title: Reverse pharmacology for developing an anti-malarial phytomedicine. The example of Argemone mexicana.
abstract: Classical pharmacology has been the basis for the discovery of new chemical entities with therapeutic effects for decades. In natural product research, compounds are generally tested in vivo only after full in vitro characterization. However drug screening using this methodology is expensive, time-consuming and very often inefficient. Reverse pharmacology, also called bedside-to-bench, is a research approach based on the traditional knowledge and relates to reversing the classical laboratory to clinic pathway to a clinic to laboratory practice. It is a trans-disciplinary approach focused on traditional knowledge, experimental observations and clinical experiences. This paper is an overview of the reverse pharmacology approach applied to the decoction of Argemone mexicana, used as an antimalarial traditional medicine in Mali. A. mexicana appeared as the most effective traditional medicine for the treatment of uncomplicated falciparum malaria in Mali, and the clinical efficacy of the decoction was comparable to artesunate-amodiaquine as previously published. Four stages of the reverse pharmacology process will be described here with a special emphasis on the results for stage 4. Briefly, allocryptopine, protopine and berberine were isolated through bioguided fractionation, and had their identity confirmed by spectroscopic analysis. The three alkaloids showed antiparasitic activity in vitro, of which allocryptopine and protopine were selective towards Plasmodium falciparum. Furthermore, the amount of the three active alkaloids in the decoction was determined by quantitative NMR, and preliminary in vivo assays were conducted. On the basis of these results, the reverse pharmacology approach is discussed and further pharmacokinetic studies appear to be necessary in order to determine whether these alkaloids can be considered as phytochemical markers for quality control and standardization of an improved traditional medicine made with this plant.
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ernest-Ansermet 30, 1211 Geneva 4, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Simoes-Pires
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ernest-Ansermet 30, 1211 Geneva 4, Switzerland.
authors.forename: Kurt
authors.initials: K
authors.lastname: Hostettmann
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ernest-Ansermet 30, 1211 Geneva 4, Switzerland.
authors.forename: Amina
authors.initials: A
authors.lastname: Haouala
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ernest-Ansermet 30, 1211 Geneva 4, Switzerland.
authors.forename: Muriel
authors.initials: M
authors.lastname: Cuendet
authors.affiliation: Department of Plant Biology, University of Geneva, Quai Ernest-Ansermet 30, CH-1211 Geneva 4, Switzerland.
authors.forename: Jacques
authors.initials: J
authors.lastname: Falquet
authors.affiliation: Institut de médecine sociale et préventive, University of Geneva, rue Michel Servet 1, CH-1211 Genève 4, Switzerland.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Graz
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ernest-Ansermet 30, 1211 Geneva 4, Switzerland.
authors.forename: Philippe
authors.initials: P
authors.lastname: Christen
keywords: Anti-malarial phytomedicine; Argemone mexicana; Reverse pharmacology; Traditional medicine