Medicinal Plants Used by Traditional Medicine Practitioners in the Management of Patients with Cancer in Selected Districts of Uganda

Casim Tolo

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Aims: Chemical toxicity is one of the major leading causes of tissues injuries, which impair the tissue’s ability to maintain normal physiological functions. Pterocarpus erinaceus is a medicinal plant use as traditional remedy for the treatment of several disorders associated with tissues injuries. This study therefore aimed at investigating tissues protective efficiency of Pterocarpus erinaceus leaves extract in carbon-tetrachloride-induced hepatic and hematological injuries in rats. Materials and Methods: Leaves of Pterocarpus erinaceous after collection were air-dried and pulverized. It was extracted with methanol and the methanolic extracts were used. Acute toxicity and hepatoprotective studies against CCl4 toxicity were conducted. Rats were grouped into; Group 1: Normal control (liquid paraffin, vehicle 1ml.kg), Group 2: Negative control (received 1ml/kg CCl4), Group 3: Positive control (received 1ml/kg CCl4 +100ml/kg Silymarin), Group 4-6: Extract treated rats (received 1ml/kg...

Background Limonoids are a class of highly oxygenated modified triterpenoids with a diverse range of biological activities. Although with restricted occurrence in the plant kingdom, these compounds are found extensively in the Meliaceae and Rutaceae families. Limonoids are of great interest in science given that the small number of plant families where they occur exhibit a broad range of medicinal properties that promote health and prevent disease. Main text The Meliaceae family includes the genus Khaya and comprises tree species that have been used in traditional medicine to treat several ailments. In recent years, the genus Khaya has attracted much research interest owing to the presence of limonoids in different plant parts of a few species that can serve as therapeutic molecules in the pharmaceutical industry. In this study, a literature search over the past two decades (2000–2020) was conducted on the biological activities of limonoids in the genus Khaya using different databas...

Journal Pre-proof Medicinal plants used by traditional medicine practitioners to boost the immune system in people living with HIV/AIDS in Uganda G. Anywar, E. Kakudidi, R. Byamukama, J. Mukonzo, A. Schubert, H. Oryem-Origa PII: S1876-3820(19)30986-2 DOI: https://doi.org/10.1016/j.eujim.2019.101011 Reference: EUJIM 101011 To appear in: European Journal of Integrative Medicine Received Date: 8 October 2019 Revised Date: 15 November 2019 Accepted Date: 15 November 2019 Please cite this article as: { doi: https://doi.org/ This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier. Medicinal plants used by traditional medicine practitioners to boost the immune system in people living with HIV/AIDS in Uganda Anywar G*1, 4, Kakudidi E1, Byamukama R2, Mukonzo J3, Schubert, A4, Oryem-Origa H1, 1 Department of Plant Sciences, Microbiology & Biotechnology, College of Natural Sciences, Makerere University, P.O. Box 7062, Kampala, Uganda 2 Department of Chemistry, College of Natural Sciences, Makerere University, P.O. Box 7062, Kampala, Uganda 3 Department of Pharmacology & Therapeutics, College of Health Sciences, Makerere University, P.O. Box 7062, Kampala, Uganda 4 Fraunhofer Institute for Cell Therapy & Immunology (IZI), Perlickstraße 104103, Leipzig, Germany Corresponding author: godwinanywar@gmail.com / ganywar@cartafrica.org /ganywar@cns.mak.ac.ug of Abstract ur na lP re -p ro Introduction: People living with HIV/AIDS (PLHIV) widely use medicinal plants for boosting immunity and managing infections. The aim of this study was to document the medicinal plant species used by herbalists to boost the immune system of people living with HIV/AIDS in Uganda. Materials and Methods: Semi-structured questionnaires were administered to 90 herbalists to obtain ethnobotanical information on medicinal plant species used from different parts of Uganda. A detailed literature review of the pharmacology, phytochemistry, toxicology and other traditional used of the documented medicinal plants was also conducted. Results: Seventy-one medicinal plant species from 37 families and 64 genera were identified. Trees contributed 38.0% of the species used and herbs 35.2%. The majority of the herbal medicines were made from leaves (35.6%), bark (24.1%) and roots (20.7%). Zanthoxylum chalybeum Engl. and Psidium guajava L. were the most widely used species with citation frequencies (CF) of 11 each. These were followed by Warburgia ugandensis Sprague, Acacia hockii De Wild. and Bridelia micrantha (Hochst.) Baill (CF = 8 each), Mangifera indica L., Markhamia lutea (Benth.) K. Schum., Aloe vera (L.) Burm.f. and Erythrina abyssinica DC. (CF = 7 each). Most traditional medicine practitioners (TMP) (85.6%) used herbs for boosting immunity for PLHIV, whether or not the patients were on antiretroviral treatment. The patients often disclosed their sero-status to the TMP who considered all PLHIV to be immunocompromised. Conclusion: Herbalists widely prescribe medicinal plant species for boosting or restoring the immunity in PLHIV in Uganda. Key words: Medicinal plants, Ethnobotanical survey, immunomodulation, herbalists, HIV/AIDS, Uganda. Jo 1.0 Introduction A healthy immune system is involved defending the body from attacks but when compromised, it can lead to the development of several chronic illnesses which conventional medicine has not adequately addressed [1,2]. AIDS is the commonest immunosuppressive disease in the world [3]. It is caused by HIV, which attacks and destroys the body’s immune system, particularly CD4 cells (T cells), and leads to a state of immunodeficiency and susceptibility to infections [3,4]. The concept of modulating our immune responses as a cure to various illnesses 1 has stimulated a lot of interest [5,6]. Modulation of the immune system is highly desirable in counteracting conditions of compromised immunity [7], such as AIDS. Immunomodulators are biomolecules of synthetic or biological origin capable of regulating, suppressing and stimulating parts of the immune system [8,9]. Natural immunomodulators are often used to restore compromised immunity by activating the host’s defensive mechanism [10]. Regrettably, most immunostimulants and immunosuppressants in clinical use are either cytotoxic [8,11] or even cause fatalities [12]. Conversely, natural products are generally reconsidered to be safer, more accessible and easy to prepare and apply [13,14]. Several plant species have been frequently used in traditional medicine to treat disorders of the of immune system [6,15], and thus represent a source for potential immunomodulating adjuvants [16]. Different studies have demonstrated novel and significant immunomodulatory activities ro in various plant species [6,17,18]. Immunomodulatory agents can also be used as immune -p stimulators to reduce the side effects of drug-induced immunosuppression [6,7,19,20]. One of the most important uses of herbal medicines in HIV infection is in boosting the immune re system [21]. This has created a demand for traditional medicine that boost immunity or improve health and wellbeing [22], especially by many PLHIV [23–26]. Thus an ur na lP ethnobotanical study was conducted to documented medicinal plant species specifically used for boosting immunity in immunocompromised people living with HIV/AIDS in Uganda 2.0 Methods 2.1 Study area A survey was carried out in the districts of Arua in the Northwest, Dokolo in the North, Mbale and Iganga in the East, Bushenyi in the West, Rakai in the South, Luwero (Figure 1), as part Jo of a larger study conducted by Anywar et al. [23]. Figure 1: Map of Uganda showing study sites. Adopted from Anywar et al. [23]. 2.2 Study design Ninety herbalists were interviewed in an ethnobotanical study carried out in 2017, in the respective districts. Different languages were spoken in the different districts surveyed (Table 1). 2 Table 1: Languages spoken & Number of TMP interviewed by districts Only herbalists who belonged to local association and had been administering herbs for boosting immunity in PLHIV for a minimum of 5 years were included in the study. Semistructured interviews were conducted with regard the criteria the TMP used for assessing ones immune status, the medicinal plant species they used to restore immune function and the methods of preparation. 