Reverse pharmacology of medicinal plants: Good luck or efficient method?

Reverse pharmacology has frequently been advocated in India and China (among other places), as a method based on the search for documented therapeutic effects of plants in ancient texts (Vaidya, 2006). Another definition of reverse pharmacology, inspired by ethnopharmacological approaches [Carvalho et al, 1991], begins with a documented outcome as observed by patients.

Both approaches will be discussed, the latter in view of our experience with the “success story” of “improved traditional medicines” in Mali [Graz et al. 2011; Willcox et al., 2011]. In this context, the first step was a population-based ethnomedical survey which included patient accounts of recent experiences of the therapeutic itinerary (cure, worsening or adverse events after using traditional preparations) and interviews of traditional medicine practitioners [Diallo et al., 2006]. The traditional preparation based on Argemone mexicana (AM) appeared as the recipe associated with the best outcome among patients with presumed malaria. In subsequent clinical studies (a dose-escalating and a randomized controlled trial) in the village where the AM preparation was used, its safety and clinical efficacy was found non-inferior to the standard imported drug artesunate-amodiaquine in terms of clinical outcomes (need for second-line treatment, incidence of new episodes of malaria) [Willcox et al., 2007; Graz et al., 2010]. Several studies found that AM also has in vitro activity against P. falciparum (Adjobimey et al., 2004; Diallo et al., 2006). In terms of “evidence-based medicine”, AM can now be proposed for pilot introduction in public health programs with careful evaluation of its impact.

However, a problem remains: how to check the quality of the plant? Even if three alkaloids (berberine, protopine, allocryptopine) were detected by bio-guided fractionation and showed a significant in vitro activity [Simoes-Pires, 2009], some questions require further investigation. Are these alkaloids solely or even partially responsible for the clinical efficacy? In that case, are these alkaloids metabolized into more or less active compounds? Is there a synergy effect? Several research approaches are being explored in order to answer these questions: early ADME studies, including microsome metabolization and Caco-2 permeability assays; in vitro activity profiling of the alkaloids and metabolites; pre-clinical and clinical pharmacokinetics of the candidate compounds alone and/or after ingestion of the decoction.

References:

Adjobimey, T., Eday'e, I., Lagnika, L., Gbenou, J., Moudachirou, M., Sanni, A., 2004. C. R.

Chimie 7, 1023–1027.

Carvalho, L. H., M. G. Brandao, et al. (1991). "Antimalarial activity of crude extracts from Brazilian plants studied in vivo in Plasmodium berghei-infected mice and in vitro against Plasmodium falciparum in culture." Braz J Med Biol Res 24(11): 1113–1123. Diallo, D., Graz, B., Falquet, J., Traoré, A.K., Giani, S., Mounkoro, P.P., Berthé, A., Sacko, M., Diakité, C., 2006. Trans. R. Soc. Trop. Med. Hyg. 100, 515–520.

Graz, B., Willcox, M. L., Diakité, C., Falquet, J., Dackuo, F., Sidibe, O., Giani, S., Diallo, D., 2010. Trans. R. Soc. Trop. Med. Hyg. 104, no1, 33–41.

Graz B, Kitua AY, Malebo HM. To what extent can traditional medicine contribute a complementary or alternative solution to malaria control programmes? Malar J. 2011 Mar 15;10 Suppl 1:S6. [Epub ahead of print]. http://www.malariajournal.com/supplements/10/S1

Simoes-Pires, C. Thèse de doctorat. Université de Genève, 2009.– Sc. 4129.–2009/07/27

Vaidya ADB. 2006. Reverse pharmacological correlates of ayurvedic drug actions. Indian J Pharmacol. 38: 311–315 Willcox M. L., Graz, B., Falquet, J., Sidibe, O., Forster, M., Diallo, D., 2007. Trans. R. Soc. Trop. Med. Hyg. 101, 1190–1198.

Willcox ML, Graz B, Falquet J, Diakite C, Giani S, Diallo D. A "reverse pharmacology" approach for developing an anti-malarial phytomedicine. Malar J. 2011 Mar 15;10 Suppl 1:S8. [Epub ahead of print]