Antimalarial Plants Used across Kenyan Communities

Malaria is one of the serious health problems in Africa, Asia, and Latin America. Its treatment has been met with chronic failure due to pathogenic resistance to the currently available drugs. This review attempts to compile phytotherapeutical information on antimalarial plants in Kenya based on electronic data. A comprehensive web search was conducted in multidisciplinary databases, and a total of 286 plant species from 75 families, distributed among 192 genera, were retrieved. Globally, about 139 (48.6%) of the species have been investigated for antiplasmodial (18%) or antimalarial activities (97.1%) with promising results. However, there is no record on the antimalarial activity of about 51.4% of the species used although they could be potential sources of antimalarial remedies. Analysis of ethnomedicinal recipes indicated that mainly leaves (27.7%) and roots (19.4%) of shrubs (33.2%), trees (30.1%), and herbs (29.7%) are used for preparation of antimalarial decoctions (70.5%) and infusions (5.4%) in Kenya. The study highlighted a rich diversity of indigenous antimalarial plants with equally divergent herbal remedy preparation and use pattern. Further research is required to validate the therapeutic potential of antimalarial compounds from the unstudied claimed species. Although some species were investigated for their antimalarial efficacies, their toxicity and safety aspects need to be further investigated.


Introduction
Globally, malaria continues to be in the top list of the major global health challenges. A global estimate of 655,000 malarial deaths was reported in 2010 of which 91% were in Africa and 86% of these were children under 5 years of age [1,2]. Africa is particularly more susceptible, and conservative estimates cited that malaria causes up to 2 million deaths annually in Africa [3,4].
e World Health Organization reported that about 2 billion people in over 100 countries are exposed to malaria, and the situation is exacerbated on the African continent which is characterized by limited access to health services and chronic poverty [5]. In East Africa and Kenya particularly, malaria remains endemic in the Lake Victoria basin and the coast with the country's highest rate of infection at 27% (6 million cases) in 2015 from 38% in 2010 [6,7]. e Kenyan population at risk of malaria as of 2016 was estimated at 100% [5]. Anopheles gambiae and A. funestus are the primary vectors of malaria in East Africa [8], while Plasmodium falciparum and P. vivax are the deadliest malarial parasites in sub-Saharan Africa. e misuse of chloroquine in the management of malaria has led to the development of chloroquine-resistant parasites worldwide [9]. In Kenya, the use of chloroquine has been discontinued as the first line treatment for malaria due to the prevalence of resistant P. falciparum strains [10,11]. Artemisinin-based combination therapy (ACT) is currently the only available treatment option for malaria as the quinolines (quinine, chloroquine, and mefloquine) have been reported to cause cardiotoxicity, and the malarial parasites have already developed sturdy resistance to them [12,13]. Unfortunately, resistance of P. falciparum to artemisinin has also been reported elsewhere [14].
e Kenyan government has attempted to reduce malaria incidences in Kenya through several approaches including entomologic monitoring, insecticide resistance management, encouraging the population to sleep under insecticide-treated mosquito nets, intermittent preventive treatment for pregnant women, and indoor residual spraying [6,7,15,16]. e situation has been made more complicated by the emergence of pyrethroid-resistant mosquitoes throughout Western Kenya which prompted the government to declare no spraying of mosquitoes between 2013 and 2016 [6].
Malaria may manifest with relatively simple symptoms such as nausea, headache, fatigue, muscle ache, abdominal discomfort, and sweating usually accompanied by high fever [17]. However, at advanced stages, it can result in serious complications such as kidney failure, pulmonary oedema, brain tissue injury, severe anaemia, and skin discoloration [5,18]. Conventional treatment is usually costly, and in rural Kenya just like in other parts of the world, the use of plants for either preventing or treating malaria is a common practice [3]. e current study attempted to gather comprehensive ethnobotanical information on various antimalarial plants and their use in Kenyan communities to identify which plants require further evaluation for their efficacy and safety in malaria management.

