphenols (particularly catechins), tocopherol, vitamin C, as well as other antioxidants. The polyphenols are believed to be responsible for most of tea's role in promoting good health. Although black, green and oolong teas have different polyphenol compositions due to processing differences, they all have been shown to provide the above health benefits. The differences between the teas are depicted below. As you can see, the main difference between the "real" teas is simply in how the leaves are processed. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 7 Green Teas (Japanese, Chinese, Gunpowder, etc...) Green teas are the freshest and least processed because they are not at all fermented. Of all "real" teas, green tea has the lightest and most subtle taste. Black Teas (Darjeeling, Earl Grey, China Black, Jasmine, etc...) Black tea is simply green tea that has been fermented for around 6 hours. Fermentation turns the green leaves black and alters the polyphenol content, though it is still very high in antioxidants. Black teas have the strongest taste. Oolong Teas These teas are made from green teas that are briefly fermented. Therefore, they are a compromise between black and green tea in both taste and color. *To get the benefits claimed above, opt for a "real" tea variety (green, black, or oolong), as opposed to an herbal tea *Steep tea for about 3 minutes; this time allotment enables the health promoting compounds to be released; steeping for much longer turns the tea bitter and releases too much tannin, which can irritate the digestive tract, cause constipation, and decrease iron absorption. *Hot or Cold? Go for what you like! Bottled teas, iced tea, and teas made from mixes are also all rich in polyphenols. However, keep iced tea fresh, the polyphenol content starts to deteriorate after a few days. If you are worried about the caffeine content of tea, opt for the decaffeinated varieties...they provide the same health benefits without keeping you up all night. The next time you reach for a warm, soothing cup of tea, opt for either green, black or oolong varieties, and steep for about 3 minutes. If you prefer the iced kind, follow the same guidelines but make sure to finish it within a few days before the antioxidant content starts to decline. A few cups of tea a day may help keep the heart doctor and dentist away, as well as cancer and Alzheimer's disease at bay. Drinking eight cups of tea daily might sound a bit too much for some people, but health experts say the intake can help fight heart disease, improve brain power and also boost longevity. Independent Dietician, Dr Carrie ‘u to s esea h o affei e at Ki g s College, London, saw her review 47 published studies to reach the conclusion that caffeinated drinks such as tea, coffee and cocoa have positive effects on mental function, increasing alertness, feelings of well-being and short-term memory. P e ious studies ha e al ead li ked the d i k s healthy antioxidant properties and high flavonoid content to preventing heart disease and cutting the risk of some cancers3. Ruxton has supported earlier reports by claiming that an optimal intake of 400mg of caffeine a day leads to ke e efits i te s of e tal fu tio a d hea t health . Orange peel is some-times added to tea She assessed three studies, accounting for almost 90,000 patients, to find that drinking 4 cups of tea or coffee a day reduced chances of cardiovascular disease. She referred to another study of 26,500 middle-aged smokers, which hinted that men who ingested more than 2cups of tea a day pulled down the probability of getting a stroke by 20 %. Ruxton insisted that she ai ed to de u k false eliefs su ou di g caffeine. Moreover, she asserted that people who avoid drinking team might be doing more harm than good. People ho ut out caffeinated drinks may miss out on the potential health benefits of the compounds the o tai , the Dail E p ess uoted he as saying. She further suggested that there was o eed fo pa e ts to stop hild e f o drinking tea and coffee. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 8 Tea contains catechins, a type of antioxidant. In a freshly picked tea leaf, catechins can compose up to 30% of the dry weight. Catechins are highest in concentration in white and green teas, while black tea has substantially fewer due to its oxidative preparation. Antioxidant content, measured by the lag time for oxidation of cholesterol, is improved by the cold water steeping of varieties of tea. Tea also contains L-theanine, and the stimulant caffeine at about 3% of its dry weight, translating to between 30 mg and 90 mg per 8 oz (250 ml) cup depending on type, brand,[and brewing method. Tea also contains small amounts of theobromine and theophylline. Due to modern environmental pollution, fluoride and aluminium have also been found to occur in tea, with certain types of brick tea made from old leaves and stems having the highest levels. This occurs due to the tea plant's high sensitivity to and absorption of environmental pollutants. Although tea contains various types of polyphenols and tannin, it does not contain tannic acid. Tannic acid is not an appropriate standard for any type of tannin analysis because of its poorly defined composition. Recent studies have shown that drinking black tea can improve the function of the endothelial cells, which line the interior of blood vessels. Endothelial dysfunction is an early indicator of blood pressure changes. Other research has suggested that the flavonoids fou d i tea a i p o e the lood essel s to e a d edu e od eight a d a do i al fat. These fi di gs have important public health implications in light of the high rates of high blood pressure worldwide and the importance of high blood pressure as a risk factor for heart disease and death, the researchers added. In fact, she claimed it was better than juice in some regards. Also, Dr Catherine Hood, of the Tea Ad iso Pa el, ag eed to ‘u to s lai s. “he said, Caffei ated d i ks ha e ee u fai l demonised. Black tea, in particular, contains polyphenols, which are natural plant a tio ida ts. These ha e e efi ial effe ts o many biochemical processes in the body because they protect cells against harmful free adi als. she said. Fla o oids a e thought to be especially useful, with a number of studies reporting a link between them and lower risk of hea t atta k. she added. Suffering from blood pressure? Then, drink at least three cups of black tea daily which may help you lower your pressure, scientists have claimed. Researchers at the University of Western Australia found that people who drank three cups of black tea a day managed to lower their blood pressure (BP) levels by an average of two to three points. That may not sound like much, but even small reductions in BP levels can have a major impact on the prevalence of high blood pressure (hypertension) and risk of heart disease, the esea he s said. At a population level, the observed differences in BP would be associated with a 10 % reduction in the prevalence of hypertension and a seven % to 10 % reduction in the risk of heart disease a d st oke, stud autho Jo atha Hodgson was quoted as saying by WebMD. In the study, the researchers looked at the effect of black tea on blood pressure levels among 95 men and women who were regular tea drinkers. Their average systolic blood pressure (the top number in a blood pressure reading) was between 115 and 150 at the start of the study. Half of the participants drank three cups of black tea per day for six months, and the other half drank a placebo drink with a similar flavour and caffeine content. Both groups were similar in terms of gender, age, and weight status. By the end of the study, those who drank black tea experienced an average reduction of between two and three points in their 24-hour average systolic blood pressure level and about two points in their diastolic (the lower number in a blood pressure reading) level. Tea is sometimes taken with milk This is the first time that long-term use of black tea has been shown to lower blood pressure in people with normal to high-normal blood pressure, said the researchers who detailed their finding in the Archives of Internal Medicine. There are a number of potential explanations for this health benefits PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 9 Review Article Menstrual Blood-Embracing Scenario of Futuristic Regenerative Medicine Languluri Reddenna1*, Sree Nagavalli K2, Kummara Naga Pujitha3 1 Department of Pharmacy Practice, Rajiv Gandhi Institute of Medical Sciences, Kadapa, Andhra Pradesh, India 2 Department of Pharmacy Practice, S.J.M College of Pharmacy, Chitradurga, Karnataka, India 3 Department of Medicine, Rajiv Gandhi Institute of Medical Sciences, Kadapa, Andhra Pradesh, India *reddennapharmd@gmail.com ABSTRACT Women produce natural life; but now they will add medically to save lives through the Endometrial Regenerative Cells (ERC) or stem cells reaped from unwanted menstrual fluid, recognized to be the most revolting stage of woman's life. Menstrual blood, as researchers said that, is found to be the most potent source of stem cells so far. Discovering curative power of stem cells has been a revolutionary breakthrough in the field of surgery and medicine till date, which has actually given many the precious gift of life. The uterine endometrial lining, a annoying source of stem cells, is shed in menstrual process every month. In the rebuilding process that ranges over seven days, billions of cells develop creating almost 5 millimeter-thick lining. These self-renewing cells, also called Endometrial Regenerative Cells, can be developed into other tissues under controlled laboratory conditions and have multipotent markers analogous to stem cells from other sources. The requirement for regenerative therapies incorporating cells that have the ability to engraft and differentiate is vast. Mesenchymal stem cells resulting from bone marrow are presently in clinical trials after demonstrating safety and efficacy in animal models for allogeneic use due to their immunosuppressive proper-ties. Due to their simplicity of collection and isolation, MenSCs would be a great impending basis of multipotent cells if they also showed these properties. Keywords: Menstrual Blood, Regenerative Medicine, Stem Cells, Endometrial Regenerative Cells INTRODUCTION Women create life; but now they will contribute medically to save lives through the Endometrial Regenerative Cells (ERC) or stem cells harvested from discarded menstrual fluid, known to be the most disgusting phase of woman's life. Menstrual blood, as researchers say, is found to be the most potent source of stem cells so far. Discovering curative power of stem cells has been a revolutionary breakthrough in the field of surgery and medicine till date, which has actually given many - the precious gift of life. Endometrial regenerative cell opportunity The company has developed a novel type of stem cell, the Endometrial Regenerative Cell (ERC) that appears to have the major attributes desirable in an ideal cellular therapy: a) They are derived from non-controversial sources; b) The activity of the cells is not substantially neutralized by the immune system, allowing for How to cite this article: L Reddenna, SK Nagavalli, KN Pujitha, Menstrual Blood-Embracing Scenario of Futuristic Regenerative Medicine, PharmaTutor, 2014, 2(3), 9-16 PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 10 use of cells from one standardized source (e.g. universal donor); c) The cells can be administered intravenously since they home to injured or degenerated tissue. Medistem scientists demonstrated that ERC's are capable of transforming into major tissues of the body including heart, lung, liver, brain, and blood vessels. It was published that ERC's also produce large amounts of therapeutic factors, in some situations at higher levels than other types of stem cells. Medistem collaborators have demonstrated that ERC's are potent inducers of new blood vessel formation in animals lacking proper circulation. To date studies have demonstrated that ERC's do not cause adverse effects when administered at therapeutically-relevant doses to animals. Medistem plans to enter clinic trials using ERC's for a condition that will demonstrate proof of concept and safety in a rapid and cost effective way. [1-9] CRITICAL LIMB ISCHEMIA Approximately 160,000 amputations occur each year due to critical limb ischemia, an advanced form of atherosclerosis. Various types of stem cell therapies have been demonstrated to exert positive effects on this condition through stimulating production of new blood vessels. Unfortunately, the majority of such therapies are impractical or costly. For example, the administration of a patient's own bone marrow stem cells into the ischemia muscle has been reported to improve pain free walking distance and reduce need for amputation. However bone marrow extraction and processing is a fairly involved procedure that is not currently feasible on a wide-spread basis. The threshold for clinical success using stem cells in CLI is theoretically lower than for other indications since the stem cells are not required to completely differentiate and generate a new organ. For a therapeutic effect the stem cells need only to stimulate the production of new blood vessels, a process called "angiogenesis". In patients with CLI the new blood vessels start providing oxygen and nutrients to the previously ischemic tissue, resulting in healing of ulcers and restoration of leg function. Approaching Critical Limb Ischemia with ERC-142 Bone marrow transplantation is the only successful stem cell therapy that has saved hundreds of thousands of lives. Arguably its success is attributed to the fact that the bone marrow stem cells were required to do what they were naturally meant to do: make blood. ERC's have a specialized function in the endometrium: to make new blood vessels. With every menstrual cycle the endometrium builds up and then sloughs off. This rapid accumulation of highly vascularized tissue, we believe, is associated with the natural ability of the ERC to generate new blood vessels. Medistem's first clinical use of the ERC in the USA is aimed at using this natural ability of ERC's to make new blood vessels in patients with CLI. Medistem's CLI product is ERC-142, a standardized, "universal donor" cell preparation that is delivered frozen to the doctor's office, and when ready for use is injected into the ischemic muscle of patients with CLI. The planned clinical trials of ERC-142 will assess the ability of this new stem cell population to improve circulation of patients with CLI who have no option but amputation. Expansion of ERC Angiogenesis Candidates Therapeutic angiogenesis is considered a "Holy Grail" of biologics. While the ERC-142 program will spearhead clinical development, Medistem plans to concurrently develop other ERC-based products for therapeutic angiogenesis in other conditions. Ischemic heart conditions are believed to affect approximately 1 out of 100 people, being considered a $25 billion/year market in the US alone. Stimulation of angiogenesis by other stem cells has been demonstrated to improve animal models of stroke, liver failure, and wound healing. [10-16] PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 11 STEM CELLS- EXHIBITING LIFE Stem cells can be termed as undifferentiated cells having distinctive ability to divide mitotically and differentiate into nerve cells, blood cells, muscle cells or any specialized cell when needed. Limitations of conventional cell sources Stem cells harvested from the customary sources like embryos or adult tissues, have their own set of limitations. Embryonic stem cells can build any cell type required but has serious ethical and host rejection issues associated with it because the harvesting process destroys the fetus involved. Bone marrow harvesting is an invasive and tedious procedure that yields very small quantity of regenerative cells whose powers are limited as is the case with umbilical cord blood cells, though it has no ethical concerns. Some researchers are trying to use skin cells to derive stem cells, where the procedure takes help of few viruses to embed number of genes. One of these genes is known to be cancerous. Stem cells from these conventional sources have been employed to treat blood-related disorders including leukemia. But ERC will help in devising treatments of numerous diseases such as cardiac disease, diabetes, neurological disorders like spinal cord injury, Parkinson's and Alzheimer's diseases and also, assisting aesthetics-related anti-aging therapies. Regenerative medicine redefined The uterine endometrial lining, a rich source of stem cells, is shed in menstrual process every month. In the rebuilding process that ranges over seven days, billions of cells develop creating almost 5 millimeter-thick lining. These self-renewing cells, also called Endometrial Regenerative Cells, can be developed into other tissues under controlled laboratory conditions. These cells possess multipotent markers similar to stem cells from other sources. These Endometrial stem cells were first discovered by an Australian researcher Caroline Gargett from Monash University. She was enthralled to find that a sanitary waste could be so resourceful, citing her findings as "very interesting and very significant". She found the cells exhibiting characteristics similar to adult stem cells. Advantages of endometrial regenerative cells Stem cells from menstrual blood are easier to collect through a harmless procedure. An inexpensive source, it is not painful to the donor women and can be collected for about 35 years of a woman's menstruating age. However, younger women yield better quality of endometrial progenitor cells. Moreover, it takes care of ethical concerns as linked to the embryonic source and there is no fear of tissue rejection too. With multitude of benefits associated with these newly discovered stem cells, potential treatments could be devised for several medical conditions. The ERC's can be processed and preserved effortlessly for future implementation. Researchers say that these cells have a higher reproduction rate, doubling every 19.4 hours, compared to the elemental cells from other sources. Compared to bone marrow, menstrual blood yields almost 30 times more stem cells. These "pluri-potent" cells can develop into cardiac, hepatic, pleural, respiratory epithelial, adipocytic, osteogenic, pancreatic, and neurocytic cells, i.e. roughly nine cell categories, so far the highest known for any stem cell source. This implies that many medical conditions that have no cure till date, may find a new therapy though this regenerative medium. Host rejection is not a trouble with the ERC's because they possess an immune system defining suppressing effect, enabling many patients other than the donor to accept curative therapies. [17-25] Banking the ERC Florida-based Cryo-Cell International, known to be the biggest cord blood bank, also claims to have found stem cells in menstrual fluid. Chief scientist at Cryo-Cell, Julie Allickson described the cells as "highly proliferative which can differentiate into at least five separate lineages and express stem cell markers." "C'Elle" - CryoCell's menstrual blood-banking initiative takes PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 12 care of sample-collection, processing and storing cells. Giving life a definite hope with thorough advancements going on, medical fraternity is sure that the future of regenerative medicine has arrived. While more in-depth researches are required to establish medical employment of endometrial stem cells, the new finding is definitely a momentous achievement in the field of stem cell transplant. Menstruation is really not bad at all - ERC brings along a promising step in the realm of regenerative medicine and surgery, to give life. The question then becomes whether there is a source of multipotent stromal stem cells that can be safely obtained, in a renewable fashion, and maintain potency to differentiate. Recently, stromal cells were identified in endometrial tissue. [26, 27] However, obtaining the cells directly would be a very invasive procedure. The endometrial lining of the uterus has a remarkable capacity for regeneration. During each menstrual cycle there is vast growth of tissue and blood vessels, which is shed at the end of the cycle. The shed blood and tissue contain a heterogeneous population of cells including some with regenerative capacity. [28] The uterine stromal cells have similar multipotent markers commonly found in bone marrow mesenchymal stem cells and May actually originate in part from bone marrow. [2931] Important markers for determining multipotency are Oct-4 and SSEA-4, which are found to be expressed in many multipotent and pluripotent stem cells including ESCs, along with the cell surface marker c-kit (CD117). [32-34] In order to evaluate the practicality of obtaining multipotent stem cells from the uterus, in a safe and reproducible manner, we analyzed the shed menstrual blood and tissue to identify stromal cells (MenSCs). We present here a population of MenSCs that express the multipotent markers Oct-4, SSEA-4, and c-kit, along with their ability to be directionally differentiated in vitro into multiple cell lineages derived from mesoderm and ectoderm and the ability to be easily expanded. Work done so far in the area of menstrual stem cells various research groups throughout the world are now exploring this new source of stem cells. In 2007, Bio Communicable Research Institute, Wichita, USA, reported about the Endometrial Regenerative cells as a Novel Stem cell Populatio . Last ea C o I te atio al company has discovered the fact that menstrual blood can be used to isolate stem cells. In the same year, Keio University scientist tried to use them for generating heart tissues. Dr Amit N. Patel and others from Pittsburgh have found out about the pluripotency and self renewal capability of MenSC. Recently life cell international, Chennai, India have come up with a plan to launch the first menstrual stem cell bank in India. Cells discarded from womb lining during a woman's period are new type of stem cell Dr Xiaolong Meng of the Bio-Communications Research Institute in Wichita, Kansas, led the research team consisting of scientists from the University of Alberta, University of Western Ontario and Medistem Laboratories. The team identified a new type of stem cell that can be reproducibly isolated from menstrual blood collected from healthy female subjects. "We have many problems with our current methods of stem cell therapy, like those taken from bone marrow," commented Dr Meng, "They may be rejected by the recipient and/or have limited potential to generate new tissue. Now we've found a possible new way to overcome these difficulties by using cells from menstrual blood." The growth of new blood vessels from preexisting blood vessels is an essential part of the uterine or womb phase of the menstrual cycle. Cells collected from the menstrual blood of women include types which can be cultured in the laboratory, which replicate almost 70 times in a very rapid time span. This replication rate is far faster than cells which are currently used, taken from umbilical cord blood and bone PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 13 marrow. The cells are so unique in their ability to develop into at least 9 different cells including heart, liver and lung, that researchers called the cells Endometrial Regenerative Cells (ERC). Not only do ERC replicate at a phenomenal rate of almost every 20 hours, but they produce unique growth factors at a rate of almost 100,000 greater than cells from umbilical cord blood. A mere 5ml of menstrual blood collected from a healthy woman provided enough cells which after two weeks of culture provided beating heart cells. The results of this breakthrough research indicate that these cells could be cultured at a large scale, thereby providing an alternative to the current methods of using bone marrow and umbilical cord blood, which itself poses threats of rejection. MENSTRUATION YIELD ADULT STEM CELLS Menstruation may have a fringe benefit as a source of adult stem cells. Scientist report that menstrual blood contains adult stem cells that can develop into nine different types of cells: ● Heart cells ● Pancreatic cells ● Lung cells ● Liver cells ● Nerve cells ● Fat cells ● Muscle cells ● Bone cells Cell procurement and processing An endometrial/menstrual cell sample was procured by using a Divacup (Kitchener, ON) during the first few days of a menstrual cycle. The cells were harvested with the informed consent of the donor as approved by an institutional review board. The cells were transferred in phosphate-buffered saline (PBS) with penicillin/streptomycin and heparin. The sample was shipped at 4°C until it reached the processing laboratory within 24–48 h after procurement. The sample was centrifuged and supernatant was evaluated for bacteria. The cells were then cultured. Growth, multipotent marker expression and characterization of MenSCs MenSCs rapidly expand at a doubling rate of 24–3 6 h; starting with 50,000 cells we obtained 48,000,000 by day 26and they maintained diploid cells with-out chromosomal aberrations as determined by karyotype analysis at passage. Moreover, RTPCR data demonstrated that MenSCs expressed the multipotent marker Oct4 at passage 12, but not SOX-2 or Nanog. Flow cytometric analysis illustrated that MenSCs were positive for stromal cell and/or mesenchymal stem cell markers such as CD44, CD 105, CD166, CD90, CD49f, MHC I, CD29, and CD9 while negative for CD38, CD133, CD45, CD34, MHC II, and LIN, and mildly positive for CXCR4 related to stem cell homing. In addition, flow cytometric analysis confirmed that MenSCs highly expressed the pluripotent marker SSEA-4 and c-kit+ (CD117). Also, SSEA-4 and c-kit+ were colocalized on isolated clones from MenSCs. Cultured MenSCs appeared to have stromal cell morphology. Stromal stem cells have been shown to have great potential for future use in clinical translation of regenerative therapies. [3537] We have presented a population of stromal cells isolated from human menstrual blood (MenSCs). The MenSCs are characterized at both the cellular and molecular level, along with the ability to easily expand and differentiate. This study demonstrates that MenSCs are a unique cell population that can be safely isolated and provide an expandable source of stem cells from child-bearing aged women. The expression of multipotent markers Oct-4, SSEA4, and c - kit (CD1 17) in the MenSCs is not common in most other adult stem cells. We have isolated clones with positive c-kit and SSEA-4 colocalization. This unique population of MenSCs is different than one recently described by Cui et al., which demonstrated skeletal muscle differentiation where they found menstrual blood cells expressing the following flow profile: positive CD13, CD29, CD44, CD54, CD55, CD59, CD73, CD90, CD105, MHC-I and negative CD14, CD31, CD34, CD45, CD50, c-kit, CD133, MHC-II. Cells have the multipotent PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 14 markers mentioned above, which are absent in the cells identified and used by Cui et al.[38] Also, the MenSCs appear to have similar characteristics as the human endometrial stem cells identified by Cho et al. [39] with c-kit (CD117), Matthai et al. [40] with Oct-4, clonally expanded by Gargett et al. [41], and the mouse endometrial stem cells identified by Cervello et al. with both c-kit+ (CD1 17) and Oct-4. Thus, it could be interpreted that MenSCs are the shed version of endometrial stem cells that can be easily harvested in a noninvasive manner. The expression of multipotent markers is indicative of cells that have the capacity to differentiate into cell types derived from multiple germ layers. The transcription factor Oct-4 and SSEA-4 both are markers expressed by human embryonic stem cells [42], which are also highly expressed in our MenSCs, and may explain the rapid cell expansion. It may also explain the ability to be direction-ally differentiated into several cell types. The differentiated cell types demonstrate plasticity of the MenSCs by the fact that cells have not only phenotypic cell surface markers by flow cytometry and immunocytochemistry but also mRNA expression. These data demonstrate that MenSCs are expandable and express multipotent stem cell markers. The need for regenerative therapies incorporating cells that have the ability to engraft and differentiate is vast. However, the ideal cell would also have the ability to be used in an allogeneic manner. Mesenchymal stem cells derived from bone marrow are currently in clinical trials after demonstrating safety and efficacy in animal models for allogeneic use due to their immunosuppressive proper-ties. [43-49] Due to their ease of collection and isolation, MenSCs would be a great potential source of multipotent cells if they also exhibited these properties. CONCLUSION The need for regenerative therapies incorporating cells that have the ability to engraft and differentiate is vast. However, the ideal cell would also have the ability to be used in an allogeneic manner. Mesenchymal stem cells derived from bone marrow are currently in clinical trials after demonstrating safety and efficacy in animal models for allogeneic use due to their immunosuppressive proper-ties. Due to their ease of collection and isolation, MenSCs would be a great potential source of multipotent cells if they also exhibited these properties. ↓ REFERENCES 1. Cervello I, Martinez-Conejero J. A, Horcajadas J. A, Pellicer, A, Simon C. Identification, characterization and co-localization of label-retaining cell population in mouse endometrium with typical undifferentiated markers. Hum. Reprod.2007, 22:45–51. 2. Chan, R. W, Schwab K. E, Gargett C. E. Clonogenicity of human endometrial epithelial and stromal cells. Biol. Reprod, 2004, 70:1738–1750. 3. Cho, N. H, Park Y. K.; Kim, Y. T.; Yang, H.; Kim, S. K. Lifetime expression of stem cell markers in the uter¬ine endometrium. Fertil. Steril. 2004, 81:403–407. 4. Cogle, C. R.; Yachnis, A. T.; Laywell, E. D.; Zander,D. S.; Wingard, D. R.; Steindler, D. A.; Scott, E. W. Bone marrow transdifferentiation in brain after transplantation: A retrospective study. Lancet, 2004, 363:1432– 1437. 5. Cui, C. H.; Uyama, T.; Miyado, K.; Terai, M.; Kyo, S.; Kiyono, T.; Umezawa, A. Menstrual blood-derived cells confer human dystrophin expression in the murine model of Duchenne muscular dystrophy via cell fusion and myo¬genic transdifferentiation. Mol. Biol. Cell, 2007, 18:1586–1594. 6. De Coppi, P.; Bartsch, G.; Siddiqui, M. M.; Xu, T.; Santos, C. C.; Perin, L.; Mostoslavsky, G.; Serre, A. C.; Snyder, E. Y.; Yoo, J. J.; Furth, M. E.; Soker, S.; Atala, A. Isolation of amniotic stem cell lines with potential for therapy. Nat. Biotech, 2007, 25:100–106. 7. Delo, D. M.; De Coppi, P.; Bartsch, Jr., G.; Atala, A. Am¬niotic fluid and placental stem cells. Methods PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 15 Enzymol. 2006, 419:426–438. 8. Gang, E. J.; Bosnakovski, D.; Figueiredo, C. A.; Visser, J. W.; Perlingeiro, R. C. SSEA-4 identifies mesenchymal stem cells from bone marrow. Blood, 2007, 109:1743–1751. 9. Gargett, C. E. Identification and characterization of hu¬man endometrial stem/progenitor cells. Aust. NZ J. Obs¬tet. Gynaecol., 2006, 46:250–253; 10. Greco, S. J.; Liu, K.; Rameshwar, P. Functional similari¬ties among genes regulated by OCT4 in human mesenchy¬mal and embryonic stem cells. Stem Cells, 2007, 25:3143–3154. 11. Henderson, J. K.; Draper, J. S.; Baillie, H. S.; Fishel, S.; Thomson, J. A.; Moore, H.; Andrews, P. W. Preimplanta¬tion human embryos and embryonic stem cells show com-parable expression of stage-specific embryonic antigens. Stem Cells, 2002, 20:329–337. 12. Kearns, M.; Lala, P. K. Bone marrow origin of decidual cell precursors in the pseudopregnant mouse uterus. J. Exp. Med., 1982, 155:1537–1554. 13. Le Blanc, K. Immunomodulatory effects of fetal and adult mesenchymal stem cells. Cytotherapy, 2003, 5:484–489. 14. Ludwig, T. E.; Levenstein, M. E.; Jones, J. M.; Berggren, W. T.; Mitchen, E. R.; Frane, J. L.; Crandall, L. J.; Daigh, C. A.; Conard, K. R.; Piekarczyk, M. S.; Llanas, R. A.; Thomson, J. A. Derivation of human embryonic stem cells in defined conditions. Nat. Biotechnol, 2006, 24:185–187. 15. Mattai, C.; Horvat, R.; Noe, M.; Nagele, F.; Radjabi, A.; Van Trotsenburg, M.; Huber, J.; Kolbus, A. Oct-4 expres¬sion in human endometrium. Mol. Hum. Reprod, 2006, 12:7–10. 16. Minguell, J. J.; Erices, A.; Conget, P. Mesenchymal stem cells. Exp. Biol. Med, 2001, 226:507–520. 17. Nandoe Tewarie, R. D.; Hurtado, A.; Levi, A. D.; Groten¬huis, J. A.; Oudega, M. Bone marrow stromal cells for repair of the spinal cord: Towards clinical application. Cell Transplant. 2006, 15:563–577. 18. Patel, A. N.; Geffner, L.; Vina, R. F.; Saslavsky, J.; Urschel, Jr., H. C.; Kormos, R.; Benetti, F. Surgical treat¬ment for congestive heart failure with autologous adult stem cell transplantation: A prospective randomized study. J. Thorac. Cardiovasc. Surg. 2005, 130:1631–1638. 19. Schwab, K. E.; Chan, R. W.; Gargett, C. E. Putative stem cell activity of human endometrial epithelial and stromal cells during the menstrual cycle. Fertil. Steril, 2005, 84:1124– 1130. 20. Schwab, K. E.; Gargett, C. E. Co-expression of two peri¬vascular cell markers isolates mesenchymal stemlike cells from human endometrium. Hum. Reprod. 2007, 22:2903–2911. 21. Taylor, H. S. Endometrial cells derived from donor stem cells in bone marrow transplant recipients. JAMA 2004, 292: 81–85. 22. Thomson, J. A.; Itskovitz-Eldor, J.; Shapiro, S. S.; Waknitz, M. A.; Swiergiel, J. J.; Marshall, V. S.; Jones, J. M. Embryonic stem cell lines derived from human blas-tocysts. Science, 1998, 282:1145–1147. 23. Toma, C.; Pittenger, M. F.; Cahill, K. S.; Byrne, B. J.; Kessler, P. D. Human mesenchymal stem cells differenti¬ate to a cardiomyocyte phenotype in the adult murine heart. Circulation, 2002, 105:93–98. 24. Vilquin, J. T.; Rosset, P. Mesenchymal stem cells in bone and cartilage repair: Current status. Regen. Med. 2006, 1:589– 604. 25. Yao, S.; Chen, S.; Clark, J.; Hao, E.; Beattie, G. M.; Hayek, A.; Ding, S. Long-term self-renewal and directed differentiation of human embryonic stem cells in chemi¬cally defined conditions. Proc. Natl. Acad. Sci. USA 2006, 103: 6907–6912. 26. Cho, N. H.; Park, Y. K.; Kim, Y. T.; Yang, H.; Kim, S. K. Lifetime expression of stem cell markers in the uter¬ine endometrium. Fertil. Steril., 2004, 81:403–407. 27. Schwab, K. E.; Chan, R. W.; Gargett, C. E. Putative stem cell activity of human endometrial epithelial and stromal cells during the menstrual cycle. Fertil. Steril. 2005, 84:1124– 1130. 28. Cui, C. H.; Uyama, T.; Miyado, K.; Terai, M.; Kyo, S.; Kiyono, T.; Umezawa, A. Menstrual blood-derived cells confer human dystrophin expression in the murine model of Duchenne muscular dystrophy via cell fusion and myo¬genic transdifferentiation. Mol. Biol. Cell, 2007, 18:1586–1594. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 16 29. Kearns, M.; Lala, P. K. Bone marrow origin of decidual cell precursors in the pseudopregnant mouse uterus. J. Exp. Med. 1982, 155:1537–1554. 30. Schwab, K. E.; Gargett, C. E. Co-expression of two peri¬vascular cell markers isolates mesenchymal stemlike cells from human endometrium. Hum. Reprod. 2007, 22:2903–2911. 31. Taylor, H. S. Endometrial cells derived from donor stem cells in bone marrow transplant recipients. JAMA 2004, 292: 81–85. 32. Gargett, C. E. Identification and characterization of hu¬man endometrial stem/progenitor cells. Aust. NZ J. Obs¬tet. Gynaecol. 2006, 46:250–253. 33. Greco, S. J.; Liu, K.; Rameshwar, P. Functional similari¬ties among genes regulated by OCT4 in human mesenchy¬mal and embryonic stem cells. Stem Cells, 2007, 25:3143–3154. 34. Yao, S.; Chen, S.; Clark, J.; Hao, E.; Beattie, G. M.; Hayek, A.; Ding, S. Long-term self-renewal and directed differentiation of human embryonic stem cells in chemi¬cally defined conditions. Proc. Natl. Acad. Sci. USA 2006, 103: 6907–6912. 35. Toma, C.; Pittenger, M. F.; Cahill, K. S.; Byrne, B. J.; Kessler, P. D. Human mesenchymal stem cells differenti¬ate to a cardiomyocyte phenotype in the adult murine heart. Circulation, 2002, 105:93–98. 36. Vilquin, J. T.; Rosset, P. Mesenchymal stem cells in bone and cartilage repair: Current status. Regen. Med. 2006, 1:589– 604. 37. Zurita, M.; Vaquero, J. Functional recovery in chronic paraplegia after bone marrow stromal cells transplanta¬tion. Neuroreport, 2004, 15:1105–1108. 38. Cui, C. H.; Uyama, T.; Miyado, K.; Terai, M.; Kyo, S.; Kiyono, T.; Umezawa, A. Menstrual blood-derived cells confer human dystrophin expression in the murine model of Duchenne muscular dystrophy via cell fusion and myo¬genic transdifferentiation. Mol. Biol. Cell, 2007, 18:1586–1594. 39. Cho, N. H.; Park, Y. K.; Kim, Y. T.; Yang, H.; Kim, S. K. Lifetime expression of stem cell markers in the uter¬ine endometrium. Fertil. Steril. 2004, 81:403–407. 40. Mattai, C.; Horvat, R.; Noe, M.; Nagele, F.; Radjabi, A.; Van Trotsenburg, M.; Huber, J.; Kolbus, A. Oct-4 expres¬sion in human endometrium. Mol. Hum. Reprod, 2006, 12:7–10. 41. Gargett, C. E. Identification and characterization of hu¬man endometrial stem/progenitor cells. Aust. NZ J. Obs¬tet. Gynaecol. 2006, 46:250–253. 42. Henderson, J. K.; Draper, J. S.; Baillie, H. S.; Fishel, S.; Thomson, J. A.; Moore, H.; Andrews, P. W. Preimplanta¬tion human embryos and embryonic stem cells show com-parable expression of stage-specific embryonic antigens. Stem Cells, 2002, 20:329–337. 43. Le Blanc, K. Immunomodulatory effects of fetal and adult mesenchymal stem cells. Cytotherapy, 2003, 5:484–489. 44. Ludwig, T. E.; Levenstein, M. E.; Jones, J. M.; Berggren, W. T.; Mitchen, E. R.; Frane, J. L.; Crandall, L. J.; Daigh, C. A.; Conard, K. R.; Piekarczyk, M. S.; Llanas, R. A.; Thomson, J. A. Derivation of human embryonic stem cells in defined conditions. Nat. Biotechnol. 2006, 24:185–187. 45. Mattai, C.; Horvat, R.; Noe, M.; Nagele, F.; Radjabi, A.; Van Trotsenburg, M.; Huber, J.; Kolbus, A. Oct-4 expres¬sion in human endometrium. Mol. Hum. Reprod. 2006, 12:7–10. 46. Minguell, J. J.; Erices, A.; Conget, P. Mesenchymal stem cells. Exp. Biol. Med. 2001, 226:507–520. 47. Nandoe Tewarie, R. D.; Hurtado, A.; Levi, A. D.; Groten¬huis, J. A.; Oudega, M. Bone marrow stromal cells for repair of the spinal cord: Towards clinical application. Cell Transplant. 2006, 15:563–577. 48. Patel, A. N.; Geffner, L.; Vina, R. F.; Saslavsky, J.; Urschel, Jr., H. C.; Kormos, R.; Benetti, F. Surgical treat¬ment for congestive heart failure with autologous adult stem cell transplantation: A prospective randomized study. J. Thorac. Cardiovasc. Surg. 2005, 130:1631–1638. 49. Schwab, K. E.; Chan, R. W.; Gargett, C. E. Putative stem cell activity of human endometrial epithelial and stromal cells during the menstrual cycle. Fertil. Steril. 2005, 84:1124– 1130. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 17 Review Article Surfactants: Basics and Versatility in Food Industries Rakesh K. Sharma* Applied Chemistry Department, Faculty of Technology & Engineering, The M. S. University of Baroda, Kalabhavan, Vadodara, Gujarat, India. *raksharmain@yahoo.com, rksharmamsu@gmail.com ABSTRACT Surfactant, as a a e iatio of su fa e a ti e age t , is a o ga i o pou d that is a phiphili o p isi g oth h d ophili g oups o o l efe ed to as pola heads a d h d opho i g oups o pola tails . Based o the ele t o ha ges of the pola head parts, surfactants are classified as anionic, cationic, nonionic, zwitterionic. Many other pecular class of compounds also categorized in the types of gemini, cyclodextrin based, polymeric surfactants etc. Due to their some interesting properties such as nontoxicity, higher rate of biodegradability, high foaming capacity and optimal activity at extreme conditions like temperatures, pH and salinity, surfactants have been increasingly attracting the attention of the scientific and industrial community. Biocompatible, biodegradable, and/or nontoxic emulsion-based formulations of surfactants have great potential for applications in the food preparation and processing. Basics of surfactants and mainly there way of utility as food emulsifiers in food industries is thoroughly discussed. Key words: Surfactants, Fatty Acids, Monoglycerides, Emulsifiers, Food Industries INTRODUCTION A Surface Active Agent, Surfactant, is a substance, when present in system has the characteristics of adsorbing on to the surface/interface of the system and of altering to a mark degree of the surface/interfacial free e e g of the s ste . In general, many solutes even when present in very low concentration alter the surface energy of their solvents in their solutions to an extreme degree are considered as the Surfactants. Fig.1 :Surface active agent (Surfactant) molecule Surfactants are amphiphiles containing both hydrophobic (nonpolar) and hydrophilic (polar) moieties that confer ability to accumulate between fluid phases such as oil/water or air/water, reducing the surface and interfacial tensions and forming micelles/emulsions. This is a uniqueness and versatility of these compounds. In English the term surfactant designates a substance which exhibits some superficial or interfacial activity. It is worth remarking that all amhiphiles do not display such activity; in effect, only the amphiphiles with more or less equilibrated hydrophilic and lipophilic tendencies are likely to migrate to the surface or interface. It does not happen if the amphiphilic molecule is too hydrophilic or too hydrophobic, in which case it stays. In other languages such as French, German or Spanish the word "surfactant" does not exist, and the How to cite this article: RK Sharma, Surfactants: Basics and Versatility in Food Industries, PharmaTutor, 2014, 2(3), 17-29 PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 18 actual term used to describe these substances is based on their properties to lower the surface or interface tension, e.g. tensioactif(French), tenside(German), tensioactivo(Spanish). This would imply that surface activity is strictly equivalent to tension lowering, which is not absolutely general, although it is true in many cases. Good starting points to get information and understanding about the surfactants are found in classic books like those of Rosen [1], Myers [2], Mittal [3,4] and Shinoda [5]. Other books on su fa ta ts i ludi g Ka sa s, Industrial Applications of Surfactants Series [7,8] and the Marcel Dekker Inc. (dekker.com/) was publishing more than 100 volumes in Surfactant Science Series [9] since 1966. There are also glossaries and dictionaries available which one covering terminology in surfactant science and technology [10]. The most comprehensive source for surfactant information on the internet is p o a l Hui e s The Surfactants Virtual Library, which contains over 1000 links to surfactant and detergent related web sites [11]. Conventional surfactants are amphipathic molecules with polar head groups, which may be anionic, cationic, non-ionic and zwitterionic, and hydrophobic tails, that may be hydrogenated or fluorinated, linear or branched. Recently, some interest has been devoted to the new class of so-called Gemini surfactants. They are composed of two polar heads flanked by a spacer to which hydrophobic tails are linked; the spacer can be rigid or flexible, polar or apolar. Attention has been also addressed to polymeric surfactants which are copolymers with two or more blocks having variable monomeric compositions. A peculiar class of surfactants is represented by the cyclodextrins which possesses the properties of inclusion and of self-organization simultaneously, resulting very promising materials for an enhanced encapsulation of variety of solutes sparingly soluble in water [12]. Fig.2 : Classification of Surfactants The most commonly used anionic surfactants are alkyl sulphates, alkyl ethoxylate sulphates and soaps. Most of the anionic surfactants are carboxylate, sulfate and sulfonate ions [13]. The straight chain is a saturated/unsaturated C12-C18 aliphatic group. The water solubility potential of the surfactant is determined by the presence of double bonds in it [14]. Cationic surfactants are mainly cetrimide which has tetradecyltrimethyl ammonium bromide with minimum amount of dodecyl and hexadecyl compounds. Other cationics are benzalkonium chloride, cetylpyridinium chloride etc are effective compounds. Non-ionic surfactants contribute to making the surfactant system less hardness sensitive. Fig.3 : Few examples of Surfactants PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 19 The nonionic surfactant can be of polyol esters, polyoxyethylene esters, and poloxamers or pluronics which are poly(oxyethylene)poly(oxypropylene)-poly(oxyethylene) tri-block copolymers. The polyol esters include glycol and glycerol esters and sorbitan derivatives. Polyoxyethylene esters majorly include polyethylene glycol (PEGs). The most commonly used nonionic surfactants are ethers of fatty Alcohol15. Amphoteric surfactants are very mild, making them particularly suited for use in personal care preparations over sensitive skins. They can be anionic, cationic or non-ionic in solution, depending on the acidity or pH of the water. Those surfactants may contain two charged groups of different sign. The frequently used compound is alkyl betaines [15]. The chemical structures of few commonly used surfactants are shown in Fig.3 APPLICABILITY OF SURFACTANTS In recent years, surfactants have been widely applied, such as wetting agents, enhance oil recovery (EOR), emulsifiers and/or manufacturing textiles and leather finishing agents to reduce surface tension or speed the drying process [7]. Due to their interesting properties such as lower toxicity, higher degree of biodegradability, higher foaming capacity and optimal activity at extreme conditions of temperatures, pH levels and salinity, these have been increasingly attracting the attention of the scientific and industrial community. The world production of soaps, detergents and other surfactants was about 18 Mt (million tons) in 1970, 25 Mt in 1990 and 40 Mt in 2000 (not counting polymeric surfactants) [7,8]. Fig.4 represents the advancement in utilization of surfactants in various industries like personal care, pharmaceutical, food, paint, agriculture, paper, mineral processing, electrical, etc. Versatile surfactants applied in industries in general as follows; • Foods – emulsions, foams, dispersions, fouling etc. • Pharmaceuticals – emulsions, dispersions, fouling, etc. • Household products – dirt removal, foam control etc. • Paints & coatings – cleanliness, wetting, adhesion, wicking, dispersion stability • Mineral Processing – froth flotation • Semi-conductors – cleanliness, adhesion of thin layers, characterization of surface treatments • Heavy industry – lubrication/wear, degreasing • Crude oil – oil recovery • Paper – printing, adhesion in packaging etc. • Biomaterials – fouling, tissue adhesion Fig.4: Important surfactant-based products in the current market. