Simoes-Pires Claudia, Hostettmann Kurt, Haouala Amina, Cuendet Muriel, Falquet Jacques, Graz Bertrand, Christen Philippe
School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ernest-Ansermet 30, 1211 Geneva 4, Switzerland.
Department of Plant Biology, University of Geneva, Quai Ernest-Ansermet 30, CH-1211 Geneva 4, Switzerland.
Int J Parasitol Drugs Drug Resist. 2014 Jul 30;4(3):338-46. doi: 10.1016/j.ijpddr.2014.07.001. eCollection 2014 Dec.
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.
几十年来，经典药理学一直是发现具有治疗作用的新化学实体的基础。在天然产物研究中，化合物通常仅在经过全面的体外表征后才进行体内测试。然而，使用这种方法进行药物筛选成本高、耗时且效率往往很低。反向药理学，也称为床边到实验台，是一种基于传统知识的研究方法，涉及将经典的从实验室到临床的途径转变为从临床到实验室的实践。它是一种跨学科方法，专注于传统知识、实验观察和临床经验。本文概述了反向药理学方法在墨西哥刺蓟煎剂中的应用，该煎剂在马里被用作抗疟传统药物。墨西哥刺蓟是马里治疗非复杂性恶性疟疾最有效的传统药物，如先前发表的那样，该煎剂的临床疗效与青蒿琥酯-阿莫地喹相当。本文将描述反向药理学过程的四个阶段，并特别强调第四阶段的结果。简而言之，通过生物导向分级分离分离出别隐品碱、原阿片碱和小檗碱，并通过光谱分析确认了它们的身份。这三种生物碱在体外显示出抗寄生虫活性，其中别隐品碱和原阿片碱对恶性疟原虫具有选择性。此外，通过定量核磁共振测定了煎剂中三种活性生物碱的含量，并进行了初步的体内试验。基于这些结果，对反向药理学方法进行了讨论，并且似乎有必要进行进一步的药代动力学研究，以确定这些生物碱是否可被视为用于该植物制成的改良传统药物的质量控制和标准化的植物化学标志物。
