Plants used traditionally to treat malaria in Brazil: the archives of Flora Medicinal

The archives of Flora Medicinal, an ancient pharmaceutical laboratory that supported ethnomedical research in Brazil for more than 30 years, were searched for plants with antimalarial use. Forty plant species indicated to treat malaria were described by Dr. J. Monteiro da Silva (Flora Medicinal leader) and his co-workers. Eight species, Bathysa cuspidata, Cosmos sulphureus, Cecropia hololeuca, Erisma calcaratum, Gomphrena arborescens, Musa paradisiaca, Ocotea odorifera, and Pradosia lactescens, are related as antimalarial for the first time in ethnobotanical studies. Some species, including Mikania glomerata, Melampodium divaricatum, Galipea multiflora, Aspidosperma polyneuron, and Coutarea hexandra, were reported to have activity in malaria patients under clinical observation. In the information obtained, also, there were many details about the appropriate indication of each plant. For example, some plants are indicated to increase others' potency. There are also plants that are traditionally employed for specific symptoms or conditions that often accompany malaria, such as weakness, renal failure or cerebral malaria. Many plants that have been considered to lack activity against malaria due to absence of in vitro activity against Plasmodium can have other mechanisms of action. Thus researchers should observe ethnomedical information before deciding which kind of screening should be used in the search of antimalarial drugs.


Background
Flora Medicinal is an ancient and small pharmaceutical laboratory established, in early 1915, by Mr. José Monteiro da Silva, a Medical Doctor in Rio de Janeiro. Mr. Monteiro da Silva was an idealist who believed that the Brazilian rainforest had an enormous potential for research and discovery of new drugs. For more than 40 years Mr. Monteiro da Silva had organized a group of technicians and scientists who made a great number of excursions into Brazilian rainforest, collecting plant specimens and information. Although he had also edited the Revista da Flora Medicinal, a scientific paper in which he described his discoveries, a considerable part of his research remains unpublished. During the '30 s and '40 s, the Revista da Flora Medicinal was translated to French and republished by the Institut Pasteur, in Paris, which allowed some of his findings to be used by the international pharmaceutical industry. During his activities, Mr. Monteiro da Silva and his team described more than 200 new medicinal plants from this region. One of his targets was the study of new antimalarial plants, as at his time malaria was a concerning health problem in Brazil. In the following years, quinine, its derivatives and other drugs helped to control malaria. Nowadays, however, its incidence is again growing worldwide, and Plasmodium falciparum is getting more resistant to the usual antimalarial drugs [1]. It is estimated that 62% of P. falciparum around the world presents with mono or multiresistant drug profile [1]. The World Health Organization estimates that there are between 300 and 500 million new cases of malaria worldwide, every year, mostly in Africa, Asia, South Pacific Islands and South America, which causes, at least, 3 million deaths [2,3]. The main drugs developed for malaria and used up to now (quina alkaloids derived drugs and artemisinin) were discovered based on traditional use and ethnomedical data [4,5]. New efforts to search for novel drugs for treating malaria are very important in countries like Brazil, where many endemic areas still exist [6]. The study of well-documented data such as the archives of Flora Medicinal can point out traditional and probably effective treatments that had not been yet subjected to testing.

Materials and methods
All documents, including books, hand notes, unpublished studies and the issues of Revista da Flora Medicinal, belonging to the library of Mr. Monteiro da Silva, were examined for information about botanical therapies and plant species used for malaria. Any data or references to plants used for malaria were carefully inserted into a template, and botanical name and classification were reexamined and confirmed with four major plant databases -The Missouri Botanical Garden's VAST [7], the International Plant Names Index[8], the New York Botanical Garden vascular plants database [9] and the Brazilian's Northeast Plants Database [10]. Other information existing in modern databases such as Pubmed (U.S. National Library of Medicine's database that is searchable on the Web) were also examined and compared to other ethnopharmacological studies and current published data. A review of plants with possible antimalarial activity reported in ethnomedical studies or in pharmacological and biochemical research was also made .

Results
The results are summarized on A greater proportion of the plants reported as antimalarial belong to the families Asteraceae (six species), Rubiaceae (five), Apocynaceae (four), and Simaroubaceae (four).

Discussion
Most research for antimalarial new drugs is only focused on direct activity against Plasmodium species. But attention to ethnomedical information gathered by Monteiro da Silva suggests that other effects should be investigated. For example, some plants are referred to enhance the action of other herbs, which can indicate an increase on permeability of the Plasmodium membrane to antiparasitic substances, or an inhibition of pump mechanisms of eliminating the drugs [58,59]. Considering that one of the common mechanisms of drugs resistance is the reduction of permeability, the development of drugs that enhance parasite permeability could be of valuable help in the treatment of infectious diseases [60,61]. Other possible mechanism of action is interference with parasite enzymes used for protection against antiparasitic drugs [62].
Some plants with noticeable ethnopharmacological use in malaria showed only weak or even no activity against Plasmodium in vitro [55]. For example, Mikania glomerata, Melampodium divaricatum, Galipea multiflora, Aspidosperma polyneuron, and Coutarea hexandra had their antimalarial activity confirmed by clinical observations of medical doctors (Table 1), an information that yields a high probability of accuracy.
Some authors have underestimated the traditional plants used for malaria based exclusively on low activity against Plasmodium in vitro or in animal models [55]. This can be a mistake of strategy or even methodology.
There are many explanations for the absence of in vitro activity of an effective antimalarial drug. As an example, the active principle could be formed by hepatic metabolism, or as a result of transformation by gut bacteria. Other possible mechanisms of action include immunomodulation or interference with the invasion of new red blood cells by parasites, which can be species specific. Therefore studies in human subjects, as well as the observance of ethnomedical detailed data, are urged in order to exclude or confirm the activity of herbs traditionally used to treat malaria.   Xylopia sp extracts proved active against P. falciparum with IC 50 between 3 and 10 mcg/ ml.