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 20 The widespread importance of surfactants in practical applications, and scientific interest in their nature and properties, have precipitated a wealth of published literature on the subject and many ways these materials are exploited by research community through quality papers in various journals(Fig.5). Fig.5 : Reputed core research journals of Surfactant Science SURFACTANT IN FOOD INDUSTRIES Due to their unique chemical structure, surfactants strongly affect the stability of colloid systems and can interact with all the main components of flour (starch, gluten and lipids). Surfactants act as lubricants, emulsify oil or fat in butters, build structure, aerate, improve certain qualities of the final product, extend shelf life, modify crystallization, prevent sticking, and retain moisture [16]. Naturally occurring surfactants such a lecithin from egg yolk and various proteins from milk are used for the preparation of many food products such as mayonnaise, salad creams, dressings, deserts, etc. Alanine, phenylalanine, leucine and isoleucine contain nonpolar aliphatic and aromatic side chains. Amino acids, such as arginine, lysine and tryptophane, contain amino groups, which promote cationic character to the protein. Aspartic and glutamic acids possess side chains with carboxyl groups, which contribute to anionic character. The nature, number and location of the polar amino acids determine the isoelectric point of a protein; e.g., the pH at which the protein is uncharged. In food systems where the pH is above the isoelectric point, the protein will behave as the anionic emulsifiers, while at pH values below their isoelectric point, it will become cationic. One complicating factor in using emulsifiers is that their charge makes them vulnerable to interactions with other charged species, such as calcium ions and some gums16. Later, polar lipids as monoglycerides were introduced as food emulsifiers. More recently, synthetic surfactants such sorbitan esters (Tweens) and their ethoxylates and sucrose esters have been widely applied in food emulsions. In commercial food emulsifiers, in general, the hydrophilic part can consist of glycerol, sorbitol, sucrose, propylene glycol or polyglycerol. The lipophilic part is formed by fatty acids derived from fats and oils such as soybean oil, rapeseed oil, coconut oil and palm kernel oils. Emulsions in Foods The understanding of the formation, structures, and properties of emulsions is essential to the creation and stabilization of various structures in foods. Three main type of emulsions (shown in Fig.6) organized in foods are as follows; PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 21 i) Oil-in-Water (O/W) emulsions: Droplets of oil are suspended in an aqueous continuous phase. Such emulsions exist in many forms of food like creamers, cream liqueur, whippable toppings, ice creams mixes, mayonnaises. The properties of such emulsions are controlled through the surfactants utilized and the other components present in water phase. ii) Water-in-Oil (W/O) emulsions: Droplets of water are suspended in an oily continuous phase. Mainly these emulsions exist in butter, margarines, and fat-based spreads. The stability of these emulsions depends more mainly on the properties of fat or oil, dispersed phase and also surfactant used in water phase. iii) Water-in-Oil-in-Water (W/O/W) emulsions: In effect, an o/w emulsions whose droplets themselves contain water droplets. This type of emulsion often found in variety of baked products. Fig.6 : Type of emulsions in Foods A large number of surfactants traditionally used in foods which are water soluble as well as water insoluble. Surfactants, which have a Krafft point beneath room temperature, are classified as water insoluble as a contrast to ionic surfactants like SDS, which are classified as water soluble, because they form transparent aqueous solutions with large concentrations. Due to Micellization of Surfactant, aqueous solutions with high surfactant concentrations are transparent low viscosity liquids, which would indicate very significant solubility in water. However, in order to understand emulsion stability it is essential to realize that the surfactant molecules are not at all soluble to this extent. Generally surfactants/emulsifiers can be characterized by the Hydrophilic Lipophilic Balance. The balance is measured on molecular weight and is an indication of the solubility of the emulsifier. The HLB scale varies between 0 and 20. An emulsifier with a low HLB value is more soluble in oil and promotes waterin-oil emulsions. An emulsifier with a high HLB value is more soluble in water and promotes oilin-water emulsions. The HLB value is a somewhat theoretical value, it only considers water and oil, and food systems are more complicated. But the HLB value of an emulsifier can be used as an indication about its possible use. The second group of surfactants, the i solu le o es, diffe s f o the fi st g oup only by the structure of the association. This difference is in reality important to comprehend the stability of food emulsion [17]. The emulsion stabilization is in the phenomena at the critical surfactant concentration, when the selfaggregation in water is started (Fig.7). For the water soluble surfactant the association is PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 22 limited to spherical aggregates, micelles, which form a thermodynamically stable dispersion in water, the system remains a one phase transparent liquid. In case of water insoluble surfactant the association structure is a lamellar liquid crystal (shown in Fig.7) which does not have size limitation like the micelle, the association continues infinitely and distinct a separate phase appears. For the water soluble surfactants the adsorption of the surfactant to the interface increases with concentration in the aqueous solution until the CMC is reached, at which the surfactant has formed a monolayer at the interface. After that point the additional surfactant forms micelles, in the bulk. Fig.7 : Surface tension of aqueous solutions of surfactants The water insoluble surfactants behave in a completely different manner. It forms a separate phase and the adsorption to the oil/water interface is now not a question of individual molecules; the adsorption is mainly adjudged by the three interfacial free energies with four possible dispersed structures(Fig.8). Fig.8 : Arrangements for an emulsion with LC as 3rd phase In the Fig.8, the repulsion between the liquid crystal particles and the oil drops are sufficient to prevent aggregation (provide colloidal stability) and they exist as separate entities. If flocculation occurs, three arrangements are possible depending on the magnitude of the PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 23 interfacial free energies, which are O/W , O/LC a d LC/W emulsions. The emulsion now has increased the number of phases from two to three, and the presence of the third phase has three vital consequences. It radically changes the volume ratios in the emulsion, it gives rise to another structure during emulsification and the temperature variation during and after the emulsification has decisive effect on the properties. The most complex colloids and emulsions are those of food and food products, which are difficult to stabilize, because a large number of microstructures of combinations of proteins, carbohydrates, fats and lipids etc. are present. This almost infinite number of combinations are organized and arranged in very complex internal microstructures with various types of assemblies such as dispersions, emulsions, foams, gels, etc. In addition, Mother Nature has provided us with many small molecular weight molecules with surfactants that are known, as food additives (vitamins, antioxidants, acidulants, enzymes, flavors, etc.). The additives have many functional properties and play significant role in food quality and long-term stability [17]. Common Food emulsifiers/surfactants Surfactant molecules, which are part of these emulsions, play a major role in determining the microstructure of the product and in affecting its structural and textural stability in the food. Commercially utilized common surfactants or food emulsifiers are listed in Table-1. Here in the table, an E-number is a reference number given to food additives that have passed safety test and have been approved for use throughout the European Union and Switzerland (the "E" stands for "Europe"). They are commonly found on food labels throughout the European Union[18]. Safety assessment and approval are the responsibility of the European Food Safety Authority. Today the worldwide food surfactant production has reached approximately 500,000 tons from 20 different types with a 3% annual growth[19]. Surprisely about 50% of surfactants are used in bakery products. Table-1 : Most common food surfactants/emulsifiers used in the food industries. Name of Food surfactant/Emulsifier Code name E-Number Lecithins Lecithins E 322 Polyoxyethylene sorbitan esters Polysorbates/Tweens E 432 – 436 Mono- and diglycerides of fatty acids MDG/ Monoglycerides E 471 Acetic acid esters of MDG ACETEM E 472 a Lactic acid esters of MDG LACTEM E 472 b Citric acid esters of MDG CITREM E 472 c Mono- and diacetyl tartaric acid esters of MDG DATEM E 472 e Sucrose esters of fatty acids Sucrose esters E 473 Polyglycerol esters of fatty acids Polyglycerol esters E 475 Polyglycerol polyricinoleate PGPR E 476 Propane-1,2-diol esters of fatty acids Propylene glycol esters E 477 Sodium stearoyl-2-lactylate SSL E 481 Calcium stearoyl-2-lactylate CSL E 482 Sorbitan fatty acid esters Spans E 491 – 495 The chemical structure of commercial food emulsifiers is represented in Table-2. In most cases, the hydrophilic part is of glycerol, sorbitol, sucrose, propylene glycol or polyglycerol and lipophilic, hydrophobic part is formed by fatty acids derived from fats and oils. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 24 Table-2 : Chemical structure of MOST common food Surfactants/emulsifiers used in the food industries. Food Surfactants/Emulsifiers Lecithins Polyoxyethylene sorbitan esters (Polysorbates/Tweens) O O O C O R" O O O P O O HO n HO R' O HO O O Mono- and diglycerides of fatty acids (MDG) O X R O O O O n OH HO O O O O HO n O O Acetic acid esters of MDG (ACETEM) Lactic acid esters of MDG (LACTEM) O HO O O HO O HO O O O O Citric acid esters of MDG (CITREM) O CH3 Mono- and diacetyl tartaric acid esters of MDG (DATEM) COOH O COOH CH3 O O O O COOH COOH COOH Sucrose esters of fatty acids (Sucrose esters) Polyglycerol esters of fatty acids (Polyglycerol esters) Propane-1,2-diol esters of fatty acids (Propylene glycol esters) Sodium stearoyl-2-lactylate (SSL) O HO O O O HOOC COCH3 COCH3 Polyglycerol polyricinoleate (PGPR) HO CH3 O O Calcium stearoyl-2-lactylate (CSL) Sorbitan fatty acid esters (Spans) PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 25 Manufacture of Food emulsifiers/surfactants Lecithin (E322) is a mixture of phospholipids, it consists of a glycerol backbone with phosphatidyl groups. The phosphatidyl groups are phosphate esters of diglyceride. Lecithin is a natural emulsifier, obtained mainly from vegetable oilseeds and egg yolk. Basic source for manufacture of food emulsifiers is actually come out from fats or oils or fatty acids. Main food emulsifiers, monoglycerides are produced with the reaction of fats or oils or fatty acids with glycerol. Such monoglycerides can be further processed by esterification with organic acids like acetic acid, lactic acid, citric acid and tartaric acid, produces ACETAM, LACTEM, CITREM as well as DATEM, respectively. Even some important hydrophilic alcohols can be used for the manufacturing of food emulsifiers (shown in Fig.9). Fig.9 : Source and manufacturing of Food emulsifiers/surfactants PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 26 FEW APPLICATIONS OF FOOD EMULSIFIERS / SURFACTANTS IN FOOD INDUSTRIES Surfactants are involved in the production of many common food items and can be found in the extraction of cholesterol, solubiliztion of oils, liquor emulsification, prevention of component separation, and solubiliztion of essential nutrients. The nontoxicity of lecithin leads to its variety of uses in food, as an additive or emulsifier. In confectionery, lecithin reduces viscosity, replaces more expensive ingredients, controls sugar solidification and the flowness properties of chocolate, helps in the homogeneous mixing and it can be used as a coating. In emulsions and fat spreads, it stabilizes emulsions, reduces spattering during frying, and improves texture of spreads and flavour release. In dough s and bakery, it reduces fat and egg requirements, helps even distribution of ingredients in dough, stabilizes fermentation, increases volume, protects yeast cells in dough when frozen, and acts as a releasing agent to prevent sticking and simplify cleaning. It improves wetting properties of hydrophilic powders (e.g., low-fat proteins) and lipophilic powders (e.g., cocoa powder), controls dust, and helps complete dispersion in water to adsorb at interfaces. Lecithin keeps cocoa and cocoa butter in a candy bar from separating. In margarines, especially those containing high levels of fat (>75%), lecithin is added as an 'antispattering' agent for shallow frying. Margarine is an example of a W/O emulsion which consisting of 80% fat, the hot homogenized mixture of fat crystals, oil and water. It does not have to be a stabile emulsion since the emulsion is quickly set by rapid chilling. Lecithin, a typical ingredient in margarine, enhances the solubility of monoglycerides in the oil blend, and monoglycerides reduce the interfacial tension between the oil and water phases. If we discuss about an ice cream, partially frozen foam that is 40–50% air (by volume). The first step in formulating ice cream is to create an emulsion. The homogenization step forces the hot ingredients (milk fats, milk solids-no-fat, sweeteners, corn-syrup solids, stabilizers/ emulsifiers, other dry solids) through small stirring under moderate pressure. Diameter of fat droplet decreases to . to . μ approximately, allowing a large surface area for adsorption of proteins (which in responsible for stabilization of emulsion), and the uniformity of drop sizes result in greater stability of fat droplets during ageing process and made more uniform final food product. The adsorption of emulsifiers (such as Lecithins, Tweens, MDG) decreases the interfacial tension between fat globules and the surrounding liquid phase, even more than does just mere adsorption of proteins (to about 2.2 dyne/cm). The stabilizers (such as guar, carboxymethyl cellulose, xanthan, etc.) are used to produce smoothness in body and texture, reduce the ice content and lactose crystal growth during storage, provide the product uniformity and resist against easy melting [20]. The second stage in ice cream production is foaming and emulsion destabilization. This is analogous to the foaming step in whipped cream [21,22]. Air is incorporated by whipping or by air injection. The added shear causes controlled partial coalescence (enhanced by the adsorbed surfactants), causing air to be trapped in clumped fat globules, and also ice formation. When whipping and freezing occur simultaneously, good fat destabilization is achieved and a complex internal structure is achieved [20]. Surfactants are a key component in the manufacture of edible coatings. A finish coat or polish may be added to chocolate- and sugarpanned confectionery products to produce an aesthetically pleasing gloss. These are commonly alcohol-based shellac and corn zein coatings, but may also include water-based whey proteins [23]. Surfactants are added to create a dispersion of the coating particles, which then allows for proper wetting and adhesion over the candy surface. The problem PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 27 with chocolate blend coating is happened when the fat crystalizes and the cocoa butter separates. MDG, LACTEM, polysorbates are added as crystal modifiers/emulifiers to stabilize the coating. The latter may also be used to increase the palatability of the confection by forming an emulsion between the fat and mouth saliva, which minimizes the waxy mouthfeel [24]. As monoglycerides, MDGs increase the fermentation stability of dough, bread and fermented bakery goods. The general dosage is 0.2% of the flour weight. Other major uses of MDGs are sponge cakes and cakes margarines, ice creams and chewing gums [19]. Diacetyltartaric acid esters, DATEM, are commonly used as dough conditioners for all baked products, particularly yeast-leavened products, white bread and in flour mixes for quality foods. Their approximate dosage is between 0.2% and 0.5% of the flour weight. They are also used in dairy products and approved for use in special infant formulae based on crystalline amino acids [16]. Sodium stearoyl-2-lactylate (SSL) and calcium stearoyl2-lactylate (CSL), commonly applied anionic surfactants in breadmaking processes to improve dough gas retention and stability to yield a finer structure in the final product. SSL is used in yeast-leavened products usually in a dosage of about 0.4%. They are also used in breakfast cereals, cookies, crackers, cereal and potato based snacks and quick cook rices [16,25]. In the USA sucrose esters are used in breads but oppsitely the use of sucrose esters is not permitted in breads at Europe. As sucrose esters have excellent ability to stabilize emulsions these are utilized to dressing sauces, mayonnaise-like products, and ice creams. The use of sucrose ester in infant foods is very vital. During the production of infant formulas (given instead of milk) the proteins which are already in the product are usually enough to ensure colloid stability of the emulsion. However, in the case of hypoallergenic products containing hydrolyzed proteins, peptides or free amino acids, the use of emulsifiers is necessary to stabilize the emulsion. That is the reason why sucrose esters are used in special baby formula products made for allergic infants [19,25]. Polyglycerol esters of fatty acids are applied in the formulation of low fat margarines, spreads, butter creams and breakfast cereals. Special types of polyglycerol esters are used as crystallization inhibitors in the oil and fat industry to prevent the formation of turbidity of sunflower oils during storage. Sorbitan esters of fatty acids (Span series) and their ethoxylated derivatives Polysorbates (Tween series) are excellent emulsifiers, aerating agents and lubricants in cakes, toppings, cookies and crackers. Polysorbate 60 is used as dough strengthener co-emulsifier in bakery products. The usual dosage is 0.2% of flour weight. Polysorbate 80 is often used in dairy products, ice creams, and whipped cream and non-dairy cream alternatives [26]. Surfactant mixtures are usually much more effective than using a single surfactant alone. Therefore, surfactants are usually used in combinations. For example a common bread surfactant combination contains mono- and diglycerides of fatty acids. A fluid cake shortening (semisolid fats used in food preparation, especially for baked goods) can contain a combination of Polysorbate 60, glyceryl monostearate and propylene glycol monostearate. Other popular example in food was shown in beer manufacturing [26]. The quality of beer is mainly judged by the foam creation of the dispensed beer. Desirable visual qualities include stability, lacing (adhesion), whiteness, creaminess and strength. Foam stability is the perceived best indicator of a good beer. Foam stabilization comes from amphipathic polypeptides from malt and bitter compounds, particularly iso-α-acids, and from the absence of lipophilic materials. Unlike champagne, where foam film lifetimes are short (hydrodynamic control), beer foam has a slower drainage rate due to the effect of disjoining PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 28 pressure of two interfaces in close proximity. A beer that has smaller bubbles of uniform size tends to have more stable foam. Several reviews have been written on this aspect of beer (and champagne) foams [27,28]. CONCLUSIONS Surfactants are amphiphilic compounds containing both hydrophobic (nonpolar) and hydrophilic (polar) moieties that confer ability to accumulate between fluid phases such as oil/water or air/water, reducing the surface and interfacial tensions and forming emulsions and micelles. The surface activity properties make surfactants one of the most important and versatile class of chemical products, used on a variety of applications in household, food, paint, paper, and agriculture industries. Surfactant molecules, which are an important part of the food emulsions, play a key role in determining the microstructure of the product and in affecting its structural and textural stability in the food. Naturally occurring surfactants like lecithins, MDGs, various saturated, unsaturated and trans fatty acids and functionalized proteins as well as synthetic surfactants Tweens, SSL, CSL and sucrose esters etc. are often used in the preparation of food products such as mayonnaise, salad creams, dressings, deserts, coffee, icecreams etc. Also the biocompatible, biodegradable, and/or nontoxic emulsion-based formulations of surfactants like ACETAM, LACTEM, CITREM as well as DATEM have great potential for food applications and which are discussed. Acknowledgement Financial assistance from University Grants commission (UGC), New Delhi Project no. F.411327/2012(SR) is gratefully acknowledged. ↓ REFERENCES 1. Rosen, M .J., Surfactants and Interfacial Phenomena, Wiley, New York, NY, 2nd edn., 1989. 2. Myers, D., Surfactant Science and Technology, VCH, New York, 1988. 3. Solution Chemistry of Surfactants, ed. Mittal, K. L., Plenum, New York, 1(2), 1979. 4. Solution Behaviour of Surfactants, ed. Mittal, K. L. and Fendler, E. J., Plenum, New York, 1(2), 1979. 5. Shinoda, K., Nakagawa, T., Tamamushi, B-I. and Isemura, T., Colloidal Surfactants, Some Physicochemical Properties, Academic Press, New York, 1963. 6. Industrial Applications of Surfactants, ed. Karsa, D.R., Royal Society of Chemistry, Cambridge, UK, 1987. 7. Industrial Applications of Surfactants III, ed. Karsa, D.R., Springer-Verlag, Heidelberg, Germany,1992. 8. Industrial Applications of Surfactants IV, ed. Karsa, D.R., Royal Society of Chemistry, Cambridge, UK, 1999. 9. Surfactant Science Series, Marcel Dekker, New York, vol. 1–109, 1966–2002. 10. Schramm, L. L., Dictionary of Colloid and Interface Science, John Wiley & Sons, New York, 2001. 11. Huibers, P., The Surfactants Virtual Library; (surfactants.net). 12. Holmberg, K., Jonsson, B., Kronberg, B. and Li d a , B., “u fa ta t a d Pol e i Aqueous “olutio , Wile & “o s, . 13. Remington, A.R.G., The science and practice of pharmacy, 19th edition, Easton, PA, Mack publishing, 1995, 1 : 250–251. 14. Zagrafti, G., The science and practice of pharmacy, 19th edition, Easton, PA , Mack publishing, 1995, 1 : 241-251. 15. Zhang, W., Dai, X., Zhao, Y., Lu, X. and Gao, P., Langmuir, 2009, 25(4) : 2363-2368. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 29 16. Hase huettl, G.L., “ thesis a d Co e ial P epa atio of Food E ulsifie s, I Food Emulsifiers a d Thei Appli atio s , eds. Hasenhuettl, G.L. and Hartel, R.W., Chapter-2, Springer Science, New York, 2008. 17. Kralova, I. and “jo lo , J., “u fa ta ts used i Food Che ist , J. Dis. Sci. Tech., 2009, 30 :1363. 18. Web source; ec.europa.eu/food/food/fAEF/additives 19. Whitehurst, R.J., (ed) Emulsifiers in food technology, Oxford: Blackwell Publishing Ltd., 2004. 20. Goff, H. D., Int. Dairy J., 1997, 7 : 363. 21. Leser, M. E. and Michel, M., Curr. Opin. Colloid Interface Sci., 1999, 4 : 239. 22. Stainsby, G. and Dickinson, E., Actual. Chem., 1988, 3 : 35. 23. Trezza, T. A. and Krochta, J. M., J. Food Sci., 2000, 65 : 658. 24. Dziezak, J. D., Food Technol., 1988, 172. 25. Csáki, K. F., Med Hypotheses, 2011, article in press 26. Polysorbates, Evaluation report of food additives, Food safety commission, June 2007. 27. Evans, D. E., J. Am. Soc. Brewing Chem., 2002, 60 : 47. 28. Bamforth, C. W., J. Sci. Food Agric., 2000, 80 : 1371. LOWER-INTENSITY STATIN COMBINATION THERAPY MAY UTILIZE FOR HIGH-RISK ATHEROSCLEROTIC CARDIOVASCULAR DISEASE For atherosclerotic cardiovascular disease risk reduction, American College of Cardiology and the American Heart Association guidelines recommend initiating moderate or high-intensity statin monotherapy as the first-line strategy. But some patients do not tolerate or respond to high-intensity statin monotherapy due to adverse effects or those who have limited LDL cholesterol response. Adverse effects are more common with higher-intensity statin regimens, and musculoskeletal adverse events occur frequently among patients with the C variant in the SLCO1B1 gene. Pharmacogenetic variability may also decrease statin efficacy. Dr. Gudzune and team compare the effectiveness, safety, and tolerability of moderated combination therapy of statin with another lipid-modifying medication (bile acid sequestrant, ezetimibe, fibrate, niacin, or ω-3 fatty acid) with those of higher-intensity statin monotherapy among high-risk patients. The results after study suggest that moderated statin combination therapy with bile acid sequestrants and combination of ezetimibe and lower-intensity statin decreases LDL cholesterol to a similar or greater extent compared with higher-intensity statin monotherapy among patients at high risk for atherosclerotic cardiovascular disease. They noted insufficient evidence regarding LDL cholesterol reduction when comparing moderated combination therapy with fibrates, niacin, or ω-3 fatty acids to higher-intensity statin monotherapy. Though they notified that this strategy should be used with caution due to lack of evidence on long-term clinical benefits and harms. This study was first published in Annals of Internal Medicine on 11th February 2014, doi:10.7326/M132526. The whole study was funded by the Agency for Healthcare Research and Quality. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 30 Review Article A Review: Formulation of Fast Dissolving Tablet Patel Zinkal K,* Patel Rahul R, Kanu R Patel, Mukesh R Patel Department of Pharmaceutics, Shri B.M.Shah College of Pharmaceutical Education and Research, Dhansura Road College campus, Modasa, Arvali, Gujarat, India *zinkal.pharm27@yahoo.in ABSTRACT As pharmaceutical scientists are attaining a better understanding of biochemical and physicochemical properties related to the drug action, the drug delivery systems are becoming simple. Recent advances in Novel Drug Delivery Systems (NDDS) aim for designing dosage forms, convenient to be manufactured and administered, free of side effects, offering immediate release and enhanced bioavailability, so as to achieve better patient compliance Oral delivery is currently the gold standard in the pharmaceutical industry where it is regarded as the safest, most convenient and most economical method of drug delivery. Fast dissolving tablet is designed to allow administration of an oral solid dose form in the absence of water or fluid intake. Such tablets when put on the tongue. It readily dissolve or disintegrate in the saliva without chewing or water within <60 seconds. Fast- or mouth dissolving tablets have been formulated for pediatric, geriatric, and bedridden patients and for active patients who are busy and traveling and may not have access to water. This review includes requirements for fast disintegrating tablets, salient features, advantages, limitations, challenges in formulation, various technologies developed for fast disintegrating tablets, patented technologies, evaluation methods and various marketed products. Keywords: Superdisintegrating Agents, Fast Dissolving Tablet, Enhanced Bioavailability, Oral Route. INTRODUCTION Oral delivery is currently the gold standard in the pharmaceutical industry where it is regarded as the safest, most convenient and most economical method of drug delivery. Oral route of drug administration become popular route for systemic effects due to ease of ingestion, accurate dosage, self-medication, pain avoidance. Fast dissolving drug delivery system are Novel Drug Delivery techniques aim for designing dosage forms, convenient to be manufacture and administer without water, free of side effects, offering immediate release and enhanced bioavailability, so as to achieve better patient compliance. [1] This segment of formulation is especially designed for pediatric, geriatric, bedridden, psychotic patients who are unable to swallow or refuse to swallow conventional oral formulation and also for active patients who are busy and traveling and may not have access to water. United States Food and Drug Administration (FDA) defined fast dissol i g ta let FDT as a solid dosage form containing medicinal substance or active ingredient which disintegrate or dissolve rapidly ithi se o ds he pla ed upo the to gue. Fast dissolving tablets are also known as mouthdissolving tablets, rapid dissolving, melt-in mouth tablets, Orodispersible tablets, rapimelts, porous tablets, quick dissolving, quick melt, and quick disintegrating tablets. [2] How to cite this article: ZK Patel, RR Patel, KR Patel, MR Patel, A Review: Formulation of Fast Dissolving Tablet, PharmaTutor, 2014, 2(3), 30-46 PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 31 Conventional tablet Fast dissolving tablet Figure: 1.1 Timely comparisons between Conventional & Fast dissolving tablet CRITERIA FOR FAST DISSOLVING DRUG DELIVERY SYSTEM [3] The tablets should: ● Not require water to swallow, but it should dissolve or disintegrate in the mouth within a seconds. ● Be compatible with taste masking. ● Have a pleasant mouth feel. ● Leave minimum or no residue in the mouth after oral administration. ● Exhibit low sensitive to environmental condition as temperature and humidity. [4] ● Allow the manufacture of the tablet using conventional processing and packaging equipments at low cost. ● Allow high drug loading. ADVANTAGES OF FDT [5] ● Ease of Administration to the patient who cannot swallow and therefore improved patient compliance ● No water needed which is useful for patients who are traveling and do not have immediate access to water. ● Rapid dissolution, absorption of the drug and hence increase bioavailability ● Pregastric absorption of drug can increase oral bioavailability of drug, and as a result of reduces dose administration. ● The risk of chocking or suffocation during oral administration of conventional formulation due to physical obstruction is avoided, thus providing improved safety. ● Good chemical stability as conventional oral solid dosage form. ● Convenience of administration and accurate dosing as compared to liquid formulation. ● Cost effective ● Have sufficient strength to withstand the rigors of the manufacturing process and post manufacturing handling. ● Advantageous over liquid formulation in terms of administration as well as transportation.[6] ● Reduced first pass metabolism. LIMITATIONS OF FDT [7] PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 32 ● The tablets usually have insufficient mechanical strength. Hence, careful handling is required. ● The tablets may leave unpleasant taste and/or grittiness in mouth if not formulated properly ● Drugs with larger doses are difficult to formulateinto FDT e.g. rifampin (600 mg), ethambutol (1000mg) etc. DRUG SELECTION CRITERIA [8] ● Able to permeate the oral mucosa. ● At least partially non-ionized at oral cavity PH. ● Have the ability to diffuse and partition into the epithelium of upper GIT. ● Small to moderate molecular weight. ● Low dose drugs mostly less than 50 mg. ● Drug should have good stability in saliva and water. ● Drugs which have lower bioavailability, are good candidates for FDT. ● Short half life and frequent dosing drugs are unsuitable for FDT. ● Very bitter taste and unacceptable odor drugs are unsuitable for FDT. ● Pharmaceutical Companies have formulated FDT for various categories of drugs such as neuroleptics, cardiovascular agents, analgesics, antiallergic, antiepileptics, anxiolytics, sedatives, hypnotics, diuretics, antiparkinsonism agents, anti-bacterial agents and drugs used for erectile dysfunction. THE NEED FOR DEVELOPMENT OF FDT [9] Patient factors FDTs are suitable for those patients (particularly pediatric and geriatric patients) who are unable to swallow traditional tablets and capsules. These include the following: ● Patients who have difficulty in swallowing oral tablet ● Patients incompliance due to fear of chocking ● A middle-aged patient undergoing radiation therapy may be too nauseous to swallow H2blocker ● A psychotic patient who may try to hide a conventional tablet under his or her tongue to avoid their daily dose of an atypical antipsychotic ● A patient with persistent nausea, who may be journey, or has little or no access to water. [10] Effectiveness factor Dispersion of drug in oral cavity causes pregastric absorption which avoids first pass hepatic metabolism which increase the bioavailability. Furthermore, safety profiles may be improved for drugs. Manufacturing and marketing factors As a drug nears the end of its patent life, it is possible for pharmaceutical manufacturers to develop a given drug entity in a new and improved dosage form. A new dosage form allows a manufacturer to extend market exclusivity, unique product differentiation, value-added product line extension, and extend patent protection, while offering its patient population a more convenient dosage form. CHALLENGES IN FORMULATING FDT [11] Palatability As most drugs are unpalatable, orally disintegrating drug delivery systems usually contain the medicament in a taste-masked form. FDT disi teg ate o dissol e i patie t s oral cavity, thus releasing API comes in contact with taste buds, so taste-masking become a critical to patient compliance Mechanical strength Order to allow FDTs to disintegrate in oral cavity, they are either vary porous or compressed into tablets with very low compression force, which makes tablets friable, difficult to handle and requiring specialized packing. These tablets have very poor mechanical strength Hygroscopicity PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 33 Several fast dissolving dosage forms are hygroscopic in nature and not able to maintain physical integrity under normal conditions of temperature and humidity. So, require special packaging Amount of drug The application of technologies used for ODTs is limited by the amount of drug that can be incorporated into each unit dose. For lyophilized dosage forms, the drug dose must be lower than 400 mg for insoluble drugs and less than 60 mg for soluble drugs. This parameter is particularly challenging when formulating a fast-dissolving oral films or wafers. Aqueous solubility Water-soluble drugs pose various formulation challenges because they form eutectic mixtures, which result in freezing-point depression and the formation of a glassy solid that may collapse upon drying because of loss of supporting structure during the sublimation process. Such collapse sometimes can be prevented by using various matrix-forming excipients such as mannitol than can induce crystallinity and hence, impart rigidity to the amorphous composite. Size of tablet The degree of ease when taking a tablet depends on its size. It has been reported that the easiest size of tablet to swallow is 7-8 mm while the easiest size to handle was one larger than 8 mm. Therefore, the tablet size that is both easy to take and easy to handle is difficult to achieve INGREDIETS MOSTLY USED IN FDT [12, 13] Super Disintegrants Disintegrants play a major role in the disintegration and dissolution of FDT. It is essential to choose a suitable disintegrant, in an optimum concentration so as to ensure quick disintegration and high dissolution rates. Super disintegrants provide quick disintegration due to combined effect of swelling and water absorption by the formulation. Due to swelling of superdisintegrants, the wetted surface of the carrier increases, this promotes the wettability and dispersibility of the system, thus enhancing the disintegration and dissolution. Sodium starch glycolate, Ac-di-sol (croscarmellose sodium), Crospovidone, Microcrystalline cellulose, Pregelatinised starch are some of examples of disintegrants. Sugar Based Excipients Sugar based excipients are used for taste masking and as bulking agents. Most of the dugs are having unpleasant or bitter taste. And the basic requirement for designing FDTs is that the drug should not have disagreeable taste. Sorbitol, mannitol, xylitol, dextrose, fructose, etc. are mainly used. Aqueous solubility and sweetness impart a pleasing mouth feel and good taste masking. Antiadherents Antiadherents are used to reduce the adhesion between the powder (granules) and the punch faces and thus prevent sticking to tablet punches. They are also used to help protect tablets from sticking. Most commonly used is magnesium stearate. Binders Binders hold the ingredients in a tablet together. Binders ensure that tablets and granules can be formed with required mechanical strength, and give volume to low active dose tablets. Binders are usually ● Saccharides and their derivatives: sucrose, lactose, starches, microcrystalline cellulose and cellulose ethers such as Hydroxypropyl cellulose (HPC) , xylitol, sorbitol or maltitol; ● Protein: gelatin ● Synthetic polymers: polyvinylpyrrolidone (PVP), polyethylene glycol (PEG). PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 34 Disintegrants Disintegrants expand and dissolve when wet causing the tablet to break apart in the digestive tract, releasing the active ingredients for absorption. Disintegrant types include: ● Water uptake facilitators ● Tablet rupture promoters Example: cross linked polyvinyl pyrrolidone (crospovidone), cross linked sodium carboxymethyl cellulose (croscarmellose sodium), sodium starch glycolate. Fillers or diluents Fillers fill out the size of a tablet or capsule, making it practical to produce and convenient for the consumer to use. A good filler must be inert, compatible with the other components of the formulation, nonhygroscopic, relatively cheap, and preferably tasteless or pleasant tasting. Plant cellulose (pure plant filler) is popular filler in tablets or hard gelatin capsules. Dibasic calcium phosphate is another popular tablet filler. Other examples of fillers include: lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate, vegetable fats and oils Flavours Flavours can be used to mask unpleasant tasting active ingredients and improve the likelihood that the patient will complete a course of medication. Flavourings may be natural (e.g. fruit extract) or artificial. Example: mint, cherry, anise, peach, apricot, liquorice, raspberry, vanilla Colours Colours are added to improve the appearance of a formulation. Colour consistency is important as it allows easy identification of a medication. Lubricants Lubricants prevent ingredients from clumping together and from sticking to the tablet punches or capsule filling machine. Lubricants also ensure that tablet formation and ejection can occur with low friction between the solid and die wall. Common minerals like talc or silica, and fats, e.g. vegetable stearin, magnesium stearate or stearic acid are the most frequently used lubricants in tablets or hard gelatin capsules. Glidants Glidants are used to promote powder flow by reducing interparticle friction and cohesion. These are used in combination with lubricants as they have no ability to reduce die wall friction. Examples include fumed silica, talc, and magnesium carbonate. Preservatives Some typical preservatives used in pharmaceutical formulations are: ● Antioxidants like vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium ● Citric acid and sodium citrate ● Synthetic preservatives like the parabens: methyl paraben and propyl paraben. Sweeteners Sweetners are added to make the ingredients more palatable, especially in chewable tablets such as antacids or liquids like cough syrup. Therefore, tooth decay is sometimes associated with cough syrup abuse. Sugar can be used to disguise unpleasant tastes or smells. Sublimating Agents The use of sublimating agents including camphor, menthol, and thymol was explored. The addition of camphor lowered the disintegration time (<30 s) further, but the percent friability was increased. SUPERDISINTEGRANTES [14] Use of disintegrates in FDT is basic approach. It is essential to choose a suitable disintegrates, in an optimum concentration to ensure PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 35 disintegration and dissolution.it provide quick disintegration due to combined effect of swelling and water absorption by the formulation. Use of superdisintegrantes like cross-linked cellulose, cross-linked PVP, crosslinked starch, cross-linked alginic acid. Figure: Tablet Disintegration and Subsequent Drug dissolution Mechanism of Action of Superdisintegrats By Capillary Action When we put the tablet into suitable aqueous medium, the medium penetrates into the tablet and replaces the air adsorbed on the particles, which weakens the intermolecular bond and breaks the tablet into fine particles. Water uptake by tablet depends upon hydrophilicity of the drug /excipient and on tableting conditions. For these types of disintegrants, maintenance of porous structure and low interfacial tension towards aqueous fluid is necessary which helps in disintegration by creating a hydrophilic network around the drug particles. By Swelling Perhaps the most widely accepted general mechanism of action for tablet disintegration is swelling Tablets with high porosity show poor disintegration due to lack of adequate swelling force. On the other hand, sufficient swelling force is exerted in the tablet with low porosity. It is worthwhile to note that if the packing fraction is very high, fluid is unable to penetrate in the tablet and disintegration is again slows down. Because of Heat of Wetting (Air Expansion) When disintegrants with exothermic properties gets wetted, localized stress is generated due to capillary air expansion, which helps in disintegration of tablet. This explanation, however, is limited to only a few types of PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 36 disintegrants and can not describe the action of most modern disintegrating agents. Due to Release of Gases Carbon dioxide released within tablets on wetting due to interaction between bicarbonate and carbonate with citric acid or tartaric acid. The tablet disintegrates due to generation of pressure within the tablet. This effervescent mixture is used when pharmacist needs to formulate very rapidly dissolving tablets or fast disintegrating tablet. The effervescent blend is either added immediately prior to compression or can be added in to two separate fraction of formulation. By Enzymatic Reaction Enzymes presents in the body also act as disintegrants. These enzymes destroy the binding action of binder and helps in disintegration. Actually due to swelling, pressure exerted in the outer direction or radial direction, it causes tablet to burst or the accelerated absorption of water leading to an enormous increase in the volume of granules to promote disintegration. Due to Disintegrating Particle/Particle Repulsive Forces Guyot-Hermann has proposed a particle repulsion theory based on the observation that nonswelling particle also cause disintegration of tablets. The electric repulsive forces between particles are the mechanism of disintegration and water is required for it. Researchers found that repulsion is secondary to wicking. Due to Deformation Hess had proved that during tablet compression, disintegrated particles get deformed and these regain their normal structure when they come in contact with aqueous media or water. Occasionally, the swelling capacity of starch was improved when granules were extensively deformed during compression. This increase in size of the deformed particles produces a break up of the tablet MAJOR THEORIES IN FDT TECHNOLOGY 1. Mechanisms of granule aggregation The binding mechanisms of agglomeration were first defined and classified by H. Rumpf. The mechanisms can be divided into five major groups. Solid bridge: The solid bridge can be formed through sintering. If the temperature of the mixture rises above approximately two thirds of the melting temperature or softening range of the solid, diffusion of an atoms or molecules from one particle to another occurs at the point of contact. Formation of solid bridges can also occur by a chemical reaction or a hardening binder. Adhesion and cohesion forces: Some materials, such as finely divided solids, can easily attract free atoms or molecules from the surrounding atmosphere. A thin adsorption layer can be developed on each particle and such layers contact and penetrate each other to form a strong bond. Surface tension and capillary force: Free water or capillary condensation can develop liquid bridges. They often lead to formation of solid bridges. Attraction force between solid particles: At extremely small distances between the adhesion partners these forces can be very high but, due to their short-range effect, they diminish quickly with increasing distance at the coordination points. Van der waals forces attract the particles at close range. Unsatisfied valences exist on newly created surfaces during grinding or compression. Interlocking Bonds: Interlocking bonds occur if the particulate solids have elongated shape. In highpressure agglomeration, another interlocking mechanism may occur if a mixture of rigid and plastic materials is compacted PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 37 2. Disintegration The complete disintegration defined by U.S. Pharmacopoeia XX is "The state in which any residue of the unit, except fragments of insoluble coating or capsule shell remaining on the screen of the test apparatus is a soft mass having no palpably firm core." Several mechanisms like Evolution of gas: The basis of effervescent tablets is the reaction of sodium bicarbonate with citric or tartaric acid to yield carbon dioxide upon contact with water. Release of gas generates enough pressure to disintegrate a tablet Adsorption: The heat of wetting of the ingredients that occurs when the tablet is immersed in a fluid causes the entrapped air in the tablet to expand and disintegrate a tablet. This proposal, however, is questionable. It is not clear whether the amount of heat generated can cause sufficient increase in the volume of air to cause pressure build up thus breaking a tablet apart. This mechanism can provide only a partial explanation. Effect of water absorption (wicking): Disintegrants such as starch introduce water into a tablet and form a large system of capillaries inside the tablet to cause tablet disintegration. Swelling: Disintegrants such as Ac-Di-Sol and various starches are reported to swell when moisturized. Swelling of these disintegrants will produce enough pressure to disintegrate a whole tablet. The tablets made at low pressure have high porosity. When starches swell, it will not generate enough pressure because of the high empty space. Medium pressure creates just enough space that allows water to come in and exert high pressure when starches swell. High pressure is thought to squeeze most porosity away and the water cannot flow into a tablet. 3. Water absorption The affinity that a substance has for absorbing water from its vapor state is generally referred to as Hygroscopicity. Even the relatively weak bond of physical sorption, for which the heat of adsorption is comparable to the heat of condensation, can provide this driving force over a large range in relative humidity. For water- soluble substances, dissolution of the molecules at solid surfaces can occur once multilayer condensation is established. TECHNIQUES FOR FDT [15] Direct Compression Direct compression represents the simplest and most cost effective tablet manufacturing techniques. It is easiest way to manufacture tablet. Conventional equipments, commonly available experiments and limited number of processing steps are involved in direct compression.[17] Superdisintegrants A disintegrate is a substance in a tablet formulation that enables the tablet to break up into smaller fragments. Superdisintegrants are used at a low level in the solid dosage foam, typically 1-10 % by weight relative to the total weight of the dosage unit. Example of superdisintegrants are crosscarmellose sodium, crospovidone and sodium starch glycolate. Microcrystalline cellulose and low substituted hydroxypropyl cellulose were used as disintegrate agents in the range of 8:2-9:1 to prepare fast dissolving tablet. Agar powders used as disintegrate for the development of rapidly disintegration tablets by enhancing the porosity of agar by water treatment. Sugar based excipients This is another approach to manufacture FDT by direct compression. The use of sugar based excipients especially bulking agents like dextrose, fructose, isomalt, lactilol, maltilol, maltose, mannitol, sorbitol, starch-hydrolysate, polydextrose and xylitol, which display high PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 38 aqueous solubility and sweetness, and hence impart taste masking property and a pleasing mouth feel. [18] Advantages of direct compression ● High doses can be accommodated and final weight of the tablet can exceed that of other methods. ● Easiest way to manufacture the tablets. ● Conventional equipment and commonly available excipients are use. ● A limited no. Of processing steps are involved. Cost-effectiveness Freeze-Drying or Lyophilization Freeze drying is the process in which water is sublimed from the product after it is frozen. This technique creates an amorphous porous structure that can dissolve rapidly. This method generally used for drying the heat sensitive drug. The active drug is dissolved or dispersed in an aqueous solution of a carrier/polymer. The mixture is done by weight and poured in the walls of the preformed blister packs. The trays holding the blister packs are passed through liquid nitrogen freezing tunnel to freeze the drug solution or dispersion. Then the frozen blister packs are placed in refrigerated cabinets to continue the freeze-drying. After freezedrying the aluminum foil backing is applied on a blister-sealing machine. Finally the blisters are packaged and shipped. The freeze-drying technique has demonstrated improved absorption and increase in bioavailability. The major disadvantages of lyophilization technique are that it is expensive and time consuming; fragility makes conventional packaging unsuitable for these products and poor stability under stressed conditions. Spray Drying [16] In this technique, gelatin can be used as a supporting agent and as a matrix ,citric acid as acidic ingredient, sodium bicarbonate as alkaline ingredients, mannitol as a bulking agent and sodium starch glycolate or crosscarmellose or crospovidone are used as superdisintegrants. Tablets manufactured from the spray-dried powder have been reported to disintegrate in less than 20 seconds in aqueous medium. This spray-dried powder, which compressed into tablets showed rapid disintegration and enhanced dissolution. Sublimation This process involves addition of some inert volatile substances like urea, urethane, naphthalene, ammonium carbonate, benzoic acid, phthalic anhydride, camphor etc. to other excipients and the compression of blend into tablet. Removal of volatile material by sublimation creates pores in tablet structure, due to which tablet dissolves when comes in contact with saliva. Additionally several solvents like cyclohexane, benzene etc. can also be used as pore forming agents. Fast dissolving tablets with highly porous structure and good mechanical strength have been developed by this method. Fig. : schematic diagram of sublimation technique. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 39 Melt Granulation In this process, FDTs can be prepared by incorporating a hydrophilic waxy binder (super polystate) like PEG-6-stearate. Super polystate is a waxy material with melting point of 3337°C. It not only acts as a binder and increases the physical resistance of tablets, but also helps in the disintegration of tablets as it melts in the mouth and solubilizes rapidly leaving no residue. Super polystate was incorporated in the formulation of FDTs by melt granulation method where granules are formed by the molten form of this material Mass-Extrusion This technology involves softening the active blend using the solvent mixture of watersoluble polyethylene glycol and methanol and subsequent expulsion of softened mass through the extruder or syringe to get a cylinder of the product into even segments using heated blade to form tablet. The dried cylinder can also be used to coat granules for bitter drugs and thereby achieve taste masking Effervescent Agent Addition Method In this method a mixture containing tartaric acid and an alkaline substance such as sodium bicarbonate is prepared by mortar pestle and preheated at 80°C. It is helpful in removing the residual or absorbed moisture. The mixture is then mixed with superdisintegrants and finally compressed to form tablets Taste Masking Method Usually, microencapsulation is used to mask the bitter taste of drug. The active drug is encapsulated in an immediate release matrix. In FDTs, the rapid disintegration is achieved by using effervescent agents. The taste masking method involves the compression of taste masked microcrystal of active drug compound along with swelling and disintegrating agent. Tablet Molding In this technology water soluble ingredients are used, so that tablet disintegrate and dissolve rapidly. Molding process is of three types: Solvent method: Solvent method involves moistening the powder blend with a hydro alcoholic solvent followed by compression at low pressures in molded plates to form a wetted mass (compression molding). The solvent is then removed by air-drying. The tablets manufactured in this manner are less compact than compressed tablets and possess a porous structure that hastens dissolution. Heat method: The heat molding process involves preparation of a suspension that contains a drug, agar and sugar (e.g. mannitol or lactose) and pouring the suspension in the blister packaging wells, solidifying the agar at the room temperature to form a jelly and drying at 30○C under vacuum. No vaccum lyophillization: This process involves evaporation of solvent from a drug solution or suspension at a standard pressure. The mechanical strength of molded tablets is a matter of great concern, Phase Transition Process Tablets were produced by compressing a powder containing two sugar alcohols with high and low melting points and subsequent heating at a temperature between their melting points. Before heating process, the tablets do not have sufficient hardness because of low compatibility. The tablet hardness was increased after heating, due to the increase of inter particle bonds or the bonding surface area in tablets induced by phase transition of lower melting point sugar alcohol. Cotton Candy Process This process is so named as it utilizes a unique spinning mechanism to produce floss-like crystalline structure, which mimic cotton candy. Cotton candy process involves formation of matrix of polysaccharides or saccharides by simultaneous action of flash melting and PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 40 spinning. The matrix formed is partially recrystallized to have improved flow properties and compressibility. This candy floss matrix is then milled and blended with active ingredients and excipients and subsequently compressed to FDTs Nanonization Involves size reduction of drug to nano size by milling the drug using a proprietary wet-milling technique. The nanocrystals of the drug are stabilized against agglomeration by surface adsorption on selected stabilizers, which are then incorporated into FDTs. It is used for poorly water soluble drugs. It leads to higher bioavailability and reduction in dose, cost effective manufacturing process, conventional packaging due to exceptional durability and wide range of doses (up to 200 mg of drug per unit). IMPORTANT PATENTED TECHNOLOGIES FOR FDT [19] ● Zydis Technology Zydis formulation is a unique freeze dried tablet in which drug is physically entrapped or dissolved within the matrix of fast dissolving carrier material. When zydis units are put into the mouth, the freeze-dried structure disintegrates instantaneously and does not require water to aid swallowing. To impart strength and resilience during handling, polymers such as gelatin, dextran or alginates are incorporated. These form a glossy amorphous structure, which imparts strength. To obtain crystallinity, elegance and hardness, saccharides such as mannitol or sorbitol are incorporated. Water is used in the manufacturing process to ensure production of porous units to achieve rapid disintegration while various gums are used to prevent sedimentation of dispersed drug particles in the manufacturing process. Collapse protectants such as glycine prevent the shrinkage of zydis units during freeze-drying process or long-term storage. Zydis products are packed in blister packs to protect the formulation from moisture in the environment. ● Wow Tab Technology Yamanouchi patented this technology. WOW means without water. This technology utilizes conventional granulation and tableting methods to produce FDTs employing low- and highmouldability saccharides. Low mouldability saccharides are lactose, mannitol, glucose, sucrose, and xylitol. High-moldability saccharides are maltose, maltitol, sorbitol, and oligosaccharides. When these low- and highmoldable saccharides are used alone tablets obtained do not have desired properties of rapid disintegration and hardness, so combinations are used. The active ingredient is mixed with a low mouldability saccharide (eg. lactose, glucose, and mannitol) and granulated with a high mouldability saccharide (eg. Maltose, oligosaccharides) and compressed into table. Thus tablets obtained showed adequate hardness and rapid disintegration. Because of hardness, shows fast salvation in mouth and offer a very pleasant the tablet is more stable in the environmental conditions mouth feel. The general manufacturing method of tablets than the Zydis or Orasolv and is fit for both usual bottle by this technology involves preparation of sucrose and blister packaging. Durasolv Technology This technology is patented by CIMA Labs. The tablets produced by this technology utilize the conventional tableting equipment. Tablets in this are formulated by using drug, nondirect compression fillers, and lubricants. Nondirect compressible fillers are dextrose, mannitol, sorbitol, lactose, and sucrose, which have advantage of quick dissolution and avoid gritty texture. The tablets have disintegration time less than 60 seconds. In this technology more amounts of hydrophobic lubricants, can be used in the formulation. Low compressive force is PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 41 required to compress the tablet. The production cost is significantly less because direct compression method and conventional package equipment are employed. Orasolv Technology This technology is patented by CIMA Labs. This includes use of effervescent disintegrating agents compressed with low pressure to produce the FDTs. The evolution of carbon dioxide from the tablet produces fizzing sensation, which is a positive organoleptic property. Concentration of effervescent mixture usually employed is 20-25% of tablet weight. The particle coating which is used for taste masking purpose is not cracking at the time compression force. As tablets are prepared at low compression force, they are soft and fragile in nature. This initiated to develop Paksolv, a special packaging to protect tablets from breaking during storage and transport. Paksolv is a dome-shaped blister package, which prevents vertical movement of tablet within the depression. Paksolv offers moisture, light, and child resistance packing. Dispersible Tablet Technology Lek, Yugoslavia patents this technology. It offers development of FDTs with improved dissolution rate by incorporating 8-10% of organic acids and disintegrating agents. Disintegrating agent facilitates rapid swelling and good wetting capabilities to the tablets that results in quick disintegration. Disintegrants include starch, modified starches, microcrystalline cellulose, alginic acid, cross-linked sodium carboxy methyl cellulose and cyclodextrins. Combination of disintegrants improves disintegration of tablets usually less than 1 min Frosta Technology This technology patents by Akina. It utilizes the concept of formulating plastic granules and compressing at low pressure to produce strong tablets with high porosity. Plastic granules composed of: Porous and plastic material, Water penetration enhancer and binder. The process involves usually mixing the porous plastic material with water penetration enhancer and followed by granulating with binder. The tablets obtained have excellent hardness and rapid disintegration time ranging from 15 to 30 s depending on size of tablet. Pharmaburst Technology SPI Pharma, New Castle, patents this technology. It utilizes the coprocessed excipients to develop FDTs, which dissolves within 30-40 s. This technology involves dry blending of drug, flavour, and lubricant followed by compression into tablets. Tablets obtained have sufficient strength so they can be packed in blister packs and bottles. Lyoc Lyoc technology is patented by Pharmalyoc. Oil in watr emulsion is prepared and placed directly into blister cavities followed by freeze-drying. Non-homogeneity during freeze-drying is avoided by incorporating inert filler to increase the viscosity finally the sedimentation. High proportion of filler reduces porosity of tablets due to which disintegration is lowered. Flashtab Technology Prographarm labs have a patent over this technology. In this technology, microgranules of the taste‐masked active drug are used. These may be prepared by using conventional techniques like coacervation, microencapsulation, and extrusionspheronisation. All these processes utilize conventional tableting technology. These taste‐ masked micro crystals of active drug, disintegrating agent, a swelling agent and other excipients like soluble diluents etc. are compressed to form a multiparticulate tablet that disintegrates rapidly. Disintegrating agents include reticulated polyvinylpyrrolidine or carboxy methylcellulose. Swelling agents PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 42 include carboxy methylcellulose, starch, modified starch, microcrystalline cellulose, carboxy methylated starch, etc. These tablets have satisfactory physical resistance. Disintegration time is within 1 min. Nanocrystal Technology Decreasing particle size increases the surface area, which leads to an increase in dissolution rate. This can be accomplished predictably and efficiently using NanoCrystal technology. NanoCrystal particles are small particles of drug substance, typically less than 1000 nanometers (nm) in diameter, which are produced by milling. Na oC stal™ Fast dissol i g te h olog provides for: a. Pharmacokinetic benefits of orally administered nanoparticles (<2 microns) in the form of a rapidly disintegrating tablet matrix b. Exceptional durability, enabling use of conventional packaging equipment and formats (i.e., bottles and/or blisters). c. Wide range of doses (up to 200mg of API per unit). d. Employment of non moisture sensitive substances. NanoCrystal colloidal dispersions of drug substance are combined with water‐soluble GRAS (Generally Regarded As Safe) ingredients, filled into blisters, and lyophilized. The resultant wafers are remarkably robust, yet dissolve in very small quantities of water in seconds. It is considered that this technology reduces the particle size, which is beneficial to enhance the dissolution, hence bioavailability Advatab Technology During the production process of FDTs, the lubricant is coated on each tablet surface by a spray. The produced tablets are stronger and harder than conventional due to which saliva cannot penetrate easily [10]. High drug loading is possible in this technology. Additionally, there is no requirement of special packaging and, also, the tablet can be packaged in both pushthrough blisters and standard bottles. It is reported that AdvaTab tablets disintegrate within less they than 30 seconds due to quick penetration of saliva in pores of tablet in mouth. Quicksolv Technology Both the drug and excipients are dissolved in water and frozen. Add second solvent to the frozen mixture. And finally after a few hours, the second solvent is removed, which results in formation of a porous matrix. The second solvent may be acetone or ethanol. Always the matrix composition should be immiscible to the second solvent. The drug should be in fine size and have good stability in aqueous medium Flashdose Technology It utilizes Shearform technology along with Ceform technology to avoid the bitter taste of the drug. Shearform technology prepares the floss matrix. Matrix is composed of drug and excipients. Floss refers to fibrous material, which is similar to cotton-candy fibres. These cotton-candy fibres are prepared by saccharides such as lactose, sucrose, fructose and polydextrose. Tablets prepared by this technology possess high porosity. Also, as tablets contain sugar, it shows fast salvation in mouth and offer a very pleasant mouth feel. The general manufacturing method of tablets by this technology involves preparation of sucrose solution (80%) and addition of 1 % surfactant. Surfactant helps in maintaining the structural integrity of the floss fibres. Then this whole product is subjected to the flash heat process. In this process, the heat provokes an interior flow state of the carrier substance. Then this processed material is passed through an exit, where a spinning head operated at 2000-3600 rpm. The role of spinning head is to throw the floss under centrifugal force and produce long floss fibres. These fibres are PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 43 generally amorphous in nature. Mix the drug and required excipients with floss fibres and finally compressed. EVALUATION PARAMETERS [20] Pre-compression Parameters ● Bulk density (Db) It is the ratio of total mass of powder to the bulk volume of powder. It was measured by pouring the weight powder (passed through standard sieve # 20) into a measuring cylinder and initial weight was noted. This initial volume is called the bulk volume. From this the bulk density is calculated according to the formula mentioned below. It is expressed in g/ml and is given by: Db = M/ Vb Where, M is the mass of powder, Vb is the bulk volume of the powder Tapped density (Dt) It is the ratio of total mass of the powder to the tapped volume of the powder. Volume was measured by tapping the powder for 750 times and the tapped volume was noted if the difference between these two volumes is less than 2%. If it is more than 2%, tapping is continued for 1250 times and tapped volume was noted. Tapping was continued until the difference between successive volumes is less than 2 % (in a bulk density apparatus). It is expressed in g/ml and is given by: Dt = M / Vt Where, M is the mass of powder, Vt is the tapped volume of the powder Where, ø - is the angle of repose, h - height in cm, r - radius in cms. The powder mixture was allowed to flow through the funnel fixed to a stand at definite height(h). The angle of repose was then calculated by measuring the height and radius of the heap of powder formed. Care was taken to see that the powder particles slip and roll over each other through the sides of the funnel. Relationship between angle of repose and powder flow property. SR.NO. 1 2 3 4 Angle of repose (0) <20 20-30 30-34 >34 Type of Flow Excellent Good Passable Very Poor (Angle of Repose as an Indication of Powder Flow Properties) ● A gle of repose θ The friction forces in a loose powder can be measured by the angle of repose (θ). It is an indicative of the flow properties of the powder. It is defined as maximum angle possible between the surface of the pile of powder and the horizontal plane tan ( ø) = h / r ( ø ) = tan-1 (h / r) ● Carr s i de or % o pressi ilit It indicates powder flow properties. It is expressed in percentage and is give Dt – Db I = ------------ *100 Dt Where, Dt is the tapped density of the powder and Db is the bulk density of the powder. % Compressibility 5-12 12-16 18-21 23-35 33-38 < 40 ● Flow ability Excellent Good Fair Passable Poor Very Poor Very Very Poor (relationship between % compressibility and floe ability) Hausner ratio Hausner ratio is an indirect index of ease of ● PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 44 powder flow. It is calculated by the following formula. Dt Hausner ratio = ------Db Where, Dt is the tapped density. Db is the bulk density. Modified Disintegration Test: A petridish (10cm diameter) was filled with 10 ml of water. The tablet was carefully put in the center of petridish and the time for the tablet to completely disintegrate into fine particles was noted. ● Dissolution test The dissolution methods for FDT are practically identical to conventional tablet when FDT does not utilize taste masking. Commonly the drugs may have dissolution conditions as in USP monograph. 0.1N HCl, pH 4.5 and pH 6.8 buffers should be used for evaluation of FDT in the same way as their ordinary tablet counterparts. USP 2 paddle apparatus is most suitable and common choice for dissolution test of FDT tablets as compared to USP1 (basket) apparatus due to specific physical properties of tablets. In paddle apparatus the paddle speed of 25-75 rpm is commonly used. Since the dissolution of FDTs is very fast when using USP monograph conditions hence slower paddle speeds may be utilized to obtain a comparative profile. Large ta lets ≥ g a a p odu e a ou d i the dissolution vessel which can be prevented by using higher paddle speeds. ● Post-Compression Parameters ● Weight variation 20tablets were selected randomly from the lot and weighted individually to check for weight variation. Weight variation specification as per I.P. is shown in table No.5 Average Weight of Tablet % Deviation 80 mg or less ±10 80-250 ±7.5 250 mg or more ±5 (Weight Variation Specification as per IP) Hardness The limit of hardness for the FDT is usually kept in a lower range to facilitate early disintegration in the mouth. The hardness of the tablet may be measured using conventional hardness testers (Monsanto tablet hardness tester). It is expressed in kg/cm2 or pound. ● Friability To achieve % friability within limits (0.1- . ℅ for an FDT is a challenge for a formulator since all methods of manufacturing of FDT are responsible for increasing the % friability values. F ia ilit of ea h at h as easu e i Ele t o la f ia ilato . Te p e-weighed tablets were rotated at 25 rpm for 4 min or total 100 times dropping a tablet at height of 6 inches in each revolutions, the tablets were then reweighed and the percentage of weight loss was calculated by the following equation. W I - WF F= x 100 WI WI = Initial Weight Of Tablet WF = Final Weight Of Tablet ● Wetting time Wetting time is closely related to the inner structure of the tablets and to the hydrophilicity of the excipient. To measure wetting time, five circular tissue papers of 10 cm diameter are placed in a petridish with a 10 cm diameter. Ten millimeters of water-containing Eosin, a watersoluble dye, is added to petridish. A tablet is carefully placed on the surface of the tissue paper. The time required for water to reach upper surface of the tablet is noted as a wetting time. It is obvious that pores size becomes smaller and wetting time increases with an increase in compression force or a decrease in porosity. A linear relationship exists between wetting time and disintegration time. Thus ● PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 45 wetting is the important step for disintegration process to take place. Water absorption ratio A piece of tissue paper folded twice was placed in a small Petri dish containing 6 ml of water. A tablet was put on the paper & the time required for complete wetting was measured. The wetted tablet was then weighed. Water absorption ratio, R, was determined using following equation, R = 100 (Wa-Wb) / Wb Wb = The weight of the tablet before keeping in the petridish Wa = The wetted tablet from the petridish is taken and reweighed. ● BRAND NAME Pepcid RPD Zofran ODT Torrox MT Olanex instab Tempra Quicklets Cibalgina DueFast Maxalt MLT Zyprexia Felden fast melt Stability Study (Temperature Dependent): The fast dissolving tablets stored under the following conditions for a period as prescribed by ICH guidelines for accelerated studies. (i) 40 ± 1°C (ii) 50 ± 1°C (iii) 37 ±1°C and RH 75% ± 5% The tablets were withdrawn after a period of 15 days and analyzed for physical characterization such as visual defects, Hardness, Friability, Disintegrations, and Dissolution etc. The data obtained is fitted into first order equations to determine the kinetics of degradation. Accelerated stability data are plotting according Arrhenius equation to determine the shelf life at 25°C. ● MARKETED FORMULATION OF FDT API COMPANY Famotidine Merck and Co., NJ, USA Ondansetron Glaxo Wellcome, Middlesex, UK Rofecoxib Torrent pharmaceuticals , India Olanzapine Ranbaxy lab. Ltd. New-Delhi, India Paracetamol Cima Labs,Inc. Ibuprofen Eurand International Rizatriptan Merck and Co., NJ, USA Olanzapine Eli lilly, Indianapolis, USA piroxicam Pfizer Inc., NY, USA ↓ REFERENCES .Gupta A, Mish a AK, Ba sal P, “i gh ‘, ‘e e t t e ds of fast dissol i g ta lets –an overview of fo ulatio te h olog . I t. J. Pha . Bio. , , -10. .Goel H, ‘ai P, ‘a a V, Ti a i AK, O all disi teg ati g s ste : i o atio i formulation and te h olog . ‘e e t Pate t O D ug Deli a A d Fo ulatio . , , -274. .Ku a “, Gupta “, “ha a P, A e ie o e e t t e ds i o al d ug deli a -fast dissolving fo ulatio . Ad a es I Bio.‘es. , , -13. 4.Lokesha Puttali G, Ku hu Ka itha, fast disi teg ati g ta let: A o e ie of fo ulatio ,te h olog a d e aluatio . ‘es. J. Pha . Bio. Che. “ i. , , -601. .Jaga i H, Patel ‘, Upadh a P, Fast dissol i g ta let : p ese t a d futu e p ospe ts. Journal Of Advances In Pharmacy And Healthcare Research. 2011, 2(1), 5-6. .Nika A, Kodade K, Ga a e V, Mouth dissol i g ta lets:a o e ie . Pha a olog o li e . , 562-586. .De jit B, Chi a ji B, Augs u ge L, Fast dissol i g ta lets :a o e ie . J. Che. Pha . ‘es. , 1(1), 163-177. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 46 .You o g Fu, “hi he g Ya g, “eo g Hoo Jeo g, “usu u Ki u aa d, Ki a Pa k, O all fast disintegrating tablets :development, technologies, taste- aski g a d li i al studies. C iti al ‘e ie s™ In Therapeutic Drug Carrier System. 2004, 21(6), 433-475. .“iddi ui N, Ga g G, “ha a P, Fast dissol i g ta lets: p epa atio , ha a te izatio a d e aluatio : a o e ie . I t. J. Pha .“ i. ‘es. , , -95. 10.Mizumoto T, Masuda Y, Ando S, Yamamoto T, Yonemo hi E, Te ada K, Fo ulatio desig of a o el fast disi teg ati g ta lets. I t. J. Pha . , -2), 83-90. .Ba da i “, Mittapalli ‘K, Ga u ‘, ‘ao YM, O odispe si le ta lets: a o e ie . Asia J. Pha . 2008, 2, 2-11. 12.Late s, yi-ying yu, Ba ga AK, Effe ts of disi teg atio –promoting agent, lubricants and moisture t eat e t o opti ized fast disi teg ati g ta lets. I t. Jou al Of Pha a euti s. , , -11. .Mulla e MP, Ha o k BC, Ca lsol GT, The Po de flo a d o pa t e hanical properties of su ose a d th ee high i te sit s eet e s used i he a le ta lets. I t. J. Pha . , -2), 227236. .Kau T, Gill B, Gupta GD, Ku a “, Mouth dissol i g ta lets: a o el app oa h to d ug deli a . I t. J. Curr. Pharm. Res. 2011, 3(1), 1-7. .Do etti L, Fast elti g ta lets: de elop e t a d te h olog . Pha a euti al Te h. D ug Deli e . 2001, 44-50. .Co ele “, ‘a o JP, Fo ulatio a d p odu tio of apidl disi teg ati g ta lets lyophilization using hydrochlorothiazide as a odel d ug. I t. J. Of Pha . , , -225. 17.Rawa-Qalaji M, “i o s F, Fast disi teg a te su li gual ta lets: effe ts of epi eph i e load ta lets ha a te isti s. AAP“. Pha .“ i. Te h. , , E -E7. 18.Gosai A R, Patil S B, “a a t K K , Fo ulatio a d e aluatio of o o-dispersible tablet of o da set o h d o hlo ide di e t o p essio usi g suppe disi teg a t. I t. J. Pha . “ i. A d Nanotechnology. 2008, 1(1), 106-111. .“hegoka ‘, Mulle ‘H, Na o stals : i dustrially feasible multifunctional formulation technology fo poo l solu le a ti ies. I te atio al Jou al Of Pha a euti s. , -2), 129-139. .A del a G, P i dee P, Eoua i C, Joa hi J, Pi e elle P, Dete i atio of the i -vitro disintegratio p ofile of apidl disi teg ati g ta lets a d o ellatio ith o al disi teg atio . I t. J. Pharm. 2005, 292(1-2), 29-41. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 47 Review Article African Herbal Plants used as Anti-Malarial Agents - A Review Enegide Chinedu*, David Arome, Solomon F. Ameh Department of Science Laboratory Technology (Physiology & Pharmacology Technology), University of Jos, Jos Nigeria *chinex.snow@gmail.com ABSTRACT Malaria is an infectious disease caused by single-celled obligate parasite known as Plasmodium and is transmitted to man through the vector Anopheles mosquito. It has persistently been a major public health problem to the global community. As estimate has shown that globally, about 3.3 billion people were at risk of malaria in the year 2011. It has now been ranked among the world's top killer infectious diseases and remains the most prominent cause of death and illness in Africa particularly among pregnant women and children under the age of five years. Due to the development of drug-resistance by the malaria parasites and also the development of resistance to various insecticides by the vector, development of new antimalarial agents is imperative and herbal plants have for long been a major source of new drug discovery. Consequently, in various African countries, several plants have been reported to be having antimalarial effects and are being applied traditionally as antimalarial agents. The purpose of this review article therefore, is to collate and document different plants used traditionally as antimalarials in six African countries (Nigeria, Ghana, Ethopia, Benin, Cameroon and Togo). One hundred and fifteen herbal plants from the six African countries have been captured in this article due to their local usage as antimalarial agents. The array of medicinal plants employed as antimalarial agents in Africa, unveils a promising source for the development of new and better antimalarial drugs. Scientific investigations should therefore be carried-out on them. Keywords: Malaria treatment, herbal plants, Africa INTRODUCTION Malaria is an infectious disease caused by single-celled obligate parasite known as Plasmodium and is transmitted to man through the vector Anopheles mosquito. The various plasmodium species are Plasmodium ovale, Plasmodium vivax, Plasmodium malariae, Plasmodium knowlesi and Plasmodium falciparum. Plasmodium falciparum is however known to be the most deadly specie. Malaria is usually characterized by headache, chills, fever, myalgias, malaise and gastrointestinal upset. The most deadly complications however include respiratory distress resulting from metabolic acidosis, severe anaemia and cerebral malaria which may lead to death. [1] Malaria has persistently been a major public health problem to the global community. [2] Estimate has shown that globally, about 3.3 billion people were at risk of malaria in the year 2011. Malaria has now been ranked among the world's top killer infectious diseases and remains the most prominent cause of death and illness in Africa particularly among pregnant women and children under the age of five years. [3, 4] Though several malaria control programs have been put in place by various countries, it seems only a little success have been achieved. Various therapies have been developed for the treatment of malaria some which includes How to cite this article: E Chinedu, D Arome, SF Ameh, African Herbal Plants used as Anti-Malarial Agents A Review, PharmaTutor, 2014, 2(3), 47-53 PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 48 Chloroquine, Mefloquine, Quinine, Primaquine, Artemisinin and its derivatives like artesunate, artemether and arteether. However, the treatment and control of malaria have now evolved to a more complicated process. This is due to the development of drug-resistance by the malaria parasites and also the development of resistance to various insecticides by the vector (Anopheles mosquito). [5 - 7] Hence, the development of new antimalarial agents is imperative and herbal plants have for long been a major source of new drug discovery. APPLICATION OF HERBS IN THE TREATMENT OF MALARIA IN AFRICA Africa is said to be having the highest burden of malaria, this is due to the fact that Plasmodium falciparum (which is the most deadliest specie) occurs more in Africa and have led to an increased mortality rate (of about 600,000 deaths yearly) as well as morbidity. [8, 9] In fact, about 80% cases of malaria and 90% malaria deaths are from Africa. [10] Estimates have revealed that about 3.5 - 4 billion people globally, depend on herbs for drugs to treat of several ailments. [11] Africa has been known to be among the highest patronizers/consumers of herbal medicines. About 80% populations in most African countries rely on traditional medicines (especially herbs) for primary health care. [12] History has revealed the successful use of plants/plant products in the treatment of several ailments including malaria. Records have even shown that some of the currently used antimalarial drugs were derived from plants. For example, the premiere antimalarial drug, was gotten in 1820 from the stem-bark of Cinchona plant. Even Artemisinin the now famous antimalarial drug, was gotten from the plant Artemisia annua. [13 - 16] These and many more successes in herbal medicine research have therefore encouraged more investigations on various herbal plants used traditionally as antimalarial agents. Consequently, in various African countries, several plants have been reported to be having antimalarial effects and are being applied traditionally as antimalarial agents. The purpose of this review article therefore, is to collate and document different plants used traditionally as antimalarials in six African countries (Nigeria, Ghana, Ethopia, Benin, Cameroon and Togo). This is important because herbal plants have always been a vital source for developing new drugs, hence novel antimalarial compounds/drugs may be developed from them if further scientific studies are carried-out on them. Table 1: African plants locally used in malaria treatment Country Nigeria Botanical Name Khaya grandifoliola Azadirachta indica Chromolaena odorata Lecaniodiscus cupanioides Ananas comosus Cymbopogon citratus Cajanus cajan Heliotropium indicum Carica papaya Rytigynia nigerica Morinda morindiodes Family Meliaceae Meliaceae Compositae Sapindaceae Bromeliaceae Poaceae Fabaceae Boraginaceae Caricaceae Rubiaceae Rubiaceae Local Name Oganwo Dogonyaro Ewe Awolowo Orinbo arinka Ope-Oyinbo Kooko-Oba Otili Ogberi-akuko Ibepe Elegun oko Ponju owiwi Pycnanthus angolensis Cajanus cajan Myristicaceae Fabaceae Akomu Waken suya Part Used Bark Bark, leaves Root, leave Leave, stem Unripe Fruit Leaves Leaves Whole plant. Leaves, fruit Root, Bark Aerial part, Root, bark Bark Leaves PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org Reference [17] [17] [17] [18] [17] [17] [18] [17] [17] [18] [18] [17] [19] 49 Ghana Ocimum gratissimum Citrus medica Vernonia amygdalina Sclerocarya birrea Solanum nigrum Theobroma cacao Allium sativum Ceiba pentandra Spondias mombin Labiatae Rutaceae Compositae Anacardiaceae Solanaceae Malvaceae Liliaceae Bombacaceae Anacardiaceae Efirin-nla Osan were Ewuro Danya Odu Koko Ayuu Araba Iyeye Hyptis suaveolens Citrus paradisi Labiatae Rutaceae Jogbo Osan gerepu Garcina kola Gossypium hirsutum Abrus precatorius Physalis angulata Guttiferae Malvaceae Fabaceae Solanaceae Goro Ela owu Oju ologbo Koropo Rauvolfia vomitoria Apocynaceae Asofeyeje Argemone Mexicana Psidium guajava Lophira alata Quassia amara Senna podocarpa Anogeisus leiocarpus Acanthospermum hispidum Ficus platyphylla Papaveraceae Myrtaceae Ochnaceae simaroubaceae Caesalpiniaceae Combretaceae Asteraceae Moraceae Mafowokon Gilofa Ponhan Raken giwa Asunwonibile Sisinrah Bongore Selinge Khaya senegalensis Strychnos spinosa Xeroderris stuhlmannii Sterculia setigera Ricinus communis Pseudocedrela kotschyi Ocimum canum Nauclea latifolia Paullinia pinnata Indigofera pulchra Ozoroa insignis Lannea acida Jatropha gossypiifolia Pterocarpus erinaceus Hyptis spicigera Combretum ghasalense Mitragyna inermis Strychnos innocua Cochlospermum tinctorium Meliaceae Loganiaceae Fabaceae Sterculiaceae Euphorbiaceae Maliaceae Lamiaceae Rubiaceae Sapindaceae Fabaceae Anacardiaceae Anacardiaceae Euphorbiaceae Papilionoideae Lamiaceae Combretaceae Rubiaceae Loganiaceae Bixaceae Koke Dajekokora N/A Bulinyanie Beton Kpela Worobagnui Gongan Chiau Balesama Dato Gbentore Natogyere Pulinyie Donbeleva Kpamara Yiele Kolan Gbelonbile Leaves Leaves, fruit Leaves Stem bark Leaves Stem bark Bulb Leaves Leaves, stem bark Leaves Leaves, root, fruit Stem bark Leaves Leaves Leaves, whole plant Roots, barks, leaves Leaves Bark, leave Stem bark Leaf Bark, leaves Leaves, twigs Whole plant. Leaves, stem bark Stem bark Leaves Leaves Leaves Leaves Twigs, leaves Whole plant Leaves, root Leaves Whole plant Twigs, leaves Leaves Leaves Leaves Leaves Whole plant Stem bark Leaves Roots PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org [17] [18] [17] [19] [17] [18] [17] [17] [18] [17] [17] [19] [17] [18] [17] [17] [18] [17] [18] [19] [17] [15] [15] [15] [15] [15] [15] [15] [15] [15] [15] [15] [15] [15] [15] [15] [15] [15] [15] [15] [15] [15] [15] 50 Ethopia Benin Cameroon Togo Vabine Konkon N/A Roots Roots Roots [15] [15] [20] Asparagus africanus Gnidia stenophylla Plumbago zylonica Withania somnifera Euclea schimperi Warburgia ugandesis Vernonia bipontini Clerodendrum myricoides Acanthospermum hispidum Heliotropium indicum Carpolobia lutea Dialium guineense Byrsocarpus coccineus Pupalia lappacea Anchomanes difformis Tamarindus indica Zea mays Allium cepa Haemastotaphis barteri Pennisetum glaucum Fabaceae Moraceae Menispermacea e Liliaceae Thymeleaceae piumbaginaceae Solanaceae Ebenaceae canellaceae Plantaginaceae Lamiaceae Asteraceae Boraginaceae Polygalaceae Leguminoseae Comaraceae Amaranthaceae Araceae Caesalpiniaceae Poaceae Liliaceae Anacardiaceae Poaceae N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A Djabbé Masardji Tigneree Tursujee Gawri [20] [20] [20] [20] [20] [20] [20] [20] [21] [21] [21] [21] [21] [21] [21] [22] [22] [22] [22] [22] Cuviera longiflora Piliostigma thonningii Cassia italic Vismia guinesis Musa sinensis Rubiaceae Caesalpiniaceae Caesalpiniaceae Asteraceae Musaceae N/A Barkedji Wabderehi N/A Banana Dacrydes edulis Sorghum bicolour Sclerocarya birrea Voandzei subterranean Kotschya speciosa Arachis hypogeal Acanthospermum hispidum Burseraceae Poaceae Anacardiaceae Fabaceae Leguminoceae Fabaceae Asteraceae )o o Muskuwari Eedi Biriji N/A Arachide Mazaivri Eucalyptus globules Acacia nilotica Myrtaceae Mimosaceae Klatusse Gabdé Parkia biglobosa Corchorus olitorius Coula edulis Hibiscus sabdariffa Tectona grandis Blighia sapida Mimosaceae Tiliaceae Olacaceae Malvaceae verbenaceae Saindaceae Naredje Lalo Walnut Folere Tantouna Kpizou Roots, leaves Roots Roots Roots Roots Bark Leaves Roots Aerial part Leaves Leaves Leaves Leaves Leaves Roots Fruits, leaves Flowers Bulb Ripe fruits Roots and seeds Leaves Barks Leaves Stem bark Leaves and roots Leaves Roots Barks Seeds Whole plant Seeds Leaves and roots Leaves Barks and seeds Roots Seeds Stem bark Flowers Leaves Root Cassia sieberiana Ficus gnaphalocarpa Cissampelos mucronata PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org [23] [22] [22] [23] [22] [23] [22] [22] [22] [23] [22] [22] [23] [22] [22] [22] [23] [22] [24] [24] 51 Citrus aurantiifolia Sarcocephalus latifolius Securidaca longepedunculata Pericopsis laxifola Trichialia emetic Anthocleista djalonensis Ocimum americanum Hyptis suaveolens Philenoptera cyanescens Excoecaria graphamii Phyllanthus amarus Jatropha gossypiifollia Euphorbia hirta Bridelia ferruginea Gymnosporia senegalensis Borassus aethiopum Rutaceae Rubiaceae Polygolaceae FabaceaeMimosoideae Meliaceae Gentianaceae Lamiaceae Lamiaceae FabaceaeFaboideae Euphorbiaceae Euphorbiaceae Euphorbiaceae Euphorbiaceae Euphorbiaceae Celastraceae Arecaceae Akanka Kidjitchilou Fozi Tchemany Fruit Leave Root Stem bark [24] [24] [24] [24] Adjindjinkpizou Assoubobissaou Kozosogan Botifadini Tchele Root Stem bark Leaves Leaves Leaves [24] [24] [24] [24] [24] Katchikadou Seniseniyo Sawou Kovoyoyilim Kolou Tchintchingan Kpirou Stem bark Root Leaves Root Root Root Root [24] [24] [24] [24] [24] [24] [24] N/A=Not available DISCUSSION Knowledge concerning herbal medicines in Africa is currently transmitted from one generation to another principally by verbal medium without concise documentation. This has therefore led to the availability of only minute documented information about traditional herbal medicine in Africa. This article however, documents several medicinal plants used as antimalarial agents in various African countries. One hundred and fifteen herbal plants from six African countries have been captured in this article due to their local usage as antimalarial agents. The array of medicinal plants employed as antimalarial agents in Africa (Table 1), unveils a promising source for the development of new and better antimalarial drugs. This is however very important due to the current urgent need for novel antimalarial drug development so as to curtail the challenges being faced currently in the treatment/control of malaria. [25] This need have turned the search-light of the scientific community towards herbal medicine. Though herbal medicines are broadly employed in the treatment of malaria, and are said to be characterized with several advantages (which include more affordable and easy accessibility than Western drugs), they are as well with some limitations. Some of the limitations are non-established dosage and unpredictable efficacy. This therefore calls for critical investigations on these herbs so as to ascertain their pharmacological information as well as toxicity profile. These investigations should include both pre-clinical and clinical trials. This should also include studies based on observation of patients using the antimalarial herbs, employing the guidelines outlined by the Research Initiative on Traditional Antimalarial Methods. [26, 27] These studies need to be carried-out, so as to obtain reliable information on the actual effects of the antimalarial herbs on humans. ↓ REFERENCES 1. Bahekar S, Kale R. Herbal Plants Used For the Treatment of Malaria- A Literature Review. Journal of Pharmacognosy and Phytochemistry 2013; 1: 6 pp 141-6. . U ited Natio s Child e s Fu d UNICEF The P es i e . The glo al ala ia u de . UNICEF 2000;18:1-16. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 52 3. Schanzt-Dunn J, Nour N N. Malaria and Pregnancy: A Global Perspective. Rev Obstet Gynecol. 2009;2(3):186-192. 4. Dharani N, Rukunga G, Yenesew A, Mbora A, Mwaura L and Jamnadass R. Common Antimalarial Trees and Shrubs of East Africa. World Agroforestry Centre. 2008 ISBN: 978-92-9059-238-9 5. Antimalarial drugs. K D Tripathi. Essentials of Medical Pharmacology. 6th Edition, 2006. Jaypee Brothers Medical Publishers (P) Ltd. Pp. 780-96. 6. Zhang H, Paguio M and Roepe P D. The antimalarial drug resistant protein Plasmodium falciparum chloroquine resistance transporter binds chloroquine. Biochemistry, 2004;43:8290-8296. 7. Karunamoorthi K and Sabesan S. Insecticide Resistance in Insect Vectors of Disease with Special Reference to Msquitoes: A Potential Threat Global Public Health. Health Scope 2013;2(1):4-18. 8. Greenwood B and Mutabingwa T. Malaria in 2002. Nature 2002;415: 670 - 672 9. Fidock, D.A., Rosenthal, P.J., Croft, S.L., Brun, R., Nwaka, S. Antimalarial drug discovery: efficacy models for compound screening. Nat. rev./Drug Disc., 2004;3: 509-520 10. Chinedu E, Arome, D and Solomon F A. Herbal Plants a Reliable Source for Drug Discovery and Development. PHARMATUTOR-ART-2017. Available online at http://www.pharmatutor.org/articles/herbal-plants-reliable-source-drug-discovery-development (accessed on December 9th, 2013). 11. World Health Organization, World malaria report: 2012, WHO Press, Geneva Switzerland 2012. 12. World Health Organization factsheet No134. Traditional medicine. WHO Press, Geneva Switzerland 2008. 13. Philipson J D and wright C W. Can ethnopharmacology contribute to the development of antimalaria agents. J. Ethnopharmacol., 1991; 32: 115 – 165. 14. Basco L K, Mitaku S, Skaltsounis A L, Ravelomanaintsoa N, Tillequin F, Koch M and Le Brass J. In vitro activities of acridone alkaloids against Plasmodium falciparum. Antimicrob. Agents Chemother. 1994; 38: 1169 – 1171. 15. Asase A, Oteng-Yeboah A A., Odamtten G T. and Simmonds M S J. Ethnobotanical study of some Ghanaian anti-malarial plants. Journal of Ethnopharmacology 2005; 273–279. 16. Taylor N D L. Plant Based Drugs and Medicines 2000. Available online at chemistry.about.com/gi/dynamic/offsite.htm?site=rain%2Dtree.com/plantdrugs.htm (accessed December 12th, 2013). 17. Odugbemi T O, Akinsulire O R, Aibinu I E and Fabeku P O. Medicinal Plants Useful for Malaria Therapy in Okeigbo, Ondo State, Southwest Nigeria. Afr. J. Trad. CAM. 2007; 4 (2): 191- 198. 18. Idowu O A, Soniran O T, Ajana O and Aworinde D O. Ethnobotanical survey of antimalarial plants used in Ogun State, Southwest Nigeria. African. Afr. J. Pharm. Pharmacol., 2010;4(2): pp. 055-060. 19. Ibrahim H A, Imam I A, Bello A M, Umar U, Muhammad S and Abdullahi S A. The Potential of Nigerian Medicinal Plants as Antimalarial Agent: A Review. International Journal of Science and Technology 2012;2(8):pp 600-605. 20. Guta M. Presentation on: Development of Anti Malarial Herbal Drugs From Local Medicinal Plants Of Ethiopia. Ethiopia health and nutrition research institute 2012. 21. Ganfon H, Gbaguidi F, Frederich M, Moudachirou M and Quetinleclercq J. In Vitro Evaluation of Antiplasmodial Activity Of Plant Samples Used In Traditional Medicine In Benin. Université Catholique de Louvain, Belgium 2008. 22. Pierre S, Toua V, Tchobsala, Fernand-N T F, Alexandre-Michel N N and Jean M. Medicinal Plants Used In Traditional Treatment of Malaria in Cameroon. Journal of Ecology and the Natural Environment 2011; 3(3): pp. 104-117. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 53 23. Zofou D, Tene M, Ngemenya M N, Tane P And Titanji V P K. In vitro Antiplasmodial Activity and Cytotoxicity of Extracts of selected Medicinal plants Used by Traditional Healers of Western Cameroon. Malaria Research and Treatment volume 2011. 24. Tchando T, Karou S D, Agban A, Bako M, Batawila K, Bawa M L, Gbessor M and de Souza C. Medicinal plants use in Togo (Africa) with emphasis on timing. Phcog Res 2012;4:92-103. 25. Randrianarivelojosia M, Rasidimanana V T, Rabarison H, Cheplogoi P K, Ratsimbason M, Mulholland D A and Mauclère P. Plants traditionally prescribed to treat tazo (malaria) in the eastern region of Madagascar. Malaria Journal 2003, malariajournal.com/content/2/1/25 26. Mojab F. Antimalarial natural products: a review. Avicenna Journal of Phytomedicine 2012;2(2):5262. 27. Willcox M. Personal Communication at the Third MIM Pan-Af i a Mala ia Co fe e e. Glo al Advances in Malaria Research: Evidence-Based De isio Maki g fo Mala ia Co t ol Poli . PHARMA FACTS Did ou k o … → Eighty percent of people infected with the Ebola virus, will die from this disease. → There are approximately 96,000 km of blood vessels in the human body. → When you were born, you had 300 bones. Now you have 206, if you are an adult. The rest of the bones have not disappeared – they have merely fused together. → Abilify (Aripiprazole) is best selling drug after Q4 2013, manufactured jointly by Bristol-Myers Squibb and Otsuka Pharmaceutical. Patent of this molecule will expire in October 2014. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 54 Review Article Futuristic Drug Delivery System Microemulsions: A Review Shingitha K.P Department of Pharmacy, Noida Institute of Engineering and Technology, Greater Noida , Uttar Pradesh, India shingithanair@gmail.com ABSTRACT Recently microemulsions have attracted great attention as they help to optimize efficiency of wide range of products and processes. Microemulsion is isotropic, thermodynamically stable multicomponent fluids which is composed of water, oil, surfactant or cosurfactant where the diameter of the droplet of the microemulsion is in the range of 100Ao TO 1000Ao.Microemulsion are unique class of optically transparent (translucent) solution which comprises of the colloidal system that are attracting many scientific and technological interest past few decades. This interest is due to their properties like ultra low interfacial tension, large interfacial tension and solubilization capacity of both oil and water soluble drugs. KEYWORDS: Composition, Method of preparation, Applications. INTRODUCTION Emulsion is heterogeneous system where immiscible liquids are dispersed as droplet form in liquid system. They are thermodynamically unstable systems which are stabilized with the component which exhibit emulsifying properties thus making it kinetically stable. There has been a revolution in the last two decades in the utilization of microemulsion systems in a variety of chemical and industrial processes. Microemulsions have shown a wide range of applications starting with enhanced oil recovery in the 70's, expanding to a wide range of chemicals and entering the pharmaceutical and cosmetic formulation area a decade ago.[1] Microemulsions have been widely studied to enhance the bioavailability of the poorly soluble drugs. They offer a cost effective approach. Microemulsions have very low surface tension and small droplet size which results in high absorption and permeation. Microemulsions have the ability to deliver larger amounts of water and topically applied agents into the skin than water alone or other traditional vehicles such as lotions or creams because they act as a better reservoir for a poorly soluble drug through their capacity for enhanced solubilization [2] The main difference between macroemulsions and microemulsions lies in the size and shape of the particles dispersed in the continuous phase: these are at least an order of magnitude smaller in the case of microemulsions (10-200 nm) than those of conventional emulsions (1-20 m). Macroemulsions consist of roughly spherical droplets of one phase dispersed into the other whereas microemulsions constantly evolve between various structures ranging from droplet-like swollen micelles to bicontinuous st u tu es, aki g the usual oil i ate a d ate i oil disti tio so eti es irrelevant.[3] The key differences between ordinary emulsions (macro emulsions) and microemulsions are shown in Table 1. How to cite this article: KP Shingitha, Futuristic Drug Delivery System Microemulsions: A Review, PharmaTutor, 2014, 2(3), 54-60 PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 55 Table 1. Comparison of Microemulsion with Conventional Emulsion S. No 1 2 3 4 Property Appearance Optical Isotropy Interfacial Tension Microstructure 5 6 Droplet Size Stability 7 8 Phases Preparation 9 Viscosity Microemulsion Transparent (or translucent) Isotropic Ultra low Dynamic(interface is continuously and spontaneously fluctuating) 20-200 nm Thermodynamically stable Monophasic Facile preparation, relatively lower cost for commercial production Low viscosity with Newtonian behaviour Self – microemulsifying drug delivery systems (SMEDDS) are not exactly microemulsions but are related with each other. It is composed of oil, surfactant and cosurfactant and has the ability to form o/w microemulsion when dispersed in aqueous phase under gentle agitation. The agitation required for the selfemulsification comes from stomach and intestinal motility [4,5]. COMPOSITION Today, a variety of oil and surfactants are available which can be utilized for the formulation of microemulsion but their toxicity, irritation potential and unclear mechanism of action limit their use. It is essential to select material that are biocompatible, non-toxic, clinically acceptable and use emulsifiers in appropriate concentration range which will result in mild and non – aggressive microemulsions. Thus importance is given on the use of generally regarded as safe (GRAS) excipients. Oil Phase Emulsion Cloudy Anisotropic High Static > 500 nm long shelf-life Thermodynamically unstable (kinetically will eventually phase separate Biphasic Require a large input of energy, higher Higher viscosity The oil has the ability to penetrate thereby swelling the tail group region of the surfactant monolayer and thus influencing curvature. Short chain oils penetrate the tailgroup region to a greater extent than long chain alkanes, and hence swell this region to a greater extent, resulting in increased negative curvature (and reduced effective HLB) [6]. Saturated (for example, lauric, myristic and capric acid) and unsaturated fatty acids (for example, oleic acid, linoleic acid and linolenic acid) have penetration enhancing property of their own and they have been studied since a long time. Fatty acid esters such as ethyl or methyl esters of lauric, myristic and oleic acid have also been employed as the oil phase. Surfactants The surfactant chosen must be able to lower the interfacial tension to a very small value which facilitates dispersion process during the preparation of the microemulsion and provide a flexible film that can readily deform around the droplets and be of the appropriate lipophilic character to provide the correct curvature at the interfacial region. It is generally accepted PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 56 that low HLB surfactants are favoured for the formulation of w/o microemulsion, whereas surfactants with high HLB (>12) are preferred for the formation of o/w microemulsion. Surfactants having HLB greater than 20 often require the presence of cosurfactants to reduce their effective HLB to a value within the range required for microemulsion formation [7] Cosurfactants In most cases, single-chain surfactants alone are unable to reduce the o/w interfacial tension sufficiently to enable a microemulsion to form [8-11] . The presence of cosurfactants allows the interfacial film sufficient flexibility to take up different curvatures required to form microemulsion over a wide range of composition [12-14]. METHOD OF PREPARATION Phase Titration Method Microemulsion can be prepared by phase titration method (spontaneous emulsification methods) and can be depicted with the help of phase diagram. The phase diagram is useful in understanding the complex series of interactions that can occur when different components are mixed. Depending upon the chemical composition and concentration microemulsions are formed with various association structures (including emulsion, micelles, lamellar, hexagonal, cubic, and various gels and oily dispersion). A quaternary phase diagram is difficult and time consuming compared to pseudo ternary phase diagram. The region can be separated into w/o or o/w microemulsion by simply considering the composition that is whether it is oil rich or water rich. Observations should be made carefully so that the metastable systems are not included. The methodology has been comprehensively discussed by Shafiq-un-Nabi et al. [15].Fig. (1).depicts the pseudoternary phase diagram of oil, water and surfactant showing microemulsion region. Fig. (1). Pseudoternary phase diagram of oil, water and surfactant showing microemulsion region. Phase Inversion Method Phase inversion of microemulsions occurs upon addition of excess of the dispersed phase or in response to temperature. During phase inversion drastic physical changes occur including changes in particle size that can affect drug release both in vivo and in vitro. These methods make use of changing the spontaneous curvature of the surfactant [7]. For non-ionic surfactants, this can be achieved by changing the temperature of the system, forcing a transition from an o/w microemulsion at low temperatures to a w/o microemulsion at higher temperatures (transitional phase inversion)[7]. During cooling, the system crosses a point of zero spontaneous curvature and minimal surface tension, promoting the formation of finely dispersed oil droplets. This method is referred to as phase inversion temperature (PIT) method. Instead of the temperature, other parameters such as salt concentration or pH value may be considered as well instead of the temperature alone.