An Alternative Paradigm for the Role of Antimalarial Plants in Africa

Abstract

<jats:p>Most investigations into the antimalarial activity of African plants are centered on finding an indigenous equivalent to artemisinin, the compound from which current frontline antimalarial drugs are synthesized. As a consequence, the standard practice in ethnopharmacological research is to use<jats:italic>in vitro</jats:italic>assays to identify compounds that inhibit parasites at nanomolar concentrations. This approach fails to take into consideration the high probability of acquisition of resistance to parasiticidal compounds since parasite populations are placed under direct selection for genetic that confers a survival advantage. Bearing in mind Africa's long exposure to malaria and extensive ethnobotanical experimentation with both therapies and diet, it is more likely that compounds not readily overcome by<jats:italic>Plasmodium</jats:italic>parasites would have been retained in the pharmacopeia and cuisine. Such compounds are characterized by acting primarily on the host rather than directly targeting the parasite and thus cannot be adequately explored<jats:italic>in vitro</jats:italic>. If Africa's long history with malaria has in fact produced effective plant therapies, their scientific elucidation will require a major emphasis on<jats:italic>in vivo</jats:italic>investigation.</jats:p>

New Chemotherapeutic Strategies Against Malaria, Leishmaniasis and Trypanosomiases

“…It can be envisaged that the chronic forms of leishmania and trypanosoma infection could also take advantage of this immunomodulatory approach, although knowledge concerning the response of the human immune system to these infections is still incomplete and somewhat controversial [245,246]. The validity of targeting host mechanisms instead of using direct antiparasitic drugs is supported at the conceptual and practical level by the problem of resistance, which is due to be developed, sooner or later, against virtually all drugs targeting a definite metabolic step of the parasite [247]. The long-term advantages of host resistance improvement are attested by the field observation that all of the malaria-related haemoglobin variants found in Africa result in a physiologically significant reduction in parasite adhesion to endothelial cells [248], and in the ultimate better outcome of the immune response [249].…”

New Chemotherapeutic Strategies Against Malaria, Leishmaniasis and Trypanosomiases

“…Accordingly, drugs targeting cytoadherence do not impose a strong selective pressure on the parasite. Plant components such as cocoa flavonoids could be promising candidates for malaria therapy, not so much as to lead to healing, but as agents able to reduce the severity of cytoadherence-mediated complications (cerebral malaria and acute respiratory distress, which are not rapidly affected even by fast-acting parasiticidal drugs) and to facilitate immunity-mediated parasite clearance [247]. New anti-cytoadherence compounds were also identified by using the crystal structure of human ICAM 1 as a basis to screen in silico for inhibitors of cytoadherence.…”

Antimalarial Use of Malagasy Plants Is Poorly Correlated with Performance in Antimalarial Bioassays

“…As a result, the development of new treatments, including herbal treatments (see Willcox et al 2004), is of great interest, and studies that screen medicinal plants for antimalarial activity are fairly common. Despite those research efforts, no new pharmaceuticals have been derived from antimalarial plants since the artemisinin derivatives obtained from the Asian antimalarial plant Artemisia annua L. Recently, Maranz (2012) proposed the provocative hypothesis that the reason no antimalarial drugs have been developed via screening of African antimalarial plants is that the particularly high prevalence of malaria in affected African regions, compared to other tropical or subtropical areas, allows parasites to rapidly evolve resistance to any substance that directly kills them, even if it contains multiple active compounds. Hence, African medicines (and, he further plausibly suggests, bitter wild foods) are proposed to affect malaria only indirectly, by increasing host resistance or by inhibiting non-essential parasite activities such as cytoadhesion.…”

“…Maranz (2012) offered two major points of empirical evidence for the lack of direct antiplasmodial activity of African antimalarial plants: the low rate of discovery of highly active crude extracts, or highly active single molecules, in a few African screening studies or reviews of antimalarial plants (Soh and Benoit-Vical 2007; Pillay et al 2008; Rukunga et al 2009), and the fact that local malaria death rates drop substantially when pharmaceutical antimalarials become available (which shows, minimally, that the latter are more potent, until resistance develops). Another point he might have added is that, while Western physicians expect the result of antimalarial treatment to be rapid total parasite clearance, in a high-transmission area this may be clinically unimportant (Willcox et al 2011) or actually detrimental, as persistent low-level infection may reduce the risk of significant illness in the likely event of future exposure (Sondén et al 2015).…”

“…Targeted screening of medicinal plants has been repeatedly reported to increase the percentage of samples displaying bioactivity. Contrarily, Maranz (2012) suggested that African antimalarial plants were unsuitable sources of antimalarial drugs because high prevalence of malaria would result in rapid evolution of resistance to active compounds that directly targeted the parasite. As malaria is highly prevalent in much of Madagascar, it was of interest to determine whether Malagasy antimalarial plants would outperform randomly selected plants in conventional antimalarial assays being conducted as part of a discovery program.…”