Literature Search Strategy and Inclusion and Exclusion
Criteria. Relevant literature pertaining to antimalarial plants and their use in management of malaria and malarial symptoms in Kenya were sourced from Scopus, Web of Science Core Collection, PubMed, Science Direct, Google Scholar, and Scientific Electronic Library Online from November 2019 to February 2020 following procedures previously used [19][20][21]. e searches were performed independently in all the databases. Key search words such as malaria, vegetal, traditional medicine, ethnobotany, alternative medicine, ethnopharmacology, antimalarial, quinine, chloroquine, antimalarial activity, antiplasmodial activity, malaria management, and Kenya were used. All publishing years were considered, and reports with information on antimalarial or medicinal plants in Kenya were carefully screened.
us, references contained within the returned scientometric results were assessed concerning their inclusion in the study, and further searches were carried out at the Google search engine using more general search terms, to broaden the search, as follows: words: malaria, plants, plant extract, vegetal, vegetal species, vegetal extract, traditional medicine, alternative medicine, complementary therapy, natural medicine, ethnopharmacology, ethnobotany, herbal medicine, herb, herbs, decoction, infusion, macerate, concoction, malaria fever, malaria incidence, and Kenya were used. e last search was done on 15 th February 2020. e search outputs were saved wherever possible on databases, and the author received notification of any new searches meeting the search criteria from Science Direct, Scopus, and Google scholar. For this study, only full-text original research articles published in peer-reviewed journals, books, theses, dissertations, patents, and reports on antimalarial plants or malaria phytotherapy in Kenya written in English and dated until February 2020 were considered.
Missing information in some studies particularly the local names, growth habit of the plants, and misspelled botanical names were retrieved from botanical databases: e Plant List, International Plant Names Index, NCBI taxonomy browser and Tropicos, and the Google search engine. Where a given species was considered as distinct species in different reports, the nomenclature as per the botanical databases took precedence. e traditional perception of malaria as well as the families, local names (Digo, Giriama, Kamba, Kikuyu, Kipsigis, Kuria, Luo, Markweta, Maasai, Nandi, and Swahili), growth habit, part (s) used, preparation, and administration mode of the different antimalarial plants were captured.

Data Analysis. All data were entered into Microsoft
Excel 365 (Microsoft Corporation, USA). Descriptive statistical methods, percentages, and frequencies were used to analyze ethnobotanical data on reported medicinal plants and associated indigenous knowledge.
e results were subsequently presented as tables and charts.

Not reported
Not specified Tree Not specified [3] Evidence-Based Complementary and Alternative Medicine 5 Sida cordifolia L.