[7] CHARACTERISATION The characterization of these systems is highly challenging due to small size with fluctuating boundaries and complex structure. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 57 Physicochemical characterization of microemulsion systems are: 1. Phase stability and phase behavior, 2. Microstructure, dimension (size and size distribution), shape and surface features (specific area, charge, and distribution), 3. Local molecular arrangements, interactions and dynamics. Among these properties, particle size, interactions, and dynamics are of great importance as they help in controlling various properties of microemulsions. In particular, the size distributions of microemulsions give essential information for a reasonable understanding of the mechanism governing both the stability and penetration into the membrane [16, 17]. Many technologies like dynamic light scattering (DLS) [18, 19], small angle neutron scattering (SANS) [20-22] and small angle X-ray scattering (SAXS) [23-28] have been in growing use in particle size characterization. Other methods include electrokinetic chromatography, conductance, viscosity, electrical birefringence, infrared spectroscopy and calorimetry. APPLICATIONS Some of the application of microemulsion in pharmaceutical industries are: Oral Drug Delivery System Large amount of proteins and peptides are being synthesized due to advancement in pharmaceutical and biotechnology area. Conformation on stability, biodegradability and short half life cause difficulty in their formulation for oral administration. Therefore microemulsions are studied for protection of biodegradable drugs. Microemulsions help to enhance the solubilization of the poorly soluble drugs and overcome the bioavailability problems. This is particularly important for the BCS class II or class IV drugs. Microemulsions behave as solvent for these drugs and can be optimized to ensure consistent bioavailability. They can be used for the delivery of hydrophilic drugs e.g proteins and peptides. Moreover, these systems have been reported to protect the incorporated drugs against oxidation, enzymatic degradation [29] and enhance the [30] membrane permeability . Presently, Sandimmune Neoral® (Cyclosporine A), Fortovase® (Saquinavir), Norvir® (Ritonavir), etc. are the commercially available SMEDDS formulations. Topical Drug Delivery System Administration of drug via skin has been extensively studied and found the drug transport due to the administration of microemulsion was better than ointment, gels and creams. Microemulsion is multicomponent system. The skin irritation aspect must be considered if applying for longer duration of time. There are several advantages of incorporating microemulsion in transdermal drug delivery system. Some of them are listed below: 1. The permeation rate of the drug from microemulsion may be increased, since the affinity of a drug to the internal phase in microemulsion can be easily modified to favour partitioning into stratum corneum, using different internal phase, changing its portion in microemulsion [31]. 2. The surfactant and co surfactant in the microemulsion may reduce the diffusional barrier of the stratum corneum by acting as penetration enhancers [32]. 3. The percutaneous absorption of drug will also increase due to hydration effect of the stratum corneum if the water content in microemulsion is high enough [33]. 4. A large amount of drug can be incorporated in the formulation due to the high solubilizing capacity that might increase thermodynamic activity towards the skin [34]. Surface area is assumed to be high due to small droplet size. Therefore, droplets settle down to close contact with the skin providing high concentration gradient and improved drug PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 58 permeation. Moreover, low surface tension ensures good contact to the skin. Also, the dispersed phase can act as a reservoir making it possible to maintain an almost constant concentration gradient over the skin for a long [35] time . The liquid, transparent, multicomponent systems according to the invention of Muller et al. contained the active agents in a solution of an oily and optionally an aqueous component in the presence of surfactants and cosurfactants[34] Parenteral Drug Delivery System The formulation of lipophilic and hydrophobic drugs into parenteral dosage forms has been difficult. O/w microemulsions are beneficial in the parenteral delivery of sparingly soluble drugs where the administration of suspension is not desirable. They provide a means of obtaining relatively high concentration of these drugs which usually requires frequent administration. Other advantages are that they exhibit a higher physical stability in plasma than liposomes or other vesicles [36] Antifungal Superficial mycoses usually respond to topical therapy. In the settling of eczema, topical antifungal agents such as ketoconazole are used to reduce the fungal infection caused by Pityrosporum ovale or Malassezia furfur. Antifungal agents e.g miconazole, ketoconazole, and itraconazole being lipophilic in nature have been formulated as microemulsions to impart to them the advantages like ease of preparation due to spontaneous formation, thermodynamic stability, transparent and elegant appearance, increased drug loading, enhanced penetration through the biological membranes, increased bioavailability compared to conventional dosage forms. .[37,38] Microemulsion based gels for vaginal delivery of clotrimazole and fluconazole were developed and compared with the marketed clotrimazole gel (Candid-V® gel) by in vitro methods [39]. These microemulsion based gels showed significantly higher in vitro bioadhesion, antifungal activity as compared to that of Candid-V® gel.[40] Ocular Drug Delivery System Eye drops account for 90% of the available ophthalmic formulations due to their simplicity and convenience. However, rapid precorneal loss caused by drainage and high tear fluid turnover is amongst the major problems associated with topical ophthalmic drug delivery. Only 5% of the applied drug in eye drops penetrates the cornea and reaches the intraocular tissues with the rest of the dose undergoing transconjunctival absorption or drainage via the nasolacrimal duct before transnasal absorption. This results in loss of drug into the systemic circulation and provides undesirable systemic side effects. Accordingly, microemulsions provided a promising alternative with improved ocular retention, increased corneal drug absorption and reduced systemic side effects whilst maintaining the simplicity and convenience of the dosage form as eye drops. [41] ↓ REFERENCES 1. Bidyut KP, Satya PM. Uses and applications of microemulsions. Current Science 2001;80(8): 990-1001. 2. Derle DV, Sagar BSH, Microemulsion as a vehicle fortransdermal permeation of nimesulide. Ind. J. Pharm. Sci. 2006; 68(5): 622-625. 3. Nirmala Grampurohit, Padmini Ravikumar* and Rashmi Mallya.Microemulsions For Topical Use– A Review.Ind J Pharm Edu Res, 2011; 45(1):100-107 4. Cho, Y.W., Flynn, M.J., Shepherd, T.S.: US5665700 (1998). 5. Pouton CW. Formulation of self-microemulsifying delivery system.Adv Drug Del Rev 1997; 25: 47-58. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 59 6. Ghosh PK, Murthy RSR. Microemulsions: A potential drugdelivery system. Curr Drug Deliv 2006; 3: 167-180. 7. Sushama Talegaonkar*, Adnan Azeem, Farhan J. Ahmad, Roop K. Khar, Shadab A. Pathan and Zeenat I. Khan ,Microemulsions: A Novel Approach to Enhanced Drug Delivery, Recent Patents on Drug Delivery & Formulation 2008,8(2), 238-257 8. Bhargava HN, Narurkar A, Lieb LM. Using microemulsions fordrug delivery. Pharm Tech 1987; 11: 4652. 9. Kreuter J. Microemulsions; In: Colloidal drug delivery systems.New York: Marcel Dekker 1994; 31-71. 10. Lawrence M.J. Surfactant systems: microemulsions and vesicles asvehicles for drug delivery. Eur J Drug Metab Pharmacokinet 1994;3: 257-269. 11. Tenjarla S. Microemulsions: an overview and pharmaceutical applications. Crit Rev Therapeut Drug Carrier Syst 1999; 16: 461-521. 12. Ghosh PK, Murthy RSR. Microemulsions: A potential drugdelivery system. Curr Drug Deliv 2006; 3: 167-180.[43] Lawrence MJ, Rees GD. Microemulsion based media as novel drugdelivery systems. Adv Drug Del Rev 2000; 47: 89-121. 13. Aboofazeli R, Lawrence CB, Wicks SR, Lawrence MJ. Investigationsinto the formation and characterization of phospholipidmicroemulsions III. Pseudo-ternary phase diagrams of systemscontaining water-lecithin-isopropyl myristate and either an alkanoicacid, amine, alkanediol, poly ethylene glycol alkyl ether or alcoholas co-surfactant. Int J Pharm 1994; 111: 63-72. 14. Stilbs P, Lindman B, Rapacki K. Effect of alcohol cosurfactantlength on microemulsion structure. J Colloid Interface Sci 1983;95: 583-585. 15. Shafiq-un-Nabi S, Shakeel F, Talegaonkar S, et al. Formulationdevelopment and optimization using nanoemulsion technique: Atechnical note. AAPS Pharm Sci Tech 2007; 8(2): E1-E6. 16. Constantinides PP, Yiv SH. Particle size determination of phaseinvertedwater-in-oil microemulsions under different dilution andstorage conditions. Int J Pharm 1995; 115: 225-234. 17. Mueller BW, Mueller RH. Particle size distributions and particlesize alterations in microemulsions. J Pharm Sci 1984; 73: 919-922. 18. Kang BK, Chon SK, Kim SH, et al. Controlled release of paclitaxelfrom microemulsion containing PLGA and evaluation of antitumouractivity in vitro and in vivo. Int J Pharm 2004; 286: 147-156. 19. Porras M, Solans C, Gonzalez, C, Martinez A, Guinart A,Gutierrez, JM. Studies of formation of w/o nanoemulsions. ColloidSurf A: Physicochem Eng Asp 2004; 249: 115-118.[50] Burnett GR, Rees GD, Steytler DC, Robinson BH. Fluorescencecorrelation spectroscopy of water-in-oil microemulsions: anapplication in specific characterization of droplets containingbiomolecules. Colloids Surf A: Physicochem Eng Asp 2004; 250:171-178. 20. Silas JA, Kaler EW. Effect of multiple scattering on SANS spectrafrom bicontinuous microemulsions. J Colloid Interface Sci 2003;257: 291-298. 21. Pedersen JS. Analysis of small-angle scattering data from micellesand microemulsions: Free-form approaches and model fitting. CurrOpin Colloid Interface Sci 1999; 4: 190-196. 22. Podlogar F, Gasperlin M, Tomsic M, Jamnik A, Bester Rogac M.Structural characterisation of waterTween 40®/Inwitor 308® isopropylmyristate microemulsions usinf different experimentalmethods. Int J Pharm 2004; 276: 115-128. 23. Kawakami K, Yoshikawa T, Moroto Y, et al. Microemulsionformulation for enhanced absorption of poorly soluble drugs: I.Prescription design. J Control Release 2002; 81: 65-74. 24. Glatter O, Orthaber D, Stradner A, et al. Sugar-ester nonionicmicroemulsion: Structural characterization. J Colloid Interface Sci2001; 241: 215-225. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 60 25. Kumar P, Mittal KL. Microemulsions in foods; In: Handbook ofMicroemulsion Science and Technology. New York, MarcelDekker 1999; 789. 26. Solans C, Kuneida H. Microemulsions in the pharmaceutical field:perspectives and applications; In: Industrial Applications ofMicroemulsions. New York, Marcel Dekker 1997; 98-120. 27. Solans C, Kuneida H. (ed.), Microemulsions in foods: Propertiesand applications; In: Industrial applications of microemulsions.New York, Marcel Dekker, 1997; 148. 28. Danino D, Gupta R, Satyavolu J, Talmon Y. Direct Cryogenictemperaturetransmission electron microscopy imaging ofphospholipids aggregates in soybean oil. J Colloid Interface Sci2002; 249: 180-186. 29. Sariciaux MJ, Alan L, Sado PA. Using microemulsion for drugdelivery of therapeutic peptides. Int J Pharm 1995; 12: 127-136. 30. Swenson EC, Curatolo WJ. Intestinal permeability enhancementfor proteins, peptides and other polar drugs: mechanism andpotential toxicity. Adv Drug Del Rev 1992; 8: 39-42. 31. Kreilgaard M. Influence of microemulsion on cutaneous drugdelivery. Adv Drug Delivery Rev 2002; 54: S77-S98. 32. Rhee Y-S, Choi, J-G, Park E-S, Chi S-C. Transdermal delivery ofketoprofen using microemulsions. Int J Pharm 2001; 228: 161-170. 33. Mohammed C, Manoj V. Aerosol-OT microemulsions as transdermalcarriers of tetracaine hydrochloride. Drug Dev Ind Pharm2000; 26: 507-572. 34. Hua L, Weisan P, Jiayu L, Ying Z. Preparation, evaluation andNMR characterization of vinpocetine microemulsion fortransdermal delivery. Drug Dev Ind Pharm 2004; 30: 657-666. 35. Elena P, Paola S, Maria RG. Transdermal permeation ofapomorphine through hairless mouse skin from microemulsions. IntJ Pharm 2001; 226: 47-51. 36. Shaw JM. In: Lipoproteins as carriers of pharmacological agents.Marcel Dekker, New York 1991; 97139. 37. Tenjarla SN. Microemulsions: An overview andpharmaceutical applications. Critical Reviews TM inTherapeutic Drug Carrier Systems.1999;16:461–521. 38. Lieberman HA, Rieger MM, Banker GS. PharmaceuticalDosage Forms: Disperse Systems. 2nd ed. Vol 1.New York :Marcel Dekker Inc; 1996. 211–281, 315–370. 39. Yogeshwar B, Vandana P. Microemulsion-Based VaginalGel of Clotrimazole: Formulation, In vitro Evaluation,and Stabi l i ty Studies. AAPS PharmSciTech.2009;10(2):476-481. 40. Yogeshwar B, Vandana P. Microemulsion based vaginal gel of fluconazole: formulation, in vitro and in vivoevaluation Intl J Pharm. 2009;365(1-2):175-179. 41. Microemulsions For Topical Use– A ReviewNirmala Grampurohit, Padmini Ravikumar* and Rashmi MallyaInd J Pharm Edu Res 2011; 45;1 PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 61 Review Article Review: An Overview on Floating Drug Delivery System Hemant Maheta,* MR Patel, KR Patel, MS Patel Department of Pharmaceutics, Shri B.M.Shah College of Pharmaceutical Education and Research, Modasa, Gujarat, India. *hsmehta19@gmail.com ABSTRACT The purpose of writing this review on floating drug delivery systems was special focus on the principle mechanism of floatation to achieve gastric retention. Conventional oral dosage forms has short residence times & unpredictable gastric emptying time. The idea of gastric retention comes from the need to localize drugs at a specific region of gastrointestinal tract (GIT) such as stomach in the body. Many drugs get absorbed only in the upper intestinal tract, designing such molecules as once-daily formulations are exclusive for these molecules. Thus GI retention platforms had emerged. Gastroretentive drug delivery systems are designed to be retained in the stomach for a prolonged time. Gastroretentive drug delivery systems have potential for use as controlled release drug delivery system. The use of floating drug delivery system is one method to achieve prolonged gastric residence times, providing opportunity for both local & systemic drug action. Thus, gastroretention could help to provide greater availability of new products and consequently improved therapeutic activity and substantial benefits to patients. This article aims at reviewing the floating drug delivery system including types, approaches for designing the floating dosage form, advantages & disadvantages of FDDS. Keywords: Gastric residence time, Gastroretention, Gastrointestinal tract, narrow absorption window, floating drug delivery systems. INTRODUCTION The focus of pharmaceutical research is steadily shifted from the development of new chemical entities to the development of novel drug delivery system of existing drug molecule to maximize their effectiveness in terms of therapeutic action, reducing frequency of dosing and wastage of drugs, patient compliance and reduced adverse effects.[1] To minimize drug degradation and loss, to prevent harmful side-effects and to increase drug bioavailability and the fraction of the drug accumulated in the required zone, various drug delivery and drug targeting systems are currently under development. Oral drug delivery is the most desirable and preferred method of drug delivery for achieving both systemic and local therapeutic effects. For many drugs, conventional oral formulations provide clinically effective therapy while maintaining the required balance of pharmacokinetic and pharmacodynamic profiles with an acceptable level of safety to the patient. The real challenge in the development of a controlled drug delivery system is not just to sustain the drug release but also to prolong the presence of the dosage form in the stomach or the upper small intestine until all the drug is completely released in the desired period of time. [2, 3] The gastro intestinal tract (GIT) is the major route of drug delivery to the systemic circulation. Oral controlled release dosage forms are not How to cite this article: H Maheta, MR Patel, KR Patel, MS Patel, Review: An Overview on Floating Drug Delivery System, PharmaTutor, 2014, 2(3), 61-71 PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 62 suitable for a variety of important drugs, characterized by a narrow absorption window in the upper part of the GIT. This is due to the relatively less transit time of the dosage form in these anatomical segments. Thus after only a short period of less than 6 h, the controlled release formulation has already left the upper GIT and the drug is released in short, non absorbing distal segment of the GIT. This results in a short absorption phase, which is then accompanied by lesser bioavailability. These types of problem can be overcome by floating drug delivery system. [4-7] Definition of floating drug delivery systems: [8] Floating drug delivery systems (FDDS) are those systems which have a bulk density less than gastric fluids and because of this, these systems remains buoyant (3-4 hours) for a prolonged period of time in the stomach without affecting the gastric emptying rate. The drug is released slowly at the desired rate from the system and after release of the drug; the residual system is emptied from the stomach. As a result GRT is increased and fluctuations in plasma drug concentration can be better controlled. Mechanism of Floating Systems: [9] While the system is floating on the gastric content the drug is released slowly at the desired rate from the system. After release of drug, the residual system is emptied from the stomach. However, besides a minimal gastric content needed to allow the proper achievement of the buoyancy retention principle, a minimal level of floating force is also required to keep the dosage form reliably buoyant on the surface of the meal. To measure the floating force kinetics, a novel apparatus for determination of resultant weight has been reported in the literature. The apparatus operates by measuring continuously the force equivalent to F as a function of time that is required to maintain the submerged objects. The apparatus helps in optimizing FDDS with respect to stability to stability and durability of floating forces produced in order to prevent the drawbacks of unforeseeable intragastric buoyancy capability variations. F = F buoyancy - F gravity = (D f - D s) g v Where, F = Total vertical force, Df = fluid density, Ds = object density, v = volume Fig: 1 Mechanism of Floating Systems APPROACHES TO DESIGN THE VARIOUS FLOATING DOSAGE FORM: [10-15] Two types of floating Dosage systems Singleand multiple-unit floating dosage systems have been designed by using the following approaches. SINGLE-UNIT DOSAGE FORMS Low-density approach In this approach, the globular shells with density lower than that of gastric fluid can be used as carrier for drug for making single-unit floating dosage form. Popcorn, polystyrol and PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 63 poprice have been used as drug carriers in coated shells. For the undercoating of these shells sugar polymeric materials such as methacrylic polymer and cellulose acetate phthalate have been exploited. These shells are then further coated with a mixture of drug polymer. Depending on the type of release desired, either of the polymer ethyl cellulose or hydroxypropyl cellulose can be used. The product floats on the gastric fluid and gradually releases the drug for a long period of time. better than conventional one to solve the solubility problem. Fluid- filled floating chamber In this type of dosage forms, a gas-filled floatation chamber is incorporated into a microporous component that covers the drug reservoir. Along the top and bottom walls there is provision for opening through which the GIT fluid enters into the device to dissolve the drug. The side walls in contact with the fluid are sealed to ensure undissolved drug remains in the device. The fluid present in the system for floatation could be air or any other suitable gas, liquid, or solid that has an appropriate specific gravity and should be inert. This device should be of swellable size. Device remains floats within the stomach for a long period of time and slowly releases the drug. After the complete release of the drug, the shell disintegrates, goes to the intestine, and finally eliminated from the body. 3-layer principle By the development of an asymmetric configuration drug delivery system, 3-layer principle has been improved.3-layer principle helps in modulating the release extent and for achieving zero-order release kinetics. The design of the system is such that it floats on the stomach content and prolong gastric residence time which further results in longer total transit time which maximize the absorptive capacity and hence better bioavailability is achieved. These benefits can be applicable to drugs with pH-dependent solubility, drugs which are absorbed by active transport mechanism from the small intestine or the drugs with narrow absorption window. Hydrodynamically balanced systems (HBS) These systems enhance the absorption because they are designed such that they stay in GIT for prolong time. Drugs which have a better solubility in acidic environment and site-specific absorption in the upper part of GIT are suitable candidates for such systems. These dosage forms must have a bulk density of less than 1. It should maintain its structural integrity and should constantly release the drug .The solubility of chlordiazepoxide hydrochloride29 is 150 mg/mL at pH 3 to 6 and is ~0.1 mg/mL at neutral pH. So, HBS capsule of this drug is a Bilayer and matrix tablets Floatable characteristics also shown by some types of bilayer and matrix tablets. The polymers which have been exploited are sodium carboxymethylcellulose (CMC), hydroxypropyl cellulose, Hydroxypropyl methylcellulose, ethyl cellulose and Crosspovidone. Problems with single-unit formulations Single-unit formulations can stick together or being obstructed in the GIT, which can cause irritation. MULTIPLE-UNIT DOSAGE FORMS Multiple-unit dosage form is designed to develop a reliable formulation that provide all the benefits of a single-unit form and also overcome the disadvantages of single-unit formulations. Microspheres have been used because of their high loading capacity. The polymers such a albumin, starch, gelatin, polyacrylamine, polymethacrylate and polyalkylcyanoacrylate have been used for the preparation of microspheres. Microspheres PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 64 show an excellent in vitro floatability because of its characteristic internal hollow structure. Several devices of carbon dioxide multiple-unit oral formulations have been described in the recent patent literature with features that unfold, extend or are inflated by carbon dioxide generated in the devices after administration. CLASSIFICATION OF FLOATING DRUG DELIVERY SYSTEM: [16-25] FLOATING DRUG DELIVERY SYSTEM NonEffervescent system Effervescent system Gas generating system Single layer Floating Tablet Bilayer Floating Tablet Multiple unit type pills Floating system with ion exchange resin Volatile liquid containing system Intragastric gastrointestinal Inflatable gastricintestinal floating A) Effervescent system:These are matrix types of systems prepared with the help of swellable polymers (methylcelluose and chitosan) and various effervescent compounds(sodium bicarbonate,tartaric acid, and citric acid).They are formulated in such a way that when come in contact with acidic gastric contents, co2 liberate and gas entrapped in swollen hydrocolloids which provides buoyancy to the dosage form. a) Volatile liquid containing systems: The GRT of a drug delivery system can be sustained by incorporating an inflatable chamber, which contains a liquid (such as ether, cyclopentane), that gasifies at body temperature to cause the inflammation of the chamber in the stomach. The device may also Single layer Floating tablet Bilayer Floating Tablet Alginate beads Hollow microspheres consist of a bio-erodible plug made up of PVA, Polyethylene, etc. that gradually dissolves and causing the inflatable chamber to release gas and collapse after a predetermined time to permit the spontaneous ejection of the inflatable systems from the stomach. Intragastric floating gastrointestinal drug delivery system This system can be made to float in the stomach, because of floating chamber, which may be a vacuum of filled with air or a harmless gas, while drug reservoir is encapsulated inside a micro porous compartment. Inflatable gastrointestinal delivery system In these systems an inflatable chamber is incorporated, which contains liquid ether that PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 65 gasifies at body temperature to cause the chamber to inflatable in the stomach. These systems are fabricated by loading the chamber with the drug reservoir, which can be a drug impregnated polymeric matrix, than encapsulated in a gelatin capsule. After oral administration the capsule dissolves to release the drug reservoir together with the inflatable chamber. The inflatable chamber automatically inflates and retains the drug reservoir into the gastric fluid. b) Gas generating systems: In these system effervescent reactions occurs between carbonates/bicarbonates salts and citric/tartaric acid to liberate CO2, which gets entrapped in the gelling matrix of the systems. Thus decreasing its specific gravity and making it to float over the gastric fluid. I) Floating pills: These systems consist of two layers, inner effervescent layer containing sodium bicarbonate and tartaric acid, the outer swellable polymeric membrane. The inner layer is further divided into two sub layers to avoid physical contact between sodium bicarbonate and tartaric acid. When this pill is immersed in buffer solution at 37°C, it settles down at the bottom and buffer solution enters into the effervescent layer through the outer swellable membrane. Swollen pills or balloons are formed due the generation of carbon dioxide as a result of reaction between sodium bicarbonates and tartaric acid. The carbon dioxide generated is entrapped within the delivery system making the device to float. These systems were found to float completely within 10 minutes and have good floating ability independent of pH, viscosity of the medium and the drug is released in a controlled manner. II) Floating capsules: Floating capsules are prepared by filling a mixture of sodium alginate and sodium bicarbonate, these float due to the generation of carbon dioxide which gets trapped in the hydrating gel network on exposure to an acidic environment. III) Floating systems with ion exchange resins: These systems are formulated by using ion exchange resin that is loaded with bicarbonate by mixing the beads with sodium bicarbonate solution. These loaded beads were then surrounded by a semi permeable membrane to avoid the sudden loss of carbon dioxide. Upon coming in contact with gastric contents there is an exchange of chloride and bicarbonate ions resulting in generation of carbon dioxide thereby carrying beads toward the top of gastric contents and producing a floating layer of resin beads, which releases the drug at a predetermined. IV) Tablet a) Intragastric single layer floating tablets or Hydrodynamically Balanced system These formulations have bulk density lower than gastric fluids and thus float in the stomach that increases the gastric emptying rate for a prolonged period. These are formulated by intimately mixing the gas (CO2) generating agents and the drug within the matrix tablet. The drug is released slowly at a desired rate from the floating system & the residual system is emptied from the stomach after the complete release of the drug. This leads to and increases in the gastric residence time & a better control over fluctuations in plasma drug concentration. b) Bi-layer tablet Bilayer tablet can also prepared by gas generating matrix in one layer and second layer with drug for its sustained release effect. c) Triple layer tablet Triple layer tablet also having first swellable floating layer, second sustained release layer of two drugs and third rapid dissolving layer PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 66 B) Non-effervescent systems: This type of system after swallowing swells unrestrained via. Imbibition of gastric fluid to an extent that it prevents their exit from the stomach. These systems may be referred to as the plug t pe s ste si e the ha e a tendency to remain lodged near the pyloric sphincter. One of the formulation methods of such dosage forms involves the mixing of drug with a gel, which swells in contact after oral administration and maintains a relative integrity of shape and a bulk density of less than 1. This is based on the mechanism of swelling of polymer or bio adhesion to mucosal layer in GIT. The most commonly used excipients are gel forming materials such as polycarbonate, poly acrylate, polystyrene etc. this hydrocolloid starts to hydrate by first forming a gel at the surface of the dosage form. The resultant gel structure then controls the rate of diffusion of solvent-in and drug-out of the dosage form. The various types of this system are as follows: Single layer floating tablets This can be formulated by intimate mixing of drug with gel forming hydrocolloid, which swells in contact with gastric fluid and maintain bulk density of less than 1. The air entrapped by the swollen polymer confers buoyancy to these dosage forms. Bilayer floating tablets A bilayer tablet contains two layers, one is immediate release layer which releases the initial dose from system while the other is sustained release layer which absorbs the gastric fluid and maintains a bulk density of less than 1 and thereby it remains buoyant in the stomach (Fassihi and Yang developed a zeroorder controlled release). Multilayer tablet composed of at least 2 barrier layers and one drug layer. All the layers are made of swellable, erodible polymers and the tablet was found to swell on contact with aqueous medium. As the tablet dissolved, the barrier layers eroded away to expose more of the drug. Gas evolving agent is added in either of the barrier layers, this caused the tablet to float and increased the ete tio of ta let i a patie t s sto a h. Colloidal gel barrier systems It contains drug with gel forming hydrocolloids meant to remain buoyant on stomach contents. This system incorporates a high level of one or more gel forming highly swellable cellulose type hydrocolloids. On coming in contact with gastric fluid, the hydrocolloids in the system hydrate and form a colloidal gel barrier around the gel surface. The air trapped by the swollen polymer maintains a density less than unity and confers buoyancy to this dosage forms. Microporous Compartment System This technology is based on the encapsulation of drug reservoir inside a microporous compartment with aperture along its top and bottom wall. The peripheral walls of the drug reservoir compartment are completely sealed to prevent any direct contact of the gastric mucosal surface with the un-dissolved drug. In stomach the floatation chamber containing entrapped air causes the delivery system to float over the gastric contents. Gastric fluid enters through the apertures, dissolves the drug, and carries the dissolved drug for continuous transport across the intestine for absorption. Alginate beads To develop Multi-unit floating dosage forms the freeze-dried calcium alginate has been used. Spherical beads of approximately 2.5 mm in diameter can be prepared by the precipitation of calcium alginate via dropping sodium alginate solution into aqueous solution of calcium chloride. The beads are then separated snap and frozen in liquid nitrogen, and freeze dried at -40°C for 24 hours, leading to the formation of porous system, which can maintain a floating force over 12 hours. On the other hand, PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 67 multiple-unit dosage forms appear to be better suited since they claimed to reduce the inter subject variability in absorption and lower the probability of dose-dumping Hollow microspheres A novel emulsion solvent diffusion method was used to prepare hollow microspheres loaded with drug in their outer polymer shelf. The ethanol: dichloromethane solution of the drug and enteric acrylic polymers is poured in to an agitated aqueous solution of PVA that was thermally controlled at 40°C.The gas phase generated in dispersed polymer droplet by evaporation of dichloromethane formed in internal cavity in microspheres of the polymer with drug. The microballons floated continuously over the surface of acidic dissolution media containing surfactant for greater than 12 hours. The drug released was high in pH 7.2 than in pH 6.8. Hollow microspheres (micro balloons), loaded with ibuprofen in their outer polymer shells were prepared by a novel emulsion-solvent diffusion method. Ideal drug candidates for floating drug delivery: ● Drugs those are locally active in the stomach. Eg. Misoprostol, antacids etc. ● Drugs which have narrow absorption window in the GIT. Eg. Furosemide, L-dopa, Para-amino benzoic acid, riboflavin.etc. ● Drugs that exhibit low solubility at high pH values. Eg. Diazepam, Chlordiazepoxide, Verapamil hydrochloride. ● Drugs those are unstable in the intestinal or colonic environment. E.g. Captopril, ranitidine HCl, Metronidazole. ● Drugs that disturb normal colonic microbes. E.g. antibiotics against Helicobacter pylori. ● Drugs having a specific site of absorption in the upper part of small intestine. ● Drugs having a bulk density of less than 1 to remain in the stomach for a prolonged period of time. FACTORS AFFECTING GASTRIC RETENTION: [26] A) PHYSIOLOGICAL FACTORS:a) Density: Gastric retention time is a function of dosage form buoyancy that is dependent on the density. A buoyant dosage form having a density less than that of the gastric fluids floats, since it is away from the pyloric sphincter, the dosage unit is retained in the stomach for a prolonged period. A density of less than 1.004g/ml i.e. less than that of gastric contents has been reported. b) Size: Dosage form units with a diameter of more than 7.5mm are reported to have an increased GRT compared with those with a diameter of 9.9mm. c) Shape of dosage form: Tetrahedron and ring shaped devices with a flexural modulus of 48 and 22.5 kilo pounds per square inch (KSI) are reported to have better GRT 90% to 100% retention at 24 hours compared with other shapes. B) BIOLOGICAL FACTORS: a) Fed or unfed state: Under fasting conditions, GI motility is characterized by periods of strong motor activity or the migrating myoelectric complex (MMC) that occurs every 1.5 to 2 hours. The MMC sweeps undigested material from the stomach. However, in the fed state, MMC delayed and GRT is considerably longer. b) Nature of meal: Feeding of indigestible polymers or fatty acid salts can change the motility pattern of the stomach, to a fed state, thus decreasing the PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 68 gastric emptying rate and prolonging drug release. c) Caloric content: GRT can be increased by 4 to 10 hours with a meal that is high in proteins and fats. d) Frequency of feed: The GRT can increase by over 400 minutes, when successive meals are given compared with a single meal due to the low frequency of MMC. e) Gender: Mean ambulatory GRT in males (3.4±0.6 hours) is less compared with their age and race matched female counterparts (4.6±1.2 hours), regardless of the weight, height and body surface. f) Age: Low gastric emptying time is observed in elderly than do in younger subjects. Intrasubject and intersubject variations also are observed in gastric and intestinal transit time. Elderly people, especially those over 70 years have a significantly longer GRT. g) Posture: GRT can vary between supine and upright ambulatory states of the patient. An upright position protects floating forms against postprandial emptying because the floating form remains above the gastric contents irrespective of its size. In supine subjects large dosage forms experience prolonged retention. The gastric retention of floating forms appear to remain buoyant anywhere between the lesser and greater curvature of the stomach. On moving distally, these units may be swept away by the peristaltic movements that propel the gastric contents towards the pylorus, leading to significant reduction in GRT compared with upright subjects. h) Concomitant drug administration: Anticholinergic like atropine and propentheline opiates like codeine and prokinetic agents like metoclopramide and cisapride, affect the gastric emptying and hence gastric residence time of an oral dosage form. Methods for Preparing Floating Dosage Form [26] Direct compression technique Involves compressing tablets directly from powdered material without modifying the physical nature of the material itself. Direct compression vehicles or carriers must have good flow and compressible characters these properties are imparted by predisposing these vehicles to slugging, spray drying or crystallization. Most commonly used carriers are di calcium phosphate trihydrate, tri calcium phosphate etc. Melt granulation technique It is a process by which the pharmaceutical powders are agglomerated by using a melt able binder and no water or organic solvents are required for granulation. Because there is no drying step, the process is less time consuming and uses less energy. Granules were prepared in a lab scale high shear mixer, using a jacket temperature of 60 °c and an impeller speed of 20000 rpm. Melt solidification technique This process involves emulsification of the molten mass in the aqueous phase followed by its solidification by chilling. The carriers used for this technique are lipids, waxes, polyethylene glycols. Drug is incorporated into these carriers to achieve controlled release. Wet granulation technique Wet granulation process involves the wet massing of powders, wet sizing or milling and drying. Wet granulation forms the granules by binding the powders together with an adhesive instead of compaction. The wet granulation PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 69 technique employs a solution suspension or slurry containing a binder which is usually added to the powder mixture however the binder may be incorporated into the dry powder mix and the liquid may be added by itself. The method of introducing the binder depends on its solubility and on the components of the mixture since, in general, the mass should merely be moist rather than wet or pasty, and there is a limit to the amount of solvent that may be employed. Once the granulating liquid has been added mixing continues until a uniform dispersion is attained and all the binder has been activated. Then the wet mass is made to undergo wet screening by passing through a hammer mill or multi mill equipped with screens having large perforations. The milled wet mass is dried by either using tray drier or fluidized bed drier, after complete the drying lubrication materials is blended with dried granules. This lubricated granules is made to undergo compression. Effervescent technique: The floating chamber of the drug delivery system can be filled with inert gas [CO2] by the effervescent reaction between organic acid [citric acid] and bicarbonate salts. Spray drying techniques: It involves dispersing the core material in a liquefied coating material and spraying the core-coating mixture in to the environment to effect solidification of coating. Solidification is accomplished by rapid evaporation of the solvent in which coating material is solubilised. Advantages of FDDS: [27] ● FDDS is highly advantageous in the treatment of the disorders related to the stomach. As the prime objective of such systems is to produce a gastro retentive product or a product which has an enhanced retention time in the stomach. ● Drugs with considerably short half life can be administered in this manner to get an appreciable therapeutic activity. ● Enhancement of the bioavailability for drugs which can metabolized in the upper GIT. ● They also have an advantage over the conventional system as it can be used to overcome the adversities of gastric retention time as well as the gastric emptying time. ● The duration of treatment through a single dose, which releases the an active ingredient over an extended period of time ● The active entity is delivered specifically to the site of action, thus minimizing or eliminating the side effects Disadvantages of FDDS: [27] ● The major disadvantage of floating system is requirement of a sufficient high level of fluids in the stomach for the drug delivery to float. However this limitation can be overcome by coating the dosage form with the help of bioadhesive polymers that easily adhere to the mucosal lining of the stomach. ● Gastric retention is influenced by many factors such as gastric motility, pH and presence of food. These factors are never constant and hence the buoyancy cannot be predicted. Drugs that cause irritation and lesion to gastric mucosa are not suitable to be formulated as floating drug delivery systems. ● High variability in gastric emptying time due to its all (or) non-emptying process. ● Patients should not be dosed with floating forms just before going to bed. ● Floating system is not feasible for those drugs that have solubility (or) stability problem in gastric fluids. ● The dosage form should be administered with a minimum of glass full of water (200-250 ml). ● The drugs, which are absorbed throughout GIT, which under go first-pass metabolism (Nifedipine, Propranolol etc.) are not desirable candidate. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 70 MARKETED PRODUCTS OF GASTRORETENTIVE DRUG DELIVERY SYSTEMS Brand name Valrelease® Madorap® HBS (Prolopa® HBS) Liquid Gaviscon® Topalkam® Almagate Flot Coat® Conviron® Cytotech® Cifran OD® Delivery System Floating capsule Floating, CR cap Effervescent Floating liquid alginate preparations Floating liquid alginate preperation Floating dosage form Colloidal gel forming FDDS Bilyer floating capsule Bilayer Floating Capsule Gas-generating floating form DRUG (dose) Diazepam (15 mg) Benserazide (25 mg) and L-Dopa (100 mg) Al hydroxide (95 mg), Mg Carbonate (358 mg) Company Name Hoffmann-LaRoche Roche Products,USP Al-Mg antacid Pierre Fabre Drug, France Pierre Fabre Drug, France Ranbaxy, India Al-Mg antacid Ferrous Sulphate Misoprostol (100µg/200µg) Ciprofloxacin (1 gm) GlaxoSmithkline, India Pharmacia, USA Ranbaxy, India CONCLUSION Developing an efficient FDDS is a real challenge and the drug delivery system must remain for a sufficient time in the stomach. Various techniques and approaches have been employed to develop FDDS has emerged as one of the most promising gastro-retentive drug delivery system. The FDDS has an additional advantage for drugs that are absorbed primarily in the upper part of the GIT, i.e., the stomach, duodenum, and jejunum. Recently many drugs have been formulated as floating drug delivery systems with an objective of sustained release and restricting the region of drug release to stomach. The principle of buoyant preparation offers a simple and practical approach to achieve increased gastric residence time for the dosage form and sustained drug release. The most important criteria which has to be looked into for the productions of a floating drug delivery system is that the density of the dosage form should be less than that of gastric fluid. And hence, it can be concluded that these dosage forms serve the best in the treatment of diseases related to the GIT and for extracting a prolonged action from a drug with a short half life. ↓ REFERENCES 1. Arora S, Ahuja A. Floating drug delivery system: A Review. J. AAPS Pharm Sci Tech 2005; Vol.6 (03): 372-390. 2. Deshpande AA, Rhodes CT, Shah NH, Malick AW. Controlled-release drug delivery systems for prolonged gastric residence: An overview. Drug Dev and Ind Pharm 1996; 22:631-9. 3. Hwang SJ, Park H, Park K. Gastric retentive drug-delivery systems. Crit Rev Ther Drug Carrier Syst 1998; 15:243-83. 4. Degen LP, Peng F, Collet A, Rossi L, Ketterer S, Serrano Y, et al. Blockade of GRP receptors inhibits gastric emptying and gallbladder contraction but accelerates small intestinal transit. Gastroenterology 2001; 120:361-8. 5. Kydoneius A. Controlled Release Technologies. 2nd Ed. New York: Marcel Dekker; 1991; 24-109. 6. Petrakis IE, Kogerakis N, Vrachassotakis N, Stiakakis I, Zacharioudakis G, Chalkiadakis G. Hyperglycemia attenuate erythromycin-induced acceleration of solidphase gastric emptying in healthy subjects. Abdom Imaging 2002; 27:309- 14. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 71 7. Silang R, Regalado M, Cheng TH, Wesson DE. Prokinetic agents increase plasma albumin in hypoalbuminemic chronic dialysis patients with delayed gastric emptying. J Kidney Dis 2001; 37:287- 93. 8. Garg S and Sharma S. Gastroretentive Drug Delivery System, Business Briefing: Pharmatech. 2003;160166 . Ti e a s J, Moёs AJ, Ho ell do floati g dosage fo s float? I t. J. Pha a euti s. , , 207-216. 10. Yang L and Fassihi R. Zero order release kinetics from self correcting floatable configuration drug delivery system. J Pharm Sci. 1996; 85:170- 173. 11. Burns SJ, Attwood D and Barnwell SG. Assesment of a dissolution vessel designed for use with floating and erodible dosage forms. Int J Pharm. 1998; 160:213-218. 12. Joseph NJ, Laxmi S and Jayakrishnan A. A floating type oral dosage form for piroxicam based on hollow microspheres: in vitro and in vivo evaluation in rabbits. J Control Release. 2002; 79:71-79. 13. Sheth PR and Tossounian JL. Inventors. Sustained release pharmaceutical capsules. US patent. 1978; 4:126-672. 14. Soppimath KS, Kulkarni AR, Rudzinski WE and Aminabhavi TM. Microspheres as floating drug delivery system to increase the gastric residence of drugs. Drug Metab Rev. 2001; 33:149-160. 15. Ichikawa M, Watanabe S and Miyake Y. A new multiple unit oral floating dosage system. I: Prepration and in vitro evaluation of floating and sustained-release kinetics. J Pharm Sci. 1991; 80:10621066. 16. Chawla G, Gupta P, Koradia V and Bansal AK. Gastroretention: A Means to Address Regional Variability in intestinal drug Absorption, Pharmaceutical technology. 2003; 27(2):50-68. 17. Chandel A, Chauhan K, Parashar B, Kumar H and Arora S Floating drug delivery systems: A better approach. International Current Pharmaceutical Journal. 2012; 1(5):110-118. 18. Rubinstein A and Friend DR. Specific delivery to the gastrointestinal tract, in: A. J. Domb (Ed.), Polymeric sitespecific Pharmacotherapy, Wiley, Chichester. 1994; 282-283. 19. Vyas SP and Roop KK. Controlled Drug Delivery Concepts and Advances, First Edition, New Delhi. 2002; 196- 217. 20. Jain NK. Progress in Controlled and Novel Drug Delivery Systems. First Ed. CBSS. Gopalakrishnan. Journal of Pharmaceutical Science and Technology. Publishers and Distributors, New Delhi, Bangalore. 2004; 3(2):84-85. 21. Goyal M, Prajapati R, Purohit KK and Mehta SC. Floating drug delivery system, Journal of current pharmaceutical research. 2011; 5(1): 7-18. 22. Klausner EA, Sara E, Lavy E, Friedman M and Hoffman A. Novel levodopa gastro-retentive dosage form: in-vivo evaluation in dogs. J. Control. Release. 2003; 88:117-126. 23. Kale RD and Tayade PT. A multiple unit floating drug delivery system of Piroxicam using Eudragit polymer. Indian J PharmScie. 2007; 69(1):120- 123. 24. Sangekar S. Evaluation of effect of food and specific gravity of the tablets on gastric retention time. Int J Pharm. 1987; 35(3):34-53. 25. Moursy NM, Afifi NH, Ghorab DM and El-Saharty Y. Formulation and evaluation of sustained release floating capsules of Nicardipine hydrochloride. Pharmazie. 2003; 58: 38-43. 26. Kamalakkannan V, Py at hikod A, Vis a adha VP, E ha e e t of D ugs ioa aila ilit Floating Drug Delivery System-A ‘e ie . I t. J. D ug Deli e . , , -570. 27. Geetha A, Rajendrakumar J. A Review on floating drug delivery system. Int. J. Pharmaceutical Research & Biomedical Analysis, 2012, 1(1), 1-13. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 72 Review Article A Review: Effect of Diabetes on Vascular Endothelium Yogesh K. Patil* Department of Pharmacology, Shree Mahavir Institute of Pharmacy, Nashik, Maharashtra *yogesh_kpatil85@yahoo.co.in ABSTRACT Endothelial dysfunction is mainly observed in diabetics. The main role of endothelium is to control the tone of the vascular smooth muscle through the production of vasodilator mediators like nitric oxide (NO), prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF). Impaired endotheliumdependent vasodilation has been observed in vascular beds of different animal models of diabetes and in humans with type 1 and 2 diabetes. Hyperglycaemia causes repeated acute changes in intracellular metabolism and causes activation of polyol pathway, activation of protein kinase C, advanced glycation end product and increased oxidative stress. Keywords: Diabetes, Endothelial dysfunction, Endothelium-derived hyperpolarizing factor INTRODUCTION Endothelial dysfunction plays a key role in the pathogenesis of diabetic vascular disease. The endothelium controls the tone of the underlying vascular smooth muscle through the production of vasodilator mediators. The endothelium-derived relaxing factors (EDRF) comprise nitric oxide (NO), prostacyclin, and a still elusive endothelium-derived hyperpolarizing factor (EDHF). Impaired endothelium-dependent vasodilation has been demonstrated in various vascular beds of different animal models of diabetes and in humans with type 1 and 2 diabetes. Loss of the modulatory role of the endothelium may be a critical and initiating factor in the development of diabetic vascular disease.