2.3 Collection of plant specimens Plant voucher specimens were collected from the field with the assistance of the herbalists of following standard guidelines described in Martin [27]. The specimens were taken to the Makerere University Herbarium for identification. Classification of the plant species was done ro using theplantlist database at http://www.theplantlist.org accessed on 4thJanuary-March, 2018 at 18:09 EAT. Plant family names were verified using the Angiosperm Phylogeny Group IV. -p 2.4 Ethical considerations The Higher Degrees Research and Ethics Committee of the School of Biomedical Sciences, re College of Health Sciences, Makerere University and the Uganda National Council of Science and Technology (UNCST) cleared this study, (Ethical clearance No. HS 2233). All the ur na lP herbalists were required to consent in writing prior to participating in the study. 2.5 Data analysis The data obtained was analysed and presented using descriptive statistics. In addition, an extensive literature review was conducted to ascertain the pharmacological, biological and clinical evidence supporting the use of the documented plant species as immunomodulators. In addition, an extensive review of published literature on the immonomodulatory or Jo immmunostimulatory properties of the documented medicinal plant species was conducted. We also searched for other known therapeutic or pharmacological properties and ethnomedicinal uses of the documented plant from various databases and publishers such as Google scholar, web of science and PubMed. The results of the review were analysed to give a comparison on the use of these plant species in our study vis-à-vis what is done elsewhere. Results 3.1 Socio-Demographic characteristics of the traditional medicine practitioners’ 3 The average age of the herbalists was 51.1 years. The majority of the herbalists were men (66.7%) with primary level education (34.4%). About one third of the TMP (30.0%) had no education whereas 5.5% had obtained tertiary level education. Most TMP were Christians (74.5%), Muslims (24.4) and animists (1.1%). The TMP were predominantly subsistence farmers (73.3 %). While the rest were full-time TMP (3.3%), traditional birth attendants (3.3%) and businesses owners (7.8%) run various. The rest did various jobs to supplement their incomes. 3.2 Medicinal plant species used Seventy-one medicinal plant species from 37 families and 64 genera were documented (Table of 2). With the exception of two species Amaranthus and Aloe, the rest were identified to species level. Fabaceae had 11 species, Asteraceae (5) and Pyllanthaceae (4). Acanthaceae, ro Anacardiaceae, Apocynaceae, Bignoniaceae and Rubiaceae had 3 species each. The plant species used were trees (38.0%) and herbs (35.2%), while shrubs contributed (19.7%), climbers -p (5.6%) and scramblers (1.4%). Leaves were the most frequently used plant parts (35.6%), re followed by bark (24.1%) and roots (20.7%). The medicinal species used with the highest frequency of mention were; Psidium guajava L. and Zanthoxylum chalybeum Engl. (11 each), Warburgia ugandensis Sprague, Acacia hockii ur na lP De Wild. and Bridelia micrantha (Hochst.) Baill (8 each), Mangifera indica L., Markhamia lutea (Benth.) K. Schum., Aloe vera and Erythrina abyssinica DC. (7 each). Table 2: Medicinal plants used by TMP to boost the immune system in immunocompromised patients living with HIV/AIDS 3.3 Preparation and administration of traditional herbal medicines by TMP Decoctions (boiling) single plant species was the most commonly used method of preparation used (43.8%). This was followed by teas/infusions (20.0%), decoctions with other herbs Jo (18.8%). A peculiar method of preparation was the use of clay “tablets” locally called “mumbwa” in the Luganda language (Plate 1). The TMP make clay tablets by crushing particular herbs and mixing them with wet clay. The tablets are then moulded and dried (3.8%). The use of clay tablets was only recorded in central and eastern Uganda. Although most of the medicines were prepared with water, occasionally honey and milk were used. Honey served as a medicine, excipient and a sweetener to improve palatability. 3.4 Diagnosis and treatment of PLHIV with herbal 4 The herbalists used one’s HIV sero-status as a proxy for immunosuppression even if the patients were asymptomatic. Most of the TMP (77%) relied on laboratory tests from modern health facilities for confirmatory diagnosis of the patients’ sero-status. The majority of the herbalists (85.6%), reported that some of their patients were taking both ARV and herbal medicines. The patients often disclosed their sero-status to the TMP. Patients took herbal preparations mainly to improve their general wellbeing and quality of life. Improvement in the immune system was inferred from reduced frequency of illness, improved appetite, strength and vitality, as well as remission of some of the opportunistic infections. The herbalists also claimed that there was a reduction in severity of the ARV side effects experienced by patients of such as nausea and fatigue experienced by the patients when they used herbal medicines. Table 3 presents a cross-reference of the medicinal plant species and any known ro immunostimulatory or other relevant pharmacological effects and other ethnomedicinal uses in relation to HIV/AIDS. -p Table 3: Cross reference of medicinal plants species used to boost the immune system in PLHIV in Uganda re 4.0 Discussion 4.1 Medicinal plant species used and knowledge of TMP ur na lP The use of medicinal plants species to boost immunity and stimulate appetite in PLHIV has previously been reported [6,15,371]. Most of the plant species in this study are widely used in different parts of Uganda for treating various diseases [371,372]. They have several pharmacological activities that have been reviewed in table 3. The most frequently used plant species have the following pharmacological, phytochemical and toxicological profiles properties: P. guajava contains meroterpenoids with antitumor activity [278]. It also has antibacterial Jo [279], antiinflamatory [280] and immunomodulatory properties [281]. Z. chalybeum has skimmianine with in vitro antiviral activity against measles virus [341]. W. ugandensis is immunostimulatory [145], antimicrobial [146] and anti-inflammatory [147]. It contains several phytochemicals such as ugandensolide, ugandensidial, muzigadial, polygodial, waburganal and cinnamolide [148,149] A. hockii has antipyretic properties [206] with no available reports on other pharmacological properties and toxicology. However, other Acacia spp have been shown to have anti-HIV activity. They include A. catechu which suppresses HIV-1 infection 5 in vitro [373], A. auriculiformis [374] and A. mellifera [375] with in vitro anti-HIV activity. M. indica has antimicrobial [64], anti-inflammatory and immunomodulatory properties. M. indica extracts are administered as nutritional supplement in AIDS and cancer [65] and contain several phytochemicals such as protocatechic acid, catechin, mangiferin and γ–aminobutyric acid [63]. M. lutea has been shown to have antiviral properties with various phenylpropanoid glycosides such as luteoside A, B & C [137]. B. micrantha has antiviral-against HIV-1 reverse transcriptase [289]. It also has antidiarrhoeal, antiinflammatory, antimalarial, antinociceptive properties [290] and is rich in phenolics [291], alkaloids, flavonoids, steroids, tannins & saponins [292]. A. vera has antiinflamatory properties and stimulates immunity [353,354]. E. abyssinica has anticancer properties due to the presence of compounds such as pterocarpans of [217] and antimicrobial properties due to the presence of compounds alkaloids such as tannins ro alkaloids and flavones [88]. The TMP considered remission of opportunistic and improvement of general wellbeing of -p patients to be as a result of an improved immune system. However, there is a possibility that the herbs may have a direct antiviral effect on HIV. The in vitro antiviral activity of medicinal re plants has been demonstrated in different studies [289,376]. Ten of the plant species documented have proven antiviral activity against a range of viruses including hepatitis B, ur na lP measles and even HIV-1. The plant species with antiviral activity are: A. sativum [44], L. barteri [59], S. pyroides [68,69], E. angustifolia antiviral [117], M. lutea [137], P. granatum [260], B. micrantha (anti-HIV-1 RT [289], R. cordifolia (hepatitis B) [325], and Z. chalybeum (measles) [341]. There is also a likelihood that the reported concurrent use of ARV and herbal medicines by patients leads to a reduction the viral load causing a rebound of the immune system. All these plant species have no reported cases of toxicity and are considered safe from animal Jo studies (Table 3) with the exception of A. vera where cases of toxicity have been reported in both mice and humans in the form of acute hepatitis [355,356,358], B. micrantha with mild toxicity reported in brine shrimp assays [72,293] and Z. chalybeum which is associated with impaired kidney function and neoplasms in experimental animals at high doses [342,343]. 