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Des sources du savoir aux médicaments du futur

 | 
Jacques Fleurentin
, 
Jean-Marie Pelt
, 
Guy Mazars

3. Médicaments du XXIe siècle

Conception of an antimalaria medicinal product from plants used in traditional medicine

Guy Balansard

Résumé

Abstract
The methodology adopted aims at validating remedies used in traditional medicine and enhancing plants open for development.
The process is three-staged:
- Ethnobotanical surveys, first with a general scope and then targeting the plant selected;
- Phytochemical, pharmacological and toxicological studies;
- Development of a drug, following the procedure to obtain permission to market a herbal medicinal product (cf. Cahier published by Agence Française no. 3) including a pharmaceutical dossier, a short-term toxicological study and, after being authorised by an ethics committee, a clinical study.

Texte intégral

1The purpose of this paper is to submit a procedure aiming at validating traditional practice and enhancing plants used in traditional medicine.

2The example selected is the case of traditional remedies used for the treatment of malaria, and the objective is to prepare a medicinal product from a plant used in traditional medicine.

3The work we report about is the result of scientific cooperation between Faculté de Médecine et de Pharmacie in Bamako, Mali and Marseilles, France.

4Why did we select Bamako, Mali?

5Because the way traditional medicine is structured and managed can be considered as exemplary.

6The approach we have adopted is ethnopharmacological; the aim was to prepare a medicinal product for emergent countries, i.e. a product reducing both parasitaemia and symptomatology, and featuring pharmaceutical qualities while having a simple composition, so that production could be envisaged at a cost adapted to the modest financial means that can be earmarked for health care.

7Research work developed in 3 stages:

8Inquiries: a total of three inquiries were conducted, in alternation with pharmacological and phytochemical studies.

9Pharmacological and phytochemical studies

10Designing a medicinal product following the recommendations of full market approval (FMA in abridged form), corresponding to the Cahier de lAgence n° 3, on a basis of a comprehensive pharmaceutical assessment dossier and a short-term toxicological study.

Inquiries

11There is in Bamako, Mali, a central organisation called Département de Médecine Traditionnelle (Department for Traditional Medical Practice - DMI), headed by Prof. A. KEITA.

12This department is a division of Institut National de Recherche en Santé Publique (National Institute of Research for Public Health - INRSP); in charge of 8 regional centres for traditional medical practice, in particular those in Kolokani, Sikasso and Bandiagara, where the inquiries were carried out.

13Three consecutive inquiries, in alternation with laboratory tests, made it possible to select the plant to be developed.

14The first inquiry was carried out with traditional practitioners working in Bamako.

15It focussed on plants that they use to treat feverish diseases and permitted the identification of 19 species, among which the most widely used are Mitragyna inermis and Nauclea latifolia - which are often combined in traditional preparations - and Trichilia roka. These 3 species, as well as Clinus oppositifolius, which is used universally in the treatment of feverish affections in Northern Mali, were selected for further research.

16Preliminary tests carried out on aqueous, methanolic and chloroformic extracts of these 4 species led to keeping only Mitragyna, Nauclea and Glinus.

17A second inquiry was conducted to confirm and complement the information collected about the traditional mode of preparation applied to Nauclea and Mitragyna. This second inquiry was carried out in 2 regional centres for traditional medical practice in Kolokani and Sikasso.

18In more than half of the cases, the Mitragyna inermis leaves and the Nauclea latifolia bark are associated and used as a maceration and - more frequently - as a decoction. The product is generally absorbed per os or in a bath. The duration of the treatment is generally 2 to 7 days according to the healers. Some of them recommend not to use the aqueous decoction with pregnant women.

19At the end of this second inquiry, we carried out a phytochemical and pharmacological study on these 2 species and on Glinus, and we could establish that the antiplasmodic action of Nauclea and Mitragyna is due to alkaloids and that of Glinus to saponosides.

20A study of in vitro and in vivo mutagenesis carried out on the alkaloidal extract of Nauclea and Mitragyna, and on the saponic extract of Glinus permitted to establish that the alkaloids in Nauclea latifolia have an in vitro and in vivo mutagenic action.

21Moreover, in spite of the advantage offered by Glinus oppositifolius, the low density of biotopes in Mali made it difficult, at the beginning, to develop an anti-malaria medicine from this plant.

22This is the reason why we decided to go on with our work using the leaves of Mitragyna inermis, whose alkaloids had shown, on the occasion of precedent research, that they have a choleretic action and do not have any hepatic toxicity.

Mitragyna inermis

23The Mitragyna alkaloids are mainly composed of oxindolic, tetra- and pentacyclic derivatives.

24We isolated all the alkaloids, separated various fractions and isolated speciophyllin and iso-rhynchophyllin. We did not establish any significant difference in activity between the isolated alkaloids, the alkaloidal fractions and the complete alkaloids.Therefore we went on with our experimentation on total alkaloids by setting up a dosage method permitting to evaluate all the alkaloids in the leaves, both in the traditional preparations and in the extract that we had to prepare to be able to go on with the operation.

25We then had to answer two questions:

26The first one was to determine whether the alkaloids which are un- solvable in water in normal conditions would dissolve in traditional preparations, and the second one was to measure out the alkaloids in the preparations to set the posology to be used.

27This is why we initiated a third inquiry that was carried out in Kolokani and Bandiagara, in the course of which we identified traditional practitioners who used only Mitragyna inermis and who accepted to prepare the traditional remedy in our presence.

28We recorded the quantity of plant used, the preparation mode, the pH of fluids, the volume and quantity of samples, the duration of the treatment and the set of symptoms presented by the patients consulting the healer.

29The preparations were stored and the alkaloids were dosed. The solubilisation process of alkaloids was observed and was assigned to either a highly acid pH, or to preparations requiring fermentation.

Development of a medicine following the abridged FMA procedure as described in Cahier de l'Agence no. 3.

30First we prepared a pilot batch of hydro-alcoholic leaf extract enabling us to withdraw a majority of water-soluble molecules and having an ethanolic degree high enough to extract alkaloids.

31This extract was submitted to a pharmacological study to establish the anti-plasmodic action, and a short term 28-days toxicological study with doses corresponding to the posology that should be used in therapy and to 10 times the standard posology.

32The observation of the behaviour, the biological data and the anatomical and pathological study of various organs carried out after 28 days did not reveal any anomaly.

33From there on, the galenic preparation of the finished product could be envisaged; it was decided that it would be developed in the form of a tablet, which offers a better stability in a tropical environment. The pharmaceutical, pharmacological and toxicological dossiers will be submitted to the ethics committee in Bamako; the clinical studies to be conducted in 2 villages close to Bamako will then be carried out under the supervision of Pr. Doumbo in Bamako, Mali and Pr. Delmont in Marseille, France.

Table des illustrations

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