[1] There are certain vascular effects observed due to [2] vasoconstrictors and vasodilators. Table 1. Vascular Effects of Vasoconstrictors and Vasodilators Vascular Effect Vasoconstrictors* Vasodilators # Thrombosis Increased Decreased Inflammation Increased Decreased Oxidation Increased Decreased Growth and migration of vascular Increased Decreased smooth muscle cells * Includes angiotensin II, endothelin-1. # Includes nitric oxide, endothelial derived hyperpolarizing factors, natiuretic peptide, kinins. Impaired endothelium - dependent vasodilatation may arise from several mechanisms: Decreased production of one of the EDRFs, Enhanced inactivation of EDRF, Impaired diffusion of EDRF to the underlying smooth muscle cells, Decreased responsiveness of the smooth muscle to EDRF and Enhanced generation of endothelium-derived constricting factors (EDCF). How to cite this article: YK Patil, A Review: Effect of Diabetes on Vascular Endothelium, PharmaTutor, 2014, 2(3), 72-75 PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 73 Fig 1. Mechanism of endothelial dysfunction in diabetes Aetiology of endothelial dysfunction in diabetes Hyperglycaemia induces repeated acute changes in intracellular metabolism (activation of polyol pathway, activation of diacylglycerol-protein kinase C, increased oxidative stress), as well as cumulative long-term changes in the structure and function of macromolecules through formation of advanced glycation end products (AGEs). The different pathways are discussed below. Aldose reductase (Polyol Pathway) Protein kinase C (PKC) AGEs Fig 2. Outline and interactions of hyperglycaemia-induced metabolic pathways potentially involved in the pathophysiology ofendothelial dysfunction. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 74 1. Aldose reductase (Polyol Pathway): In tissues that do not require insulin for cellular glucose uptake, such as the kidney, retina, nerves and blood vessels, hyperglycaemia activates the polyol pathway, resulting in the formation of sorbitol. Aldose reductase is the first and rate-limiting enzyme in the polyol pathway and reduces the aldehyde form of glucose to sorbitol. Glucose is reduced into sorbitol by aldose reductase, leading to depletion in NADPH. NADPH co-enzyme is essential for the regeneration of antioxidant molecules (reduced glutathione, ascorbate and tocopherol) and cofactor of eNOS. Aldose reductase inhibitors prevent the consumption of NADPH and energy in the polyol pathway and by virtue of this, may restore impaired EDRF production and endogenous antioxidant protection. So far, no studies have evaluated the potential beneficial effect of aldose reductase inhibitors on endothelial function in human diabetes. Sorbitol is then oxidized to fructose by sorbitol dehydrogenase enzyme. This reaction uses NAD+ and raises the NADH/NAD+ ratio modifying the redox state of the cells, and leading to the production of superoxide anions. Several studies suggest that abnormalities such as vascular permeability and flow could be due to an increase in the NADH/NAD+ ratio, directly by a decrease in Na+ K+ ATPase activity. 2. Protein kinase C: Hyperglycemia also increases the synthesis of diacylglycerol (DAG) by enhancing the metabolism of glucose to diacylglycerol precursors through glycolysis. This cellular metabolic regulator activates an important signal transducer, the protein kinase C (PKC) pathway. Particularly, isoform is more activated in the heart and the aorta of diabetic rats. Hyperglycemia increases diacylglycerol production and protein kinase C activation, leading to a decrease in eNOS and an increase in the production of prostanoid substances by the endothelium. The increased concentrations of endothelin-1 (ET1) in type 2 diabetes mellitus are due to the enhanced ET1 production caused by hyperglycemia, partly via activation of PKC-β a d isofo s. The adverse effects of elevated glucose levels on ACh-induced relaxation of rabbit aorta and rat pial arterioles were restored by the addition of protein kinase C-inhibitors. In addition, the glucose-induced release of vasoconstrictor prostanoids was prevented by protein kinase Cinhibition. In experimental diabetes, protein kinase C-inhibitors improved endothelial dysfunction in pial arterioles in vivo, but not in isolated mesenteric arteries. 3. AGEs: Glucose is known to bind non-enzymatically to free amino groups on proteins or to lipids. Through a series of oxidative and non-oxidative reactions, AGEs are formed irreversibly and accumulate in tissues over time. AGE formation occurs during the normal ageing process, it is markedly accelerated during diabetes, as a consequence of an increase in substrate, e.g. glucose, and in the prevailing oxidant stress in this disease. The pathogenicity of AGEs is related to their ability to accumulate in tissues with the formation of cross-links, and to generate oxygen-derived free radicals. In addition, the interaction of AGEs with their cellular receptors (RAGEs) may trigger sustained cellular activation and a further increase of the oxidative stress. Treatment with aminoguanidine, an inhibitor of AGE formation, has proven beneficial on the progression of a broad range of diabetic complications in animal models and is currently under study in human diabetes. AGEs are known to quench NO. Oxidative stress: Oxidative stress is defined as an increase in the steady-state levels of reactive oxygen species and may occur as a result of increased free radical generation and/or decreased anti-oxidant defense mechanisms. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 75 Although there is controversy about the antioxidant status in diabetes, several studies have reported decreased plasma or tissue concentrations of superoxide Dismutase, catalase, glutathione and ascorbic acid in both clinical and experimental diabetes. 1. Increase in oxidable substrates Glucose oxidation leads also to the production of reactive oxygen species (ROS), such as superoxide (O2• via the cyclooxygenase pathway, hydrogen peroxide (H2O2) and h d o l adi als HO• . “tudies o the aorta of streptozotocin-induced diabetic rat showed the hyperproduction of O2• a d H2O2, leading to the formation of hydroxyl radicals. The superoxide inhibits NO and decreases the relaxation of smooth muscle cells. In diabetic humans, the production of free radicals decreases NO secretion by endothelial cells, and also inactivates NO in the sub-endothelial space. Reactive oxygen species can also alter lipids and proteins, and accelerate the formation of AGE. NO rapidly reacts with O2• to fo pe o it ite (ONOO-), which may promote LDL oxidation. HO• is responsible for the attack by radicals on phospholipids rich cell membranes, leading to lipid peroxidation. 2. Decreased antioxidant defences Hyperglycemia also promotes glycation and inactivation of antioxidant proteins, such as Cu/Zn superoxide dismutase (SOD), leading to its inactivation and a reduction in antioxidant defense. Experimental studies in streptozotocin-induced diabetic rats have shown decreased concentrations of antioxidants like vitamin E, superoxide dismutase and catalase. For example, the consumption of NADPH by the polyol pathway leads to decreased gluthatione activity, which is an efficient system for capturing free radicals. Experimentally in vitro, when the activities of superoxide dismutase (which capture O2• and catalase (which capture H2O2) were maintained, the endothelial function was not altered even in cases of hyperglycemia.[3] CONCLUSION Diabetes leads to acute changes in endothelium which resulted in endothelial dysfunction. Endothelial dysfunction is mainly occurred due to imbalance between vasoconstrictor and vasodilator mediators in body. Diabetes resulted into increase in oxidative stress which means increase in the steady-state levels of reactive oxygen species and may occur as a result of increased free radical generation and/or decreased anti-oxidant defense mechanisms. Nitric oxide is potent vasodilator present in our body which is released from endothelium. To prevent its metabolism is most important to treat diabetes or to reverse endothelial dysfunction. At the same time vasoconstrictor mediator are also important. ↓ REFERENCES 1. Vriese AS, Verbeuren TJ, Voorde JV, Lameire NH, Vanhoutte PM. Review Endothelial dysfunction in diabetes. British J Pharmacol .2000; 130: 963 –74. 2. Hsueh WA, Lyon CJ, Quinones MJ. Review Insulin Resistance and the Endothelium. The Am J Med. 2004; 117: 109-14. 3. Guerci B, Bohme P, Schwartz AK, Zannad F, Drouin P. Endothelial Dysfunction and Type 2 Diabetes Part 2: altered endothelial function and the effects of treatments in type 2 diabetes mellitus. Diabetes Metab (Paris). 2001; 27: 436-47. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 76 Review Article A Review on Ethnopharmacological Potential of Ricinus Communis Linn. KM Preeti, Ansu Bala Verma, Department of Pharmacology, Rameshwaram Institute of Technology and Management, Lucknow, Uttar Pradesh, India preeti30sept@gmail.com ABSTRACT In recent years, Ricinus communis Linn. has become a subject of interest because of its beneficial effects on human health. The present ethnopharmacological review was conducted to evaluate the therapeutic properties of Ricinus communis by scientific evidences. It belongs to the family Euphobiaceae which is commonly known as castor. Ricinus communis is found though out the hotter parts of India. This plant is extensively used in Ayurveda, Unani, Siddha, Homeopathic and Allopathic system of medicine as cathartic. Traditionally this plant is used as laxative, purgative, fertilizer and fungicides etc. whereas the plant possess beneficial effects as antioxidant, antifertility, anti-inflammatory , antimicrobial, CNS stimulant, antidiabetic, insecticidal, larvicidal, antinociceptive, antiasthmatic, antiulcer, immunomodulatory, hepatoprotective, lipolytic, wound healing and central analgesic and many other medicinal properties. The extracts or the isolated compounds of this plant have been found to have potent activity against various ailments. The aim of present article is to explore the pharmacological or medicinal importance of the plant Ricinus communis linn. Keywords: Ricinus communis, Ethnopharmacology, Phytochemical Constituents. INTRODUCTION Erand has been freely used all over India since centuries. In day to day life, it is commonly used as a purgative. The botanical name of erand is Ricinus communis and it belongs to family Euphorbiaceae. [1] The seeds, seed oil, leaves and the roots of erand have great medicinal value. The plant is equally useful, both internally as well as externally. Externally, castor is effectively used in the diseases of vata associated with pain and swellings. Internally, erand is used as a potent drug in treating diseases of vata viz. arthritis, sciatica, facial palsy, paralysis, bodyache, tremors, headache etc.[2] The plant is native of India and cultivated throughout the country in gardens and fields and also grows wild in waste places. R.communis is a small wooden tree which grows to about 6 meters in height and found in South Africa, India, Brazil, and Russia. Stems of Ricinus communis have Anticancer, Antidiabetic and Antiprotozoal activity.[3] In the Indian system of medicine, the leaf, root and seed oil of this plant have been used for the treatment of inflammation and liver disorders [4], as they have been found to be anti-nociceptive [5], hepatoprotective [6], laxative [7] and diuretic [8]. Morphology The castor oil plant is a fast-growing, suckering perennial shrub or occasionally a soft wooded small tree up to 6 meter or more, but it is not hardy in nature. This plant was cultivated for leaf and flower colors and for oil production. [9] How to cite this article: KM Preeti, AB Verma, A Review on Ethnopharmacological Potential of Ricinus Communis Linn., PharmaTutor, 2014, 2(3), 76-85 PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 77 Leaves are alternate, curved, cylindrical, purplish petioles, sub peltate, drooping, stipules large, ovate, yellowish, united into a cap enclosing the buds, deciduous, blade 6-8 inches across, palmately cut for three quarters of its depth into 7-11 lanceolate, acute, coarsely serrate segments, smooth blue green, paler beneath, red and shining when young. Flowers are monoecious, large, arranged on the thick rachis of an oblong, spicate panicle, which is at first terminal but becomes lateral by the growth of an axillary bud beneath it; male flowers shortly stalked, on branched peduncles at the base of the panicle, pedicels articulated about the middle; female flowers sessile, at the upper part; bracts broadly triangular. Fruit is blunt, Figure1: Plant Vernacular names English : Castor, Castor-oil plant Hindi : Arand, Arand, Andi, Rend Sanskrit : Gandharvahasta, Vatari Gujrat: Erandio, Erando Assam: Eda, Era Kanada: Haralu, Oudala, Gida Malyalam: Avanakku Marathi: Errand Bengali: Bherenda [12] Taxonomical classification greenish, deeply-grooved, tricoccus capsule, less than an inch long, with the prominences of the ovary becomes sharp, weak, spreading spines, 3-celled, dehiscing loculicidally and septicidally into 6 valves. Seeds are ovoid, flatte ed, ea l ⅝ i h lo g ¼ oad, smooth, shining, pinkish- grey, prettily mottled with dark brown, caruncle large, subglobular, raphe faintly raised, running down centre of ventral surface, embryo large in axis of the endosperm, cotyledons foliaceous, broadly ovate, with a cordate base, veined.[10] Roots are light in weight almost straight with few rootlets, outer surface dull yellowish brown, nearly smooth but marked with longitudinal wrinkels. [11] Figure2 :Fruit Kingdom: Plantae Order: Malpighiales Family: Euphorbiaceae Sub Family: Acalyphoideae Tribe: Acalypheae Sub Tribe: Ricininae Genus: Ricinus Species: communis Benefits of the plant Castor oil is widely used as a catharatic, and also for lubrication and illumination. The oil as PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 78 such or after modification finds extensive applications in industry, particularly in USA. Bulk of the commercial oil is generally processed in a number of ways and then used for different purposes. The treated oil finds use in products like paints, enamels and varnishes, oiled fabrics, linoleum, patent leather, flypaper, typewriting and printing inks, greases and special lubricants, polishes, waxes, cutting, dielectric and condenser oils, softening agent for gelatin in rayon sizing, nitrocellulose-baking finishes, hydraulic brake fluids, urethane foams and rubber substitutes, cosmetics, pharmaceuticals and insecticidal formulations. Oil from the perennial types is used for illumination and lubrication while that from the annual types is preferred for medicinal use. Castor oil is often given orally, alone or with quinine sulphate to induce labour in pregnancy at term. The oil can be used as a vehicle for parenteral administration of steroidal hormones. It is used in the preparation of liquid disinfectants like phenyls. It is an excellent illuminant and has been used in lamps from very early times in India. It is used in soap making. Castor cake is used as manure in India. It is rich in nitrogen and other minerals, and has been found to be suitable as manure for paddy, sugarcane, tobacco etc. Leaves are occasionally fed to cattle. They are reported to increase the yield of milk. The powdered leaves are used for repelling aphids, mosquitoes, white flies and rust mites. The insectisidal activity is probably due to the presence of the alkaloid ricinine in them. Expressed juice and aqueous and alkaline extracts of the leaves were active against mycobacteria and yeast. Leaves are said to use in the form of a poultice or fomentation on sores, boils and swellings. Leaves coated with oil and warmed, are commonly applied over the abdomen to give relief in the flatulence in the children. An infusion of leaves is used for stomache-ache, and as a lotion for the eye. Pounded leaves are said to give relief in caries, and are applied over guineaworm sores to extract the worm. Fresh juice of leaves is reported to be used as an emetic in the poisoning by narcotics like opium; it is also considered useful in jaundice. Leaves are considered lactagogue and are applied as poultice over the breasts or taken internally in the form of juice. Roots are administered in the form of a decoction for lumbago and allied complaints, in the form of a paste for toothache. Root bark is reported to be a powerful purgative. [13,14,15] Phytochemical constituents The presences of various phytoconstituents in different parts of Ricinus communis Linn have been reported. Fatty acid Seed oil of castor-plant showed the presence of fatty acid , ricinoleic acid (12-hydroxyoctadec-9enoic acid). Ricinoleic acid comprises over 84% while other fatty acids present were linoleic (7.3%), oleic (5.5%), palmitic (1.3%), stearic (1.2%) and linolenic (0.5%), respectively. [16] Essential oil The GC-MS analyses of R. Communis essential oil using capillary columns has shown compounds like @-thujone (31.71%), @-pinene (16.88%), camphor (12.92%) and camphene (7.48%). [17] Triterpenoid saponin The Seeds of Ricinus communis showed the presence of Triterpenoid Saponin, 3-O- β -Dglucoronopyranosyl- → -α –Lrhamnopyranosyl- → β- D-glucopyranosyl]α, α-hydroxy methyl olean-12-ene-28-oic acid. [18] Triacylglycerols Five types of castor bean seed oil triacylglycerols were identified as triricinolein, RRR (84.1%),diricinoleoylstearoylglycerol, RRS (8.2%), diricinoleoyloleoyl-glycerol, RRO (5.6%), diricinoleoyllinoleoylglycerol, RRL (1.2%) and PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 79 diricinoleoylpalmitoyl-glycerol, respectively. [16] RRP (0.9%) Flavonoid The dried leaves of R. communis showed the presence of six flavones glycosides kaempferol3-Oβ-D-xylopyranoside, kaempferol-3-O-β-Dglucopyranoside, quercetin-3-O-β-D xylopyrano side, quercetin-3-O-β-D-glucopyranoside, kaem pferol-3-O-β-rutinoside and quercetin-3-O-βrutinoside. [19] Seed and leaf of R. Communis also showed the presence of flavonoids like pu i -o-para ou a o l, p u i -o-para [20] coumaroyl. Protein Seeds of ricinus communis contain three toxic proteins Ricin A, B and C and one ricinus agglutinin. [21] Steroid Entire plant of Ricinus communis showed the presence of steroid Brassicasterol and Campesterol. [22] Table no1. Stucture of phytochemical constitutes Name of phytoconstituents Ricinin Anthocyanins The stem bark of the castor plant showed the presence of Anthocyanins, cyanidin 3-O-βxylopyranoside-5-O-β- glucopyranoside (21 %) , cyanidin 3-O-β xylopyranoside-5-O-(6'''-Omalonyl-β- glucopyranoside) (79 %) and cyanidin 3-O-β-xylopyranoside-5-O-(6'''Omethylmalonate- β-glucopyranoside). [23] Tannins The leaf extracts of Ricinus communis showed the presence of tannins such as catechin and gallic acid. Alkaloid Alkaloids are present in the aerial parts of the Ricinus communis. The root of Ricinus communis showed the presence of indole 3 acetic acid and the ricinin (0.55%) and NDemethylricinin (0.016%). alkaloid present in the leaf of plant. [19] Structure Reference 19 N-demethylricinine 19 α-thujone 17 α-pinene 17 PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 80 camphor 17 Ricinoleic Acid 16 Oleic Acid 16 linoleic Acid 16 Table 2. Report on Ethnopharmacological activities Activity Plant part/extract Animal / Experimental model Result Analgesic activity Seed / oil Mice and rat / Hotplate method, tail clip method and tailimmersion method Antiarthritic activity Leaves / Hydroalcoholic extract ‘ats / F eu d s adjuvant induced arthritic rats Antiinflammatory activity Leaves / 80% Mathanolic extract Wistar Rat / Carrageenan-induced paw edema (Acute model) and cotton pellet induced granuloma models (Sub-chronic model) In analgesic studies, castor oil showed more significant analgesic activity at 1000 mg/kg(8.37±0.41**) and (4.90 ± 0.19**) then 500mg/kg tested dose level.. The analgesic activity of castor oil was however, less than that of pentazocine. The results suggest that castor oil possesses significant analgesic property. Ricinus communis leaves extract show the significant antiarthritic effect at the 200mg/kg and 400mg/kg dose level. It might be speculated due to phytochemicals present such as flavonoids and saponin.. The results of 80% methanolic extract (500 mg/kg) and total flavonoids fractions (50 mg/kg) were at par with diclofenac sodium (20 mg/kg).Ricinus communis leaves have anti-inflammatory potentials and flavonoids are dominating this activity in the extract. Antiasthmatic Root / Ethanolic extract Rats / Milk induced leucocytosis and eosinophilia , Passive cutaneous The ERCR significantly decreases Milk induced leucocytosis and eosinophilia and protect degranulation of mast cells in mice. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org Ref. 24 25 26 27 81 anaphylaxis test , Mast cell degranulations Antidandruff activity Leaves / Aqueous , methanolic , chloroform and petroleum ether extract Anti dandruff assay with DMSO Antidiabetic activity Root / Ethanolic extract Alloxan induce diabetes mellitus Antinociceptive Leaves / Methanolic extract Acetic acid induced writhing test , Formalin induced paw licking and Tail immersion method Antiulcer activity Seed / oil Rats / Gastric cytoprotection method , aspirin induce gastric mucosal damage , pyloric ligation. At same dose ERCR inhabited passive cutaneous anaphylaxis in rats. Hence ERCR shows antiasthmatic activity may be due to the presence of flavonoids and saponins. R.commuis leaf extracts has antidandruff effects and due to its potential bioactive compounds. Phytochemical screening of various solvent extracts of R.communis leaves revealed the presence of flavonoids, saponins, tannins, phlobatannins and terpenoids methanolic extracts exhibited significant activity (8.20 ± 0.3). Aqueous extracts of the leaves recorded appreciable inhibitory activity (5.74 ± 0.8) when compared with chloroform (1.66± 1.2) and petroleum ether extracts. Petroleum ether extract gave a mean zone of inhibition of 0.90 ± 0.3 mm, showing the ineffectiveness of the extract. Blood glucose concentration of rats administered Ricinus communis reduced from 390.0 to 148.5 or 61.9%. Results from this study have confirmed the hypoglycaemic efficacy of root extract of Ricinus communis in rats. The results indicated that MRCL exhibited considerable Antinociceptive activity against three classical models of pain in mice at doses of 100, 125 and 150 mg/kg bw. Preliminary phytochemical analysis suggested the presence of saponin, steroids and alkaloids. The result of indicate that the higher dose of castor oil 1000mg/kg (UI ; 2.35 ± 0.15) was effective in protecting ulcer. It appears that castor oil possess antiulcerogenic principles like flavonoids tannins and saponins. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 28 29 30 31 82 Antimicrobial and Antifungal activity Leaves / Methanolic , Ethanolic and Water extract Bacteria and fungi / Agar well diffusion method and agar tube dilution method Hepatoprotective activity Leaves / Ethanolic extract Rats / carbon tetra chloride (Ccl4) induced hepatotoxicity Hypolipidmic activity Root / Aqueous extract Pap-method , Polyvinylsulphate method , Dextran sulphate-Mg2+ method and glycerolphosphate oxidase method In-vitro Immunomodulat ory activity Leaves / Mathanolic extract Qualitative nitroblue terazolium tert , phagocytosis of killed candida albicans, nutrophil locomotion chemotexis test Bio-Insecticidal activity Leaf , root and seed Kernel / Aqueous Field-cage experiments-Direct treatment of diamondback moth Methanolic leaf extracts were found to be more active against Gram positive bacteria as well as Gram negative bacteria than ethanol and aqueous leaf extracts. Methanolic as well as aqueous leaf extracts of Ricinus communis were effective in inhibiting the fungal growth. The hepatoprotective activity was studied in liver by measuring the parameters like serum levels of Glutamic oxaloacetate transaminase (SGOT), Glutamic pyruvic transaminase (SGPT), Bilirubin, Alkaline phosphatase (ALP) and histological changes in liver of different groups of animals were observed. The results of the present study showed that, the levels of SGOT, SGPT, ALP, Bilurubin were significantly increased in hepatotoxin treated group (P<0.001) when compared with control group. A significant reduction in the ratio of High density lipoprotein to Low density lipoprotein compared with the diabetic untreated rats is suggestive of the ability of the extract to reduce atherosclerosis, a complication of diabetes. The isolated compound (tannin) of R.communis was tested at concentrations, viz 10 µg/ml, 20 µg/ml, 40 µg/ml, 100 µg/ml and 1000 µg/ml. The isolated compound showed predominantly significant activity on human neutrophils in all the parameters tested, which was comparable to the standard and control at different concentrations, indicating the possible immunomodulating effect. In view of the low oviposition rates, oviposition deterrent, immature mortality, and the relatively low persistence of the toxic ricin oil, it PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 32 33 29 34 35 83 extract In-vitro Cytotoxic activity Leaves/essent ial oil In-vitro Antioxidant activity Stems / petroleum ether , benzene , chloroform , methanol, 50% methanol crude, aqueous crude extract infested cabbage plant in cage experiments, Residual activity of the botanical treatments, Effect of different treatments on the oviposition behaviour of P. xylostella. HeLa cells/MTT test DPPH Method, Nitric Oxide Radical Inhibition Method can be expected that the use of R. communis product be suitable for P. xylostella population density reduction in the field. At a concentration of 3 mg/ml, essential oil destructed HeLa cells by about 30%, however at a concentration of 4 mg/ml, almost all HeLa cells were destructed. Cytotoxicity was expressed as the concentration of oil inhibiting cell growth by 50% (IC50). The IC50 value of R. communis essential oil was evaluated to 2.63 mg/ml. The six extracts Ricinus communis stem and two standards tested for antioxidant activity using DPPH method, the benzene and 50% methanol successive extracts showed the maximum antioxidant activity with IC50 values of 36.19 ± 2.332 µg/ml and 34.40 ± 5.98 µg/ml, respectively. The methanol and chloroform extract also showed antioxidant activity with IC50 values of 64.18 ± 3.20 and 66.17 ± 6.30 µg/ml. The distilled water crude extracts showed IC50 values of 106.14±4.33 µg/ml, respectively. The Ricinus communis stem extracts also produce antioxidant activity due to the Presence of flavonoids in their extracts. 36 37 DISCUSSION AND CONCLUSION Plants have been used as a source of medicine since the dawn of civilization. These medicines occupied a distinct place in the life right from the primitive period till date and provided information on the use of plants or plant products and products as medicine. The use of medicinal plants in the management of various illnesses is due to their phytochemical constituents and dates back antiquity. It is very essential to have a proper documentation of medicinal plants and to know their potential for the improvement of health and hygiene through an ecofriendly system. 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D and Sanda K., Bio-insecticidal effects of plant extracts and oil emulsions of Ricinus communis L. (Malpighiales: Euphorbiaceae) on the diamondback, Plutella xylostella L. (Lepidoptera: Plutellidae) under laboratory and semi-field conditions., Journal of Applied Biosciences; 43: 2899 – 2914; ISSN 1997–5902 . )a ai ), Cho a I.B, Ma sou ‘.B, Béki A, Gha sallah N, Kad i A., Esse tial oil of the lea es of Ricinus communis L.: In vitro cytotoxicity a d a ti i o ial p ope ties, Lipids in Health and Disease, 2012, 11:102. . “i gh ‘.K, Gupta M.K, Kati a D, “ i asta a A a d “i gh P., I -Vitro Antioxidant Activity Of The “u essi e E t a ts of ‘i i us o u is “te s, ,: IJP“‘ Vol. , Issue . PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 86 Review Article Biotechnology for a Better World Nirav.R. Soni Department of Quality Assurance, A-One Pharmacy College, Anasan, Ahmedabad, Gujarat, India nirav_sonic@yahoo.com ABSTRACT Pharmaceutical Biotechnology is not a source of energy, but a scientific method that provides tools to produce energy based entirely on modern biotechnological techniques, as to date encompass a wider range of altogether newer medicinal compounds, e.g., antibiotics, vaccines development and monoclonal antibodies (MABs) that may now be produced commercially using well-defined, optimized and improved fermentative methodologies. In fact, genetic engineering has brought in a sea change by virtue of the directed construction of microorganisms resulting in a plethora of newer life-saving drugs. Focus on a variety of research areas including health/medicine, food science, environmental science and agri- science and also bioenergy development. Keywords: Biotechnology, Newer Medicinal compounds, Genetic Engineering INTRODUCTION Biotechnology is a huge part of our everyday lives. Biotechnology is the application to industry of advances made in the technique and instrument of research in the biological sciences to improve plants or animals or to develop microorganisms for specific uses. ● Higher yields and quality of foods. ● Less acres used ● Longer shelf life ● Decreased molds ● Respecting society values ● Awareness ● Visionary & Pragmatic What is biotechnology? It is the manipulation of living organisms and organic material to serve Human Needs. e.g. yeast in bread making and alcohol production ,use of beneficial bacteria (penicillin) to kill harmful organism, cloning of plant & animal, artificial insemination [1]. Biotechnology Benefits and Risks [1-5]: ● Decreasing reliance on pesticides ● Insect resistance management ● Gene flow and out crossing ● Non-target organisms ● Human, wildlife and environmental health ● Preserving genetic diversity in plants and animals ● Economic impacts Biology +Technology =Amazing Innovations. Biotechnology Strategy [2]: ● Simplicity/flexibility ● Excellent ● Lower grower cost ● Healthy environmental sciences ● Reduced herbicide residues Goal [3,5,8]: The need for new technologies is great, as the various described below: ● "In Modern Era, there are some 900 million people who do not have access to sufficient How to cite this article: NR Soni, Biotechnology for a Better World, PharmaTutor, 2014, 2(3), 86-92 PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 87 food to meet their needs because of lack availability in Human population." ● ‘e e a le e e g te h olog a age e t promoting village project, also ICU ventilator, Evapotranspiration. HSR(Human source radiation edu e p oje t , Bio di e sit . ● "(Global Climate Change-GCC) and alterations in land use will exacerbate the problems of regional production and demands for food." ● "Malnutrition (e.g. Marasmus and kwashiorkor) plays a significant role in half of the nearly 12 million deaths each year of children under five in developing countries." "In addition to lack of food, deficiencies in micro-nutrients (especially vitamin A, iodine and iron) are widespread [4,6,7,9]." ● Food i fe tio a d outside the environmental pollution as a major role for our health and also adulterated medicines, markers and herbal drugs to harmful our body and to a e o e ou life. ● To p ope Guida e o ditio a d situatio according to need for farmer and at the same time, biotechnology can help farmers produce more nutritious crops, while sustaining the land's ability to support continued farming and may reduce the need for costly inputs such as fertilizer and non-renewable resources, such as oil a d atu al gas. ● "In developing countries about 750 million of the poorest people according to up to 2012 year live in rural areas where the local production of food is the main economic activity. Without successful agriculture, these people will have neither employment nor the resources they need for a better life Farming the land is the engine of progress in less developed countries [15,16]." INNOVATION [11-17]: Innovation benefits should be recommended are: 1. MEDICAL SCIENCE ● Biomedical KIT ● Neurosciences & Neurobiology ● Infectious Diseases of Humans ● Non-infectious Diseases of Humans ● Immunobiology ● Human Genetics/ Genome Analysis ● Bio-Medical Instrumentation ● Therapeutics & Posology ● Vaccines & Diagnostics ● Medicine adultred reducization ● Forensic medi bio technology ● Bio medico technology ● Bio anthropology –Human lineage 2. ENVIRONMENTAL BIOSCIENCE ● Plant Biodiversity ● Microbial Biodiversity ● Pollution Management ● Bio remediation ● Afforestation & Conservation 3. ANIMAL SCIENCES ● Breeding, Embryo transfer and related areas ● Genetic enhancement, transgenics ● Diagnostics & Vaccines (improved & recombinant) ● Zoonotic diseases ● Immunobiology ● Feed and Nutrition 4. AQUACULTURE ● Breeding & Genetic Enhancement ● Feed, nutrition, pro biotics ● Culture/hatchery technologies in new and non-traditional species ● Vaccines, immune stimulants, diagnostics ● Genomics, genes of interest 5.MARINE SCIENCES ● Marine species other than Fish ● Marine Microbiology/ flora & fauna ● Extremophilic Organisms ● Genomics, genes of interest 6.FOOD SCIENCES ● Food Processing/ Packaging/ Preservation / safety PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 88 ● Food Additives /Ingredients ● Food-borne diseases/ Diagnostics ● Quality Control/Assay Systems. 7.BIOTECHNOLOGY & SOCIETY ● SC/ST or Weaker Sections ● Women Oriented ● Rural Development ● Biovillage ● Enzymes Liquefying, proteolytic, maltogenic and isomeric enzymes ● Bio pesticides Nematodes, pheromones, natural products and derivatives, and insects ● Bio plastics Hospital fibers, straps, cutlery, straws, belts (natural/organic/functional), phyto-pharmaceutical ● Bio-fuels Electricity, fuel additives, methanol, ethanol * ● Bioreactors Mining, enzymes 8. BIOINFORMATICS, BIOCOMPUTING, STRUCTURAL / THEORETICAL BIOLOGY, DATABASE DEVELOPMENT, ALGORITHMS / SOFTWARE DEVELOPMENT, COMPUTER APPLICATIONS FOR GENOMICS/PROTEOMICS ETC 9. AGRICULTURE & ALLIED AREAS ● Field Crop ● Horticulture & Plantation Crops ● Forestry Species, Fuel Fodder, Biomass ● Plant Molecular Biology ● Biological Control of Plant Pests, Diseases and Weeds ● Biofertilizers ● Medicinal and Aromatic Plants ● Seri-Biotechnology / Sericulture – host plants ● Tissue Culture Plants ● Biodiversity Conservation & Bioprospecting 10. BASIC RESEARCH TABLE :- Innovative ideas and their application. Sr.no Innovative Ideas Application Biomass & Material produced by or remaining after the death of organism (e.g. 1. Biodiversity bacteria, animal, plant) [31] Such type of oil is useful for health in human body like canola oil is versatile and healthy oil for every day cooking. In such type of Modern Generation 90% cases people suffering From Diabetes ,cancer and holeste ole i et …Also , GIT a e , IB“ I ita le o el “ d o e-)so 2. GM technology these can be prevented by healthy oil and diet. Also, GM technology can provide such type of fruits /vegetables resistant to disease or viruses that have otherwise proven untreatable [18-21]. It containing washing powders cleans clothes at lower temperatures resulting huge energy savings. Also made up of biotech cotton shirts. So resist attaching disease via bacteria, virus or other infectious organisms. 3. Enzymatic Enzymes can help reduce the amount of bleaching needed for paper production and also remove inks for paper to be recycled. Also helpful in speedup fermentation in beer [23, 25, 45-49]. Biotechnology can convert agricultural residues into advance biofuels for cleaner and more efficient transport, which will give a new income to farmers. Genetic engineering of model plants like tomato, tissue culture of cereals & pulses, isolation and analysis of genes would emerge as 4. Agricultures important items in the area of agricultural applications. To develop varieties of cassava that more efficiently absorb trace metals and micronutrients from the soil, have enhanced starch quality and contain PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 89 more beta-carotene and other beneficial vitamins and minerals. A strain of "golden rice" that packs more and iron and beta carotene, a precursor of Vitamin A, could be on the world market within a few years - helping the more than 100 million children worldwide who suffer from vitamin A deficiency, the developing world's leading cause of blindness, as well as some 400 million women of childbearing age who are iron-deficient, placing their babies at risk of physical and mental retardation, premature births and natal mortality. fruits and vegetables that could one day deliver life-saving vaccines such as a banana that could soon deliver the vaccine for Hepatitis B, and a potato that provides immunization against the Norwalk virus - making it possible to inoculate against deadly diseases with locally grown crops that are easy to handle, distribute and administer [24,28,32] 5. 6. 7. Use of predictive biomarkers, support the identification of most effective edi i es to the patie t s. O pha Medi i al P odu ts OMPs o l treatment for rare disease, chronicle and life threatening. Also Modern Medicines biotech medicines help multiple sclerosis patients recover a high mobility of patients. Vaccine development for infectious and vector borne diseases, e.g. Insulin is a life saving biotech medicine for patients with diabetes [27-35]. For useful for IBS-prevented by made nanocrystals. Also stem cell treatment. In AIDS and swine flu prevented by made up of macromolecule bio-merge medicines. Also useful for Lipid nano bio technology [29-31]. Also Nano Biotechnology useful in asthma –Thymol in thymus vulgarize to make (virtual crystallography suspension as well as i.v administration drug.)[5056] . Effective treatment technologies for water, land and air pollution, waste management and recycling, reclamation/ remediation, conservation of biodiversity emerge as life science and biotechnological applications to Industrial environmental preservation [34-42]. Medical and Scientific Devices, scientific biotechnology and hospital industry such as ultra low freezers for sperm and eggs storage, thermal cyclers for biotechnology research and imaging systems such as lithotripter and magnetic resonance imager (MRI) for hospital use [49-56] . * Biosensors or Enzyme Electrodes invariably refer to such devices that sense and analyze biological information(s), namely ; blood pressure (BP), temperature, heart rate, sophisticated determination of chemical and enzymes in body fluids. Types of innovative ideas listed below: Sr.no Innovations 1. Health care 3. Genetic- modification(GM) 5. Enzymatic 7. Human source radiation reducized Sr.no 2. 4. 6. 8. Innovations Human Life styles & mental fertility Biomass and bioremediation Industrial Waste water treatment PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 90 9. 11. 13. 15. 17. 19. 21. 23. 25. 27. 29. 31. 33. 34. Nano biotechnology House treatment biotechnology Food & agriculture Biotechnology Cosmetic biotechnology Waste paper treatment Cloth washing powder Turn bioplant technology(BPT) Bio gas Biofe tilize f o o s du g & Birds Excreta Municipal garbage treatment Cosmo biotechnology Reduced ultraviolate rays Transgenic plant Horticulture Herbicides resistant crops Expected Results: Biotechnology ● To be the basis for the knowledge based economy. ● To create a jobs and wealth. ● To clean up toxic wastes. ● To capture excess carbon to help reduce GCC(Global Climate Change) ● Generate clean energy sources (e.g. Hydrogen) ● To cure and prevent diseases. ● To increase survival. ● To i p o e patie t s ualit of life. ● To help the environment ● To feed the world ● To develop more efficient industrial processes. ● To make crops and animals more resistant to disease , pests and environmental conditions. ● To grow more nutritious and abundant produce. ● Incorporate vaccines into food products. ● To improve inside as well as outside environment 10. 12. 14. 16. 18. 20. 22. 24. 26. 28. 30. 32. 33. 35. Forensic biotechnology Wear (clothes) biotechnology Industrial biotechnology Wireless biotechnology Fuels and carbo gas treatment GCC-global climate changes Marine sources Vermiculture &vermicompost Organic farming Bio –flavour technology Pharmacogenomics Phytoremedation Animal insemination Vioextractive metallergy ● To return to the plant based economy. ● Reduces impact from pesticides. ● To optimize renewable resources ● To be competitive Innovation for the benefit of patients e.g. Human insulin – for treatment of Diabetes, Monoclonal antibody (MABs)–for treatment of cancer. CONCLUSION In innovation various types of application under biotechnology are: food & environment security, improveness of biological product safety and greeny biology and Discard biomass and convert into bio-diversity. The main purpose of the advance technology produces health safety and keep maintain environmental condition and minimization risk of hazards and clean up to toxic wastes, enhancing modern technology which is useful to safety and maintaining life sciences. This all are effort send to our government. ↓ REFERENCES 1.Dr.Ashutoshkar, Pharmaceutical biotechnology, New age international publishers 2006 2. No th Ca oli a Biote h olog Ce te . A out Biote h . ncbiotech.org/aboutbt/main.cfm PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 91 3.Principles of biotechnology nal.usda.gov/bic/Education_res/iastate.info/bio1.html 4. Biotechnology for the 21st Century: New Horizons. nal.usda.gov/bic/bio21 5. Definition of Biotechnology-Economic Research Service at United States Department ofAgriculture. ers.usda.gov/whatsnew/issues/biotech/define.htm 6. U ited “tates Depa t e t of Ag i ultu e Ag i ultu al Biote h olog Co epts a d Defi itio s . biotechknowledge.com/showlib.php3?1739 7. Bio s guide to Biote h ology. bio.org/aboutbio/guide1.html 8. Journal of the Ameri a Dieteti Asso iatio Positio of the A e i a Dieteti Asso iatio : Biotechnology and the Future of Food. biotechknowledge.com/showlib.php3?1594 9.What The Experts Say About Food Biotechnology ificinfo.health.org/foodbiotech/whatexpertssay.htm 10. Food Biotechnology-Benefits for the Developing Countries. ificinfo.health.org/insight/janfeb99/foodbiotechnology.htm 11. Backgrounder- Food Biotechnology. ificinfo.health.org/backgrnd/BKGR14.htm 12. Bio s guide to Biote h ology. bio.org/aboutbio/guide3.html 13. Press Releases. nature.com/nbt/press_release/nbt1199.html 14. Bio s guide to Biote h olog . io.org/aboutbio/guide4.html 15. Ne Yo k Ti es Edito ial, titled: Food….people ho ould ha e the ost to lose ,No e e 19,1999. 16. National and International Policy Making in Biotechnology.biotechknowledge.com/showlib.php3?194 17. Food Biotechnology: Health and Harvest for Our Times. ificinfo.health.org/brochure/biobroch.htm 18. IFIC Foundation- Americans Remain Positive on Food Biotechnology. ificinfo.health.org/press/positivebio.htm 19. Myths and Facts about Food Biotechnology, Food Insight, September/October 1999, PP2-3. 20. Cou il fo Ag i ultu al “ ie e a d Te h olog : Appli atio s of Biote h olog to C ops: Be efits a d ‘isks , Issue Paper, Number 12, Dec. 1999. 21. U.S. Food and Drug Administration Center for food Safety and Applied Nutrtion: Q & A Sheet: June 1992. vm.cfsan.fda.gov/~lrd/bioqa.html 22. U.S. Food and Drug Administration Center for food Safety and Applied Nutrtion: October-November 1997. vm.cfsan.fda.gov/~tdms/pubalgry.html 23. Genetically Engineered Foods, Fears and Facts: FDA. Consumer 27(1). January/February1993, page no.11-14. fda.gov/fdac/100_toc.html 24. Bio s edito s a d epo te s guide to iote h olog . io.o g/a outbio/guide2000/guide00_toc.html 25. Hoban TJ, Kendall PA. Consumer Attitudes about Food Biotechnology. Project Report1993, Raleigh, NC: North Carolina State University and Colorado State University;1993:1-36. 26.Bruhn CM. Consumer concerns and educational strategies: focus on biotechnology, Food Technology 1992,46(3):80-102 27. Public Perceptions of Biotechnology. A Summary of Research by Dr. Thomas Hoban at North Carolina State University. 4.ncsu.edu/~hobantj/biotech.htm 28. The Council for Biotechnology Information. whybiotech.com 29. Bronzino, Joseph D. The Biomedical Engineering Handbook. Boca Raton: CRC Press;IEEE Press, 1995. 30. Christou, Paul, and Harry Klee._Handbook of Plant Biotechnology._Hoboken, NJ: JohnWiley, 2004. 31. Akay, Metin, ed. Time Frequency and Wavelets in Biomedical Signal Processing. IEEE Press Series in Biomedical Engineering. New Jersey: The Institute of Electrical andElectronics Engineers, 1998. 32. Avise, John C. The Hope, Hype & Reality of Genetic Engineering: Remarkable Stories from PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 92 Agriculture, Industry, Medicine, and the Environment. Oxford: Oxford University Press, 2004. 33. Brown, Terence A. Genomes. 2nd ed. Oxford: BIOS, 2002. 34. Campbell, A. Malcolm, and Laurie J. Heyer. Discovering Genomics, Proteomics, and Bioinformatics. San Francisco: Benjamin Cummings, 2003. 35. Adams, A., Gottschling, D. E., Kaiser, C. A., Stearns, T. Methods in Yeast Genetics. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1997. 36. Broach, J. R., Jones, E. W., Pringle, J. R. (Eds) The Molecular and Cellular Biology of the Yeast Saccharomyces, vol 1 Genome Dynamics, Protein Synthesis, and Energetics. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1991. 37. Brown, A. J. P., Tuite, M. F. (Eds.). Yeast Gene Analysis. Methods in Microbiology, vol. 26, Acad. Press, NY (1998). 38.Gutherie, C. and fink, G. R. (Eds.) 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CBS publishers and distributors 49. Principles of fermentation tehchnology. Second edition. P. F. Stanbury, A. Whiteshaker and S. J. Hall Aditya Books Pvt Ltd. New Delhi. 50. Microbiology, Pelczar/Chan Kreig Tata McGraw Hill edition 51. Industrial microbiology L.E. Casida, Jr. New age international publishers. 52. Fundamental principles of bacteriology. A. J. Sale, Tata McGraw Hill publishing company Ltd. 53.Fundamentals of microbiology by forbischer 54.Remington Pharmaceutical Science, latest edition 55.Microbiology by Ronald Atlas 56.Pharmaceutical microbiology, sixth edition, edited by W. B. Hugo and A. D. Rusell Blackwell science. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 93 Review Article A review on chemical and biological activity of Trifolium Pretense Neeta Chaudhary*, Shalini Tripathi Department of Pharmacognosy, Rameshwaram Institute of Technology and Management, Sitapur Road, Lucknow, Uttar Pradesh, India *neetakhanna70@gmail.com ABSTRACT Trifolium pratense L. is commonly known as red clover. Red clover acting as a diuretic, expectorant and improving circulation. Trifolium pratense isoflavones, plant based chemicals that have shown potential in the treatment of a number of conditions associated with menopause, such as hot flashes, cardiovascular health, and osteoporosis. Literature review revealed different pharmacological activities of Trifolium pratense like Biological estimation of oestrogenic activity , An ovariectomized rat model to determine the estrogenic and antiestrogenic activity, Antioxidant Profile , isoflavone biochanin A inhibits aromatase activity and expression, phase II clinical extract possesses opiate activity, Determination in vivo and in vitro anti-inflammatory activity of red clover. Keywords: Trifolium Pratense, Isoflavones, Menopause, Antioxidant, Estogenic INTRODUCTION Trifolium pratense L. is commonly known as red clover (Piersen et al., 2004). In Chinese medicine, Trifolium pratense was used as a sedative and for pain and other symptoms related to cancer, rheumatism, and gout (Duke and Ayensu, 1985). It has also been used for over 100 years in Europe and America to treat whooping cough, pain, and as a sedative and an expectorant (Hamrick JL et al., 1979). It can be grown in a wide range of soil types, pH levels and environmental conditions (Smith et al. 1985) and gives Satisfactory yield in areas that are not suitable for growing alfalfa because the soils are too wet and/or too acid. Red clover is a significant forage legume grown in eastern Canada and the north eastern United States. Through symbiotic nitrogen fixation, red clover also provides nitrogen for soils, companion crops and subsequent crops. The range of fixed nitrogen was estimated to be from 125 to 220 kg ha·1year·1 (LaRue & Patterson, 1981; Rohweder et al. 1977). These qualities have made red clover useful for hay, silage, pasture, intercropping and green manure in several countries (Smith et al. 1985). CLASSIFICATION Trifolium pratense Kingdom Subkingdom Superdivision Division Class Subclass Order Family Genus Species Plantae Tracheobionta Spermatophyta Magnoliophyta Magnoliopsida Rosidae Fabales Fabaceae Trifolium L Trifolium pratense L (plants.usda.gov/java/profile?symbol=trpr2) How to cite this article: N Chaudhary, S Tripathi, A review on chemical and biological activity of Trifolium Pretense, PharmaTutor, 2014, 2(3), 93-101 PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 94 PLANT PROFILE Other common name(s) : Beebread, cow clover, meadow clover, purple clover, trefoil, wild clover Scientific/medical name(s): Trifolium pratense Plant Parts Used: The dried and the fresh flower heads. Active Components: Red clover is one of the richest sources of isoflavones, water-soluble chemicals that act like estrogens and are found in many plants. Looks like: The plant is a perennial herb 15 to 40 cm high. The red flowers are the source of medicinal properties. Where it s gro : Commonly grows wild in meadows throughout Europe and Asia, and has now been naturalized in many other parts of the world. (akuna.net/picture/Canada_WEB/PDFs/RED%20 CLOVER.pdf) GEOGRAPHICAL DISTRIBUTION Red clover is a relatively short-lived perennial, originating from southeastern Eurasia; it is widely distributed across the temperate zones of the world (Taylor & Quesenberry, 1996). Red clover is considered to be native to Sweden and was scientifically named by Carl Linnaeus in 1753, but was first described in Sweden in 1658 by Rudbeck in the Catalogus plantarum (Nordstedt, 1920). Cultivation involving ploughing meadows and re-sowing with forage species in planned crop rotations began in the late 18th century in the southern part of Sweden; the same system came into use in the north a century later (Hagsand & Wik, 1968). Red clover lives in symbiosis with Rhizobium leguminosarum, a nitrogen-fixing, noduleforming bacterium. In a T. pratense monoculture in Sweden, the amount of fixed nitrogen (N) varies between 2.2 and 8.5 g N m-2 year-1 over four years (Carlsson et al., 2005). MORPHOLOGICAL DESCRIPTION This perennial plant is ½–2' tall, branching occasionally. The hairy stems are sprawling or erect. The alternate compound leaves are trifoliate. The lower compound leaves have long hairy petioles, while the upper leaves have short petioles or they are sessile. The leaflets are up to 2" long and ¾" across. They are ovalovate or slightly obviate; sometimes they are a little broader below the middle. Their margins are smooth and ciliate and their tips are blunt. Toward the middle of the upper surface of each leaflet, there is usually a chevron that is white or light green. The leaflets are sessile and lack petioles of their own. At the base of each compound leaf, there is a pair of ovate stipules up to ½" long. The upper stems terminate in flower heads that are spheroid or ovoid. Usually there are 1-3 leaflets immediately beneath each flower head, as well as several green bracts with tips that abruptly taper to a slender tip. Each flower head is about 1" across and consists of numerous flowers. These flowers are sessile, tubular-shaped, and spread outward in different directions. Each flower has 5 narrow petals that are pink or purplish pink, becoming light pink or white toward the base of the flower head; a rare form of this species with PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 95 white petals also exists. The upper petal is slightly longer than the lower petals. The light green calyx of each flower has 5 slender teeth and it is usually hairy. The blooming period usually occurs from late spring to mid-summer and lasts about 1-2 months. However, a few plants may bloom later in the summer or fall. The flowers have a mild honey-like fragrance, while the foliage, when it exists in abundance, produces a distinctive clover-like aroma that is quite pleasant. Each flower is replaced by a small seedpod containing 1 or 2 heart-shaped seeds. The root system consists of a taproot and produces rhizomes. (illinoiswildflowers.info/weeds/plants/red_clov er.htm) MICROSCOPICAL DESCRIPTION Fig. – 1 Trifolium (red clover) is an economicallyimportant legume (Fabaceae). The example shown here is of a mature stem at the end of primary growth, that is, the vascular bundles contain very limited amounts of secondary xylem and secondary phloem. The cortex is very narrow and is composed of chlorenchyma. The cortex is separated from the vascular bundles and the underlying pith, by a starch sheath. The pith is parenchymatous. Fig. - 2 show a detail of part of the stem, and two adjacent vascular bundles. The epidermis (EP) is thin-walled and beneath this are fourfive rows of chlorenchyma. The cortexes is separated from the stele by a starch sheath (SS) and immediately beneath this, are very conspicuous phloem fiber caps (PF), which overlie a narrow band of predominantly primary phloem (P). A fascicular cambium zone (CZ) has produced a few secondary xylem elements, but apparently, no Fig. - 2 secondary phloem (inset, below right). The stele (St) is entirely parenchymatous. (virtualplant.ru.ac.za/Main/ANATOMY/trifolium _stem.htm) TRADITIONAL USE Red clover has been used traditionally as a medicinal agent by Asian, European, and Native American cultures as an expectorant in asthma, and as an alternative (blood purifier) to treat psoriasis, eczema, and other chronic skin conditions. MEDICINAL USES AND INDICATIONS Red clover is a source of many nutrients including calcium, chromium, magnesium, niacin, phosphorus, potassium, thiamine, and vitamin C. Red clover is a rich source of isoflavones (chemicals that act like estrogens and are found in many plants). PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 96 THERAPEUTIC USES ● Red clover has a long history of traditional use in China, Europe and Russia for a variety of medical conditions including bronchial asthma, liver and digestive ailments, sore eyes and burns. It was thought to purify the blood by promoting urine, mucus and bile production and improve circulation. ● Traditionally red clover ointments have been applied to the skin to treat conditions such as psoriasis and eczema. ● There is a history of use of red clover as a short-term cough medicine for children. Red clover is a rich source of the isoflavones; formonnectin, biochanin A, daidzin and genistein which are natural hormones. ● Red clover supplements are promoted worldwide for the treatment of menopausal symptoms and the maintenance of health and welfare after the menopause. ● Cli i al t ials sho that ed lo e e t a ts may provides some benefit for hot flushes associated with the menopause. ● It is also suggested that ‘ed Clo e a use for women experiencing breast pain. e of ● The e is p o isi g e ide e fo a positi e ole for red clover in the development of osteoporosis. ● ‘ed lo e e t a ts ha e ee sho to ha e a positive effect on high blood pressure. ● Cli i al studies ha e sho ed lo e to ha e no detrimental effect on the womb or breast tissue. ● I additio it s atu al ho o al o po e ts; Red clover contains many essential vitamins and minerals like calcium, chromium, niacin, phosphorous, potassium, thiamine, magnesium, and vitamin C. ● Red clover can be found in herbal combinations thought to e useful fo o e s health. (streetdirectory.com/food_editorials/cooking/herbs _and_spices/red_clover_trifolium_pratense_side_eff ects_and_benefits.html) CHEMICAL CONSTITUENTS 35.54% isoflavones, 1.11% flavonoids, 0.06% pterocarpans, Less than or equal to 0.03% coumarins, tyramine, Daidzein, Genistein, formononetin, biochanin A, coumestrol, naringenin . (Karjalainen et. al, August 2009) Structures of main phenolics found in red clover leaves PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 97 Isoflavones Afrormosin R1 H R2 OCH3 R3 H R4 H R5 H R6 OCH3 Biochanin A OH H H H H OCH3 Calycosin H H H H OH OCH3 Daidzein H H H H H OH Formononetin H H H H H OCH3 Genistein OH H H H H OH Irilin B OH OCH3 H OH H H Irilone OH –O– - CH2– H H H Methylorobol OH H H H OCH3 OH Pratensein OH H OH H OH OCH3 Prunetin OH H CH3 H H OH Pseudobaptigenin H H H H -O- –OCH2– Texasin Flavonoids Kaempferol H R H OH H H H OCH Quercetin OH (Karjalainen et. al, August 2009) SPECTROSCOPIC DATA BY USING HPLC-MS :S. No. tR(min) λ a [M+H]+ [M+Na]+ [2M+Na]+ 1. 12.4 300 ,325 319 615 2. 12.33 300, 325 319 615 3. 4. 5. 16.58 17.44 19.48 6. 21.52 289 ,320 250, 300 250, 260, 287 260, 320 360 417 447 382 439 469 Tentative identification Phaselic acid (cis/trans) Phaselic acid (cis/trans) cis-Clovamide Daidzein-G Calycosin-G 433 455 Genistein-G PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 98 7. 22.32 262, 334 463 485 8. 9. 10. 22.92 23.53 24.37 260, 330 250, 300 255, 353 519 503 465 541 525 487 11. 24.72 255, 353 465 487 12. 13. 14. 15. 25.04 25.29 25.71 26.14 250, 287 250, 295 255, 353 250,300 533 431 551 517 555 453 573 539 16. 17. 18. 26,71 27.31 27.78 265, 350 330 263,340 449 519 549 471 541 571 19. 28.98 260, 285, 330 549 571 20. 30.16 531 553 1083 21. 30.92 250, 260, 280 250, 300 517 539 1055 22. 23. 31.45 31.71 285, 310 260,330 533 533 555 555 1087 24. 32.58 270, 340 547 569 25. 26. 33.34 35.00 260, 330 262 271 301 293 323 27. 28. 29. 30. 31. 36.10 36.58 37.58 42.45 43.84 285, 310 260, 325 250,302 260, 325 260, 325 285 533 269 285 285 301 555 291 307 307 1027 883 1055 1059 1087 559 Pratensein/Irilin B/Methylorobol-G Genistein-G-M Daidzein-G-M Quercetingalactoside Quercetinglucoside Calycosin-G-M Formononetin-G Quercetin-G-M Formononetin-GM Kaempferol-G Genistein-G-M Pratensein/Irilin B/Methylorobol-GM Pratensein/Irilin B/Methylorobol-GM PseudobaptigeninG-M Formononetin-GM Maackiain-G-M Prunetin/TexasinG-M Irilone/AfrormosinG-M Genisteina Pratensein/Irilin B/Methylorobol Maackiain Biochanin A-G-M Formononetin Prunetin/Texasina Biochanin A (Karjalainen et. al, August 2009) PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 99 REPORTED PHARMACOLOGICAL ACTIVITY 1. Biological estimation of oestrogenic activity in red clover (Trifolium pratense): relative potencies of parts of plant and changes with storage Immature ovariectomized mice were used to compare the oestrogenic activities of different parts of the same clover plants; to estimate the relative potencies of biochanin A, genistein and diethylstilboestrol; and to compare the effects of different methods of storage on the oestrogenic potency of red clover leaf and petiole. Test materials were incorporated in the diet fed to the mice and the uterine weight response was used to measure oestrogenic activity. Conclusion: Comparison of successive estimates of the relative potency of isoflavones and diethylstilboestrol indicated that the relative responsiveness to the two types of oestrogen did not remain constant. Thus comparisons of estimates of oestrogenic activity of plant material, obtained in terms of diethylstilboestrol in different experiments, could be invalid. (D. S. Flux et.al, June, 2009) 2. An ovariectomized rat model to determine the estrogenic and antiestrogenic activity of Trifolium pratense L. (red clover) extracts A red clover extract, standardized to contain 15% isoflavones was administered by gavage [250, 500 and 750 mg/(kg x d)] to virgin, ovariectomized 50-d-old Sprague-Dawley rats, for 21 d in the presence and absence of 17beta-estradiol [50 micro g/(kg x d)]. Estrogenic effects included an increase in uterine weight, vaginal cell cornification and mammary gland duct branching. Red clover produced a dose-dependent increase in uterine weight and differentiated vaginal cells at the two higher doses, but it did not stimulate cell proliferation in the mammary glands. Neither antiestrogenic nor additive estrogenic properties were observed in any of the tissues studied. Conclusion: These data suggest that red clover extract is weakly estrogenic in the o a ie to ized at odel a d ed lo e did t produce any additive estrogenic or antiestrogenic activity when administered togethe ith β-estradiol. (Burdette et.al, January, 2002) 3. Antioxidant Profile of Trifolium pratense: Examination of the antioxidant properties of five different extracts of Trifolium pratense leaves, various assays which measure free radical scavenging ability were carried out: 1,1diphenyl-2-picrylhydrazyl, hydroxyl, superoxide anion and nitric oxide radical scavenger capacity tests and lipid peroxidation assay . In addition, in vivo experiments were conducted with antioxidant systems (activities of GSHPx, GSHR, Px, CAT, XOD, GSH content and intensity of LPx) in liver homogenate and blood of mice after their treatment with extracts of T. pratense leaves, or in combination with CCl4. Besides, in the extracts examined the total phenolic and flavonoid amounts were also determined, together with presence of the selected flavonoids: quercetin, luteolin, apigenin, naringenin and kaempferol, which were studied using a HPLC-DAD technique. Conclusion: Antioxidant activity results show that the EtOAc and H2O extracts of T. pratense leaves are efficient in protection of tissues and cells from oxidative stress. Based on these results it can be concluded that the H2O and EtOAc extracts of leaves of T. pratense showed strong antioxidant activities when compared to the standards. However, the difference in the antioxidant activities of these two extracts may be due to their different phytochemical composition. The results obtained emphasize that the H2O and EtOAc extracts mainly exhibit their antioxidant PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 100 potential via free radical scavenging and electron donation. .The T. pratense leaves extracts exhibited different activities in relation to the investigated biochemical parameters. The results obtained indicate toxicity of CCl4, probably due to the radicals involved in its metabolism. In in vivo experiments the best protective effect was shown by the EtOAc and H2O extracts. Therefore, it seems reasonable to consider these leaf extracts as a new valuable source for pharmaceuticals in the promotion of health as commercial drugs. (Kaurinovic et.al, September,2012) 4. Trifolium pratense isoflavone biochanin A inhibits aromatase activity and expression: The effect of biochanin A on the gene regulation and enzyme activity of aromatase was investigated. By assaying MCF-7 cells stably transfected with CYP19, biochanin A inhibited aromatase activity and hampered cell growth attributing to the enzyme activity. In addition, 25 microm-biochanin A significantly reduced CYP19 mRNA abundance in the oestrogen receptor-negative breast cancer cells SK-BR-3. The transcriptional control of the CYP19 gene is exon-specific, and promoter regions I.3 and II have been shown to be responsible for CYP19 expression in SK-BR-3 cells. Luciferase reporter gene assays also revealed that biochanin A could repress the transcriptional control dictated by the promoter regulation. Interestingly, genistein did not inhibit aromatase but it might down regulate promoter I.3 and II transactivation. biochanin A, it might contribute to biochanin A's suppressive effect on CYP19 expression. Conclusion: biochanin A inhibited CYP19 activity and gene expression. (Wang et.al.,Aug, 2007). 5. (Trifolium pratense) phase II clinical extract possesses opiate activity: Trifolium pratense (TP) is one of the most common herbs for the relief of menopausal symptoms. In this study, investigated the affinity of TP at the mu- and delta-opiate receptors. TP extract bound to the mu-opiate receptor with a high affinity (K (i) =9.7+/1.6microg/ml). The same extract was also found to have affinity at the delta-opiate receptor with K (i) of 15.9+/-2.4microg/ml. Conclusion: These results for the first time suggest a potential new mechanism of action of TP at the opiate receptors. The essential role of the opioid system in regulating temperature, mood, and hormonal levels and actions, this may explain in part the beneficial effect of TP in alleviating menopausal symptoms. (Nissan et.al, June ,2007) 6. Determination in vivo and in vitro antiinflammatory activity of red clover dry extract: The in vitro anti-inflammatory activity was assayed by the technique using the Boyden chamber method, evaluating the leukocyte migration inhibition (chemotaxis). The in vivo anti-inflammatory activity was tested by a carrageenan-induced rat paw edema test. Conclusion: The anti-inflammatory in vitro test showed that there was a significant inhibition of leukocyte migration at the concentrations of , , , a d μg/ L of ed clover dry extract, these doses resulted in 94.73, 95.39, 94.73, 84.68 and 78.75% of inhibition for each dose, respectively. The anti-inflammatory in vivo test resulted in a significant activity in both tested doses (100 and 50 mg/kg of red clover dry extract) and at each tested time. The average percentage of edema inhibition was 63.37%. The findings of this study suggested that red clover extract might be suitable for the treatment of inflammatory diseases. (Graziele P. Ramos, et.al, Nov, 2011) PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 101 ACKNOWLEDGEMENT: I would like to record my gratitude to my esteemed respected guide Dr. (Prof.) Shalini Tripathi, Department of Pharmacy, Rameshwaram Institute of Technology and Management ↓ REFERENCES 1. Burdette J.E, Jianghua L., Lantvit ,D., Eula, L., Nancy, B., Krishna, P., Bhat,L., Hedayat,S., Richard, B., Breemen,V., Andreas, I., John, M., Norman R., Farnsworth & Bolton, J.L, Publication: J. Nutr. 2002, 132 pp::27-30. 2. Carlsson,G., Palmborg,C., Jumpponen,A., Högberg, P & Huss-Danell, K. N2 fixation in three perennial Trifolium species in communities of varied plant species richness.Input from N2fixation to northern grasslands. Acta Universitatis agriculturae Sueciae , 2005, pp: 2005:76. 3. Duke, J.A., Ayensu, E.S., 1985. Medicinal Plants of China. 4. Flux,D. S.,Munford, R.E.,Wilson,G.F,1962. Massey University College of Manawatu, Palmerston North, New Zealand. 5. Graziele,P., Ramos,M. A., Apel,C.B.,Morais,P.C.Ceolato,E.E.,Schapoval S.,,Miguel D.A., Zuanazzi,A.S., Revista Brasileira de Farmacognosia Brazilian Journal of Pharmacognosy.2012, pp: 176-180. 6. Hagsand, E.,Wik, E. 1968.Variety trials with as like clover and red clover in central and northern Norrland,pp: 1-72. 7. Hamrick,JL., Linhan,YB.,Mitton.,JB. Relationships between life history Characteristics and electrophoreticaly deteetable genetic variation in plants, 1979, pp:173-200. 8. plants.usda.gov/java/profile?symbol=trpr2 9. akuna.net/picture/Canada_WEB/PDFs/RED%20CLOVER.pdf 10. virtualplant.ru.ac.za/Main/ANATOMY/trifolium_stem.htm 11. Karjalainen,R.O., Oksanen,E., Tiitto,R.J., Savirant., Niina,M.M..,2009. Journal of the Science of food and Agriculture, 2009, 90(3), pp: 418-423. 12. Kaurinovic, B.,Popovic,M., Vlaisavljevic, S., Schwartsova , H.,2 and Vojinovic, M.,- Milorado 2012. ISSN 1420-3049 . 13. LaRue,TA., Patterson,TG. How much nitrogen do legumes flX. 1981, pp: 15-38. 14. Nissan,H.P., Jian L., Booth,N.L., Yamamura, H.I., Farnsworth, N.R., Wang,Z.J, .Department of Biopharmaceutical Sciences, University of Illinois at Chicago,USA. 2007. 15. Nordstedt, O.1920. Prima loca plantarum suecicarum. Första littera turupp gift om de i Sverige funna vilda eller förvildade kärlväxterna,pp: 1-95. 16. Norman, R., Farnsworth b, Jim, Z., Wang,a. Department of Biopharmaceutical Sciences, University of Illinois at Chicago,USA. Journal of Ethnopharmacology . 2007, pp:112. 17. Piersen,C.E.,Booth,N.L.,Sun,Y.,Liang,W.,Burdette,J.E.,VanBreemen,R.B.,Geller,S.E.,Gu,C.,Banuvar, S., Shulman, L.P., Bolton, J.L., Farnsworth, 211 N.R., 2004. Chemical and biological characterization and clinical evaluation 212 of botanical dietary supplements: a phase I red c lover extract as a model. 213 Current Medicinal Chemistry 11, pp: 1361–1374. 18. Smith,RR.,Taylor,NL.,Bowley,SR., Red clover. ln: NL Taylor(ed), Clover science and technology, 1985, pp: 457-469. 19. Taylor, NI.,Smith,RR. Red clover breeding and genetics, 1979, pp: 125-153. 20. Taylor, N.L.,Quesenberry, K.H., Red clover science. Current plant science and biotechnology in agriculture 28. Kluwer Academic Publishers, Dordrecht, Netherlands.1996, pp:226 . 21. Wang,Y., Man,GW., Chan, FL., Chen, S., Leung, LK, Department of Biochemistry, The Chinese University of Hong Kong, Shatin NT, Hong Kong. 2008 PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 102 Review Article Nutritional Value of Dry Fruits and their Vital Significance - A Review Pooja Dhiman*, Kanika Soni, Sandeep Singh Department of Applied Sciences, Chitkara University, Kalujhanda, Barotiwala, Solan, Himachal Pradesh, India *pooja.dhiman@chitkarauniversity.edu.in ABSTRACT As a snack, dried fruit is drastically superior to junk foods, such as potato chips, pretzels, candy bars, and other unhealthy indulgences people reach for when they are hungry between meals. Dry fruits are small but are extremely rich sources of minerals and proteins. Every diet specialist always recommends a handful of dry fruits in our diet in order to keep us healthy and fit. There are just umpteen varieties in dry fruits such as raisins, cashew nuts, almonds, pistachios, walnuts, dates, plums, raisins and the list goes on. Key words: Dry fruits, Anti-ageing, Weight loss, Antioxidants. INTRODUCTION Dry fruits possess a lot of medicinal properties because of the ample amount of nutrients that are present in them. Though the dry fruits are really expensive and are regarded as delicacies but the health benefits that they possess makes them worth their price. This article consists of the health benefits that different dry fruits have and therefore the reasons to include dry fruits in our diet if we want to stay healthy and sound. However, we must put some restrictions on the amount of intake of dry fruits as excess of anything can be harmful. Dried fruit contains no fat, cholesterol, or sodium. It also helps to sweeten bland food without adding refined sugars. Small bits of dried fruit can be added to plain yogurt, oatmeal, or wholegrain breakfast cereal, making it more palatable to young children and others who would not be able to stomach such foods otherwise. Dried fruits are also a food of convenience. Because the fruit is much smaller when dehydrated, it can be taken in backpacks without adding a lot of extra weight. Dried fruit is perfect for long trips. Raisins (kishmish) [4] – are the type of fruit that needs oil to help in their packaging. Many cereal giants infuse or soak thei aisi s i gl e i e so the do t clump up in the cereal boxes or, worse yet, eak so e o su e s teeth. Of ou se, the glycerine is inspected before being shipped to the cereal plants). There are some companies that do not use oil and others that (at least domestically) almost always use kosher oil. Therefore, barring Pesach, domestic raisins may be used. Almonds (badam)Just a quarter cup of almonds contains nearly 25 percent of your needed daily value of the important nutrient magnesium, plus is rich in potassium, manganese, copper, the [2] antioxidants vitamin E and selenium , and calcium. In fact, a quarter cup of almonds has How to cite this article: P Dhiman, K Soni, S Singh, Nutritional Value of Dry Fruits and their Vital Significance - A Review, PharmaTutor, 2014, 2(3), 102-108 PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 103 almost as much calcium as a quarter cup of milk. They're also great for the colon. An animal study on the effects of almonds on colon cancer found that animals (which were exposed to a colon-cancer-causing agent) given whole almonds had fewer signs of colon cancer than animals given almond oil or no almonds. Researchers suspect the benefit may be due to almonds' high fibre content. Plus, almonds are one of the best nuts for lowering cholesterol because 70 percent of the fat they contain is the healthy monounsaturated variety, which has been shown to help clear arteries. Prunes After prunes are washed, they are dehydrated until they become stone-like. This enables them to be stored in this state for up to two years. When there is an order, they are then moisturized (usually blanched with steam) until hydrated enough for packaging. Oil is not a necessary part of preparation since prunes are a large fruit and do not have a tendency to clump together as do other fruits. However, oil might be used as a polishing agent, but then it would be listed with the other ingredients. They would need a hechsher for Pesach since some have an oil coating and because potassium sorbate may be used. There can also be a corn-based glucose in the drying process that is problematic for Pesach. It is important to point out that prune juice definitely needs a reliable hechsher. Apricots (khumani)[4]Apricots are those beautifully orange coloured fruits full of beta-carotene and fibers. Nutrients in apricots can help protect the heart and eyes, as well as provide the disease-fighting effects of fibre. The high beta-carotene content of apricots makes them important heart health foods. Beta-carotene [2] helps protect LDL cholesterol from oxidation, which may help prevent heart disease. Apricots contain nutrients such as vitamin A that promote good vision. Vitamin A, a powerful antioxidant, quenches free radical damage to cells and tissues. Free radical damage can injure the eyes' lenses. BlueberriesAntioxidants are thought to protect the body against the damaging effects of free radicals[2] and the chronic diseases associated with the aging process. Fresh fruits, including blueberries and vegetables contain many of these naturally occurring antioxidants such as Vitamins C and E. Blueberries contain 14 mg of Vitamin C and 0.8 mg Vitamin E per 1 cup of blueberries. In addition, blueberries contain anthocyanins and phenolics that can also act as antioxidants. Based on data from the USDA Human Nutrition Research Center on Aging (Boston, MA), blueberries are among the fruits with the highest antioxidant activity. Peaches (aadru)Although fresh, high-quality peaches are sweet tasting, they are low in calories, with one medium peach furnishing only about 37 calories. Yellow-fleshed varieties are a good source of Vitamin A. But, making peach jam or canning peaches in sugar syrup adds calories. Cashews (kaju)Cashews are lower in fat than most nuts, and 65 percent of this fat is unsaturated fatty acids. Of this, 90 percent is oleic acid, the heart-healthy fat found in olive oil and cashews are rich in copper, magnesium, zinc, iron and biotin [2]. Walnuts (aakhrot)Walnut is the great source of the healthy omega-3 essential fatty acids[5], which have been found to protect the heart, promote better cognitive function, and provide antiinflammatory benefits for asthma, rheumatoid arthritis, eczema and psoriasis. Walnuts also contain the antioxidant compound ellaic acid [2] which is known to fight cancer and support the immune system. Even researchers have PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 104 identified 16 polyphenols in walnuts, including three new tannins, with antioxidant activity so powerful they described it as "remarkable." Walnuts are incredibly healthy for the heart. Total cholesterol and LDL (bad) cholesterol were reduced and the elasticity of the arteries increased by 64 percent. Levels of vascular cell adhesion molecules, which play a major role in reducing the development of atherosclerosis means hardening of the arteries. add protein to our diet. Pistachio nuts are an excellent source of vegetable protein. Oxidative stress can cause damage to the human body, resulting in diseases such as cancer and heart disease. Dietary antioxidants help to reduce the damage. Pistachios contain phenolic compounds[2], which are believed to account for the antioxidant capability of certain foods. The pistachio nut is placed in the highest group for antioxidants. Pecans – These natives to the southern Mississippi River valley are buttery and slightly bittersweet. The e sta d-outs in pies, quick breads, cakes, cookies, candies and ice cream. Pecans are an excellent source of over 19 vitamins and minerals including vitamins E and A, folic acid, calcium, magnesium, copper, phosphorus, potassium, manganese, several B vitamins and zinc. Recent clinical research studies evaluating the impact of pecans on serum cholesterol have found pecans can significantly help to lower blood cholesterol when consumed as a part of heart-healthy diet. In fact, a study from New Mexico State University found that eating 3/4 cup of pecans a day may significantly lower LDL (bad) cholesterol and help to clear the arteries. Plums (aalu-bukhara)Dried Plums are ready-to-eat right from the package as a healthful snack or can be used as a versatile cooking or baking ingredient. They provide potassium, soluble and insoluble fibre, phytochemicals [2] that function as antioxidants as well as some iron and Vitamin A. Dried Plums/Prunes can play an important role in promoting good digestive health. Pistachios (pista) – Pistachios have beige shells with nuts that range from dull yellow to deep green. Primarily sold as a snack food, they are easily adaptable to recipes where pecans or other nuts are used Pistachios are a good source of copper, phosphorus, potassium, magnesium, and B6. The nuts deliver 30 vitamins, minerals, and phytonutrients, so they pack a considerable wallop from a nutritional standpoint. Pistachios contain higher amounts of fibre than many high-fibre foods. Pistachios are an excellent source of dietary fibre. If there is a need to replace animal protein with vegetable protein, pistachios eaten in conjunction with proteinrich grains, vegetables and fruits, can help us to Brazil Nuts- : Brazil nuts only come from magnificent, large trees that grow wild in the Amazon rain forest. Similar to coconut in texture, the sweet, rich meat of Brazil nuts is eaten raw or roasted. These nuts are extremely nutrient-rich and contain protein, copper, niacin, magnesium, fibre, vitamin E and selenium. Selenium is a powerful antioxidant that works to neutralize dangerous free radicals. A study at the University of Illinois even found that the high amounts of selenium in Brazil nuts may help prevent breast cancer [2]. HEALTH BENEFITS OF DRY FRUITS Raisins have calcium and boron which is considered to be important for bone formation. They are also very good for eye care as they contain oxidant properties and Vitamin A, which protects eye from weakening of vision, macular degeneration and cataract. They also play a vital role in protecting our teeth against cavities, tooth decay and other dental problems. Raisins are thus beneficial for bones, eyes and for PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 105 promoting dental health. Cashew nuts also support healthy muscles and gums as they are rich in magnesium and calcium. Pistachios are also very advantageous for eye health because of the presence of carotenoids in them. Walnuts contain omega 3 fatty acids and that is h is alled the B ai Food a d he e is e important for the development of the brain. Nuts are one of the best plant sources of protein and minerals. They are rich in fibre, phytonutrients and antioxidants such as Vitamin E and selenium. Nuts are also high in plant sterols and fat but mostly monounsaturated and polyunsaturated fats (omega 3 fatty acids- the good fats) which have all been shown to lower LDL cholesterol. Many people were scared away from nuts during the low-fat craze of the last few decades, but now nuts are making a comeback. A study conducted found that eating nuts lowered the risk of heart disease and helped participants to keep their weight down. Other large-scale studies, also found that eating nuts lowered heart disease risk. Other studies have shown that nuts help lower bad "LDL" cholesterol. They are highly concentrated in both their calories and their nutrients, so we only need a small handful at a time. Eating a variety of nuts appears to be the best way to get all the different benefits each nut has to offer. 1. Protection from heart diseasesRecent medical studies indicate that nuts may play an important role in reducing the risk of heart disease. 2. Decrease in LDL cholesterolIt appears that a diet high in monounsaturated fats can reduce the level of artery damaging LDL cholesterol [1] without lowering HDL "good" cholesterol. Cashews have zero cholesterol level [8] and is very advantageous for maintain low cholesterol levels. Pistachios also contain fat and are thus very helpful in lowering high cholesterol levels. Almonds have essential fatty acids that help in reducing cholesterol and promoting blood circulation. Raisins are the ones loaded with magnesium, potassium, iron and phosphorus and thus promote blood circulation. Consuming cashew nuts, Pistachios, Almonds and Raisins is considered very effective in controlling cholesterol and providing us with a healthy body by promoting blood circulation. 3. Decrease in blood sugar levelA o di g to the stud Nuts as a epla e e t fo a oh d ates i the dia eti diet Dia etes Care, August 2011) two ounces (about 56 grams) of nuts every day can improve glycaemic control and serum lipids in people with type 2 diabetes[1]. 4. Increase in haemoglobin contentDry fruits especially almonds are considered to be very effective for improving haemoglobin. Almonds help in the formation of new blood cells and also increase the haemoglobin level in the blood. Unsaturated fats, vitamin B, phosphorus, copper and iron present in nuts helps in the proper functioning of all the crucial organs of our body. Prunes, which are a good source of potassium, Vitamin A, fibre and copper helps in keeping the energy levels high throughout the day. We should carry a handful of prunes in the pocket and munch them all through the day. Cashew nuts possess high concentration of copper and are thus vital in production of energy. They also provide greater flexibility to blood vessels. In fact, eating any dry fruit provides us with an instant supply of energy and also helps us in remaining alert thus enhancing memory improvement. 5. Improves digestionMany dry fruits have the ability to treat intestinal disturbances. Raisins, when ingested, swells up as the fibre available in them absorbs the water thereby giving us relief for constipation [8]. Pistachios also contain fibre PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 106 which helps us to feel riddled for more period of time. It also helps in operating the digestive system normally, hence preventing constipation. Dates are also well known for treating constipation. They are soaked overnight in water and are then consumed in the morning. Soaked dates provides the laxative effect and relieves us from digestion problems. Dates also help in keeping a growth check on pathological organisms, thus giving rise to friendly bacteria in intestines. Almonds can also be consumed every day to improve our digestive system. Walnuts are another dry fruits that help in easing constipation because of their laxative effects. 6. Prevent hair fallAlmonds are the most important dry fruits when it comes to treat hair problems. Applying almond oil on the scalp has proven to be very effective in curing several hair problems. It helps to prevent hair loss and adds shine and lustre to dull hair. It also promotes hair growth. Apart from this, massaging the scalp with almond oil also helps in relieving us from headache and is considered as the best home remedy to cure headache. 7. Helps in reducing body weightThe presence of high amount of dietary fibre and high energy density present in Cashew nuts are very effective for weight management. Raisins and Dates are preferred for the ones who are suffering from anaemia as these dry fruits help in weight gain and also provide the person with a lot of vitamins and minerals. 8. Controls signs of ageingRaisins contain resveratrol which is a type of antioxidant that helps to keep our skin beautiful by slowing down skin ageing. Walnuts contain high content of Omega 3 fatty acids [8] that are known to nourish dry skin and to improve its texture. A mixture of walnuts and 3 tablespoons of yogurt can be blend and applied on our face to get soft and smooth skin. Also, walnut oil has linoleic acid that prevents fine lines and wrinkles. Cashews are also used in a number of cosmetic products to prevent skin damage and to reduce tan. Cashew nut oil is used to protect cracked heels by nourishing them. Vitamin E present in Pistachios is very effective as it protects our skin from premature aging and UV rays. Pistachio oil has demulcent and antioxidant properties and it also contains carotenoids, zeaxanthin and lutein which help to smoothen our skin and neutralize free radicals, thereby preventing ageing. 9. Helps in stabilizing blood pressureAlmonds help to lower blood pressure to a great extent. Raisins helps to neutralize the acids present in blood and thus helps to check acidosis because of the presence of magnesium and potassium in it. Pistachios also help a lot in stabilizing the blood pressure and blood sugar levels according to a study performed by The University of Toronto. 10. Significance of dry fruitsDry fruits are small but are extremely rich sources of minerals and proteins. Every diet specialist always recommends a handful of dry fruits in our diet in order to keep us healthy and fit. There are just umpteen varieties in dry fruits such as raisins, cashew nuts, almonds, pistachios, walnuts, dates and the list goes on. Dry fruits possess a lot of medicinal properties because of the ample amount of nutrients that are present in them. Though the dry fruits are really expensive and are regarded as delicacies but the health benefits that they possess makes them worth their price. This article consists of the top ten health benefits that different dry fruits have and therefore the reasons to include dry fruits in our diet if we want to stay healthy and sound. However, we must put some restrictions on the amount of intake of dry fruits as excess of anything can be harmful. Dried fruits are a nutrient-dense food and a PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 107 particularly good source of dietary fibre, potassium and phenolic compounds, which are linked to a number of health benefits, including decreased risk of heart disease, diabetes and certain types of cancer. Dried fruits provide the same amount of fibre as fresh fruit. One tablespoon of raisins contains the same fibre as 27 grapes, can prevent digestive disorders and can be included in the recommended five-a-day fruit and vegetable intake. Scientific research has shown that raisins are a concentrated source of antioxidants that contribute to prevent the growth of bacteria that cause inflammation and gum disease. Consumption of certain dried fruits have shown to have important health benefits, such as improving laxation, reducing serum cholesterol, and reducing the risk of osteoporosis. Prunes have been found to increase bone density. Recent research in postmenopausal women showed that consumption of dried plums was linked increased bone mineral density, which may prevent the development of osteoporosis. Consumption of dried fruits is an effective way to increase overall intake of fruits and vegetables. DRIED FRUIT WARNING The key with nuts is simply not to over-eat them. Prunes and Pears Found to Contain High Levels of Acrylamide [3] chemicals- A carcinogenic chemical found in starchy foods cooked at high heat is also found in high quantities in dried fruit, according to a new study conducted by researchers at the Swiss Federal Institute of Technology and presented at a symposium on the chemical that took place in Boston. 1. Weight Gain: The small portion size of dried fruit makes it easy to overdo it. It takes an excess of 3,500 calories in your diet to gain 1 pound, explains MayoClinic.com. Consumption of extra dry fruits adds an additional 250 calories per day from dried fruit, which contribute to as much as 2 pounds of weight gain in a single month time span. So, it is good to serve dry fruits in portions before start eating them, to minimize the caloric intake. Single servings could include eight apricot halves, three dates, 2 tablespoons of dried cranberries or blueberries, 1 1/2 dried fig or three prunes. Each of these servings provides about 60 calories. 2. Digestion related problems: Dried fruits are high in fibre, which is good to improve regularity of bowel movement, but too much fibre affect gut, particularly if, one do not consume high-fibre foods. Dried fruits may cause one to have gas, abdominal cramping, bloating, constipation and sometimes diarrhoea. So it is advisable, to avoid these negative effects by keeping the dried fruit intake to a small amount each day or divide portion into two separate servings. If one needs to boost his/her fibre intake, slowly increase it over a period of few weeks. Take an extra one or two pieces of dried fruit every couple of days, within tolerance, until one is able to digest a full serving without having gastrointestinal related problems. 3. Sugar Crash: Some dried fruits, especially sugar-coated varieties, are high on the glycemic index. This scale rates dry fruits foods from 1 to 100. Foods with a high glycemic index rating cause blood sugar to boost, making one feel quickly energized. Unfortunately, once one hit the energy peak, blood sugar quickly drops and the person may experience a sugar crash or sudden fatigue. Raisins are somewhat high on the glycemic index scale, having a rating of 64, according to Harvard Medical School. Dates are right in the middle of the glycemic index [9]. Prunes are one of the few dried fruits that have a low glycemic index rating. This type of dried fruit has a rating of 29 on the scale. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 108 4. Tooth Decay: Dried fruits have natural fruit sugar in the form of fructose. Some types of dried fruits are coated in additional sugar to keep moisture levels to a minimum and to prevent the dried fruit from sticking to each other. Sugar is one of the main contributors to tooth decay as they stick to the teeth, forcing the sugar to stay on the teeth for a longer period of time. Risk of tooth decay can be minimised by drinking water while snacking on dried fruit. Brush and floss the teeth as soon as possible after snacking with dry fruits, to remove the sugar from the surface of the teeth. ↓ REFERENCES 1. nutfruit.org/en/did-you-know-that-br-tips-facts-and-myths-of-nuts-and-dried-fruits_44774 2. casadefruta.com/healthy-fruit-nuts.php 3. naturalnews.com/dried_fruit.html#ixzz2qeLykolp 4. indif.com/Food/refer/glossary/dry.asp 5. seedhieximpal.com/dry-fruits.htm 6. agriculturalproductsindia.com/dry-fruits-nuts/dryfruits-brazil-nut.html 7. en.wikipedia.org/wiki/Brazil_nut 8. listdose.com/top-10-health-benefits-of-eating-dry-fruits-rtr/ 9. healthyeating.sfgate.com/disadvantages-dried-fruit-3227.html CLINICAL NOTES → Glycerol Phenylbutyrate reduces hepatic encephalopathy events and ammonia levels compared to placebo in a Phase 2 trial → The largest ever trial of adult stem cell therapy in heart attack patients has begun at The London Chest Hospital in the UK → The research team of the Karolinska Institute and Uppsala University, Sweden, says a small molecule called VLX600 has been proven effective in killing dormant colon cancer cells in a variety of in vivo and in vitro models. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 109 Review Article Benzimidazole Derivatives and Its Biological Importance: A Review Vishwanadham Yerragunta*1, 2, Pratima patil2, S. Srujana2, Roopa Devi2, R.Gayathri1, Srujana1, Aary Divya2 1. Department of Pharmaceutical Chemistry, Sitha Institute of Pharmaceutical Sciences, Hyderabad, Andhra Pradesh, India. 2. Department of Pharmaceutical Chemistry, Vishnu Institute of Pharmaceutical Education & Research, Narsapur, Medak, Andhra Pradesh, India. * vishwanadham.y@gmail.com ABSTRACT Benzimidazole is a heterocyclic aromatic organic compound. This bicyclic compound consists of the fusion of benzene and imidazole. Heterocyclic compounds are occupied prominent place among various class of aromatic organic compounds. Benzimidazole are having a variety of therapeutic uses including antitumor, antifungal, antiparasitic, analgesics, antiviral, antihistamine, as well as use in cardiovascular disease, neurology, endocrinology, and ophthalmology. Keywords: Benzimidazoles, Chemistry, Medicinal Drugs, Importance. INTRODUCTION Benzimidazole is a heterocyclic aromatic organic compound. Benzimidazole moieties are a very important class of heterocyclic compounds that have many applications in pharmaceutical chemistry. This compound is bicyclic in nature which consists of the fusion of benzene and imidazole. Nowadays is a moiety of choice which possesses many pharmacological properties. The most prominent benzimidazole compound in nature is N-ribosyl-dimethylbenzimidazole, which serves as an axial ligand for cobalt in vitamin B12. [1] In 1991 benzimidazole derivatives were synthesized by derivatization at N-H of benzimidazole by electron donating group and substitution with long chain of propyl, acetamido, thio, thiazole-amino, tetramethyl piperidine on pyridine resulting in good antiulcer activity [2,3]. Based on their broad biological functions, they are used in clinical medicine as anti-ulcer, antitumor and anti-viral agents [4]. Nowadays Infectious microbial diseases are causing problems world-wide, because of resistance to number of a ti i o ial age ts βlactam antibiotics, macrolides, quinolones, and vancomycin). A variety of clinically significant species of microorganisms has become an important health problem globally. One way to fight with this challenge is the appropriate How to cite this article: V Yerragunta, P Patil, S Srujana, R Devi, R Gayathri, Srujana, D Aary, Benzimidazole Derivatives and Its Biological Importance: A Review, PharmaTutor, 2014, 2(3), 109-113 PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 110 usage of the available marketed antibiotics the other is the development of novel antimicrobial agents [5]. Hence, there will always be a vital need to discover new chemotherapeutic agents to overcome the emergence of resistance and ideally shorten the duration of therapy. Due to the structural similarity to purine, antibacterial ability of benzimidazoles are explained by their competition with purines resulting in inhibition of the synthesis of bacterial nucleic acids and proteins [6,7]. SYNTHESIS OF BENZIMIDAZOLE Several synthetic methodologies are available for the synthesis of benzimidazoles. Generally, the condensation of o-phenylene diamine with carboxylic acids and their nitrile, imidates and orthoester[8] derivatives have been widely used for benzimidazole synthesis. Direct condensation of o-aryl diamine with aldehyde is not a good synthetic route for these molecules as it yields a complex mixture of 1,2disubstituted benzimidazole and bis [9]. dihydrobenzi-midazole as side products But the use of ransition metal catalysts namely copper (II) acetate[10] and lead tetra-acetate in these reactions afforded better results. Ruthenium[11], palladium[12]and rhodium[13] catalysts have also been used. Benzimidazole is commercially available. The usual synthesis involves condensation of ophenylenediamine with formic acid,[14] or the equivalent trimethyl orthoformate: C6H4(NH2)2 + HC(OCH3)3 → C6H4N(NH)CH + 3 CH3OH R 1 O N S N H N R 2 N H3C 2. Canan KUS¸ Synthesis of New Substituted 6(morpholin-4-yl)-1H-Benzimidazole Derivatives [16] . F N N N H R1 O R1=F, Cl, OCH3, di-OCH3 3. KUS Canan, Synthesis of Some New Benzimidazole Carbamate Derivatives for Evaluation of Antifungal Activity[17]. F N R N H NH OCH3 O R= Cl, 4-morpholinyl, 1-pyrrolidinyl, 3methylpiperidin-1-yl, (pyridin-3-ylmethyl)amino. 4 Hasan KUC¸UKBAY, Ulku YILMAZ , Nihat S¸ET.AL., Synthesis and antimicrobial activities of some bridgedbis-benzimidazole derivatives [18] . 5.Michile tonilli et.al., synthesized antiviral activity of Benzimidazole derivatives. II antiviral activity of 2-phenylbenzimidazole derivatives [19] . R O N Hetero aryl REVIEW OF LITERATURE 1. Khan Farhan. R., Asnani A. J.et.al., Synthesis and Antiulcer, Anti-secretory Activity of Some New substituted 2-(Pyrimidinylsulfinyl) Benzamidazoles Derivatives [15]. N Heteroaryl = furan-3-yl; pyridin-2- l NH-R PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org ‘ = OH, 111 6. B. Guruswamy* and R. Arul et.al., have synthesized A micro-wave assisted synthesis of benzimidazole derivatives using solid support [20] . R N NH N H R= H, Fluoro, Chloro, Bromo , Trifluoro methyl , Cyano, Methoxy . 7. DT Nannapaneni, Atyam VSSS Gupta, MI Reddy, and Raidu Ch Sarva et.al., Synthesis, Characterization, and Biological Evaluation of Benzimidazole Derivatives as Potential Anxiolytics [21]. PHARMACOLOGICAL ACTIVITIES OF BENZIMIDAZOLE DERIVATIVES Drugs in this class differ from all other in that they are designed to inhibit/kill the infecting microorganism. Treatment of systemic infections with specific drugs that selectively suppress the infecting microorganism without significantly affecting the host. From this they are referred as bacteriostatic and bactericidal respectively 1. Anthelmintic These are the drugs that either kill or expel infesting helminthes. Some drugs containing benzimidazole nucleus are Thibendazole, Mebendazole, and Albendazole etc. N . R . N H R1 Mebendazole 8. Balram Soni, Mahendra Singh Ranawa et.al., synthesis and in vitro antitumor activity of benzimidazole derivatives [22]. N R N 2. Anti-ulcer drugs: These are the drugs which inhibit both basal and stimulated gastric acid secretion.Some drugs containing benzimidazole nucleus are Pantoprazole, Rabeprazole, Lansoprazole, Omeprazole etc. HC=NHNOCH 2C R1 1 2 3 4 5 6 7 8 9 10 11 R H H H H H -2NO2 -2NO2 -3NO2 -3NO2 -2Cl -2Cl R1 H -2NO2 -3NO2 -2Cl -4Cl -2NO2 -3NO2 -2NO2 -3NO2 -2NO2 -3NO2 Omeprazole 3. Anti-psychotic agents In psychosis thinking of patient becomes illogical, bizarre and loosely organized. Patient has difficulty in understanding reality and their own conditions. Some drugs containing benzimidazole nucleus are droperidol, pimozide, and benperidol PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 112 Most common antifungal agents containing imidazole nucleus are Clotriamazole, Miconazole, Ketoconazole Droperidol 4. Anti protozoal agents These are the drugs which are used to treat the amoebiasis caused by E.histolytica. They exert cytotoxicity by damaging DNA and result in DNA helix destabilization strand breakage. The antiprotozoal drugs containing imidazole nucleus are metronidazole, benznidazole. Metronidazole 5. Antifungal These are the drugs used for superficial and deep fungal infections. Fungal infections are termed mycoses and in divided in to superficial infections (skin, nails, and scalp) and systemic infections (deeper tissues and organs) some conditions are blastomycosis, histoplasmosis, candidiasis, coccibiomycosis etc. Miconazole OTHER DRUGS Pimobendan CONCLUSION The benzimidazole ring is an important pharmacophore in drug discovery. Some substituted benzimidazole derivate drugs are more potent activity. The synthesis of benzimidazole derivatives is a privileged scaffold, having a variety of therapeutic uses including antitumor, antifungal, antiparasitic, analgesics, antiviral, antihistamine, as well as use in cardiovascular disease, neurology, endocrinology. ↓ REFERENCES 1. Barker HA, Smyth RD, Weissbach H, Toohey JI, Ladd JN and Volcani BE. Isolation and properties of crystalline cobamide coenzymes containing Benzimidazole or 5,6- Dimethylbenzimidazole. Journal of Biological Chemistry. 1960;235(2):480- 488. 