4.2 Methods of preparation of medicinal plant extracts by TMP Medicinal plant products were prepared by boiling them either singly or in combination with 6 other herbs. The practice is common for TMP preparing HIV medications [23,70,79]. The consumption of clay of geophagy apparently is ancient and widely practiced in many parts of the world for religious and medicinal purposes and part of routine diet [377]. Abrahams [378] and Anywar et al. [23] have reported the ingestion of clay for therapeutic purposes in Uganda. In some instances, the moulded clay tablets were smoked. Abrahams [378]made similar findings in his study but also observed that the moulded “tablets” were marked in various distinct ways as a way of labelling them to distinguish them from others. Many soils eaten in Uganda and other parts of Africa are typical tropical red soils, which are normally rich in silica but widely, varying in elemental composition [379]. However, the kinds of of soils observed in this study were typically greyish clay soils. Such soils are high clay content are generally richer in magnesium. In addition, some of the clays are similar in composition to ro kaolin or china clay, which is a natural form of the hydrated aluminium silicate used in certain commercial diarrhoea medications [379]. In fact, clay can is used as a traditional antidiarrheal -p agent to treat acute gastroenteritis [380]. Clay serves as a preservative and binding agent for the herbal medicine [23,378], an adsorbent or detoxifier of herbal medicines [381] or to give re the medicine a distinctive smell desired by the consumer [378]. Red soils have the ability to ur na lP prevent iron deficiency in anaemia [382,383]. However, despite the widespread belief in the benefits of geophagy, especially among pregnant women in Africa, they could have limited bioavailability [382]. According to Minnich et al. [384], soils have the ability to enhance or inhibit the absorption of different elements iron absorption such as iron or potassium depending on their cation exchange capacity. This can affect the recommended dietary allowance of certain minerals in the body. Geophagy has also been associated with some nutritional disorders as well as the risk of ingesting contaminants [385], which may be radioactive substances [386] and exposure to soil-borne or geohelminth Jo infection [387]. 4.3 Treatment of PLHIV with herbal medicines The TMP prescribed herbal remedies in immunocompromised PLHIV to stimulate appetite, boost immunity and helping in regaining strength and recuperating. The patients sought ways to neutralize the side effects of the ARV by taking herbs. This is common practice in many African countries [23,388]. Patients also trusted herbal medicines and considered them effective, more readily available and affordable. Langlois-Klassen et al. [389] reported that 7 PLHIV used herbal medicines because of their familiarity with them and the desire to quickly relieve the symptoms they suffer. Generally, there is increasing use of herbal remedies in PLHIV [23,25], who report improvement in their conditions after treatment [24]. This could partly explain why PLHIV commonly look for an alternative traditional medicine parallel to conventional therapy [24]. It is also widely acknowledged that TMP provide healthcare to a substantial proportion of PLHIV in high HIV burden countries in sub-Saharan Africa [390]. 4.4 Properties and mode of action of medicinal plant species used as immune immunomodulators Of the 71 plant species, one third (22, 31.0%) have direct references in the literature pertaining of to their in vitro or in vivo immunomodulatory properties. Additionally, 17 species (23.9%) have antimicrobial or antimycobacterial properties, 11 (16.2%) have anticancer or antiproliferative ro properties, 17 (23.9%) with antimalarial or antiplasmodium activities and 16 (22.5%) have antiviral or anti-HIV activity. Other ethnobotanical studies cited point to the fact that most of -p the medicinal plants are used in treating various HIV/AIDS opportunistic infections [23,70,79]. Although some of the therapeutic or pharmacologic activities of the medicinal plants re mentioned do not play a direct role as immunomodulators, they may be beneficial in promoting health of PLHIV. For instance, plants with antimicrobial or antimycobacterial properties are ur na lP useful in PLHIV because they are frequently afflicted by opportunistic infections caused by such pathogens or cancers [3]. The plasmodium parasite impairs the immune system’s ability to trigger an efficient immune response [391]. Different mechanisms by which medicinal plant species exert their immunostimulatory effects have been studied. Some medicinal plant extracts may have significant immunostimulatory effect on both the cell-mediated and humoral immune systems in vivo [272] Others medicinal plant species may exert their immunostimulatory effects via different mediators such as the Jo induction of IFN-α and β [392], or the production of IFN-γ & IL-4 [145]. Medicinal plant extracts may also activate the immune system by; (i) triggering the alternating complement pathway and raising the number and distribution of white blood cells, and (ii) stimulating phagocytosis, T-cell production, lymphocytic activity, cytokine production, cellular respiration & enzyme secretion [116]. 4.5 Toxicity and safety of used medicinal plant species We did not find any literature on the toxicity of 15 of the plant species documented. Forty8 three of the species documented were reported to be safe or non-toxic in various studies where they were evaluated for acute and sub-acute oral toxicities mainly in animal models. The remaining 13 plant species: A. boonei, S. hadiensis, K. africana, J. curcas, M. esculenta, P. edulis, B. micrantha, H. acida, S. longipedunculata, C. articulata, Z. chalybeum, U. massaica and A. vera were reported to have varying degrees and types of toxicity, depending on the dose administered, plant part used, extraction solvent and duration of exposure as reported in table 3. For instance, although P. edulis leaves were reported to be toxic in the review [287,288], the locals in this study were using the fruits and roots as medicine. Although the roots of M. esculenta is reported to be toxic [204], the locals were using the leaves as medicine. Besides, they have over the years selected less-toxic varieties but also devised means to detoxify the of roots through prolonged boiling for example. The levels of toxicity reported also vary with dosage. It is not surprising therefore that herbalists try to regulate the doses of the medicinal ro plants they administer. -p 1.2 Potential herb-drug interactions with concurrent use of herbal medicines and ARVs Orthodox medical doctors are concerned about the potential of herb-drug interactions, which re are likely to increase with the increasing availability of ARVs and use of herbs [70]. Some medicinal plant species have been shown to have undesirable or even harmful effects when ur na lP combined with ARV. A case in point is the ARV, Indinavir, which is a protease inhibitor that is a substrate for both P-gp and CYP3A4. Pharmacokinetic interactions between indinavir and herbs such as garlic decrease its bioavailability [393]. This will have the obvious effect of making the drug less effective because the correct dose will not be achieved. However, the specific pharmacokinetic and pharmacodynamic interactions between various herbal medicines or combinations of herbal