Olngosua (Maasai)
Bark Shrub Decoction [48] Language is also known as Kikamba. Local names with language(s) not indicated are sometimes a blend of Kiswahili and other local languages or were not specified by the authors. Decoction involves boiling a plant part in water. Infusion entails soaking of a plant part in water.
e dominant use of leaves presents little threat to the survival of medicinal plants. is encourages frequent and safe utilization of the plants for herbal preparations. Roots and root structures such as tubers and rhizomes are rich sources of potent bioactive chemical compounds [33], but their frequent use in antimalarial preparations may threaten the survival of the plant species used. For example, Zanthoxylum chalybeum and African wild olive (Olea europaea) have been reported to be threatened due to improper harvesting methods [2]. us, proper harvesting strategies and conservation measures are inevitable if sustainable utilization of such medicinal plants are to be realized.
Antimalarial remedies in Kenya are prepared by different methods. ese include decoctions (70.5%), infusions (5.4%), ointments and steaming (1.3%), and roasting (0.3%). Preparation of antimalarial remedies from dry parts of one plant or several plants and ashes by using grinding stones was reported [38]. Burning, chewing, heating/roasting, pounding, and boiling or soaking in hot or cold water and milk were reported, and these are then orally administered as is the case with Western medicine [38]. Preparations for application onto the skin such as ointments, poultices, and liniments are frequently percutaneous, by rubbing or covering which are occasionally complimented by massage [38].
Rarely are antimalarial remedies administered through the nasal route. Fresh solid materials are eaten and chewed directly upon collection or after initial pounding/crushing. Dry plant materials are smoked and inhaled. ese findings corroborate observations in other countries [33,[90][91][92].
Malaria is caused by protozoan intracellular haemoparasites, and its treatment entails delivering adequate circulating concentration of appropriate antiprotozoal chemicals. e oral route is a convenient and noninvasive method of systemic treatment as it permits relatively rapid absorption and distribution of active compounds from herbal remedies, enabling the delivery of adequate curative power [93]. In addition, potential risk of enzymatic breakdown and microbial fermentation of active chemical entities may prompt the use of alternative routes of herbal remedy administration like inhalation of the steam or rubbing on the skin.
In this survey, it was noted that few plant species are used for management of malaria simultaneously in different locations. is could probably be attributed to the abundant distribution of the analogue active substances among species, especially belonging to family Asteraceae, Euphorbiaceae, Fabaceae, Meliaceae, Rubiaceae, and Rutaceae. Differences in geographical and climatic conditions may also influence the flora available in a given region. However, some plants have a wider distribution and therefore are used by most communities [34].
(ripe fruits or seeds) are done to keep mosquitoes away [17,42]. Artemisia annua L. is planted in the home vicinity or near the bedroom window to repel mosquitoes believed to cause malaria [42]. Except in the case of life-threatening illnesses or where there is concern that there may be some supernatural forces in the aetiology of the disease, malaria and its symptoms (periodic fever, sweating, headache, backache, and chills) are treated primarily using decoctions and infusions of plants. Whenever it is thought that malaria is due to supernatural forces, diviners (such as Orgoiyon among the Tugen and Oloiboni among the Maasai) are consulted [94]. Croton dichogamus Pax though used for normal malaria treatment is used by Oloiboni for treatment of malaria or other ailment(s) thought to be due to witchcraft [22]. According to indigenous diagnoses, malaria is due to the presence of excess bile in the body, so the bile has to be expelled before healing can take place. us, purgation is regarded as the key treatment regimen for malaria [22,54].
On the basis of this knowledge, different forms of herbal medications are prescribed according to the severity of the illness. Treatment of malaria is based on a number of interlinked elements: beliefs related to causation, the action or effectiveness of "modern" medicines, and the availability of plant treatments [54]. Salvadora persica L. is used for management of malarial colds, while Aneilema spekei (C. B. Clarke) is used for prevention of malaria fever [22]. e whole plant is mixed with other herbs in milk and sprinkled onto the patient. is is often administered by an Oloibon among the Maasai [22].  Evidence-Based Complementary and Alternative Medicine ough single plant parts are often used, more than one plant part, for example, decoctions from a mixture of roots of Plectranthus sylvestris together with those of Cassia didymobotrya and Clerodendrum johnstonii may be used as a remedy for malaria and headache [52]. Acacia species stem bark was reported to be used as a first treatment and is usually prepared as an overnight cold-water infusion, and then 40 ml is taken three times a day [11]. A follow-up medication would involve taking a decoction made from powders of Aloe species (leaf juice), Rhamnus staddo (stem or root bark), Clerodendrum myricoides (root bark), Warburgia ugandensis, Teclea nobilis (stem barks), and Caesalpinia volkensii, Ajuga remota Benth, Rhamnus prinoides, and Azadirachta indica leaves [11]. For this, 40 ml is taken thrice a day for 5 days.
e popular method of preparation as decoctions and concoctions suggest that the herbal preparations may only be active in combination, due to synergistic effects of several compounds that are inactive singly [95]. It is possible that some of the compounds that are inactive in vitro could exhibit activity in vivo due to enzymatic transformation into potent prodrugs [96] as reported for Azadirachta indica extracts [97].

