Resistance to Choroquine

The parasitic resistance to medications is a great interest topic due to the high morbidity and mortality associated. In this document a concept of parasitical resistance to Choroquine (CHL) is revised and some ideas of its mechanism, a possible focus is also presented to the solution of the problem by searching new anti-malarial agents through etnopharmacological methods.

Parasitic resistance is the capacity of survive to greater chemotherapeutic dose than normal. Emergence of strains of P. falciparum that are resistant to CHL has been observed since shortly after its introduction to therapeutics as antimalarial agent. During the past thirty years resistance to CHL has become widespread in all endemic areas where it is prevalent. Resistance appears to emanate from spontaneous chromosomal point mutations. Resistant mutants are able to survive in the presence of antimalarial agents. It is well recognized that erythrocytes harboring resistant strains of malaria are able to concentrate less CHL than sensitive strains. Indirect experimental evidence to resistance came from the finding that the CHL resistant phenotype is characterized by an increase in drug efflux rate compared to sensitive parasites. Resistant parasites pump CHL out 40-50 times faster than sensitive parasites.  When the cells become resistant to a wide variety of antimalarials and present cross-resistance, it is called multidrug resistance (MDR).Then the resistance or lower concentration to the drug may me caused partly by a decrease in the influx of the drug or an increase in the efflux. In resistant P. falciparum verapamil and other calcium channel blockers slows the efflux of CHL, but they do not have that effect in sensitive strains.

         Contrary to these findings there is reported that resistance to CHL could be multigenic and that there is a determinant of resistance that does not involve multidrug resistance.

Fig 1 Giemsa-stained thick blood films showing early trophozoites of P. falciparum (Courtesy JK Baird)

In malarial endemic places CHL and related quinoline derivatives are essentially useless. In addition, CHL resistant strains of P. vivax are now being reported in both Southeast Asia and South America. Where malaria has become resistant to CHL and other chemotherapeutic agent alternative drugs such as mephloquine, halofantrine, artemisin derivatives, and the combination of pyrimethamine and sulfadoxine (Fansidar) are used.  There is genetic diversity among wild strains of P. falciparum that infect humans in a given area. Thus there are differences in their sensitivity to CHL and other antimalarial agents.

There were an estimated 247 million malaria cases among 3.3 billion people at risk in 2006, causing nearly one million deaths, mostly children under five years of age. One hundred six countries were endemic for malaria in 2009, 45 within the WHO African region.

This worsening situation can be explained by resistance of P. falciparum to the current antimalarial drugs, lack of new therapeutic targets, unaffordability and poor quality of antimalarial drugs and their bad storage under tropical conditions. 

Then an urgent need for the development of new anti-malarial agents faces the scientific community. Traditional medical knowledge based on the use of natural products from plants is a promising basis for discovering new drugs. It is estimated that 80% of many developing countries population still use plant-based traditional medicines. These natural products and their derivatives represent almost half of the drugs approved since 1994 and more than 30% of the current anti-malarial market.

In this context, an ethnopharmacological survey of medical plants was carried out in Senegal and data were collected on some plants traditionally used for the treatment of malaria and fevers.

The plant extract and fractions revealed anti-plasmodial activity (IC50<5 microgr/mL) with no toxicity. Anti-plasmodial activity and toxicity of I. senegalensis are reported for the first time and showed promising results in malaria field research.

Journal Reference

Serigne O Sarr , Sylvie Perrotey , Ibrahima Fall , Said Ennahar , Minjie Zhao , Yerim M Diop , Ermanno Candolfi  and Eric Marchioni, 2011, Icacina senegalensis (Icacinaceae), traditionally used for the treatment of malaria, inhibits in vitro Plasmodium falciparum growth without host cell toxicity, Malaria Journal 2011, 10:85doi:10.1186/1475-2875-10-85

http://www.malariajournal.com/content/10/1/85