medicines and ARVs have mostly not been investigated. It is therefore important to be mindful of such potential herb-interactions when using herbs or Jo ARV. 4.8 Conclusion Herbalists widely prescribe medicinal plant species for boosting or restoring the immunity in PLHIV in Uganda. There is scientific evidence to support the use of many of the plant species as immunostimulants, from pharmacological and clinical studies. In addition, these plant species also have other pharmacologically important properties that support the immune function such as; anti-HIV, antimicrobial and anticancer activities and creation of awareness about the possible dangers of geophagy and polypharmacy. We therefore recommend further 9 studies to scientifically validate the immunostimulatory effects of the medicinal plant species used by the TMP. All research done by the authors with financial support from the Consortium for Advanced Research Training in Africa (CARTA) and DAAD: Funding Source All sources of funding should also be acknowledged and you should declare any involvement of study sponsors in the study design; collection, analysis and interpretation of data; the writing of the manuscript; the decision to submit the manuscript for publication. If the study sponsors had no such involvement, this of should be stated Authors: All research done by the authors; ro Financial support: yes; Author statement re -p Re: Author statement on submission of revised manuscript titled “Medicinal plants used by traditional medicine practitioners to boost the immune system in people living with HIV/AIDS in Uganda.” On behalf of my co-authors, I wish to state that all the comments made by the reviewers ur na lP of our manuscript have been duly attended to. A revised version of the manuscript has been uploaded attached, together with other additional documents requested for by the reviewer like the map of the study site. All the revisions have been highlighted in yellow. A corresponding detailed response to the reviewer’s comments has also been uploaded indicating point by point, the reviewer’s comments and the response made and where exactly it is located in the manuscript Conflict of interest: none Jo Conflict of Interest A conflicting interest exists when professional judgement concerning a primary interest (such as patient’s welfare or the validity of research) may be influenced by a secondary interest (such as financial gain or personal rivalry). It may arise for the authors when they have financial interest that may influence their interpretation of their results or those of others. Examples of potential conflicts of interest include employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding. 10 Word count: 3092 without references & abstract Acknowledgement This research was supported by the Consortium for Advanced Research Training in Africa (CARTA). CARTA is jointly led by the African Population and Health Research Centre and the University of the Witwatersrand and funded by the Carnegie Corporation of New York (Grant No--B 8606.R02), Sida (Grant No: 54100113), the DELTAS Africa Initiative (Grant No: 107768/Z/15/Z) and Deutscher Akademischer Austauschdienst (DAAD). The DELTAS Africa Initiative is an independent funding scheme of the African Academy of Sciences (AAS)’s Alliance for Accelerating Excellence in Science in Africa (AESA) and supported by the New Partnership for Africa’s Development Planning and Coordinating Agency (NEPAD of Agency) with funding from the Wellcome Trust (UK) and the UK government. The statements made and views expressed are solely the responsibility of the Fellow. ro We also acknowledge and thank the research assistants Kasozi Dauda, Kibuuka Sserwano Moses, Kizito Medi, Onenarach Walter & Opio Henry, for their dedicated work. We are also -p grateful to the TMP who gave their consent to take part in this study and to share their ur na lP re knowledge with us. Jo Reference: [1] M.S. Al-Haddad, F. Hamam, S.M. Al-Shakhshir, General public knowledge, perceptions and practice towards pharmaceutical drug advertisements in the Western region of KSA, Saudi Pharm. 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[23]. 38 of ro -p re ur na lP Jo Plate 1: Various clay tablets consumed by people living with HIV/AIDS in Uganda 39 Table 2: Languages spoken & Number of TMP interviewed by districts Districts & Location 1. Arua 2. Dokolo 3. Mbale 4. Iganga 5. Bushenyi 6. Rakai 7. Luwero 8. Kaabong Language spoken Lgbara Luo (Langi) Lugisu Lusoga Runyankore Luganda Luganda Ik No. of TMP interviewed 11 10 10 15 13 6 13 12 Table 2: Medicinal plants used by TMP to boost the immune system in people living with HIV/AIDS in Uganda 8. Searsia pyroides (Burch.) Moffett (AG381) H L Jo Asteraceae 14.Artemisia annua L. (AG392) 15.Arctium lappa L. (AG428) 16.Conyza pyrrhopappa Sch.Bip. ex A.Rich. (AG397) 17.Echinacea angustifolia DC. (AG419) 18.Senecio hadiensis Forssk (AG451) 19.Vernonia amygdalina Delile (AG405) Basellaceae 20.Basella alba L. (AG393) Bignoniaceae 21.Kigelia africana (Lam.) Benth. (AG401) 22.Markhamia lutea (Benth.) K.Schum. (AG367) 23.Stereospermum kunthianum Cham. (AG394) Canellaceae 24.Warburgia ugandensis Sprague (AG383) Fr Method of Preparation of Doodo [Lug] H H Sd L 2 1 Boil & eat large amounts regularly Boil with porridge/pop seeds Infusion made & drunk. H H Blb Blb 5 3 Crushed & mixed in honey Crushed & mixed in honey Mukontambaale [Lus], Kibumbu [Gis] Muyembe [Lug, Lus, Gis], Mengu [Lgb], Mahembe [Lan] Kakwansokwanso [Lug] T T B B, L 4 7 Sh L, B 1 Boiled & drunk Boil powder singly/with other herbs & drink Boiled & drunk Kutukumwe [Ru] H L 1 Boiled & drunk Mugajjangalabi [Lug] Kafulu [Gis, Lus, Lug] T H B R 4 4 Boiled & drunk Boiled & drunk Mulondo [Lug, Lus], Orono [Lan] Cl R 3 Pound, mix with water & drunk Kajjolyenjovu [Lug], Mugorora [Ru] T B, R 3 Boil with other herbs (drink)/clay tablets (chew Artemesia* Burdock* Kafugankande [Lug], Muhe [Ru], Yagyag [Lgb] Echinacea* Mugina/mubiri [Lug], Mululuza [Lug], Mubiriizi [Ru] H H H 2 1 5 Drink hot water infusion Boil & drink Boil with other herbs & drink H H Sh L R L, B, R R, L L L 1 1 4 Make tea Boil, squeeze out juice & drink Make tea Nderema [Lug] H L 5 Pound, mix in water & drink Mussa [Lug], Mufungedha/ Omwisa/Mussa [Lus], Ibologo [Lgb] Kufunga/Mwisa [Gis], Omwisya [Ru] Lusoola [Bisu], Sambya [Lgb] Kinyasira [Ru], T Fr 11 Boil & drink T T R B 7 1 Boil with other herbs & drink Boil & drink Abasi/Omuya [Lug], Balwegiira [Lus], Mwiha [Ru], Abac [Lang] T B 8 Boil & drink Amaranth*/Doodo [Lug] Mwenza [Ru] Katunguluchumu [Lug], Tungl [Lan] Katungulu [Lug] ur na lP Apiaceae 9. Centella asiatica (L.) Urb. (AG388) Apocynaceae 10.Alstonia boonei De Wild. (AG390) 11.Cryptolepis sanguinolenta (Lindl.) Schltr. (AG480) 12.Mondia whytei (Hook.f.) Skeels (AG373) Asparagaceae 13.Dracaena steudneri Engl. (AG385) PU Capparaceae 40 1 ro 2. Amaranthus sp. (AG362) 3. Aerva lanata (L.) Juss. (AG369) Amaryllidaceae 4. Allium sativum L. (AG391) 5. Allium cepa L. (AG370) Anacardiaceae 6. Lannea barteri (Oliv.) Engl. (AG377) 7. Mangifera indica L. (AG401) Hb -p Acanthaceae 1. Amaranthus dubius Mart. ex Thell. (AG361) Local Names in respective languages re Family, Scientific Name (Voucher No.) 31.Cucurbita maxima Duchesne (AG406) Euphorbiaceae 32.Jatropha curcas L. (AG429) 33.Manihot esculenta Crantz (AG426) Fabaceae 34.Acacia hockii De Wild. (AG428) 35.Acacia amythethophylla A.Rich. (AG406) 36.Acacia polyacantha subsp. campylacantha (A.Rich.) Brena (AG486) 37.Acacia seyal (L.) Willd. (AG570) 38.Albizia coriaria Oliv (AG366) 39.Erythrina abyssinica DC. (AG418) Boil with millet porridge & drink Njagga [Lug], Endaaye [Lus] H L 1 Boil with B. micrantha & drink Paapali/Mupaapali [Lug, Lus, Gis], Apapalo [Lan], Paipai [Lug] T Fr 2 Boil & drink Mbaluka [Ru] Sh B 7 Boil & drink Odugu [Lan] T Ap 4 Boil & drink Kiyondo-ekyeru [Lug], Kisanaasana [Lus] H L 4 Boil & drink Local Names in respective languages Nsujju [Lug] Hb PU Fr Method of Preparation Sc Fr 2 Eat/ Boil with other herbs Kiroowa [Lug] Muwogo [Lug] T Sh Sd L Kaasana [Lug], Okuto atino [Lang] T B Sh Sh R R Muwologoma [Lug] Kibere [Lug], Morigo [Lgb] Jo 46.Micromeria biflora (Buch.