New drugs for the treatment of human parasitic protozoa

Whereas parasitic diseases are always a heavy burden for humanity, few are the new antiparasitic molecules marketed during the last 25 years. Thus on the 1393 new molecules marketed between 1975 and 1999, only 7 have antiprotozoan properties. This talk will detail the progress made in the treatment of the intestinal protozoa, malaria, visceral leishmaniasis and toxoplasmosis, problems with which are especially confronted the European parasitologists. The treatment of Giardia and intestinal amoebas is based on 5-nitro-imidazoles derivatives. Single-dose treatments can be used with tinidazole or secnidazole. Resistance to these compounds of Giardia were described and in these cases, treatment by quinacrine or nitazoxanide are possible alternatives. Nitazoxanide is marketed in the United States and in Australia. It seems to be a well tolerated antiparasitic agent with a broad spectrum because it is active on a lot of intestinal protozoa and helminths. It acts on the same metabolic way as the 5-nitro-imidazoles (inhibition of the ferredoxine reductase) but without synthesis of free radicals and DNA deterioration of the target cell. It is thus neither teratogenic nor mutagenic. Artemisinin derivatives allowed considerable progress in the treatment of malaria. They have short half-lifes, allowing a fast parasitic clearance and these derivatives do no provoke resistance. They are first line drugs for the treatment of malaria in areas of drug resistance. The arthemeter-lumefantrine association (Riamet, Coartem) ensures a rapid disappearance of the circulating parasites and is well tolerated. Atovaquone-proguanil (Malarone) is usable in the treatment of acute malaria but also in disease prevention with the advantage of continuing drug intake for only 7 days after having left the infected area. The treatment of leishmaniasis is always delicate and is characterized by the worrying development of antimony resistances, probably related in the European zones to the treatment of dogs. Liposomal amphotricin is an alternative of choice but remains very expensive. The heating of amphotericin to 70 degrees C during 20 minutes gives it experimental properties and efficacies comparable with that of liposomal amphotericin, but at a less cost. Miltefosine, an alkyl-phospholipide antimetabolite, is very active on visceral leishmaniasis resistant to antimonial treatment. However, its long half-life could induce the emergence of resistances. Miltefosine induces much less side effects than conventional amphotericin B. The commonly used anti-toxoplasmic drugs (sulphadiazine and pyrimethamine) were marketed some 50 years ago and are only active on the rapid forms in multiplication. No drug is really efficient on the cysts although preliminary tests with atovaquone are encouraging to treat ophthalmologic forms in immunocompetent patients. To conclude, it is important to continue to search for new antiprotozoan molecules because, for some parasites, drug resistance is an important problem. Moreover, the treatment of the pregnant women, particularly during the first trimester, is often impossible and there is a lack of galenic forms easily usable in children. A better knowledge of the metabolic pathways of protozoa (particularly the apicoplast of Apicomplexa parasites) would certainly open the posssibility to identify new drugs. To reduce and delay the appearance of resistances, mass-treatments of mass should be avoided and targeted treatments prefered as well as the use of associations of molecules having different modes of action.