2. Grassi A, Ippen J, Bruno M, Thomas G and Bay P. thiazolylamino benzimidazole derivative with gastroprotective properties in the rat. Eur J Pharmacol.1991;195(2):251-9. 3. Ozkay Y, Tunali Y, Karaca H. and Isikdag I. Antimicrobial activity and a SAR study of some novel benzimidazole derivatives bearing hydrazones moiety. European Journal of Medicinal Chemistry. 2010;45(8):3293-3298. 4. Preston P N, Stevens M F G & Tennant G, Benzimidazoles and Congeneric Tricyclic Compounds, Part 2, PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 113 (John iley and Sons New York) 1980; 5. Metwally KA, Abdel-Aziz LM, Lashine el-SM, Husseiny MI and Badawy RH. Hydrazones of 2-aryl- -4carboxylic acid hydrazides: synthesis and preliminary evaluation as antimicrobial agents. Bioorg Med Chem. 2006;14(24): 8675-82. 6. Spasov A, Yozhitsa L, Bugaeva I and Anisimova VA. Benzimidazole derivatives: Spectrum of pharmacological activity and toxicological properties. Pharmaceutical Chemistry Journal. 33;5:232-243. 7. Arjmand F, Mohani B and Ahmad S. Synthesis, antibacterial, antifungal activity and interaction of CTDNA with a new benzimidazole derived Cu (II) complex. Eur J Med Chem. 2005;40(11):1103-1110. 8. Dudd L M, Venardou E, Garcia-Verdugo E, Licence P, Blake A J, Wilson C & Poliakoff M, Green Chem, 5, 2003, 187. 9. Nagata K, Itoh T, Ishikawa H & Ohsawa A, Heterocycles,61, 2003, 93. 10. Curini M, Epifano F, Montanari F, Rosati O & Taccone S, Synlett, 18, 2004, 32. 11. Chakrabarty M, Karmakar S, Ajanta M, Arima S & Harigaya Y, Heterocycles,68, 2006, 967. 12. Aliyan H, Fazaeli R, Fazaeli N, Mssah A R, Naghash H J, Alizadeh M & Emami G, Heteroatom Chem, 20, 2009, 202. 13. Zhang Z H, Yin L & Wang Y M, Catal Commun,8, 2007, 1126. 14. E. C. Wagner and W. H. Millett (1943), "Benzimidazole", Org. Synth.; Coll. Vol. 2: 65. 15. Khan Farhan. R., Asnani A. J.et.al ,International Journal of Research in Pharmaceutical and Biomedical Sciences. 2011, Vol. 2 (2) 16. Canan KUS .,Turk J Chem 26, 2002 , 559 – 564. 17. Canan KUS .,Turk J Chem 27, 2003 , 35 – 39. 18. Hasan K¨UC¸¨UKBAY, ¨Ulku¨YILMAZ., Turk J Chem 35 (2011) , 561 – 571. 19. Michile tonilli et.al.Bio-organic & medicinal chemistry 18 (2010) 2937-2953. 20. B. Guruswamy and R. Arul., Der Pharma Chemica, 2011, 3 (6):483-486 21. DT Nannapaneni, Atyam VSSS Gupta,1 MI Reddy, and Raidu Ch Sarva1 J Young Pharm. 2010 Jul-Sep; 2(3): 273–279. 22. Balram Soni, Mahendra Singh Ranawat1, Anil Bhandari2 and Rambabu Sharma ., Int. J. Drug Res. Tech. 2012, 2 (7), 479-485. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 114 Review Article Von Hippel-Lindau (VHL) Syndrome: A Critical Insight Tapan Behl*, Ishneet Kaur, Puneet Sudan, Monika Sharma, Heena Goel Department of Pharmacology, Doaba Group of Colleges, Kharar, Mohali, Punjab, India *tapanbehl31@gmail.com ABSTRACT Von Hippel-Lindau (VHL) syndrome is a rare genetic neoplastic disorder, arising from germline mutations in the VHL gene, characterized by the development of visceral cysts, specific benign and malignant tumors in multiple organ systems that have subsequent potential for spiteful change. It is caused by point mutations or deletions in a tumor suppressor gene. A tumor suppressor gene is the one which keeps cells from growing and dividing too rapidly in an uncontrolled way. Mutations in this gene prevent production of the VHL protein or lead to the production of an abnormal version of the protein. An altered or missing VHL protein cannot effectively regulate cell survival and division. As a result, cells grow and divide uncontrollably to form tumors and cysts that are characteristic of Von Hippel-Lindau syndrome. Although there is great variation in the clinical presentation , those who have a mutated gene are at greatly increased risk of developing spinal hemangioblastoma, renal cell carcinoma (RCC), retinal hemangioblastoma, cerebellar hemangioblastoma, pheochromocytoma, pancreatic and renal cysts, endolymphatic sac tumors, hemangiomas of the adrenals , liver and lungs, and papillary cystadenoma of the epididymis or broad ligament. The age at which the tumors present ranges from early childhood to the seventh decade of life. Early diagnosis, screening of family members and lifelong surveillance of VHL patients is recommended. Keywords: Hemangiomas, Pheochromocytoma, Stromal, Ophthalmoscopy, Polycythemia INTRODUCTION Von Hippel-Lindau syndrome is an autosomal dominantly inherited multi-systemic cancer disease predisposing to a variety of neoplasm (characterized by the formation of tumors and fluid-filled sacs called cysts in different parts of the body). Melmon and Rosen (1964) i t odu ed the te Vo Hippel-Li dau syndrome and described large kindred with multiple features of the disorder [1]. The incidence of von Hippel-Lindau syndrome is estimated to be 1 in 36,000 individuals. The inheritance is autosomal with high penetrance. Most people with VHL syndrome inherit an altered copy of the gene from an affected parent. However, in 20% of the cases, the altered gene is the result of a new mutation that occurred during the formation of reproductive cells (eggs or sperms) or very early in development [2]. Males and females are equally affected. Unlike most autosomal dominant conditions, in which one altered copy of a gene is sufficient to cause the disorder, two copies of VHL gene must be altered to trigger tumor and cyst formation in Von Hippel-Lindau syndrome. A mutation in the second copy of the VHL gene occurs during a pe so s lifeti e i certain cells within organs such as the brain, retina and kidneys [3]. Almost everyone who inherits one VHL mutation will eventually acquire a mutation in the second copy of the How to cite this article: T Behl, I Kaur, P Sudan, M Sharma, H Goel, Von Hippel-Lindau (VHL) Syndrome: A Critical Insight, PharmaTutor, 2014, 2(3), 114-118 PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 115 gene in some cells, leading to the features of Von Hippel-Lindau syndrome. Types * Type 1 (without pheochromocytoma) Type 1A (only without pheochromocytoma) Type 1B (without pheochromocytoma and protection from renal cell carcinoma) * Type 2 (with pheochromocytoma) Type 2A (with pheochromocytoma and hemangioblastoma) Type 2B (with pheochromocytoma and renal cell carcinoma) Type 2C (with isolated pheochromocytoma, without hemangioblastoma or renal cell carcinoma) Clinical manifestations: The diagnosis is usually made on clinical grounds. The finding of a single retinal or cerebellar hemangioblastoma, pheochromocytoma or RCC is considered sufficient to justify the diagnosis [4]. Tumors called hemangioblastomas are characteristic of Von Hippel-Lindau syndrome. These growths are made of newly formed blood vessels. Microscopically, hemangioblastoma consist of large polygonal stromal cells enmeshed in a capillary network. They are usually cherry red in colour. CNS HEMANGIOBLASTOMAS It is a chief feature of VHL occurring mostly in ● Cerebellum ● Spinal cord ● Brain stem The tumor usually grows inside the parenchyma of cerebellum, brain stem or spinal cord; it is attached to the pia mater and gets its rich vascular supply from the pial vessels [5]. Signs and symptoms of cerebellar hemangioblastoma can include ● Increased intracranial pressure and limb ataxia ● Headache ● Slurred speech ● Nystagmus ● Positional vertigo ● Labile hypertension (without pheochromocytoma) ● Vomiting ● Wide-based gait Patients with spinal cord lesions most frequently present with pain, followed by signs of segmental and long-track dysfunction due to progressive compression of the spinal cord [6]. Patients with hemangioblastoma of the brain stem present with a long history of minor neurological symptoms that, in most cases, are followed by sudden exacerbation, which may necessitate immediate neurological intervention [7]. In some patients of VHL disease, CNS hemangioblastomas may produce erythropoietin-like substances, resulting in polycythemia (usually clinically asymptomatic) at the time of diagnosis. RETINAL ANGIOMAS (HEMANGIOBLASTOMAS) Most common presenting feature of VHL disease, histopathologically similar to CNS hemangioblastoma, is associated with mainly thin-walled, capillary-like or slightly larger, blood vessels that are separated by plump, vacuolated and foamy stromal cells [8]. Ophthalmoscopy typically reveals a dilated feeder artery and draining vein. Retinal angiomas may develop within the retina or optic nerve. However, in rare cases, they may develop in the posterior pole (1%) and optic disc (8%) [9]. The lesions, if untreated, will gradually grow, bleed and leak serous fluid that will finally detach the retina [10]. It mainly includes the cumulative risk of ● Visual loss and ● Sight-threatening complications such as *Exudation *Retinal traction *Haemorrhage PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 116 Vision loss in patients with retinal hemangioblastoma may be a result of the macular edema that accompanies lesions that may be located in the periphery or at the optic disc. The symptoms of retinal detachment are ● Flashes of light ● Spots in the vision (floaters) Eye pain Light sensitivity Vision loss Headache RENAL CELL CARCINOMA (RCC) It is a type of kidney cancer accounting for the main cause of death in VHL disease. The tissue of origin of RCC is the proximal renal tubular epithelium[11]. Recent advances in understanding genetic changes associated in kidney tumor formation have led a new pathologic classification of RCC into five different types: 1. Clear cell type (65% of RCC) 2. Papillary cell type (Chromophil) (15% of RCC) 3. Chromophobe cell type (10% of RCC) 4. Oncocytoma (5% of RCC) 5. Unclassified cell type (5% of RCC): Sarcomas, collecting duct tumors, etc [12]. Symptoms include ● Abdominal pain and swelling, ● Back pain, ● Blood in the urine, ● Swelling of the veins around a testicle, ● Flank pain and ● Weight loss. Other symptoms may include excessive hair growth in females, pale skin, vision problems, anaemia (resulting from depression of erythropoietin), hypertension, hypocalcaemia, sleep disturbances and recurrent fevers [13]. RCC is difficult to treat and rarely cured once it has spread beyond the kidney and current therapies have limited efficacy. PHEOCHROMOCYTOMA It is a rare catecholamine-secreting tumor of the medulla of the adrenal glands. The diagnosis can be established by measuring amount of catecholamine and metanephrines in plasma (blood) or through a 24-hour urine collection [14]. Imaging by computed tomography of the head, neck, chest and abdomen can help localize the tumor. They may cause no symptoms, but in some cases, they are associated with ● Severe headaches ● Chest pain ● Excess sweating ● Sleeping difficulty ● Dangerously high blood pressure that may not respond to medication Patients may feel warm and have pallor of the face. Body perspiration and cool, moist hands and feet may also be found. A mass may be palpable in the neck or in deep palpation of the abdomen. Deep palpation of the abdomen may produce a typical paroxysm [15] PANCREAS Another common feature, pancreatic tumors are solid non-secretory islet cell tumors best detected by contrast enhanced MRI with early arterial phase imaging. Little is known about the origin of pancreatic cysts in general. Approximately, pancreatic cysts occur in 70% of VHL patients [16]. Based on preclinical studies, cilia loss in ductal cells is probably an important early event in pancreatic cyst development. OTHER FEATURES Some other rare features found sometimes in VHL patients include:● Endolymphatic sac tumors (ELST), which can be detected by MRI or CT imaging. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 117 ● Tinnitus, hearing loss and vertigo may occur in many cases. ● Parasympathetic paragangliomas (characterized by germline mutations in succinate dehydrogenase subunit genes). ● Epididymal cystadenomas occur in 60% of the males with VHL disease [17]. ● Broad ligament cystadenomas rarely occurs. MANAGEMENT Von Hippel-Lindau syndrome is a complex disorder. Its management is associated with the treatment of the various clinical aspects associated with it. ● For CNS hemangioblastomas, stereotactic radiotherapy may be an alternative to conventional neurosurgery for non-cystic small hemangioblastomas though adverse reactions may occur. ● Most retinal angiomas respond well to laser photocoagulation or cryotherapy. ● External beam radiotherapy (EBRT) and vitreoretinal surgery are also a useful option in the treatment of retinal angiomas [18]. ● For renal cell carcinoma, nephrectomy (surgery to remove all or a part of the affected kidney) is recommended. Other useful options are chemotherapy, immunotherapy and radiation therapy. ● Treatment of pheochromocytoma is with surgical removal but it is a high-risk procedure because intraoperative manipulation of the tumor may induce excessive catecholamine excretion, resulting in a life threatening hypertensive crisis. ● Laparoscopic adrenalectomy has been shown to be a useful technique, alternative to surgery, for treating pheochromocytoma, in patients with tumors smaller than 7 cm. ● Pancreatic neuroendocrine tumors are managed by surgical resection, depending on size and location of tumor [19]. ● For endolymphatic sac tumors, surgery is curative; can relieve vertigo and may prevent progression of hearing loss. ● Since Von Hippel-Lindau is a hereditary disease and is transmitted in an autosomal dominant manner, family members of patients with these syndromes should be educated about familial multiple-cancer syndrome, and genetic counseling should be offered to the patients and family members. ↓ REFERENCES 1. Maher ER, Iselius L, Yates JR, Littler MD, Benjamin C, Harris R, Sampson J, Williams A, Ferguson-Smith MA and Morton N: Von Hippel-Lindau disease: A genetic study. J. Med. Genet. 1991, 28: 443-447. 2. Linehan WM, Lerman MI and Zbar B: Identification of the Von Hippel-Lindau (VHL) gene: its role in renal cancer. J. Am. Med. Assoc. 1995: 273: 564-570. 3. Maher ER and Kaelin G: Von Hippel-Lindau disease:Reviews in molecular medicine. Medicine 1997, 76: 381-391. . Mel o K a d ‘ose “: Li dau s disease. Am. J. Med. 1964, 36: 595-617. 5. Ginzburg BM, Montenera WJL, Tyndel FJ, Griesman JA and McKlennan MK: Diagnosis of Von HippelLindau disease in a patient with blindness resulting from bilateral optic nerve hemangioblastomas. Am. J. Roentgenol. 1996, 159: 403-405. 6. Kovacs G and Ishikawa T: High incidence of papillary renal cell tumors in patients on chronic haemodialysis. Histopathology 1993, 22:135-139. 7. Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, Oldfield EH.: Von Hippel-Lindau disease. Lancet 2003, 361: 2059-67. 8. Maher ER., Neumann HP, Richard S: Von Hippel-Lindau disease: a clinical and scientific review. Eur J Hum Genet. 2011, 6: 617-23. 9. Richard S, Graff J, Lindau J, Resche F : Von Hippel-Lindau disease. Lancet 2004, 363: 1231-4 PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 118 10. Sano T, Horiguchi H : Von Hippel-Lindau disease. Microsc. Res. Tech. 2003, 60:159-64. 11 Huin T, Yamasaki T, Tamura K, Okuda H, Furihata M, Ashida S: Von Hippel-Lindau disease: molecular pathological basis, clinical criteria, genetic testing, clinical features of tumors and treatment. Jpn. J. Clin. Oncol. 2006, 36: 337-43. 12. Kaelin WG: The Von Hippel-Lindau gene, kidney cancer and oxygen sensing. J. Am. Soc. Nephrol, 2003,14: 2703-11 13. Gnarra JR, Duan DR, Weng Y, Humphrey JS, Chen DY, Lee S, et al.,: Molecular cloning of the von Hippel-Lindau tumor suppressor gene and its role in renal carcinoma. Clin. Oncol. 1996, 1242: 201-10. 14. Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, et al., : Identification of the von Hippel-Lindau disease tumor suppressor gene. Science, 1993, 260: 1317-20 15. Kaelin WG JR: Molecular basis of the VHL hereditary cancer syndrome. Nat. Rev. Cancer,2002, 2: 673-82. 16. Abbott MA, Nathanson KL, Nightingale S, Maher ER, Greenstein RM: The von Hippel-Lindau (VHL) germline mutation V84L manifests as early onset bilateral pheochromocytoma. Am. J. Med. Genet. A. 2006, 140: 685-90. 17. Shuin T, Kondo K, Ashida S, Okuda H, Yoshida M, Kanno H, Yao M: Germline and somatic mutations in von Hippel-Lindau disease gene and its significance in the development of renal cancer. Contrib. Nephrol, 1999, 128: 1-10. 18. Asthagiri AR, Metha GU, Zach L, Li X, Butman JA, Camphausen KA, Lonser RR: Prospective evaluation of radiosurgery for hemangioblastomas in von Hippel-Lindau disease. Neuro Oncol., 2010, 12: 80-6. 19. Bryant J, Farmer J, Kessler LJ, Townsend R.R., Nathanson KL: Pheochromocytoma: the expanding genetic differential diagnosis. J., Natl. Cancer Inst. 2003, 95: 1196-204. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 119 Review Article Medicinal value of carom seeds – An overview Pooja Dhiman*, Kanika Soni, Sandeep Singh Department of Applied Sciences, Chitkara University, Kalujhanda, Solan, Himachal Predesh, India *pooja.dhiman@chitkarauniversity.edu.in The carom seeds botanical name Trachyspermum ammi belong to the family of Apiaceae (Umbelliferae), of the genus; Trachyspermum. The Umbellifers are the members of carrot or parsley family, which includes many herbs and spices such as dill, fennel, anise seed, and caraway, is an annual herbal plant growing up to 3 feet in height. Some of the common names for the seeds are Bishop s Weed, Ajo a , carom, Caraway and thymol seeds etc. Carom seeds are ovoid, light brown colour seeds. They have narrow green leaves and small delicate flowers. The fruits pods of these plants are often called seeds for their seed-like appearance. The Carom plants are believed to have originated from Egypt in Middle East. They are widely grown in Herb Color Taste India, Afghanistan and Iran. These plants can be grown easily from the seeds. Well drained loam soil with a pH between 6.5 and 8.2 is ideal for their cultivation. They grow well in cold temperatures ranging from 15 °C to 25 °C. The plants can grow both in direct and partial sunlight. Relative humidity between 65% and 70 % are required for their proper growth. The umbels are harvested after they are properly matured. Harvesting is done during the later parts of winter or earlier in spring. These seeds are used as a spice in cooking. The umbels of the plant mature and produce the seeds. Ajwain is renowned for their medicinal value. Ajwain seeds are strongly pungent and aromatic in its taste. Active Nutritional Medicinal constitue profile per 100 property nt gram Thymol oil, Yellowish cymene, Carom brown to Hot and pinene, Seeds greyish pungent terpine, green. and limonene. Holistic benefit Uses Carom seeds can cure Carom seeds Protein - 17.1% arthritic pain, used as mouth Fat - 21.8% Carom spasmodic pain due to freshener, Mineral - 7.9% seeds have indigestion, flatulence, seasoning Fiber-21.2% acidity, migraine vegetables, antiCarbohydrates bacterial, headache, common chicken and -24.6%, anti-fungal, cold. Carom seeds are fish doses. It also contains a remedy for They are used germicidal calcium, treatment of nausea, for flavouring and thiamine, pickles and anaesthetic vomiting, anorexia, riboflavin, used to properties. dyspepsia and curb phosphorus, the desire for drinking prepare iron and niacin. alcohol. ajwein water. How to cite this article: P Dhiman, K Soni, S Singh, Medicinal value of carom seeds – An overview, PharmaTutor, 2014, 2(3), 119-123 PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 120 CAROM SEEDS AS MEDICINE Methodology for preparation of Carom Water: water is boiled for five minutes with carom seeds in it, then it is allowed to cool and drain. Whenever there is problem with gas, irregularity with bowel, a spoonful of carom water will show results in few minutes. Carom Oil is obtained from its seeds that contain 2.5% to 5% of essential oil. Their leaves and flowers are also used to extract oil. This oil contains 3560% of thymol. This oil is either colourless or pale brown in colour. Carom oil is widely used as germicide and fungicide. Due to its effects in making the digestive system strong and so metabolism work well, it helps reducing your weight naturally but temporarily. Though the effect on reducing weight may take longer, but it would not be having any side effects on the body, if carom seeds are taken in daily diet. Ajwain oil can work in relieving arthritis pain and symptoms. Carom is the main ingredient used in manufacturing most of the natural herbal products and oils. These oils can work on the inflammations and help to get rid of arthritis related pain in legs and joints. Its effect on inflammation adds value in treating arthritis symptoms. Thymol in carom seeds helps as an antibacterial to fight against bacteria in the digestive system. It can help to relieve excess gas from your body and in turn cure problems with your digestive tract. Due to its fighting power against problems caused by bacteria, Carom seed also helps to cure infections in the intestines. If one has problems with acidity, diarrhoea and flatulence, regular intake of carom seeds will help in regulating the digestive system. Carom seeds to fight against toothache by gargling with carom water to get rid of toothache. Addition of salt in carom water can strengthen weak gums and prevent further toothache. Regular practice of gargling with carom water can keep the bacteria that cause toothache away from mouth. Carom seeds can work in chasing away cough, cold and Influenza symptoms. By chewing carom seeds with or without betel leaves can help to control dry throat while coughing. To get relieved from nasal congestion, carom seeds can be smelled by crushing them on palm with thumb of another hand. When the aroma goes inside the nostrils, it fights against the congesting materials in the nasal path and push them away. Carom seeds can be used in controlling occupational or work related asthma. Drinking carom water or mixture of ajwain and jaggery are commonly known home remedies to control asthma related breathing problems and chest congestions. Carom seeds are famously used in Ayurvedic treatments and medications. CAROM SEEDS BENEFITS ● Colic- Boil 1 teaspoonful of fennel seeds and ½ teaspoonful of carom seeds in ½ litre of water. Heat the liquid slowly for 5 minutes. Cool, strain and drink a cup daily of this liquid after meals to relieve colic. ● Diabetes- Carom seeds are used to cope up with diabetes. Dry few neem leaves in the shade. Powder and store in an air tight container. At night, mix 1 teaspoonful of the powder in hot milk with ½ teaspoonfuls of powdered cumin and carom seeds. Consume it for 30 days to reduce blood sugar level. ● Deafness-Carom seeds have been used to cure deafness. Put few drops of thymol oil, obtained by extracting carom seeds and put a few drops in your ears to get rid of deafness. ● Ear pain-Heat one teaspoonful garlic and two teaspoonful carom seeds in sesame oil, till they are red in colour. Cool, strain and put a few drops of this liquid into the ears. This is also useful to treat boils in ears. ● Flatulence-Soak 3 teaspoonful of carom seeds in lime juice. Dry this in the shade. Powder and mix it with little black salt and consume 1 teaspoonful twice a day with warm water. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 121 ● Belching-Many gas related problems can be cured by a mixture of dried ginger, carom seeds and black salt. This is useful to treat problems related to gastric like gas, indigestion, and belching. It can also be taken by adding car this mixture in warm water with cardamom and drink it. ● Migraine-Wrap carom seeds in the tissue paper and smell this mixture. It is useful to reduce migraine headache. Also they can be burnt and inhaled for other problems related to head. ● Heart problems -Consume one tablespoon of carom seeds with warm water to stimulate the heart. It is also beneficial to cure chest pain. One can mix one teaspoon of jaggery with some carom seeds to get quick relief from heart problems. ● Body cleanser-Consumption of carom seeds tea can help in cleansing body toxins. Thus, this can reduce many skin and health related problems. This helps to purify blood and improve the blood circulation in body. ● Calculus- By Consuming 6 grams of carom seeds daily, one can get rid of this stone disease. ● Menorrhagia-Soak 25 gram of carom seeds in a mud pot filled with water for whole night. Grind these carom seeds and drink in the morning. This is a useful method to cure loss of appetite, flatulence and other stomach problems. Do this daily till you get the results. ● Arthritis-Carom seed oil is a very useful method to cure arthritis pain. Massage on affected joints regularly with carom seed oil to get relief from rheumatic pain. ● Diarrhoea- Carom seed is a natural remedy to cure dysentery or diarrhoea. Boil a handful of carom seeds in one glass of water. Cool and strain this carom water so that it can be consume twice a day. This is an orthodox remedy to cure indigestion and dysentery. ● Viral infections-Combined mixture of yogurt and carom seeds powder in the form of paste can be applied on face for the whole night can help to lighten acne scars. Wash it with lukewarm water in the morning for best results. ● Acidity-Mix one table spoon of carom seeds with one table spoon of cumin seeds. Consume them on a daily basis with some ginger powder. This natural remedy is a best way to cure acidity and indigestion problems. ● Constipation-Carom seeds are the best remedy to cure digestion related problems. So, it can also help to get rid of from the problem of constipation. Carom seeds do not have any side effects. ● Urticaria-Consume 1 gram of carom seeds with 3 grams of jaggery. This is a useful remedy to cure this problem of urticarial. ● Asthma-Consuming carom seeds with warm water give instant relief from cold and expel cough and mucus from the body. It is also useful for treating bronchitis and asthma. It can be consumed with jaggery twice a day. ● Digestion-Carom seeds helps to get relieve from digestive problems. Chewing 1 teaspoonful of raw carom seeds with or without sugar can help get rid of indigestion. Soak three teaspoon of carom seeds in lime juice and dry it in shade. Grind this and mix some black salt. Consume this twice a day with lukewarm water. ● Irregular Menses and Excessive Bleeding Women with the problem of irregular menses and excessive bleeding can drink ajwain water. Soak handful of carom seeds in earthen vessel filled with water at night. Grind them and drink it in the morning is a good remedy to get rid of this problem. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 122 ● Mouth problems-Carom seeds have been proven to cure toothache. Floss your mouth with one part of clove oil, one part of carom oil and water for treating tooth ache, bad odour and decay. It is the best and effective way to maintain oral hygiene in an easy way. ● Liver and kidney-Drink ajwain water for curing intestinal pain caused because of indigestion and infection. This herb is also very beneficial for curing liver and kidney malfunctions. ● Cold – Consumption of carom seeds is the best natural way to cure cold symptoms such as a blocked nose. Take a steam from ajwain seeds infused in hot water for best results in short time. ● Itching, Boils & Eczema-Grind ajwain seeds with lukewarm water to make its paste. Apply this paste on any affected part of the face or body. Also, try washing the affected part with the ajwain water for best results. In case of swelling due to boils or pimples, make the paste of ground carom seeds with lemon juice. It will be helpful in removing the swelling. ● Kidney disorder-Carom seeds are very essential to disintegrate or dissolve kidney stones. They can also be useful to treat the pain due to kidney disorders. ● Flu-Boil carom seeds with cinnamon in water. Strain & drink 4 times in a day to cure flu. ● Mosquito repellent-Mix mustard oil with ground carom seeds. Dip cardboard pieces in this mixture and tie in the corners of the room. This will help get rid of the mosquitoes from the room. ● Lost appetite-Mix and grind carom seeds, fennel seeds, dried ginger powder, salt and black cumin seeds. Add hot ghee to this mixture. Mix the mixture with cooked rice. This will surely increase lost appetite in due course of time. ● Reduce weight-Drink half glass of water with soaked carom seeds on an empty stomach. This will dissolve the fats. Consume 1teaspoonful of carom seeds on an empty stomach every morning. It helps to lose about 4 to 5 kg in a month. ● Bed Wetting-Take 50 grams black sesame, 25 grams carom seeds and 100 grams of jaggery. Mix them well. Consume this mixture 1teaspoonful twice a day. This will help in treating frequent urination and bed-wetting by children. ● Piles-Mix dried pomegranate flowers, poppy seeds and dried neem leaves. Consume this mixture with milk twice a day during bleeding piles. Drinking buttermilk with carom seeds powder and rock salt after lunch/dinner is useful for minimizing the bleeding condition of piles. ● Heals pain-Mix carom seeds, onion seeds, fenugreek seeds with saboot isabgol. Grind them all in the form of a mixture and consume 1 teaspoonful of this powder everyday in the morning. Consume this on an empty stomach for best positive results in shorter period of time. ● Sexual disability-Roast carom seeds with some tamarind kernels and clarified butter. Grind them well, take 1teaspoonful of this mixture and add to a glass of milk and honey. This is a proven method to reduce sexual disability. Consume this regularly at night for effective results. ● Breastfeeding- Carom seeds with fennel seeds are used to make ajwain aur saunf ka pani. This is useful to cleanse uterus and increase milk production. Add 1 teaspoonful of fennel seeds with ½ teaspoonful carom seeds and 1 litre of water. Boil them for 5 minutes and PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 123 cool it. Cool and consume this every day for best results. wash off with warm water. This remedy will help to lighten pimple scars to a great extent. ● Menstrual cramps- Carom seeds acts as a nerve tonic, hence it can lower menstrual cramps during menses. Thus, the benefits of carom seeds are quite wonderful. Its oil can also be applied on muscle to relax them. ● Joint pains- Mix shatavari, black cumin seeds, fenugreek seeds and carom seeds. Powder this mixture and consume ½ teaspoonful of this powdered mixture to get relief from joint pain. ● Alcoholic- This herb is also beneficial for the people who want to get rid of alcohol. Chewing carom seeds daily can help to get rid of alcohol craving. ● Sperm count- Roast ajwain seeds with some tamarind kernels and clarified butter. Grind all of these ingredients. Grind them well, take a teaspoonful of this mixture and add to a glass of milk and honey. This is a proven method to improve sperm count and treat premature ejaculation. Consume this regularly at night for effective results. ● Insecticide-They have many therapeutic uses as well as they are used widely in food preparations. Carom seeds are also used as an insecticide. Apart from this, this is an orthodox method for treating poisonous insect bites. ● Used in cooking-These seeds are widely used in Indian cooking as a spice. They can be roasted or fried in oil or added in pa hpho a . Aj ai is used i s all quantity in making biscuits, snacks, sauces, soups, soft drinks and pickles for good digestion. ● Pimple-Apply powdered carom seeds with yogurt on your face. Keep it for half an hour and ● Paralysis- Carom seeds soaked in water, if consumed daily can be useful in treating paralysis, trembling and shaking. ● Eye cleanser- Boil handful of carom seeds in a water. Cool and strain it. This water can be used to wash eyes. FACTS ABOUT CAROM SEEDS *Keep them away from humidity and also from direct sunlight. *Store them in air-tight bottle in a cool and dry place. * People with liver disease and hyperacidity should avoid this herb. *Carom seeds cannot be stored for a long time. *Avoid over consumption. It can lead to nausea, vomiting, skin irritation, allergy and headache in some people. Side-effects of overdose of carom seedsConsumption of carom seeds do not cause any harm, when consumed in moderate amounts. But overconsumption can cause some side effects in people suffering from diverticulitis conditions, liver diseases, and ulcerative colitis. As these seeds stimulate gut secretions which can worsen the condition of existing peptic ulcer. One should consult a doctor if any sideeffect occurs. ↓ REFERENCES 1. onlyfoods.net/ajwain.html 2. en.wikipedia.org/wiki/Ajwain 3. nutrition-and-you.com/ajwain.html 4. kingtutshop.com/Egyptian-Herb/Ajwain.htm 5. traditional-foods.com/profiles/ajwain-seed PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 124 Research Article Medication Safety in Children Languluri Reddenna*, Department of Pharmacy Practice, Rajiv Gandhi Institute of Medical Sciences, Kadapa, Andhra Pradesh, India *reddennapharmd@gmail.com ABSTRACT Objective: Monitoring the safety of medicine use in children is of superlative prominence, on the other hand only limited data on this aspect. In-between 1979 and 2006, the poisoning death rate cut in half, declining from 0.35 to 0.17 per 100,000 children. Therefore, the main aim of the study was to evaluate the edi atio safet i hild e s. Methods: A prospective observational study was conducted in the PICU, NICU, IP and OP department of Paediatrics at Rajiv Gandhi Institute of Medical Sciences over a 6-months period (from august 2012 to January 2013). The Institutional Ethics and Research Committee of Rajiv Gandhi Institute of Medical Sciences, Kadapa (Rc.No.413/Acad./2011-12), approved the study. All patients under 12 year of age were included in the study. Patients referred from another health facility or hospital to collect their medications from the pharmacy of the respective health clinics were excluded from the study. All documented medication orders monitored for any drug misadventures and recommended to the pediatricians. Results: Drug misadventures include medication errors 588 (84%), ADEs 27 (3.8%), ADRs 33 (4.8%) and drug interactions 52 (7.4%). Conclusion: P es i e s o kload, la k of suffi ie t k o ledge a d ti e spe t ith o e patie t a e restrains that lead to most of the mistakes. Recognition of these errors is the first step in their prevention. There is a crucial need to develop methods to reduce medication errors in children should be the major priority. It can be concluded that drug misadventures are common in children. INTRODUCTION The objective of drug therapy is the attainment of distinct therapeutic outcomes that progress a patie t s ualit of life hile di i ishi g patie t threat. With each therapy there must be a threat, it could be notorious or mysterious [1]. Monitoring the safety of medicine use in children is of superlative prominence, on the other hand only limited data on this aspect [2]. These threats demarcated as drug misadventures, which include both adverse drug reactions (ADRs) & medication errors. Deficiency of confirmation on the use of medicines in children pointers to improbability in dosing and escalations the threat of medication errors. Medication errors arise in children at analogous rates to adults however; errors had three times the expected to cause injury [3]. Neonates is a susceptible crowd for dosing and dispensing errors because of rapidly changing body surface area and weight, a rapidly evolving system of drug absorption, metabolism and excretion, an incompetence to converse with the source and off-label or unconstrained drug usage. Most of the drugs used in neonates desires a fraction of calculation and there by budding for errors. Medication errors in children are reported in literature; but to our knowledge, there are a How to cite this article: L Reddenna, Medication Safety in Children, PharmaTutor, 2014, 2(3), 124-133 PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 125 very few studies that focus on medication errors in neonatology but none from India [4]. Amongst young children, a child intake medication while unverified causes 95% of unpremeditated medication overdose stays to emergency departments and roughly, 5% are due to dosing errors through by caregivers [5]. Fifty-six children years 14 and under expire each year from unpremeditated medication overdoses. In-between 1979 and 2006, the poisoning death rate cut in half, declining from 0.35 to 0.17 per 100,000 children. Yet, among all child-poisoning deaths, the number attributable to medications increased from 36% to 64%. Medicine classes most commonly associated with error in primary care include analgesics, antibiotics, antiepileptic agents, asthma and allergy agents, vaccines and insulin products [6]. Dosing errors among studies conducted in US ranged between 15% to 34%.The incidences of dose error per 100 medication orders was 38.9 [7]. Dosing errors habitually associated in the harmful or hypothetically harmful errors, mainly during the prescribing stage. The incidence of medication errors in UK hospitals are virtually similar to those in the USA, in which prescribing errors occur in 1.5% of the prescriptions while 3 to 8% of doses given has administration errors [8, 9]. Incidence of medical errors in a tertiary care pediatric unit in India was 35.5% and severe morbidity due to errors was seen in 2.4% [10]. Commencing a number of pharmacoepidemiological studies in pediatrics well recognized that the risk of ADRs increases with the span of the patient's stay in hospital, the number of medicines she or he is accepting, the level of off-label use and the dynamics of physiological changes through early life. Moreover, retrospective and prospective monitoring from computerized medical records requiring a more or less passive role of the health professionals and it is time effective compared with other intensive surveillance systems. It will probably improve spontaneous reporting of pharmacological, unpredictable and not dose-related reactions and in part preventable, dose-related reactions to a medicine [11]. So, the present study was undertaken to evaluate the medication safety in hild e s. MATERIALS AND METHODS A prospective observational study was conducted in the PICU, NICU, IP and OP department of Paediatrics at Rajiv Gandhi Institute of Medical Sciences over a 6-months period (from august 2012 to January 2013). The Institutional Ethics and Research Committee of Rajiv Gandhi Institute of Medical Sciences, Kadapa (Rc.No.413/Acad./2011-12), approved the study. All patients under 12 year of age were included in the study. Medications, which are not available in RIMS drug formulary. Patients referred from another health facility or hospital to collect their medications from the pharmacy of the respective health clinics were excluded from the study. A standardized data collection form was designed for the purpose of this study. All documented medication orders monitored for any drug misadventures and recommended to the pediatricians. RESULTS Drug misadventures include medication errors 588 (84%), ADEs 27 (3.8%), ADRs 33 (4.8%) and drug interactions 52 (7.4%). Medication errors The total number of medication errors detected was 588 (84%) with 29.9% in NICU, 18.1% in PICU, 14.4% in pediatrics inpatient department and 37.6% in pediatrics out patient department. Majority errors were found in the age group of 1-3 years. Month wise medication errors were expressed in table 1.Types of errors were expressed in figure 1. Physiological system wise medication errors were expressed in table 2 and medicine class wise expressed in figure 2. Severity level of medication errors were expressed in table 3.Psychology of medication PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 126 errors included mistakes 286 (65%) and slips 106 (35%) is expressed in figure 3.Strategies to reduce medication errors included reduce in prescribing errors 275 (46.76%), reduce in calculation errors 172 (29.25%) and providing patient information 141 (23.97%) is expressed in table 4.We observed majority of medication error is inappropriate dose error. Therefore, we find out the incidence, nature of dosing errors and problems in scaling adult drug doses to children. Incidence of dosing errors was 35.28%. Nature of dosing errors expressed in figure 4 and Problems in scaling adult drug doses to children were expressed in table 5. Adverse drug reactions The total number of adverse drug reactions perceived was 33 (4.8%) with 1.4% in NICU, 0.9% in PICU, 1.6% in pediatrics inpatient department and 0.9% in pediatrics out patient department. Majority of adverse drug reactions were found in the age group of 1-3 years. Causality assessment of adverse drug reactions was expressed in table 9.Therapeutic group of the drugs associated with the adverse drug reactions is shown in table 10.Physiological system wise adverse drug reactions were expressed in table 11. Mechanism of adverse drug reactions was expressed in table 12. Adverse drug events Drug interactions The total number of adverse drug events noticed was 27 (3.8%) with 0.8% in NICU, 0.5% The total number of adverse drug reactions in PICU, 1.7% in pediatrics inpatient department perceived was 52 (7.4%). Majority of drug and 0.8% in pediatrics out patient department. interactions were found in the age group of 4-6 Majority errors were found in the age group of years. Severity level of drug interactions was 1-3 years. Physiological system wise adverse expressed in table 13.Types of drug interactions drug events were expressed in table 6 and include drug-drug interactions 3%, and drugTherapeutic group of the drugs associated with food interactions1.4% and drug nutrient adverse drug events was expressed in table 7. interactions0.2%. Classification of adverse drug events was expressed in table 8. Table No.1: Month wise medication errors (n=588) Month August September October November December January No. of medication orders 134 118 103 91 78 64 % 22.6 20.0 18.1 16.5 12.0 10.8 Table No.2: Physiological system wise medication errors (n=588) Physiological system Cardiovascular system Respiratory system Central nervous system Gastrointestinal system Endocrine system Genitourinary system Nutrition & Blood Infections Others No. of medication orders 2 116 57 122 1 47 35 157 47 % 0.3 19.8 9.7 20.8 0.2 8.0 5.9 26.7 8.0 PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 127 Table No. 3: Severity level of medication errors (n=588) No Error Error, No harm Error, Harm Error, Death Level of severity Category-A Category-B Category-C Category-D Category-E Category-F Category-G Category-H Category-I No. of medication orders 58 144 196 113 44 33 0 0 0 % 9.8 24.5 33.3 19.2 7.5 5.6 0 0 0 Table No.4: Strategies to reduce medication errors (n=588) Strategies Providing Patient information Reduce calculation errors Reduce prescribing errors No. of medication orders 141 172 275 % 23.97 29.25 46.76 Table No.5: Problems in scaling adult drug doses to children (n=700) Problem Age and weight Disease Pharmaceutical formulation No. of medication orders 446 219 35 % 63.7 31.3 5.0 Table No.6: Physiological system wise adverse drug events (n=27) Physiological system Cardiovascular system Respiratory system Central nervous system Gastrointestinal system No. of medication orders 1 9 3 14 % 0.1 1.3 0.4 2.0 Table No.7: Therapeutic group of the drugs associated with the adverse drug events (n=27) Therapeutic group Antihistamines Anti-e eti s Respiratory system agents Antimicrobial agents No. of medication orders 1 9 3 14 PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org % 0.1 1.3 0.4 2.0 128 Severity Severe Mild Moderate Lethal Table No.8: Severity level of adverse drug events (n=27) No. of medication orders 3 14 9 1 % 0.4 2.0 1.3 0.1 Table No.9: Causality assessment of adverse drug reactions (n=33) Causality Probable Possible Definite Unlikely No. of adverse drug reactions 13 19 1 0 % 1.8 2.7 0.1 0 Table No.10: Therapeutic group of the drugs associated with the adverse drug reactions (n=33) Therapeutic group Antihistamines Antimicrobial agents Respiratory system agents Analgesics and antipyretics No. of medication orders 1 8 9 15 % 0.1 1.1 1.3 2.1 Table No.11: Physiological system wise adverse drug reactions (n=33) Physiological system Cardiovascular system Respiratory system Central nervous system Gastrointestinal system No. of medication orders 1 11 4 17 % 0.1 1.5 0.4 2.4 Table No.12: Mechanism of adverse drug reactions (n=33) Mechanism Idiosyncrasy Hypersensitivity Intolerance Pharmacologic Severity Minor Moderate Major No. of medication orders 1 17 11 4 Table No.13: Severity of drug interactions (n=52) No. of medication orders 17 15 1 PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org % 0.1 2.4 1.5 0.4 % 2.4 2.1 0.1 129 Figure 1: Types of medication errors (n=588) Figure 2: Medicine class wise medication errors (n=588) PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 130 Figure 3: Psychology of medication errors (n=588) Figure 4: Nature of dosing errors (n=700) DISCUSSION Pediatric inhabitants by itself are a range of diverse physiologies with substantial disparity in pharmacokinetics and pharmacodynamics. Tactlessly, 50–90% of drugs used in children today never been essentially studied in this population and the consequences of drug studies done in adults are frequently extrapolated for use in children. Many drugs used in children are unlicensed, off-label, unsafely or without any confirmation of efficacy in children. A report of WHO in 2005 showed three times more medical errors in children than in adults. Result show that drug misadventures in children were common. The variables that show the most were medication errors, adverse drug reactions and drug interactions. Majority medication errors were found in the pediatrics O.P (37.6%). In our study, the most communal type of prescribing error (35.28%) was related to an incorrect dose (either too high or too low). In one study accompanied by Lesar et al. [12]establish that the most common type of prescribing error (56.1%) was related to an incorrect dose (either too high or too low).Majority of errors met in analgesics and antipyretics (23%) tracked by anti-microbial agents (18.7%) because of their regular usage. A Comparable study conducted by Rainu Kaushal [13] proved that most medication errors found in anti- infective drugs (28%). Intensity of workload was predictable to be risk factor for medication errors. Severity level assessment of medication errors revealed that majority of errors (64.7%) were dropped under the category-B, C and D (Error, No Harm). 9.8% were in the category-A (No Error) and 13.1% in the category-E, F (Error, Harm). A parallel study was conducted by Marcin JP et al [14] revealed that among the 69 patients with medication errors, 11 had errors categorized as impending to cause harm (15.9%) and 58 had errors categorized as causing no harm (85.5%). The physician psychology is a part in medication errors, which shows that 65% were mistakes and 35% were slips. P es i e s o kload, la k of sufficient knowledge and time spent with one patient are restrains that lead to most of the mistakes. Recognition of these errors is the first step in their prevention. The information PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 131 available shows that medication errors (dosing errors) are common and most of them prescribed are 10-fold higher than relative daily dose, have led to serious concerns. There is a crucial need to develop methods to reduce medication errors in children should be the major priority. Therefore, strategies to reduce medication errors shows that 46.76% were reducing in prescribing followed by 29.25% were reducing in calculation errors. It compounded by the fact that prescriptions often written by the most junior doctors who may be unfamiliar with the medicine. Our study identified higher dosing errors (35.28%) when compared to dosing errors among studies conducted in US is ranged between 15% to 34%. Eleven of the 16 studies determined that dosing errors are the most common type of medication error, three of the remaining studies determined that it is the second most common type. [15] Nature of dosing errors shows that 64.7 % prescriptions were with normal dose, 20.5% with over dose and 14.7 % with under dose. Problems in scaling adult drug doses to children show that age and weight accounts for 63.7 %, followed by disease 31.3% and pharmaceutical formulation 5%. The statement in this frame work was that reducing error would translate directly into reducing harm. Majority adverse drug events noticed was 27 (3.8%) with 1.7% in paediatrics inpatient department followed by 0.8% in pediatrics out patient department. Majority errors were found in the age group of 1-3 years. Physiological system wise adverse drug events stated that 2% accounts for gastrointestinal system followed by 1.3% respiratory system. Therapeutic group of the drugs associated with adverse drug events revealed that 2% antimicrobials, followed by 1.3% anti emetics. Classification of adverse drug events stated that mild 2%, followed by 1.3% moderate. In one study, Kaushal and colleagues[16] reported ADE rates in children on inpatient wards at two urban teaching hospitals to be 2.3 per 100 admissions (26 events),with an additional potential ADE rate of 10 per 100 admissions (115 events).In the second study, Holdsworth and coworkers [17]reported an ADE rate in pediatric inpatients(pediatric ICU and general care unit at a university hospital) of six per 100 admissions (76 events), with 61% classified as preventable, and a potential ADE rate of 8 per 100 patient days (94 events).Woods and colleagues, [18]by means of retrospective chart review of 3719 randomly selected discharges of patients between 0 and 20 years old hospitalized in Utah and Colorado, report AE rates of one per100 patients (39 events), with 59% classified as preventable. Extreme less research and information are available concerning the incidence of AEs and ADEs in outpatient settings. Gurwitz and colleagues [19] report an ADE rate of 50.1 per 1000 personyears in a large adult outpatient population, with 38% characterized as serious, life threatening, or fatal. In this study, the most common drug classes associated with outpatient ADEs were cardiovascular medications(24.5%), diuretics (22.1%), and nonopioid analgesics (15.4%).