-Ham. ex D.Don) Benth. (AG416) Lauraceae 47.Persea americana Mill. (AG421) Lythraceae 48.Punica granatum L. (AG423) Moraceae 49.Milicia excelsa (Welw.) C.C.Berg (AG431) Moringaceae 50.Moringa oleifera Lam (AG408) Myrtaceae 51.Psidium guajava L. (AG419) Passifloraceae 52.Passiflora edulis Sims (AG365) Phyllanthaceae 53.Bridelia micrantha (AG452) 54.Flueggea virosa (Roxb. ex Willd.) Royle (AG430) 55.Hymenocardia acida Tul. (AG411) 56.Phyllanthus ovalifolus Forssk. (AG376) Polygalaceae 2 1 Drink cold-water infusion & Boil & drink 8 2 2 Boil & drink/mix with other herbs Boil/Make clay tablets Boil & drink Naibeere [Lus] Mugavu [Lug], Musiita [Lus], Kiluku [Lgb] Jjirikiti [Lug], Murinzi/ Muko [Ru], Oluo [Lgb], Muyirikiti [Lus] Mwolola [Lug] Kibundabunzi [Ru] Sh L,B, Fr T B, L 4 3 Boil & drink Boil & drink T B 7 Boil & drink T Sh B L 1 1 Pound, boil & drink Boil & drink Mukuna [Lug] Nkooge [Lug] Eti [Lgb] Kiyugeyuge [Lus], Nazaka [Lgb] H T Cl Sd B, L B, R 1 3 3 Tea from roasted seed powder Boil & drink Boil singly/with other herbs/ add powder milk &drink Kamunye [Lug], Nfoodo Esitimwe [Ru] Shagamanungi [Ru] H L 1 Boil & drink H L 1 Boil & drink Ovakedo [Lug], Vadeko [Lus, Gis] T Sd, B 2 Boil & drink Mukoma mawanga [Lus] Sh R, Fr 1 Boil & drink Muvule [Lug, Lgb] T L 2 Boil & drink Molinga* T L, R 4 Boil & drink /add in sauce/stew Mupeera [Lug], Ipeera [Ru] T F 11 Eat fresh Katunda [Lug, Lus] Cl R, Fr 4 Chew/Juice/ boil & drink Katazamiti [Lug] Lukandwa [Lug] Nabbaluka/ [Lug] Mutulika [Lug] T Sh T Sh L, B Tw R L 8 2 1 4 Boil for about 2.5 hrs & drink Boil with M. indica & drink Boil & drink Boil & drink ur na lP 40.Entada abyssinica A.Rich (AG387) 41.Kotschya aeschynomenoides (Bak.) De Wild. & Devign (AG359) 42.Mucuna pruriens (L.) DC. (AG409) 43.Tamarindus indica L. (AG403) 44.Tylosema fassoglensis (Schweinf.) Torre & Hillc. (AG414) Lamiaceae 45.Hoslundia opposita Vahl (AG413) 1 of Cucurbitaceae Family, Scientific Name (Voucher No.) R ro Celastraceae 28.Cassine aethiopica Thunb. (AG374) Combretaceae 29.Combretum collinum sub sp. elgonense (Exell) Okafa (AG416) Crassulaceae 30.Kalanchoe densiflora Rolfe (AG427) Sh -p Cannabaceae 26.Cannabis sativa L. (AG410) Caricaceae 27.Carica papaya L. (AG378) Mukolokombi [Lug], Mukorokombi [Ru], Ogadaman [Lan] re 25.Capparis tomentosa Lam. (AG379) 41 [Lus], 57.Rumex usambarensis (Dammer) Dammer (AG368) 58.Securida longipedunculata Fresen. (AG363) Rubiaceae 59.Fleroya rubrostipulata (K.Schu) Y.F.Deng (AG404) 60.Gardenia ternifolia subsp. jovis-tonantis (Welw.) Verdc. (AG453) 61.Rubia cordifolia L. (AG454) 62.Sarcocephalus latifolius (Sm.) E.A.Bruce (AG415) Rutaceae 63.Citropsis articulata (Willd. ex Spreng.) Swingle & M.Kellerm (AG439) 64.Zanthoxylum chalybeum Engl. (AG632) Urticaceae 65.Urtica massaica Mildbr. (AG389) Family, Scientific Name (Voucher No.) Mufumbi-egyesha [Ru] H L Mukondwe [Lug] T R 1 Boil with millet porridge & drink Boil & drink /make clay tablets Muziko [Ru] T B 3 Boil & drink/ tea Mulema /Mulemanjovu [Lug] T B 6 Boil & drink Kasalabakessi [Lus] Mutaamataamu [Lus] Cl Sh Ap R 2 1 Boil /make tea. Add powder to in sauce/stew Mubolo [Lug] Sh B 3 Boil & drink Entale ya ddungu [Lug] T B, R 11 Boil with other herbs/singly Kicuragyenyi [Ru] Local Names in respective languages H Hb L PU 1 Fr Eat as a vegetable/add to food Method of Preparation Jo ur na lP re -p ro of Verbenaceae 66.Lantana trifolia L. (AG375) Kayukiyuki [Lug] H L 1 Boil with other herbs & drink Xanthorrhoeaceae 67.Aloe vera (L.) Burm.f. (AG398) Kigagi [Lug], Tikorotot [Ik] H L 7 Boil with other herbs/singly 68.Aloe dawei A.Berger (AG380) Kigagi [Lug] H L 1 Boil & drink 69.Aloe sp. (AG399) 1 1 Zingiberaceae 70.Curcuma longa L. (AG383) Ocaoayom [Lan] H Rh 1 Pound, soak in water & drink Zygophyllaceae 71.Balanites wilsoniana Dawe & Sprague (AG400) Naggwalimu [Lug] T L 1 Boil with other herbs & drink Key: Habit (Hb): Cl – Climber, H–Herb, Sc–Scrambler, Sh–Shrub, T–Tree, Part Used (PU): Tw– Sd–Seed, B–Bark, Twigs, L=Leaves, F–Fruit, Fr–Fronds, Rt–Root, Pl–Peel, Ap –All aerial parts:. Blb–Bulb, Rh–Rhizome; Fr – Frequency of mention, * No local name. Western name adopted Languages: [Gis] –Lugishu, [Lus] –Lusoga, [Lug] –Luganda, [Lgb] –Lugbara, [Lan] – Langi, [Ik] –Ik, [Ru] –Runyankore. NB: Water is used for preparing all the herbal medicines unless otherwise stated 42 Jo ur na lP re -p ro o f Table 3: Cross reference of medicinal plants species used to boost the immune system in PLHIV in Uganda Family & Scientific name Relevant pharmacological activity, Toxicity phytochemistry Acanthaceae 1. Amaranthus dubius Mart. Antifungal & antibacterial [28]. Alkaloids, No reports. However, A. hybridus is not toxic against brine ex Thell. flavonoids, steroids, tannins [29], rutin [30]. shrimp (LC50 6233.6 μg/ml) [31]. 2. Amaranthus sp. No reports No reports 3. Aerva lanata (L.) Juss. Immunomodulatory [35], anti-inflammatory [36] The aqueous extract is relatively safe on acute oral exposure, antimicrobial [37] antidiarrheal [38] LD50 = 22.62 g/kg body weight (bw), moderately toxic on hepatoprotective [39], anti-HIV, [40]. Phenolics, acute intraperitoneal (i.p) administration (LD50 = e.g. gallic acid, apigetrin, rutin & myricetin, 0.432 g/kg bw), but relatively safe during prolonged phytosterols, antimycobacterial [41]. exposure in albino mice [42]. Amaryllidaceae 4. Allium sativum L. In vitro viricidal effects & antiviral activity. A. sativum generally safe [47] but some side effects of Diallyl thio-sulfinate (allicin), allyl methyl excessive ingestion in humans include gastrointestinal thiosulfinate, methyl allyl thiosulfinate, ajoene, discomfort, nausea, bloating, headache, dizziness, profuse alliin, deoxyalliin, diallyl disulfide, & diallyl sweating, life-threatening haemorrhage when used with trisulfide [43], antimicrobial [44] antiproliferative anticoagulants [47–49]. [45], immunomodulatory [46]. 5. Allium cepa L. Quercetin, phenolics [53]. Antimicrobial [44] The crude extract is cytotoxic against tumoral Lucena MDR immunomodulatory [54]. human erythroleukemic & K562 cell lines [55]. Anacardiaceae 6. Lannea barteri (Oliv.) Tannins, flavonoids, steroids, quinones, saponins Orally administered methanol extracts were non-toxic (LD50 Engl. & alkaloids [58,59]. Antiviral [59], antibacterial > 2500 mg/kg bw) in acute toxicity tests in Swiss albino [60], anticonvulsant [61]. mice [62]. The i.p administered ethanol extract (LD50 = 565.7) was toxic to the same mice [61]. 7. Mangifera indica L. Protocatechic acid, catechin, mangiferin, alanine, Leaf extracts are non-toxic in ICR mice in acute & long-term glycine, γ–aminobutyric acid [63], triterpenoid & toxicity studies up to 18.4 g/kg bw [66] & not genotoxic or flavonoids. Antimicrobial [64]. Anti- clastogenic in vivo in mammalian micronucleus test up to inflammatory & immunomodulatory. Nutritional 2000 mg/kg bw [67]. supplement in AIDS & cancer [65]. 8. Searsia pyroides (Burch.) Antiviral bioflavonoids e.g. agathisflavone, No reports Moffett amentoflavone, hinokiflavone, rhusflavanone & succedaneaflavone [68,69]. Apiaceae 43 Relevant reported traditional uses Anaemia [32]. Malaria [33]. Widely consumed nutritious vegetable [34]. Inappetence, cough, nausea, flu [23]. Inflammation, skin diseases, dysentery & diarrhoea [35]. Febrile convulsions [50], infections [51], cough [52]. TB [56], malaria [57]. Diarrhoea, wounds, gastritis [58] fever [23]. Cough, convulsions [32,50], malaria [33], dysentery, stomach ache, anaemia, diarrhoea, skin infections [23]. Malaria [33], HIV/AIDS [70], diarrhoea, wounds [71], dysentery [72], skin rash [32] stomach ache [50]. 11. Cryptolepis sanguinolenta (Lindl.) Schltr. 