Adverse Side Effects, Antidotes, and Contraindications of Medicinal Plants in Kenya.
In traditional context, the pharmacological effect of medicinal plants is generally ascribed to their active and "safe" content that will only exert quick effect when taken in large quantities [22,33]. Most reviewed reports in this study did not mention the side effects of antimalarial preparations. Nevertheless, herbal preparations from some antimalarial plants were reported to induce vomiting, diarrhea, headache, and urination [22,54] ( Table 2). is may be due to improper dosage, toxic phytochemicals, or metabolic by-products of these preparations [22].
However, purgation and emesis are interpreted as signs that malaria is leaving the body and that the healing process has begun [22,54]. It is reasonable that some side effects might also be masked through the use of more than one plant (or plant parts) especially for bitter remedies (such as Ajuga remota Benth.) [11,38]. However, some herbalists are known to use more than one plant (plant parts) as a trick of keeping the secrecy of their formula [11]. Boiling of plant parts in goat fat, meat bone broth (as is done for Carissa edulis), taking decoctions mixed with milk (for Rhamnus prinoides), and mixing remedies with milk and salt for Salvadora persica L. [22] could serve as antidotes for potential side effects from use of the herbal preparations as reported elsewhere [33]. Some of the plants reported in this study such as Ajuga integrifolia and Croton macrostachyus were reported in Ethiopia to cause vomiting, nausea, headache, urination, and diarrhea when used for management of malaria [33]. Because the outcome of the treatment remains generally unclear due to lack of feedback from patients, herbalists rely on anecdotal reporting as far as efficacy and side effects are concerned.
Some antimalarial plants were reported as contraindicated to pregnant women and children (Table 2). Gathirwa et al. [50] reported that the posology of antimalarial herbal preparations in Kenya sometimes is dictated by the plant to be used, the traditional herbalist, the sex and the age of the patient, reiterating that pregnant women and children are often given lower dosages compared to other adults.
is indicates the existence of research gaps with regard to the potential toxicities and corresponding counteracting mechanisms of antimalarial plants in Kenya. is gap represents a barrier to effective development and exploitation of indigenous antimalarial plants. In essence, some of the plants listed are reported to exhibit marked toxicity. Teclea simplicifoli (roots) is regarded to be poisonous by rural Kenyans [98]. Catharanthus roseus (L.) G. Don is another such plant known to house neurotoxic alkaloids [99]. Vincristine and vinblastine in this plant are highly cytotoxic antimitotics that block mitosis in metaphase after binding to mitotic microtubules [100]. Side effects such as kidney impairment, nausea, myelosuppression, constipation, paralytic ileus, ulcerations of the mouth, hepatocellular damage, abdominal cramps, pulmonary fibrosis, urinary retention, amenorrhoea, azoospermia, orthostatic hypotension, and hypertension [101][102][103] have been documented for antitumor drugs vincristine and vinblastine derived from this plant. ese observations could partly explain why some antimalarial herbal preparations in Kenya are ingested in small amounts, applied topically, or are used for bathing. is gives a justification for the investigation of the plants for their potential toxicity.

Other Ethnomedicinal Uses of Antimalarial Plants Used in
Rural Kenya. Most of the antimalarial plant species identified are used for traditional management of other ailments in Kenya and in other countries. Ajuga remota Benth (different parts), for example, are used to relieve toothache, severe stomachache, oedema associated with protein-calorie malnutrition disorders in infants when breast-feeding is terminated, pneumonia, and liver problems [52,104,105]. Such plants are used across different ethnic communities for managing malaria and can be a justification of their efficacy in malaria treatment [19]. Table 3 shows the list of some of the antimalarial plants used in Kenya with reports of toxicity/safety, antimalarial, and antiplasmodial activity evaluation. Across African countries, many antimalarial plants captured in this review have demonstrated promising therapeutic potential on preclinical and clinical investigations [68,[106][107][108][109][110][111]. Interestingly, antimalarial compounds have been identified and isolated from some of these species [62,112].