[20,21] Similar to research of inpatient settings, the majority of preliminary research efforts concentrated on medication errors rather than ADEs. In pediatrics, few studies assess error or harm in outpatient settings. A current study of a pediatric population by McPhillips and colleagues [22] attentive on medication errors in an outpatient setting and shown 15% of all prescriptions dispensed contained a medication error; 8% of these prescriptions reflected an overdose and 7% reflected an underdose. In this study, children between 0 and 3 years of age, and children who had six or more medications dispensed are at particular risk. The medication classes utmost at risk for errors included antiepileptic medications (errors 21%of the time), asthma and allergy medications (errors 19% of the time), and analgesics (errors 16% of the time). Causality PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 132 assessment of adverse drug reactions revealed that majority was probable 2.7%, followed by possible 1.8%.Physiological system wise adverse drug reactions stated that 2.4% accounts for gastrointestinal system followed by 1.3% respiratory system. Therapeutic group of the drugs associated with adverse drug reactions revealed that 2.1%analgesics and antipyretics, followed by 1.3% respiratory system agents. Mechanism of adverse drug reactions revealed that majority was hypersensitivity 2.4%, followed by intolerance 1.5%. Severity level of drug interactions revealed that minor 2.4%, followed by moderate 2.1%.The limitation of this study is identification of less number of drug misadventures because of short period. CONCLUSION It can be concluded that drug misadventures are common in children. Moreover, retrospective and prospective monitoring from computerized medical records requiring a more or less passive role of the health professionals and it is time effective Compared with other intensive surveillance systems. It will probably improve spontaneous reporting of pharmacological, unpredictable and not doserelated reactions and in part preventable, doserelated reactions to a medicine. Acknowledgements We owe our whole hearted thanks to Principal Dr. K. Ravindra Reddy, whose constant motivation and all the timely help throughout our project work. ↓ REFERENCES 1. Leelavathi D. Acharya, Javed Shareef, Padma G. M. Rao., Study and Evaluation of Medication Errors in a multidisciplinary tertiary Care South Indian Teaching Hospital.Indian Journal of Hospital Pharmacy.2008; 45: 54-58. 2. The importance of pharmacovigilance: safety monitoring of medicinal products. Geneva, World Health Organization, 2002. 3. Kaushal R, Bates DW, Landrigan C, McKenna KJ, Clapp MD, Federico F et al. Medication errors and adverse drug events in pediatric inpatients. JAMA. 2001;285(16): 2114-2120. 4. Ross LM, Wallace J, Paton JY. Medication errors in a pediatric teaching hospital in the UK: Five years operational experience.Arch Dis Child. 2000; 83: 492-7,. 5. Bronstein AC, et al. a ual epo t of the A e i a Asso iatio of Poiso Co t ol Ce te s National Poison Data System (NPDS): 28th annual report. Clinl Toxicol, 49, 910-9412011. 6. Centers for Disease Control and Prevention. CDC WONDER Compressed Mortality File, Underlying Cause-of-Death. Centers for Disease Control and Prevention Website.Available from: wonder.cdc.gov/mortSQL.html.Accessed on: February 15, 2012. 7. McPhillips HA, Stille CJ, Smith D, et al. Potential medication dosing errors in outpatient pediatrics.J Pediatr. 2005; 147: 761-7. 8. Wong IC, Ghaleb MA, Franklin BD, et al. Incidence and nature of dosing errors in paediatric medications: a systematic review. Drug Saf.2004; 27(9):661–670. 9. Kaushal R, Bates DW, Landrigan C, et al. Medication errors and adverse drug events in paediatric inpatients. JAMA. 2001;285(16):2114–2120. 10. Mansi parihar and Gouri rao passi.Medical errors in pediatric practice.Indian pediatrics.2008; 45: 586-89. 11. Conroy S, et al. Survey of unlicensed and off label drug use in paediatric wards in European countries. British Medical Journal.2000; 320: 79-82. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 133 12. Lesar TS, Lomaestro BM, Pohl H. Medication-prescribing errors in a teaching hospital: a 9-year experience.Arch Intern Med. 1997; 157:1569–76. 13. Rainu Kaushal et al. Medication Errors and Adverse Drug Events in Pediatric Inpatients.JAMA. 2001;285(16):2114-2120. 14. Marcin JP et, al. Medication errors among acutely ill and injured children treated in rural emergency departments. Available from: jpmarcin@ucdavis.edu. 15. McPhillips HA, Stille CJ, Smith D, et al. Potential medication dosing errors in outpatient pediatrics.J Pediatr. 2005; 147:761-7. 16. Kaushal R, Bates DW, Landrigan C, et al. Medication errors and adverse drug events in pediatric inpatients. JAMA.2001; 285:2114–20. 17. Holdsworth MT, Fichtl RE, Behta M, et al. Incidence and impact of adverse drug events in pediatric inpatients. Arch Pediatr Adolesc Med. 2003;157:60–5. 18. Woods D, Thomas E, Holl J, et al. Adverse events and preventable adverse events in children. Pediatrics.2005; 115:155–60. 19. Gurwitz JH, Field TS, Harrold LR, et al. Incidence and preventability of adverse drug events among older persons in the ambulatory setting. JAMA.2003; 289:1107–16. 20. Wilcox SM, Himmelstein DU, Woolhandler S. Inappropriate drug prescribing for the communitydwelling elderly.JAMA. 1994; 272:292–6. 21. Hanlon JT, Schmader KE, Boult C, et al. Use of inappropriate prescription drugs by older people. J Am Geriatr Soc. 2002;50:26–34. 22. McPhillips HA, Stille CJ, Smith D, et al. Potential medication dosing errors in outpatient pediatrics.J Pediatr. 2005; 147:761–7. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 134 Awareness Article Challenging role of Pharmacist in Health Care The Future Prospects Nishant Verma,* Department of Pharmaceutical Chemistry, Teerthanker Mahaveer College of Pharmacy, Teerthanker Mahaveer University, Moradabad, Uttar Pradesh, India *nishantvermamiet@gmail.com MODERN PHARMACIST One who is able to provide the patient oriented services as in developed countries is called as a modern pharmacist. Such services start from obtaining patients medication history to the feedback from the same after discharge. The componential characteristics that a modern hospital pharmacist must possess include: 1. Professional knowledge 2. Computer / IT acquaintance & skill 3. Counseling and communication skills COMPUTER / IT ACQUAINTANCE & SKILL The modern pharmacist has to be adequately skilled in such an area for storing data of patient medication history to drug profile, drug stock to its expiry date details, analytical calculations to research programs etc. The use of computer in pharmacy is imminent and important. The hospital pharmacy practice involves informative interactions of in-house and distant persons to meet out the clinical emergencies. COUNSELING AND COMMUNICATION SKILLS A modern pharmacist in order to perform patient oriented services, needs to perform The apeuti D ug Mo ito i g a d consequently to individualization of dosage regimen. Hospital pharmacists are involved in the treatment process of the patients from the beginning viz; from taking medication history to selection, dispensing and monitoring of drug therapy. ENDEAVOURS, CHALLENGES & MISPERCEPTIONS OF PHARMACY PROFESSION During the concurrent professional scenario, the community pharmacists provide only dispensing services within pharmacies. Many opine that the presence of pharmacists in community pharmacies is merely to satisfy the current legal requirements. They only count and pack tablets and capsules and distributes these to consumers. There is need to adopt new concepts of clinical & patient oriented practices. There is requirement to make medicines safe for patients by providing counseling than for proper use, clarifying correct dosages and right application. It involves checking new treatments that are compatible with other medicines that the patients might be taking. The future of pharmacy does not seem to lie merely in dispensing of medication batter in provision of relevant drug information and drug therapy recommendation to patients. A clinical pharmacist is an important source for furnishing clinical aspects of the drugs and delivery system particularly with respect to the safety and efficacy parameters. AN ANTIBIOTIC PHARMACIST Endeavours to become a source of peculiar aspects of antibiotic therapy, monitoring of antibiotic consumption, participation in infection control, formulary development and appraisal of new antimicrobials. The addition of a dedicated antibiotic pharmacist to a counseling team may be beneficial to patients to reduce medication errors and time spent at hospitals. How to cite this article: N Verma, Challenging role of Pharmacist in Health Care The Future Prospects, PharmaTutor, 2014, 2(3), 134-136 PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 135 RETAIL PHARMACISTS: may check the probable harmful effects of self medication by imparting relevant drug information to the consumers. ACADEMIC PHARMACISTS: help the general public by creating awareness on safe use and administration of drugs. PHARMA JOURNALISTS: provide drug information in various print media like journals, magazines, bulletins, newspapers etc. which may play a crucial role in making the patients familiarised and comfortable with the drug used and proper mode of administration. CHALLENGES & PROBLEMS: these include understanding of the technical complexities, gross assessment of physico chemical aspects, ensuring appropriate administration and reckoning use of the drug, making the patient ready, comfortable and compatible with the health care delivery system. STRATEGIES FOR PHARMACISTS Various aspects in determining the professional strategies include: Appropriate patient counseling: The patient's choice of medicine could be lost unless a mechanism is found for rewarding professional advice rather than just dispensing of medicines. Communication: Essential tool delivering drug information i.e. dose, dosing schedule/dosing regimen, adverse and side effects, drug-drug interaction etc. Inculcation of helping attitude: It focuses principally on patience, cooperation, helpful and compassionate attitude to achieve the target of counseling of OTC consumers successfully. A vital triangular relationship: It included establishment of relationship between pharmacists, doctor, a patient to improve patient's use of medicines simplifying various complexities. COMMUNITY PHARMACY A GROWING NEED Community pharmacists serve as a major source of information to the over the counter users residing in the rural and backward areas, to convey his message to the OTC consumers via various modes like verbal discussions, presentations through charts, video clippings and provide explanations of significant pictograms to them and motivating people to increase their awareness about the OTC medications. Community pharmacy is the most structured and advanced, in developed countries such as USA, UK and other European countries, in fulfilling responsibilities such as sale of medicine, medication information, patient record keeping, running health promotion activities such as smoking cessation services, giving advice on health services, family planning, drug misuse and abuse. Community pharmacist strives for most effective, appropriate, safe and economic treatment of the patient. Adoption of Community Pharmacy Practice Technologies such as use of patient care databases, software for identification of ADRs / DI specific to patient medication history, medication therapy management modules, electronic direct prescribing, telephonic/web based prescription / non-prescription drug and/or information requests, digitally secured confidential patient data, has enhanced customer care services. OVER THE COUNTER MEDICATIONS, SELF MEDICATION AND COMMUNITY PHARMACY 1. SELF MEDICATION: Self-medication is defined as consumption of medication on self-behalf without professional supervision on medicinal products. 2. USE OF OTC DRUGS: Commonly used OTC drugs such as decongestants, expectorants, antihistamines, cough suppressants and analgesics (pain relievers) can lead to various adverse effects such as respiratory depression, cardiac arrest, serious central nervous system (CNS) related problems etc. These drugs also PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 136 pose possibility of various drug interactions for prescription drugs. complex drug therapy regimens to thereby improved therapeutic outcomes. 3. INCREASING DEMAND IN CHRONIC CARE: Chronic diseases like asthma, diabetes, cardiovascular diseases such as hypertension, Chronic obstructive pulmonary disease etc. Need expertise and prompt care till the end of medication or, throughout the entire life of a patient. PHARMACIST AND HEALTH AWARENESS The awareness and approach of each unit towards various problems is mandatory needed. Such burning areas include1. Malnutrition, weakness and anaemia, hygiene and sanitation. 2. Commonly occurring diseases like diabetes, hypertension, tuberculosis, infective diseases etc. 3. Gynaecological problems. 4. Immunization schedule. 5. Skin and contagious diseases. 6. General tendency of self medication and purchase of OTC products. 4. LIFESTYLE CHANGES AND PHARMACEUTICAL DEMANDS: The rapidly changed life style of the community requires special category of drugs to treat lifestyle illnesses. There is increasing demands for therapies such as anti-obesity drugs, anti-ageing cosmetic interventions, erectile dysfunction disorders, anti-oxidants etc., isolated protein and dietary supplements. People access to these lifestyle drugs and nutraceuticals at community pharmacy. 5. ROLE OF PHARMACISTS INVOLVING MEDICATION MANAGEMENT: a) Pharmacists are skilled at analysing complex systems serving as the best source of information about the institution's medication use system. b) Pharmacists have core knowledge of medications including their adverse effects, interactions, proper dosing and monitoring parameters. c) Pharmacists manage the institution's drug budget and are cognizant of drug costs. d) Pharmacists understand the risks inherent in the medication management process consequently can identify areas of weakness and are able to create or redesign systems to improve risk areas. e) Pharmacists continuously monitor medication related literature and are comfortable in patient counseling. f) Medication safety continues to be a challenge within health care to monitor patients on more PHARMACISTS AND GERIATRIC CARE Geriatric care requires1) Caring elderly -The pharmacist's way. 2) Dosing drugs in elderly. 3) Pharmacists manage and improve drug therapy and quality of life of geriatric patients 4) Pharmacists can provide a variety of small but important services to make them taking prescription medication easier for the elder patient. A prudent clinical monitoring of drug therapy by a pharmacist can limit adverse drug reactions and polypharmacotherapy due to a prescribing cascade. RURALISING HEALTHCARE The health care awareness needs to be proliferated to the grass root level i.e. rural areas. 1. Pharmacists are primary custodians of drug and ensure safety and suitability. 2. Checking drug-drug and drug-food interactions. 3. Identification and reporting of adverse drug reactions. Assuring the medication adherence by patient counseling. PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 137 News Corner MAST THERAPEUTICS ACQUIRE AIRES PHARMACEUTICALS, INC. Mast Therapeutics, Inc., publicly traded biopharmaceutical company headquartered in San Diego, California, announced on 10th Feb, 2014 that it has entered into a definitive agreement to acquire Aires Pharmaceuticals, Inc. (Aires), a privately-held, clinical stage pharmaceutical company developing therapies to treat pulmonary vascular disorders such as pulmonary arterial hypertension and pulmonary hypertension due to heart failure. Aires' lead product, AIR001, is an intermittently nebulized formulation of nitrite and has orphan drug status with the U.S. Food and Drug Administration and the European Medicines Agency for the treatment of pulmonary arterial hypertension. "The acquisition of Aires will enhance our pipeline with a phase 2 assets with more than 120 human subject exposures and which is a strategic complement to our lead program, MST-188. With total consideration of approximately 6% of Mast equity, it represents excellent value for our stockholders," stated Brian M. Culley, Chief Executive Officer of Mast Therapeutics, Inc. "Nitrite has demonstrable beneficial properties, including vasodilation and the reduction of inflammation and undesirable cell growth. These are important therapeutic objectives and an ideal complement to MST-188 and its ability to improve blood flow and seal cellular membranes. In addition, we intend to investigate the hypothesis that AIR001 positively affects mitochondrial activity and myocyte energetics. With this acquisition, and the initiation of our phase 2 trial of MST-188 for the treatment of acute limb ischemia later this quarter, we are taking additional steps towards building a sustainable company with a valuable pipeline addressing significant unmet needs in both specialized and major markets," Mr. Culley continued. "Another highlight of this acquisition is its favorable economics. Aires had completed several venture financings, including a $20 million Series B round. We are paying significantly less than that to acquire the program and we currently estimate that our development costs for AIR001 for the first 12 months will be approximately $2 million. Our estimated costs for AIR001 will change as we refine our development strategy over the next few months, but Aires is expected to contribute approximately $3 million of net cash at the closing of the merger, so, as currently contemplated, our first year of development of AIR001 will not require additional capital investment by Mast," Mr. Culley concluded. Under the terms of the all-stock transaction, Aires would become a wholly-owned subsidiary of Mast Therapeutics, Inc. in exchange for shares of Mast common stock representing approximately 6% of Mast's outstanding common stock, 80% of which would be subject to a six-month holdback for certain indemnification claims of Mast. There are no milestone obligations payable to Aires. The acquisition is expected to close in February 2014, subject to customary closing conditions. AIR001 (sodium nitrite) inhalation solution, also known as Aironite®, is an intermittently nebulized formulation of nitrite. Under hypoxic conditions, AIR001 is converted to nitric oxide. Nitrite mediated nitric oxide formation has several beneficial effects, including dilation of blood vessels and reduction of inflammation and undesirable cell growth. EXPERT COMMITTEE RECOMMENDS AMENDMENT OF D&C ACT AND INCLUDE SCCPS AS NEW DRUG The expert committee submitted report to ministry of health and family welfare, INDUSTRY & REGULATION NEWS PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 138 Government of India on amendment of relevant rules in the Drugs and Cosmetics Act 1940 to include stem cells and other cell based products (SCCPs) as New Drugs. Ministry had set up a committee in June 2013 under the Chairmanship of Prof. Lalji Singh, Vice Chancellor of Banaras Hindu University. They asked to suggest views and ideas on how the ministry of health and family welfare can guide and regulate the usage of stem cell and other cell based therapies in India. This decision of making committee was taken due to increasing use of stem cells and other cell based therapies in recent years by clinicians in India and internationally for treatment of human diseases. So, there is obvious need of creating perfect regulatory framework of such products. After long and careful consideration or discussion, committee recommended few points out of which main is amendment of the relevant rules in the Drugs and Cosmetics Act of 1940 so as to include SCCPs as New Drugs. Committee also suggests that there is need of set up a system which appointed technical evaluation committees and trained examiners for examining and licensing facilities where work related to SCCPs usage is being done or proposed to be done and also invite, evaluate and approve specific applications from companies, hospitals, research institutes and universities that propose to use SCCPs in clinical trials. In accordance of above report government asked Drugs Controller General of India to take forward steps and to ensure that recommendations of the Committee are implemented at the earliest and instruments for starting the regulatory process is put in place. GOVERNMENT RELEASES NATIONAL GUIDELINES FOR STEM CELL RESEARCH Basic guidelines for stem cell research were released in 2007 by joint efforts of DBT & ICMR which are revised in December 2013 after evaluating development in field of stem cell research. These newer guidelines are termed as 'National Guidelines for Stem Cell Research'. These guidelines foresee positioning National Apex Committee for Stem Cell Research and Therapy (NAC-SCRT) and Institutional Committee for Stem Cell Research (IC-SCR) to monitor and oversee activities at national level and institutional level, respectively. NAC-SCRT and IC-SCR will make certain that review, approval and monitoring of the research projects in the field of stem cell research are performed effectively as per the national guidelines. These guidelines are applied to all stakeholders who include researchers, organizations, sponsors, regulatory committees and any others associated with both basic and clinical research on all types of human stem cells and their derivatives. Guidelines clearly indicate that any stem cell use in patients other than hematopoietic stem cell is under investigation at present. In National Guidelines for Stem Cell Research exclude therapy from the title of the guidelines. This is performed due to realizing facts that stem cells are still not a part of standard of care and in developing state hence there can be no guidelines for therapy until efficacy is proven. Ministry of Health and Family Welfare has established Stem Cell division within biological division in Central Drugs Standard Control Organization for the internal evaluation of all proposals including Stem Cell concerning with clinical trial and marketing authorization before referring to CBBTDEC (Cellular Biology Based Therapeutic Drug Evaluation Committee). CBBTDEC is headed by chairmanship of Director General, ICMR & Secretary, DHR to advice DCGI in matters pertaining to regulatory pathways leading to the approval of clinical trials and market authorization for the therapeutic products derived from Stem Cell, human gene manipulation and xenotransplantation technology INDUSTRY & REGULATION NEWS PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 139 AVAXIA BIOLOGICS GOT PATENT FOR ORAL ANTI-TNF ANTIBODIES FOR IBD Avaxia Biologics Inc. (located in Lexington, Massachusetts) a clinical-stage biopharmaceutical company developing guttargeted therapeutics, announced on 11th Feb, 2014 that the company was awarded U.S. Pate t No. , , , e titled Co positio s Comprising TNF-specific Antibodies for Oral Deli e . The patent covers milk-derived anti-TNF antibodies that are orally administered within a broad dose range for the treatment of inflammatory bowel disease (IBD). The claims also cover use of these antibodies for the treatment of IBD. Importantly, the patent oadl o e s A a ia s lead p odu t, AVX- 470, which recently completed a Phase 1b clinical trial in ulcerative colitis. IBD is a serious disease affecting more than 2.5 million people. IBD refers to two related but different diseases: ulcerative colitis and Crohn's disease. These diseases cause chronic inflammation of the intestinal tract, resulting in a significant reduction in quality of life and the risk of lifethreatening complications and diseases, including cancer. As a chronic autoimmune disease, IBD is characterized by periods of active disease that alternate with periods of disease control (remission). The annual worldwide market for IBD medications exceeds $4.5 billion, approximately $2.5 billion of which represents sales of currently marketed anti-TNF antibodies. Barbara S. Fox, Ph.D., Chief Executive Officer of A a ia, said, This pate t a a d is a i po ta t milestone for our company. This is the first in a series of patents that Avaxia expects to receive on the composition of our lead clinical-stage candidate, AVX-470. Avaxia will continue to build on its strong intellectual property portfolio in the gut-targeted antibody the apeuti s field. IMB‘UVICA™ GET“ NOD F‘OM U“FDA FO‘ TREATMENT OF CHRONIC LYMPHOCYTIC LEUKEMIA - RARE BLOOD AND BONE MARROW DISEASE The U.S. Food and Drug Administration e pa ded the app o ed use of I u i a™ which contains ibrutinib, for chronic lymphocytic leukemia (CLL) patients who have received at least one previous therapy on Wednesday, 12 Fe , . I u i a™ is manufactured by Pharmacyclics based at Sunnyvale, California. CLL is a rare blood and bone marrow disease that usually gets worse slowly over time, causing a gradual increase in white blood cells called B lymphocytes, or B cells. The National Cancer Institute estimates that 15,680 Americans were diagnosed and 4,580 died from the disease in 2013. I u i a™ o ks lo ki g the e z e that allows cancer cells to grow and divide. In No e e , the FDA g a ted I u i a™ accelerated approval to treat patients with mantle cell lymphoma, a rare and aggressive type of blood cancer, if those patients received at least one prior therapy. Toda s app o al p o ides a i po ta t e treatment option for CLL patients whose cancer has progressed despite having undergone p e ious the ap , said ‘i ha d Pazdu , M.D., director of the Office of Hematology and O olog P odu ts i the FDA s Ce te fo D ug E aluatio a d ‘esea h. The FDA o pleted its e ie of I u i a s e i di atio u de the age s a ele ated app o al p o ess, which played a vital role in rapidly making this new therapy available to those who need it ost. U de the age s a ele ated app o al process, the FDA may approve a drug based on a surrogate or intermediate endpoint that is reasonably likely to predict clinical benefit. Drugs receiving accelerated approval are usually subject to an agreement to conduct confirmatory trials verifying and describing INDUSTRY & REGULATION NEWS PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 140 li i al e efit. I u i a™ fo CLL also received priority review and orphan-product designation because the drug demonstrated the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition and is intended to treat a rare disease, respectively. The most common side effects observed in the clinical study include low levels of platelets in the blood (thrombocytopenia), diarrhea, bruising, a decrease in infection-fighting white blood cells (neutropenia), low red blood cells (anemia), upper respiratory tract infection, fatigue, pain in the muscles and bones (musculoskeletal pain), rash, fever (pyrexia), constipation, swelling of tissues (peripheral edema), joint pain (arthralgia), nausea, mouth sores (stomatitis), sinus infection (sinusitis) and dizziness. GOVERNMENT TO INTRODUCE THIRD LINE TREATMENT OF HIV/AIDS IN 10 ART CENTRES ACROSS THE COUNTRY Presently, the first line and second line antiretroviral therapy (ART) is given to HIV/AIDS patients free of cost in all ART Centres across the country. The Technical Resource Group on ART on 27th December, 2013 recommended providing third line antiretroviral therapy for HIV/AIDS patients through 10 centres of excellence across the country. The process for the same has been initiated at Department of AIDS Control. Viral load testing is provided free of cost to all those eligible for ART as per guidelines across the country. As per the HIV/AIDS Bill, the Central Government or the State Government shall take measures for providing, as far as possible, anti-retroviral therapy (ART) and Opportunistic Infection (OI) management to people living with HIV/AIDS. This was stated by Shri Abu Hasem Khan Choudhury, Minister of State for Health and Family Welfare in a written reply to the Rajya Sabha on 18th Feb, 2014. NEW DRUG APPROVAL FOR TREATMENT OF NEUROGENIC ORTHOSTATIC HYPOTENSION The USFDA approved Chelsea Therapeutics's product Northera capsules (droxidopa), orphanproduct, for the treatment of neurogenic orthostatic hypotension (NOH) which is rare, chronic and often debilitating drop in blood pressure upon standing that is associated with Parkinson's disease, multiple-system atrophy, and pure autonomic failure. People ith eu oge i o thostati hypotension are often severely limited in their ability to perform routine daily activities that e ui e alki g o sta di g, said No a Stockbridge, M.D., Ph.D, director of the Division of Ca dio as ula a d ‘e al D ugs i the FDA s Center for Drug Evaluation and Research. The e a e li ited t eat e t optio s fo people with NOH and we are committed to helping ake safe a d effe ti e t eat e ts a aila le. The FDA is approving Northera under the accelerated approval program, which allows for approval of a drug to treat a serious disease based on clinical data showing that the drug has an effect on an intermediate clinical measure (in this case, short-term relief of dizziness) that is reasonably likely to predict the outcome of ultimate interest (relief of dizziness during chronic treatment). This program provides patient access to promising drugs while the company conducts post-approval clinical trials to e if the d ug s li i al e efit, hi h fo this approval is a long-term effect on patient symptoms in NOH, a chronic disease. Symptoms of NOH include dizziness, lightheadedness, blurred vision, fatigue and fainting when a person stands and common adverse events for droxidoa reported by clinical trial participants taking Northera were headache, dizziness, nausea, high blood pressure (hypertension) and fatigue. INDUSTRY & REGULATION NEWS PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 141 Pre Event 2nd PHARMA INDUSTRY-INSTITUTE INTERACTION SUMMIT (8th- 9th March, 2014) AT R. C. PATEL INSTITUTE OF PHARMACEUTICAL EDUCATION & RESEARCH R. C. Patel Institute of Pharmaceutical Education & Research, Formerly known as R.C. Patel College of Pharmacy established in June 1992 with the aim to enhance the quality education in the field of Pharmacy and empower the quality pharmacist so that they serve the society to develop lifesaving drugs. Right from its establishment the institute has maintained the quality with assurance in terms of Accreditation from National Board of Accreditation, New Delhi (NBA) twice on 2005 and 2009 for the B. Pharm course. Institute also accredited by NAAC, Bangalore for the period of 5 years. Emerging Pharma professionals of Third year, Final year B.Pharm and M.Pharm We take this privilege to invite you to the 2n Pharma Industry-lnstitute interaction summit. Come, let's share this platform with the experts from leading pharma companies and grab an opportunity to comprehend... * The needs and expectations of the Pharmaindustries * Importance of technical expertise in employability * Essentiality of positive attitude in securing expected jobs 4^ Career opportunities for pharma professionals * Soft skills and their importance in corporate life Objectives ●Bridging gaps between the expectations of Pharma Industry and output of academia ●Orienting the budding pharmacists to better career goals ●To bring senior professionals and future pharmacists under one roof for brain storming ●Enhancing employability of pharmacy graduates and post-graduates Registration includes access to all the sessions of the summit, participation in poster competition, lodging and food Eagerly Waiting to welcome you at RCPIPER. Organised by R.C. Patel Institute of Pharmaceutical Education and Research Shirpur(MS)- 425405 (PCI/AICTE approved, NAAC-accredited, NBA reaccredited, UGC-recognized, affiliated to NMU, Jalgaon) INSTITUTIONAL NEWS PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 142 Pre Event NATIONAL SEMINAR ON EMPOWERMENT OF WOMEN ON MARCH 8TH 2014: INTERNATIONAL WOMEN'S DAY AT VNIPS VISWANADHA Institute of Pharmaceutical Sciences (VNIPS) was established in the year 2008 amidst lush greenery by Viswanadha Educational Society. ABOUT POWER POWER (Pharmacists' Organization for Women Empowerment and Research) is a professional and scientific society that provides leadership, education, advocacy and resources enabling women pharmacists to achieve excellence in practice and research. It is an official and registered organization managed by women executive committee and run by a team of experienced women pharmacists. ABOUT SEMINAR VNIPS is organizing one day National Seminar o E po e e t of Wo e o th Ma h 2014 – I te atio al Wo e s Da i association with POWER. The purpose of the seminar is to discuss on various issues related to the upliftment of women in Pharmacy as well as in the society. In this progressive world, women are given equal importance! However the opportunities are not fully utilized by the women may be due to lack of awareness, social hurdles, additional responsibilities in personal life etc. The seminar is aimed to enable all women in pa ti ula o e pha a ists to ealize thei full potential and raise their profile by being active in education, in research and in career. The main objectives of this seminar are to reflect deeply over the challenges, opportunities and issues of women pha a ists i I dia a d to p o ide i puts that e po e the o e pha a ists i edu atio and research. EVENTS The seminar involves various thought provoking speeches by successful women in society of various streams like industry, academics and international grounds. In addition the seminar is equipped with competitions in the areas of • Poste p ese tatio s, • O al p ese tatio s, • Essa iti g, • Elo utio , • Ca too a d • “ho t films. * Benefit audience: All Students & Faculty of Pharmacy, Engineering, Medicine and Life Sciences. * Both boys and girls are eligible to participate. * Registration Fee: Rs. 200/* This registration fee covers all the above events, spot events, seminars, lunch, snacks and kit. * Spot registration fee Rs. 300/- (on the day of seminar) Venue: Viswanadha Institute of Pharmaceutical Sciences Mindivanipalem (V), Sontyam (Post) Anandapuram (Mandal) Visakhapatnam INSTITUTIONAL NEWS PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 143 Pre Event ONE DAY WORKSHOP IN ASSOCIATION WITH INCLINITION ON “ESSENTIALS OF MEDICAL WRITING, REVIEWING AND PUBLISHING” 15TH MARCH 2014 AT P. WADHWANI COLLEGE OF PHARMACY In Association with – Inclinition, Mumbai Sponsored by – Association of Pharmacy Professionals Yavatmal Zilla Viakas Samiti was established in the year 1985 initiated by Shri. Mukul Wasnik, Ex. Minister HRD, Shri Shivajirao Moghe, Ex. Minister for Transport and Self Employment , M. S. and Shri. Jagdish G. Wadhwani, President, Yavatmal Zilla Vikas Samiti, Yavatmal About Workshop: • Pa ti ipa ts ill lea ho to p ese t supplementary data, constructing scientific figures, tables, making the graphs, drafting and polishing, presentation of numerical data, • Use of soft a e tools fo a ti le iti g • Pa ti ipa ts ill also know the selection of journals; assessment of quality of journals (issues related to impact factor, and different indexing databases, etc) • W iti g se tio s of esea h pape i AIM‘aD and AIRDaM formats • Fo atti g of esea h a ti les – Use of proper fonts, spacing, margins, positioning of tables and figures • Ma us ipt su issio s, espo di g to reviewers and editors, reviewers view of analyzing your manuscript. • W iti g li i al stud epo ts ith fo us o ICH E3 guidelines • W iti g g a t p oposals, CTD docuements, i fo ed o se t fo s, a d i estigato s brochure. Target Audience This Workshop is targeted to students (B. Pharm, B. Sc, M. Pharm, M. Sc., Scholars), Academicians who wish to get updated with this area, display or transact knowledge are heartily welcome to attend this esteemed event. Organised By Ya at al )illa Vikas “a iti s P. WADHWANI COLLEGE OF PHARMACY Moha Phata, Dhamangaon Road, Yavatmal-445001 Phone: 07232- 245847, 238747, 247447 e-mail: pwcopytl_yml@sancharnet.in INSTITUTIONAL NEWS PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 144 Pre Event NATIONAL CONFERENCE ON NEW INSIGHTS INTO PHARMACOGENOMICS, DRUG DEVELOPMENT AND PERSONALIZED MEDICINE AT BHAGWAN MAHAVIR MEDICAL RESEARCH CENTRE, HYDERABAD It gi es us g eat pleasu e to el o e ou to the Natio al Co fe e e o Ne i sights i to Pha a oge o i s, D ug De elop e t a d Pe so alized Medi i e ei g o ga ized Bhag a Mahavir Medical Research Centre from 28th-29th April, 2014 in Hyderabad. TOPICS OF THE CONFERENCE The following topics will be covered * Genomics to Guide Differential Diagnosis & Therapy * Genomic Variation in Common Traits/Diseases * Clinical Integration of Genomic Variation * Evolving Genomic Technologies * Clinical trials * Personalized Medicine * Pharmacogenetics in clinical practice * Pharmacogenomics of Human diseases * New technologies in drug discovery and development. * Racial and ethnic drug response * Vaccines, Patient Health care * Adverse Drug Reactions * Cancer Genomics * Experimental and pre-clinical therapeutic models * Combating drug resistance * Status and future perspectives in application of Pharmacogenomics YOUNG SCIENTIST AWARDS Awards to the young scientists (below 35 years) will be given for the best oral/ poster presentations. Those who wish to participate should submit the Full paper through the Head of the Organization/Department with proof of age on or before 31st March, 2014. Organized by Bhagwan Mahavir Medical Research Centre A.C Guards, Masab Tank, Hyderabad-500004 Email id: ncpg.bmmrc@gmail.com 040-23497360, 040-66682032 Venue: Auditorium, Mahavir Hospital & Research Centre (MHRC), Hyderabad INSTITUTIONAL NEWS PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 145 Post Event ONE DAY NATIONAL SEMINAR ON DRUG DISCOVERY AND DEVELOPMENT IN ITM UNIVERSITY, GWALIOR JANUARY 18, 2014 School of Pharmacy, ITM University, Gwalior, organized a One-day National Seminar on Drug Discovery and Development with the theme Prefor ulatio : Its I pa t o Drug Deli er , on January 18, 2014. The invited speakers were from industry, academia and research background. Prof. Kamla Pathak, Professor and Dean, Rajiv Academy for Pharmacy, Mathura deli e ed le tu e o I it o dissolutio : p efo ulatio tool fo assessi g d ug deli e . Dr. Rajendra Awasthi, Associate Professor, Laureate Institute of Pharmacy, Kathog, deli e ed le tu e o Pha a euti al p odu t development: preformulation techniques and pe spe ti es . D . Dha a ja “i ga e, “ ie tist, Formulation Development, Piramal Pharmaceutical Development Services, Ahmedabad, delivered lecture on For ulatio strategies of NCE ole ules . The Welcome address was given by Prof. GT Kulkarni, Dean, School of Pharmacy, ITM University. The Chief Guest of the program was Prof. Yogesh Upadhyay, Vice Chancellor, ITM University and Key note address was delivered by Prof. RD Gupta, Advisor to Chancellor, ITM University. Dr. NK Sahu, Organizing Secretary, proposed the vote of thanks. About 150 delegates from different parts of the country attended the Program and presented their research papers in the form of posters. From left to right: Prof Kamla Pathak, Dr Dhananjay Singare, Prof RD Gupta, Prof Yogesh Upadhyay, Dr Rajendra Awasthi, Prof GT Kulkarni INSTITUTIONAL NEWS PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 146 Post Event 2nd NIRMA INSTITUTE OF PHARMACY INTERNATIONAL CONFERENCE ON “FOSTERING INNOVATION IN DRUG DISCOVERY & DEVELOPMENT” JANUARY 23-25, 2014 As healthcare services plays an important role i people s health a d pha a is a ajo pillar of the health care system. Pharmaceutical science is a group of interdisciplinary areas and a profession which is responsible for the appropriate use of medications, devices and services to achieve optimal therapeutic outcomes. An International Conference is being hosted by Institute of Pharmacy, Nirma U i e sit o Fostering Innovation in Drug rd Discovery & Development o - 25th January 2014. The aim of conference is intended to bring together academicians, researchers, industrialists, clinical practitioners and students on one platform to share their ideas and emerge with new concepts to have a knowledge sharing experience for all in the various areas of pharmaceutical sciences. Around 500 participants attended this conference. The Inauguration function was held on 23rd January in the presence of Dr. Sourav Pal Director, National Chemical Laboratory, Pune as a chief guest, Dr. Y. K. Gupta Spokesperson, AIIMS, New Delhi as a Key Note Speaker. Dr. Anup Singh Director General, Nirma University, Shri Ambubhai M. Patel Vice President, Nirma University presided the function. Prof. Manjunath Ghate, Director, Institute of Pharmacy, Nirma University welcomed the Chief Guest and Delegates. On sharing of his views on the theme of seminar, Dr. Sourav Pal emphasized on chemistry of a molecule synthesis and other disciplines of research. He emphasized on integrated disciplinary research for the better outcome. Dr. Y K Gupta from AIIMS, New Delhi talked a out Cli i al ‘esea h “ e a io i I dia: Co te po a issues . He talked a out u i ue advantages to conduct clinical trials in India is due to cost advantage, availability of large treatment naïve patient population, well qualified doctors conversant in English, to name a few. India was the second most preferred country to conduct clinical trials outside of USA in 2009 with an average annual increase of 30%. However, more recent years have witnessed a flattening and then a sharp decline in number of trials in India (529 in 2010; 253 in 2012). The number of drugs entering the Indian markets had been gradually reducing even before the current slump in clinical research activity (270 in 2008;140 in 2011; 43 in 2012). Clearly, the fruits of labour never accrued to our population. He emphasized on the strategy to optimize clinical research in Indian context. Recent changes in regulatory framework will require substantial logistic backup besides the need of imparting quick intensive training to various stake holders such as members of IECs, prospective investigators and regulators themselves. An important issue is to align the clinical research activity in our country as per our national health needs. Research in India specific problems (such as JE, Dengue, malaria, MDR TB) should be incentivized by way of faster approvals, liberal funding and extended marketing rights. It is good to have a vaccine against HPV but one against JE may be needed more and sooner. Clinical research is essential not only for developing medicines for emerging health concerns (such as XDR TB, antibiotic resistant pathogens, H1N1, Ebola virus, etc) but also for finding safer and better medicines for entrenched diseases such as HIV, Malaria, diabetes, hypertension etc. India, with its large INSTITUTIONAL NEWS PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 147 patient population, unmet health needs, and limited resources, needs to make newer and better treatment options available to its population in a quick, economical and dependable manner. For this, India must take proactive part in clinical research and assume leadership role globally. We must ensure that clinical research in our country is carried out as per global scientific standard, is moored in sound ethical foundations befitting a liberal democracy but is optimally oriented towards addressing national medical and health needs. During the conference Nirma Institute of Pharmacy Journal was released. At the end of program, Prof. (Dr.) Tejal Mehta, Organizing Secretary, NIPiCON-2014 gave the vote of thanks. The plenary lectures of Dr. C. L. Kaul, Dr. Chandrashekhar and Dr. Ashok Vaidya was chaired by Dr. C. J. Shishoo. Prof. C. L. Kaul, Former Director, NIPER, Mohali spoke o a topi I o atio i Drug Dis o er . He dis usses the issues a d path of drug discovery to development. He stressed that there is urgent need of new drugs to cure, prevent, or slow the progression of the disease. Prof. Ashok D. B. Vaidya, Research Director, ICMR Advanced Centre of Reverse Pharmacology, Kasturba Health Society, Mumbai has delivered an informative talk on Reverse Pharmacology: A Trans-Discipline For Drug Discovery and Development and its application with success stories of his team. Further he emphasized upon that drug discovery from natural source is a rigrous process and there are innumerable success stories of drug discoveries at the bedside. Dr. Chandrashekar's lecture was on the synthesis of few drug molecules for the treatment of Alzheimer and TB. He has presented a new asymmetric synthetic method for the synthesis of latest anti-TB drug Bedaquiline. LIkewise, he has presented the asymmetric synthetic route for anti-Alzheimer drug. The methods designed by him were clear and robust. Overall, it was a nice lecture with lots of impact on asymmetric organic synthesis. The lecture of Dr. K. C. Gupta, Director, CSIR, Lucknow talked about delivery of biomolecules through viral/non-viral vectors. He discussed the process of evaluation of gene transfer capacity. Chitosan Ppolyehtylamine conjugates. Moreover, the applications of the same in cancer chemotherapy were also deliberated in the lecture. The lecture was chaired by Dr. Ramesh K, Goyal, Distinguished Professor, Institute of Life Sciences, Ahmedabad University. At the end of the day various cultural programs were presented by students of the Institute of Pharmacy followed by Gala dinner. Next two days of the conference will present a powerful platform to share current status of the research in pharmaceutical industry and the institutes. The conference will also provide an opportunity to scientists and research scholars from various organizations to put forth their innovative ideas and research findings by means of more than 310 poster presentations and can also win the exciting prizes for the best paper in each thrust areas. The plenary sessions will be decorated with various eminent International and national speakers from industry as well as academics. On the second day of NIPiCON 24th January, 2014 Dr. M.C.Gohel, Former Principal, L.M.College of Pharmacy, Dr. Jyoti Paliwal, Medical AdvisorMedical Services, Troikaa Pharmaceuticals Ltd., Dr. Ashwin Barot Ayurvedic Practitioner, England, chaired the sessions. Prof. Padma Devarajan , had delivered the lecture on the discovery of a new ligand for pulmonary targeting (for treating tuberculosis disease) following oral administration. Dr. Sandip Tiwari presented various functional aspects of commonly used excipients that relate to Quality Bty Design (QbD) and discussed examples with case studies and emphasized that it is INSTITUTIONAL NEWS PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 148 imperative to improve communication between excipient supplier and user concerning excipients process capability in order for QbD to be successful. Prof. Wong Tin Wui from Malaysia discussed the Challenges of Microwave as Transdermal Permeation Enhancer. He focused on how wide range of approaches have been invented to enhance the skin permeability to drugs and how Microwave is reckoned to be the next generation technology in transdermal delivery. In after noon hours, Dr. Rajendran R. delivered a speech on pharmaceutical approach in innovation and development of herbal products. Dr. Nikolaos G.Kostopoulos Holistic Health Centre, Athens, Greece presented his experience in the practice of Holistic medicine in England and Greece during last 25 years by combining Ayurveda and Modern medicine both in a clinical and research set-up. During the afternoon session, parallel lecture sessions were conducted where distinguished speakers Dr. Munira M Momin , Dr. Vivekananda Mandal, Dr. Varun Gupta, Dr. Prateek Kumar Jain and many more presented their lectures. In the evening around 150 posters were presented in Pharmaceutics and Pharmacognosy tracks. On the third day of NIPiCON 2014 (Saturday, 25th January) the sessions were chaired by Dr. Bhaswat Chakraborty,Vice President, Research & Development, Cadila Pharmaceutical Ltd., and Dr. Vipan Dhal, Vice President & Site Head, Piramal Pharmaceutical Development Services Pvt. Ltd. Prof. Sukhinder Kaur Cheema, Head of Graduate Studies at Department of Biochemistry, Memorial University, Canada presented on comparative mechanisms by which diet and drugs regulate metabolic pathways to prevent metabolic disorders. She discussed the challenges of using drugs versus diet, and finally adoption of new strategies for the treatment of metabolic disorders associated with diabetes, obesity and cardiovascular diseases. Dr. Saranjit Singh, Professor and Head, Department of Pharmaceutical Analysis, NIPER, S.A.S. Nagar, Mohali delivered a talk on the topic Pharmaceuticals in the Environment, discussing on effect of pharmaceutical effluents, drug metabolites excreted from the body, current drug disposal methods and its effect on the environment. He expressed his concern about the presence of drug or its metabolites in ground water level of Punjab and questioned about the effect on human health. He gave the example of diclofenac side effect on vulture and thereby ecosystem. Dr. N. Udupa, Director-Research (Health Sciences) Manipal University, Manipal, Karnataka presented on Exploring Nanotechnology Through Drug Delivery For Healthcare. He emphasized benefit of nanotechnology for treating killer disease like cancer and diabetes. Use of this technology is helpful in making required quantity of the drug delivery to the site of action. This enhances patie t s o plia e a d de eases u a ted effect or side effects of a drug. Poster session covered in different areas like Medicinal Chemistry, Pharmaceutical Analysis, Quality Assurance, Clinical Pharmacy and Practic. The Conference ended with a valedictory function. Dr. Saranjit Singh, Professor and Head, Department of Pharmaceutical Analysis, NIPER, S.A.S. Nagar, Mohali was the Chief Guest. Shri. K. K. Patel, Chief Operating Officer, Nirma University graced the occasion. Dr. Manjunath Ghate, Director, institute of pharmacy welcomed the guests. Prizes were given to the best poster presentations. The function was ended with concluding remarks by Prof. (Dr.) Tejal Mehta, Organizing Secretary, NIPiCON-2014 & vote of thanks by prof. Vimal Kumar, Professor & Head, Dept. of Pharmacognosy. INSTITUTIONAL NEWS PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 149 PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org 150 www.pharmatutor.org magazine.pharmatutor.org PharmaTutor Magazine | Vol. 2, Issue 3 | magazine.pharmatutor.org