12. Mondia whytei (Hook.f.) Skeels Asparagaceae 13. Dracaena steudneri Engl. 15. Arctium lappa L. 16. Conyza pyrrhopappa Sch.Bip. ex A.Rich. f Relevant reported traditional uses Ulcers [32], malaria [78], HIV/AIDS [70,79], dermatitis [50], skin infections [23]. Toxic to rats at high doses [84].Various fractions of A. boonei extracts were both hepatotoxic & nephrotoxic in rats at 400 mg/kg bw [85]. The aqueous root extract is generally safe in Sprague Dawley rats (LD50 > 3000 mg/kg bw) [91]. Malaria [23,32,86]. Aqueous extracts were non-toxic in acute & sub-chronic toxicity studies on Wistar rats at single dose exposure up to the limit 5000 mg/kg after 90 days [96]. Loss of appetite [23,32], fever, malaria, infections [23,90]. Antifungal [97]. No reports Cough, syphilis, skin infections, TB, cough [23,32], malaria [33]. Immunomodulatory with flavonoids, phenolics, artemisinin [98], antiplasmodial [99], antimicrobial [100], anticancer [101]. The hydro-ethanolic extract was not toxic in Swiss mice up to 5000 mg/kg bw [102]. The essential oils have low relative toxicity in mice when administered i.p (LD50 = 1400 & 1832mg/kg for different samples [103]. Artemisinin is relatively safe & nontoxic in humans (LD50 > 5000 mg/kg [104]. The ethanolic root & fruit extracts are not toxic to SpragueDawley albino rats [111] & Wistar rats (LD50 > 5000 mg/kg) in oral acute & sub-acute toxicity tests [112]. Very few side effects from root preparations can occur in humans [113]. No reports Malaria [33], wounds, intermittent fevers [105]. Alstonine [80], alkaloids, saponins, flavonoids, tannins, glycosides, resins, steroids & triterpenes [81]. Anti-inflammatory [82] & antiarthritic [83]. Antiplasmodial containing with cryptolepine, cryptoheptine, like [87], antimycobacterial with tannins & flavonoids [88], antimicrobial with polyuronides, anthocyanosides & triterpenes [89], anti-inflammatory [90]. Antiinflamatory & antibacterial [93]. 2-hydroxy4-methoxybenzaldehyde [94] phenolics, flavonoids & tannins [95]. Jo ur Asteraceae 14. Artemisia annua L. re -p ro o Apocynaceae 10. Alstonia boonei De Wild. Toxicity The acetone extract was non-toxic in Swiss mice (LD50 < 4000mg/kg bw) [76]. Crude extracts were non-toxic to normal human lymphocytes [77]. lP 9. Centella asiatica (L.) Urb. Relevant pharmacological activity, phytochemistry Asiatic acid, asiaticoside & madecassic acid [73]. Tannins, essential oils, phytosterols, mucilages, resins, flavonoids, an alkaloid (hydrochotine), vallerine, fatty acids (linoleic acids, linoleic, oleic, palmitic and stearic acids) [74] Immunomodulatory [75]. na Family & Scientific name Anti-HIV-1, Wedelolactone, orobol [106], antiinflammatory [107], immunomodulatory [108]. Phytoalexins [109], lignans; arctigenin, matairesinol, arctiin, lappaol A, C & F [110]. Saponins, tannins, alkaloids, steroid glycosides, flavonoid, anthrasenosides, triterpenes [115]. 44 Malaria [92], fever, malaria, infections [90]. Arthritis & cancer in Traditional Chinese Medicine [110], infections [114]. Malaria [33], diarrhoea, headache [23]. 18. Senecio hadiensis Forssk 19. Vernonia auriculifera Hiern Basellaceae 20. Basella alba L. Antimicrobial, sesquiterpene amine farnesylamine, lupenyl acetate, oleanolic acid, βamyrin acetate, amyrin, friedelanone, friedelin acetate, α-amyrin & β-sitosterol [127], 8desacylvernodalol [128]. na Wound healing, anti-viral, anti-ulcer, antiinflammatory & hepatoprotective [131]. Alkaloids, phenols, flavonoids [132]. Antibacterial & antifungal immunomodulatory [134]. Jo ur Bignoniaceae 21. Kigelia africana (Lam.) Benth. [133], 22. Markhamia lutea (Benth.) K. Schum. Antiviral with phenylpropanoid glycosides e.g. luteoside A, B & C [137]. Anti-parasitic [138]. 23. Stereospermum kunthianum Cham. Antiplasmodial, anticonvulsant with naphthoquinones & anthraquinone [140]. Antimicrobial [141]. Antiinflamatory [142] Sterols/ triterpenes, coumarins [143]. Relevant pharmacological activity, phytochemistry Family & Scientific name f Toxicity re -p ro o 17. Echinacea angustifolia DC. Relevant pharmacological activity, phytochemistry Immunostimulatory [116], antiviral [117], antifungal & antibacterial [118]. Alkamides; caffeic acid esters, particularlyechinacoside; cynarin; polysaccharides; polyacetylenes [119]. Anti-inflammatory with sesquiterpenoids & presilphiperfolan [121]. Pyrrolizidine alkaloids [122]. lP Family & Scientific name Relevant reported traditional uses Single oral/i.v doses many times the human therapeutic doses of the juice were non-toxic to rats & mice after 4 weeks, with no mutagenicity/carcinogenicity reported in hamster embryo cells [120]. The pyrrolizidine alkaloids (PA) [122] in Senecio genus are acutely toxic, genotoxic & teratogenic to vertebrates & invertebrates [123]. Ingestion of PA in humans in herbal products is associated with acute & chronic liver toxicity [124]. No information is available on the possible irritant or toxic properties [129]. Colds, influenza infections [118]. No reports Stomach ache, constipation [32]. Low doses of aqueous fruit extract are safe but may have some hepatorenal toxic effects in Wistar albino rats at higher doses (500 mg/kg bw) [135]. Aqueous leaf extracts also potentially toxic to liver & kidney, LD50 > 3000 mg/kg bw [136]. No reports. However, 80% aqueous methanol leaf extract of M. platycalyx is non-toxic in Swiss albino mice [139]. HIV/AIDS [23,70], syphilis, stomach ache [50]. Sub-acute oral administration of aqueous bark extract was not toxic to rats after 28 days [144]. Toxicity Canellaceae 45 [117], respiratory HIV/AIDS OI [125], cancer [126], fatigue, stomach ache [23]. Fever [130], cancer [126], syphilis, fatigue [23]. Ear & eye infections [32], malaria [32,33], skin infections, anaemia, inappetence, stomach ache [23]. Bronchitis, pneumonia, coughs, gastritis, wounds, rheumatic arthritis, ulcers, dysentery & venereal diseases, febrile convulsions [142], malaria & fevers [23]. Relevant reported traditional uses Caricaceae 27. Carica papaya L. HIV/AIDS, coughs, TB, fevers, diarrhoea, skin rashes, sores, thrush & STI, herpes zoster, simplex [156,157], diarrhoea [23]. Antidepressant [158], anti-nausea [159], antinociceptive [160], anti-inflammatory & anti-HIV1 [161], immunomodulatory [162], anticancer [163], antibacterial [164]. Phytocannabinoids e.g. delta8-tetrahydrocannabinol, cannabigerol, cannabinol [165]. Frequent and prolonged use of cannabis produces both mental & physical impairment, mood disorders, exacerbation of psychotic disorders in vulnerable people, cannabis use disorders, withdrawal syndrome, neurocognitive impairments, cardiovascular & respiratory diseases [166,167]. Body weakness [32], cough, TB, pain, asthma, diarrhoea [23]. Antifungal, antimalarial [168], anticancer [169], Sub-acute oral toxicity tests of the leaf extracts in Sprague nephroprotective [170], immonomodulatory Dawley rats at up to 2 g/kg, (14 times the levels used in [168,171]. Polysaccharides, glycosides, saponins, traditional medicine in Malaysia is safe [173,174]. flavonoids & phytosterols [172]. Cough, low immunity, measles erectile dysfunction [32], abdominal pain [50], malaria [33], skin infections, ulcers, cough, anaemia [23]. Combretaceae 29. Combretum collinum sub sp. elgonense (Exell) Okafa Crassulaceae 30. Kalanchoe densiflora Rolfe f Leaf extracts were toxic to Nubian goats, sheep & calves when ingested given daily at doses ranging from 0·05 to 5g/kg/day. The main signs of poisoning were inappetence, muscular weakness, incoordination of movement, pain in the sacral region, dragging of the hind limbs, pallor of the visible mucous membranes & recumbency [154,155]. Jo ur Celastraceae 28. Cassine aethiopica Thunb. Antibacterial, wound healing [152]. Oxindole (3hydroxy-3-methyl4methoxyoxindole) [153]. re -p ro o Cannabaceae 26. Cannabis sativa L. Extracts are safe to use with no mortality at all dose levels (LD50 > 5000 mg/kg bw) in BALB/c mice [150]. lP Capparaceae 25. Capparis tomentosa Lam. Immunostimulatory [145], antimicrobial [146], anti-inflammatory [147]. Ugandensolide, ugandensidial, muzigadial, polygodial, waburganal, cinnamolide, mukaadial, muzigadiolide [148,149]. na 24. Warburgia ugandensis Sprague TB & HIV/AIDS [79,151], flu, cough [32], malaria [23,32,50]. No reports No reports Headaches [175], inappetence, syphilis, sexual dysfunctions [23]. Glucuronic, galacturonic & 4-Omethylglucuronic acid, galactose, arabinose, rhamnose, mannose, xylose & gum [176]. No reports Diarrhoea, pyomyositis & gonorrhoea [151], dysentery [177]. Anti-inflammatory [178], antibacterial, tannins, saponins, terpenoids, flavonoids and cardiac glycosides [179]. No reports but K. brasiliensis extracts had no acute toxicity on mice at 5 g/kg i.p [180]. Stomach & earache [23,181], wounds [182], fevers, cough, fatigue, ulcers, anaemia [23]. 