Toxicity, Antiplasmodial, and Antimalarial Studies.
Export of indigenous medicinal plants bring substantial foreign exchange to African countries such as Egypt [113], South Africa [114], Uganda, Tanzania, and Kenya [115]. Despite the success of traditional practices and abundance of indigenous medicinal plants (Table 1), antimalarial plants research in Kenya stops mostly on ethnobotanical surveys,    Alkaloids, saponins, tannins, glycosides; no serious toxicity reported; carpaine, an active compound against P. falciparum had high selectivity and was nontoxic to normal red blood cells [142,143] Evidence-Based Complementary and Alternative Medicine    Evidence-Based Complementary and Alternative Medicine 21   [183,184] with extensions limited to evaluation of crude extracts from plants against Plasmodium berghei [48,56,71]. A gap is evident with regard to research geared towards identifying and isolating plant bioactive compounds and establishing the efficacy and safety of medicinal plants through in vitro assays using human Plasmodium parasites and in vivo assay involving higher animal models and randomized clinical trials [50]. For example, the toxicity of 16,17-dihydrobrachycalyxolid isolated in Vernonia brachycalyx has been reported to be due to its ability to inhibit the proliferation of phytohaemmaglutinin-treated human lymphocytes [116]. A median inhibitory concentration (IC 50 ) of 7.8 μg/ml was reported, which is comparable to the median concentration obtained in the antiplasmodial assay by Oketch-Rabah et al. [58] (Table 3). To assess whether observed antiplasmodial activities are due to a specific or a general toxicity effect, the experimental selectivity index (SI) needs to be calculated for extracts and only a few studies in Kenya has attempted this [48][49][50]. It is worth noting that there is always a variation in the degree of toxicity depending on the sensitivity of the animals, tissue, or cells used, type of extract, nature of the test substance, dose, and mode of administration. In this study, 38.8% (54/139) of the total plants were evaluated for their toxicities. Of these, 41 showed low cytotoxicity with LC 50 > 20 μg/ml. Some of these plants such as Artemisia annua, Carica papaya, Flueggea virosa, and Schkuhria pinnata fortuitously showed good antimalarial activity. On the contrary, extracts of some plants used for malaria treatment with good activity are potentially toxic, for example, dichloromethane leaf extract of Microglossa pyrifolia, methanolic extract of Uvaria acuminata (CC 50 � 2.37 μg/ ml), and petroleum ether leaf extract of Vernonia amygdalina.

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Evidence-Based Complementary and Alternative Medicine budmunchiamine K, 6-hydroxybudmunchiamine K, 5-normethylbudmunchiamine K, 6-hydroxy-5-normethylbudmunchiamine K, and 9-normethylbudmunchiamine K from Albizia gummifera bark [178] had IC 50 of 0.16 μg/ml recorded against ENT30. Curine, isolated from Cissampelos mucronate roots, showed antimalarial activity against W2 isolate with IC 50 of 0.24 μg/ml [74]. At present, Artemisia annua [106,107], Azadirachta indica [108], and Vernonia amygdalina [111] have been subjected to clinical studies. Artemisinin from Artemisia annua is an ingredient of artemisinin-based combination therapy currently recommended for treatment of malaria [124]. As identified earlier, few clinical trials have been done on antimalarial plants. is is partly due to the regulatory requirements for clinical studies, as well as the financial input required.

Conclusion
Indigenous knowledge on medicinal plants in Kenya is a good resource for malaria management. However, further studies are required to isolate the active compounds in the unstudied plants which can be used to standardize plant materials so as to install a reproducible herbal medicine practice. Safety and toxicity as well as clinical studies are required as some of the plants are used as admixtures in traditional herbal management of malaria.

Data Availability
is is a review article, and no raw data were generated. All data generated or analyzed in this study are included in this article.

Conflicts of Interest
e author declares that there are no conflicts of interest regarding the publication of this paper. Acknowledgments e author is grateful to the World Bank and the Inter-University Council of East Africa (IUCEA) for the scholarship awarded to him through the Africa Centre of Excellence II in Phytochemicals, Textiles and Renewable Energy (ACE II PTRE) at Moi University, Kenya, that prompted this ethnomedical communication.
e author commends preceding authors for their fruitful quest for knowledge on medicinal plants utilized by rural communities of Kenya and Eastern Africa as a whole.