46 33. Manihot esculenta Crantz Fabaceae 34. Acacia hockii De Wild. 38. Albizia coriaria Oliv f Relevant reported traditional uses Antimicrobial, antidiarrheal [183] cucurbitacins [184]. Flavonoids, saponins, tannins. Immunomodulatory & antitumour [185]. Cucurbitaxanthin a & b [186]. The seeds are non-toxic to mice after oral administration (LD50 > 5000 mg/kg bw [187] & pigs in oral acute & subacute tests [188]. Malaria [33], fatigue [23]. Anti-HIV [189], immunomodulatory [190], antiinflammatory [191], anticancer [192]. Jatrophalactone, Jatrophalone, Jatrophadiketone [193], Curcusone B [192], curcin [194], phorbol esters [195]. Anti-inflammatory [201]. Cyanogenic glycoside (i.e. linamarin & lotaustralin) [202], pentacyclic triterpenoids maesculentins A & B [203]. Known to be toxic. Aacute poisoning due to accidental ingestion of the seeds caused nausea, vomiting & abdominal cramps [196,197]. The purified phorbol esters isolated from the oil are highly toxic to Swiss Hauschka mice (LD50 = 27.34 mg/kg bw [195]. Has potentially toxic levels of cyanogenic glucosides, constituting linamarin (95% of total cyanogen content) and lotaustralin (5%) [204]. Malaria [198], arthritis [199], gonorrhoea, dysentery [200], fatigue [23]. Antipyretic [206]. No reports No reports TB & HIV/AIDS [23,70,79], oedema [32], anaemia [50]. Diarrhoea [23]. No reports Fatigue, gonorrhoea, skin infections [23]. The ethanol extract was cytotoxic to the non-tumour cell lines, (HUVEC), CC50 = 204 μg/ml) and MRC-5, CC50 = 575 μg/ml [209]. Albizia spp. contain a toxic compound, 4′Methoxypyridoxine that is a vitamin B6 antagonist [215]. Methanol seed extracts of 9 Albizia spp. have varying degrees of acute toxicity via the i.p & oral routes of administration in OF-1 Albino mice with various disorders e.g. nervous system disturbances, hepatic functional impairment. A. greveana (LD50 = 1.13-2 mg/kg) & A. tulearensis (LD50 = 2.9-3.2 mg/kg) were the most toxic [216]. Rheumatoid arthritis [211], fever, blood tonic, skin infections, diarrhoea, fatigue [23]. Skin rash [32,33], cough [52], malaria [33], HIV/AIDS [70,79], cancer, heart diseases, allergy, nausea, headaches, skin lesions, fatigue [23]. No reports No reports Antibacterial [207], antitumour anti-inflammatory [208,209], phenols, flavonoids [208], gum, arabinogalactan-protein [210]. Antiplasmodial [212]. Oleanane-type saponins, A and B, with anticancer [213]. Oriariosides saponin & gummiferaoside. Lupeol, Lupenone, Betulinic & Acacic acid lactone, (+) – Catechin and Benzyl alcohol [214]. Jo ur 35. Acacia amythethophylla A.Rich. 36. Acacia polyacantha subsp. campylacantha (A.Rich.) Brena 37. Acacia seyal (L.) Willd. Toxicity re -p ro o Euphorbiaceae 32. Jatropha curcas L. activity, lP Cucurbitaceae 31. Cucurbita maxima Duchesne Relevant pharmacological phytochemistry na Family & Scientific name 47 Fever [52], headache and pain [205], fatigue [23]. 39. Erythrina abyssinica DC. f Relevant pharmacological activity, Toxicity phytochemistry Anticancer, pterocarpans [217]. Antimalarial The root bark is relatively safe (LD50 = 776.2 mg/kg bw) in [218], anti-mycobacterial, alkaloids, tannins the acute toxicity tests on mice [88]. flavones [88]. Flavonoids [219]. re -p ro o Family & Scientific name 40. Entada abyssinica A.Rich Antimicrobial [220]. A diterpene kolavenol, trypanocidal [221], anti-inflammatory [222]. No toxicity in mice fed on 80% ethanol extract of E. abyssinica aerial parts up to 2000 mg/kg bw in Theiller’s original albino mice [223]. 41. Kotschya aeschynomenoides (Bak.) De Wild. & Devign 42. Mucuna pruriens (L.) DC. No reports No reports Antiadhesive against Helicobacter pylori [243]. 6-furanoflavones, hoslunfuranine, 5Omethylhoslunfuranine, hosloppin, hoslundin, oppositin [244–246]. Antibacterial [249], anti-inflammatory, analgesic & antipyretic. Essential oils sesquiterpenoids; Crude extract not toxic in Swiss albino mice at a dose of 2000 mg/kg bw [247]. na lP The ethanol seed extract had no mortality. Male albino Wistar rats showed normal behaviour at doses of 250 and 2500 mg/kg bw [228] after ingestion of the extract. The ethanolic leaf extract was nontoxic in Sprague Dawley rats (LD50 < 5 g/kg) [229]. Jo ur 43. Tamarindus indica L. Anti-inflammatory. Slows progression of Parkinson’s disease, immunomodulatory [224], hepatoprotective [225]. Tetrahydroisoquinoline alkaloids [226], L-DOPA & ursolic acid. Catechols, γ-Sitosterol, caprolactam, vanillin lactoside, protocatechuic acid [227]. Anti-bacterial, anti-inflammatory [231], immunomodulatory [232], chemoprotective [233]. Phenolics, proanthocyanidins, arabinose, triterpenes, apigenin, luteolin [234]. Antiplasmodial [240], essential oils [241]. Phytoestrogens, lignans secoisolariciresinol, lariciresinol & pinoresinol [242] 44. Tylosema fassoglensis (Schweinf.) Torre & Hillc. Lamiaceae 45. Hoslundia opposita Vahl 46. Micromeria biflora (BuchHam. ex D.Don) Benth. Relevant reported traditional uses Yellow fever, convulsions, anaemia, nausea [32], OI [70,79], malaria [33], TB, syphilis [50], mental illness, chest pain, skin, infections/ lesions, ulcers, cancer, stomach aches, diarrhoea, STI, fevers [23]. Weakness, oral sores [32], cough, fever/malaria, skin infections, wounds [32,50], HIV/AIDS OI [23,70], OI, cancer, mental illness, syphilis [23]. Diarrhoea [23]. Parkinson’s disease [230], mental illness, fatigue [23]. T. indica extracts are generally safe [235]. The alcohol Convulsions, stomachache [32,237], extract of stem bark showed no signs of toxicity up to of wound healing, malaria, fever [238] diarrhoea [23,238], cough, liver diseases 2000 mg/kg/p.o [233,236] [23], dysentery [238,239]. No reports Syphilis & jaundice [23,151], diarrhoea, fatigue, fever, convulsions, wasting [23]. Considered non-toxic. Both hydro-alcoholic extracts & essential oil did not cause any behavioural changes or deaths in acute & sub-acute toxicity tests in mice [250]. 48 Malaria [32,33], skin infections [23,32], diarrhoea, yellow fever [52], HIV/AIDS [79], oral disease [248], ulcers, anaemia & fatigue [23]. Kidney stones [251]. Moraceae 49. Milicia excelsa (Welw.) C.C.Berg Myrtaceae 51. Psidium guajava L. Passifloraceae 52. Passiflora edulis Sims f Immunomodulatory effects [252]. Antiinflammatory [253], antibacterial against H. plylori [254], antiproliferative properties [255], quercetin, rutin, luteolin, apigenin [256]. Seed extract not toxic (LD50 > 10 g/kg) in acute & sub-acute oral studies in rats [257]. Leaf extracts not toxic in oral & i.p toxicity studies in mice (LD50 > 10 g/kg) [253]. Not genotoxic [258] Cough [32], diarrhoea [125], HIV/AIDS OI [79], TB [23,259]. Antiviral [260], antimicrobial [261], immunomodulatory, antiiflamatory [262]. Phenolics [263], gallotannins, ellagitannins, ellagic acid & anthocyanins [264]. The fruit extract was not toxic in chick embryo model at doses < 0.1 mg/g in both male & female OF-1 mice (LD50 = 731 mg/kg) i.p [265]. Diarrhoea, inflammation, infections, dysentery, stomach ache, for healing wounds [266,267]. Wound-healing, antibacterial [268]. Atalantoflavone, neocyclomorusin, 6geranylnorartocarpetin, cudraxanthone & betulinic acid [269], tannins, saponins, flavonoid, terpenoids, cardiac glycosides [270]. Ethanol extract is not toxic (LD50 > 5000 mg/kg) in mice [271]. Skin rash, burns [23,32], malaria [33], wounds, diarrhoea OI [23]. Immunostimulatory [272], antibacterial with alkaloids, polyphenols, flavonoids, anthraquinones, coumarins, tannins, triterpenes, sterols, saponins [273]. Leaves are genotoxic at supra-supplementation levels of 3000 mg/kg bw but are safe at levels ≤ 1000 mg/kg bw in rats [274]. Aqueous leaf extract is relatively safe when administered orally (LD50 = 1585 mg/kg) in male Wistar albino mice [275]. In Swiss albino mice the LD50 of ethanol extract was 17.8 g/kg & 15.9 g/kg for the aqueous extract& thus non-toxic [276]. Malaria, fatigue, inappetence, cough [23,239], HIV/AIDs infections, chronic anaemia & cancer [277]. Meroterpenoids with antitumor activity [278]. Antibacterial [279] & antiinflamatory [280], immunomodulatory [281]. The aqueous leaf extracts were not-toxic to rats/mice (LD50 > 5 g/kg, p.o.), 100 times the recommended dose for the treatment of diarrhoea [282]. Cough, diarrhoea [50], epilepsy, skin rashes [23]. Antibacterial [273,283], hepatoprotective [284], anticancer [285], antifungal, anti-inflammatory [286]. Ionone-I & II, passifloric acid methyl ester Orally administered leaf extracts are not toxic in Wistar albino rats up to 2000 mg/kg bw [287]. Acute human toxicity of aqueous leaf extracts showed that 9 volunteers Weakness [32], skin rash [50], fatigue, diarrhoea [23]. Jo ur Moringaceae 50. Moringa oleifera Lam re -p ro o Lythraceae 48. Punica granatum L. Relevant reported traditional uses lP Lauraceae 47. Persea americana Mill. Toxicity na Family & Scientific name caryophyllene oxide, epi-α-cadinol, β-eudesmol, oplapanone, α-Terpeneol [250]. Relevant pharmacological activity, phytochemistry 49 54. Flueggea virosa (Roxb. ex Willd.) Royle 55. Hymenocardia acida Tul. 58. Securida longipedunculata Fresen. Family & Scientific name Rubiaceae 59. Fleroya rubrostipulata (K. Schum) Y.F.Deng f presented with enhanced values of serum amylase the day after ingestion indicating pancreatic tissue toxicity. However, it had no hypnotic-sedative effects to humans & animals [288]. Toxicity The dichloromethane (LC50 = 32.0 μg/ml) [293] & ethanol (LC50 = 30 µg/ml) root extracts [72] were mildly toxic to brine shrimp. Oral administration of the stem bark extract in male Wistar rats was well-tolerated without any deaths or clinical signs of toxicity after 48 hours at 2000 mg/kg [294]. Antiplasmodial with alkaloids: securinine & Orally administered extracts caused no death in rats up viroallosecurinine [296]. 10,000mg/kg bw in acute toxicity tests [297]. Antiamoeabic: tannins, steroids, alkaloids, H. acida extracts were toxic to brine shrimp (LD50 = saponins [298], antimycobacterial [299], 24.12µg/ml) & mutagenic in vivo [303]. antiinflamatory & antinociceptive [300], antiplasmodial [301], friedelanone & other triterpenoids [302]. No reports No reports, but other species e.g. P. amarus are non-toxic Antiviral-against HIV-1 RT [289], antidiarrhoeal, antiinflammatory, antimalarial, antinociceptive [290]. Phenolics [291], alkaloids, flavonoids, steroids, tannins & saponins [292]. Antibacterial [305]. Antifungal [97]. Jo ur 56. Phyllanthus ovalifolus Forssk. Polygalaceae 57. Rumex usambarensis (Da mmer) Dammer activity, lP Phyllanthaceae 53. Bridelia micrantha (Hochst.) Baill Relevant pharmacological phytochemistry na Family & Scientific name triterpenes, re -p ro o [283]. Polyphenols, flavonoids, sterols, saponins [285]. Antiplasmodial [308], anti-inflammatory [309], antimycobacterial [310], antibacterial [311]. Methylsalicylate [312]. Alkaloids, cardiac glycosides, flavonoids, saponins, tannins, volatile oils, terpenoids & steroids [313], securidacaxanthone [314]. Relevant pharmacological activity, phytochemistry Antiplasmodial [320]. (LD50 = 774.6mg/kg bw)[304]. Relevant reported traditional uses Cancer [295], malaria [52], HIV/AIDS [79], pain, cough, chest pain [23]. Measles [50], OI [23]. Sinuses [32], diarrhoea [298], skin infections, fatigue [23]. Cough [50], mental illness, aches & OI [23]. No reports. Toxicological studies of other Rumex spp & their isolated compounds are limited. Most reports show no toxicity/mortality at the effective doses [306]. The root extract is relatively toxic to brine shrimp (LC50 = 74.18 & 77.1 μg/ml) respectively [315,316] Extracts from S. longepedunculata contain salicylates which can cause ischemic renal damage [317]. LD50 = 1.74 g/kg & 0.02 g/kg in oral & i.p. respectively for acute toxicity of the root extract in albino mice [318]. Toxicity Malaria, diarrhoea [307], gonorrhoea [305], sore throat, allergies [23]. No reports Malaria, [50], stomach aches, TB & respiratory infections [23]. 50 Malaria, fever, gonorrhoea [319], cough, fever, TB [308], ulcers, diarrhoea, fatigue, OI [23]. Relevant reported traditional uses Antiplasmodial [321] The aqueous fruit extract of G. ternifolia was safe in Wistar albino rats at low doses [322]. f 60. Gardenia ternifolia subsp. Rutaceae 63. Citropsis articulata (Willd. ex Spreng.) Swingle & M. Kellerm 64. Zanthoxylum chalybeum Engl. Cough, TB [32], haemorrhoids [50], inappetence, fatigue [23]. The aqueous stem bark and root extracts are relatively safe at lower doses in sub-acute toxicity tests in Wistar albino rats up to 500 mg/body [334] and Sprague-Dawley rats when administered orally (LD50 >5000 mg/kg bw) [335]. The ethanol extracts of the roots & fruit are also safe in Wistar albino rats [336,337]. stomach ache, malaria, diarrhoea, pain, cough, fever, headache [338], swelling, vomiting, inappetence STI [23]. Antimalarial & antiplasmodial; omubioside, katimborine coumarins, alkaloids, trigonelline & limonoid (obacunyl acetate) [218]. Saponin, tannins, glycosides [339]. Skimmianine with in vitro antiviral activity against measles virus [341] Fagaramide [78]. The crude aqueous leaf extract was nontoxic in Swiss albino mice (LD50 = 18,985 mg/kg bw) [115]. However, the aqueous root bark was slightly toxic (LD50 = 9486.83 mg/kg bw) in male Wistar rats [340]. The root extract is not toxic at 2000 mg/kg/ bw in Swiss albino mice [342]. Long term administration of low doses of the root bark extract is safe in experimental animals at 4000 mg/kg. High doses may be associated with impaired renal function & intestinal neoplasms [343]. Diarrhoea, fatigue, inappetence [23]. Antibacterial [305], anthocyanins, flavonoids, saponins, sterols & tannins [345]. Aqueous extracts are generally safe in acute toxicity & subchronic studies in male Wistar rats at single dose exposure up to the limit of 5000 mg/kg. Low level renal toxicity observed after exposures for 90 days [96]. U. massaica is teratogenic in Swiss albino mice [346]. Gonorrhoea [305]. Antiplasmodial [347], antibacterial [348]. Antiinflammatory [349], Antiproliferative, flavone glycosides [350]. Eupatorin, apigenin, cirsilineol [351]. The ethanol root extract was safe in mice (LD50 > 5000 mg/kg bw), with no signs of morbidity & significant behavioural & physical changes in rats [352], but are mildly toxic to brine shrimp (LC50 = 32.3 μg/ml) [293]. No acute toxic effect was detected at relatively high doses Malaria, yellow fever, diarrhoea, cough, fever [50,52] OI [23]. Jo ur Urticaceae 65. Urtica massaica Mildbr. The crude ethanolic extracts of the fruits in Swiss albino mice are not toxic (LD50 > 1000 mg/kg bw) [330]. The LD50 of the alcoholic root extract of R. cordifolia is 1200 mg/kg bw [331]. lP 62. Sarcocephalus latifolius (Sm.) E.A. Bruce Verbenaceae 66. Lantana trifolia L. Malaria [323], [259], fatigue, fever [23]. Antibacterial [324], hepatoprotective [325], antiviral (hepatitis B) [325], immunomodulatory [326]. Rubicoumaric & rubifolic acid [327], rubiadin [328], aphthohydroquinones, mollugin, furomollugin, rubilactone [325,329]. Phenolic, flavonoids, caffeic acid [332]. Antiplasmodial [333]. na 61. Rubia cordifolia L. re -p ro o jovis-tonantis (Welw.) Verdc. 51 TB [344], HIV/AIDS [79,259], oral disease [248], cancer, stomach aches, cough [32], mental illness [23]. 68. Aloe dawei A.Berger 69. Aloe sp. Zingiberaceae 70. Curcuma longa L. ameliorates Relevant reported traditional uses The methanol extract (at 1, 2, 4, 8 16g/kg bw) did not produce significant toxic effect in Wistar rats during acute & sub-acute tests rats [355]. The aqueous leaf extract is toxic (LD50 = 120.65) in Swiss albino mice [356]. The percentage lethality was significant in mice chronically treated with A. vera extracts [357]. In a medical case report, a 21-year-old female patient was diagnosed with A. vera-induced toxic hepatitis after admission with acute hepatitis after taking an A. vera preparation for 4 weeks [358]. No reports Stomach ache, malaria, wasting [23,32]. No reports No reports Antimicrobial, curcuminoids [360], antiinflammatory [361], anti-HIV [362], immunomodulatory [363]. Fisetin, quercetin & myricetin [364]. α & β-turmerone, α–santalene, aromatic-curcumene, oleoresins [365]. Turmeric powder/ its alcoholic extract is not toxic at 10 g/kg bw (LD50 > 15g/kg bw) in Swiss albino mice [366] or Guinea pigs & monkeys (300mg/kg/ 2.5g/kg) [367].The essential oil is safe when given orally up to 0.5 g/kg bw in Wistar rats & is not mutagenic/genotoxic [368]. Cough [32], hernia, chest pain [23]. Sterols; diosgenin 3-glucoside; phthalyl esters hydrocarbons [369]. No reports Back pain [370], OI [23]. Anti-plasmodial, steroids, triterpenoids, anthraquinolones, alkaloids & saponins [359]. No reports Jo ur Zygophyllaceae 71. Balanites wilsoniana Dawe & Sprague Antiinflamatory [353], immunotoxicity in rats [354]. activity, lP Xanthorrhoeaceae 67. Aloe vera (L.) Burm.f. Relevant pharmacological phytochemistry na Family & Scientific name re -p ro o f (500 mg/kg) of the ethanol leaf extract in male Swiss albino mice [349]. Toxicity yamogenin; Malaria, skin infections, fever [23,33] Key: OI = Opportunistic infection, STI = Sexually Transmitted Infection, p.o= per os, LD50 = Median lethal dose, bw=Body weight. All toxicity tests were acute unless where otherwise 52

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