Chemotherapy for leishmaniasis: biochemical mechanisms, clinical efficacy, and future strategies.
The 1980s have seen significant advances in the treatment of cutaneous, mucosal, and visceral leishmaniasis. Safe regimens of pentavalent antimony in the form of Pentostam (Wellcome Foundation, London; 20 mg of antimony/[kg.d] for 20-30 days) have produced initial cure rates of greater than 90% in these diseases. Biochemical investigations have demonstrated at least three parasite-specific features relevant to the mechanism of action of chemotherapeutic agents: (1) Organization of glycolytic enzymes and some enzymes of fatty acid catabolism into organelles (glycosomes) occurs in Leishmania but not in mammalian cells. Since antimony inhibits both amastigote catabolism of glucose via glycolytic enzymes and catabolism of fatty acids, the mechanism of action of antimony may relate to alteration of glycosomal structure or function. (2) Purine analogues can be utilized by the salvage pathway of purine biosynthesis in amastigotes to a greater extent than in mammalian cells, and allopurinol and allopurinol ribonucleoside are metabolized into presumably toxic nucleotides by these means. (3) Amastigote sterol biosynthesis is akin to that of such fungi as Candida in that the major demethylated sterol is of the ergostane series and in that ketoconazole inhibits its synthesis. Preliminary clinical studies suggest that the purines and the sterol inhibitors may have clinical utility as oral agents against cutaneous leishmaniasis. Possible treatment strategies for the classic and experimental agents have been proposed.
Berman
J D
JD
Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Walter Reed Army Medical Center, Washington, DC 20307-5100.
D000818:Animals; D000965:Antimony / Q000627:therapeutic use*; D000981:Antiprotozoal Agents / Q000627:therapeutic use*; D055598:Chemical Phenomena; D002621:Chemistry; D004734:Energy Metabolism; D006801:Humans; D007891:Leishmania / Q000378:metabolism*; D007896:Leishmaniasis / Q000188:drug therapy*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy*; D050356:Lipid Metabolism; D011073:Polyamines / Q000378:metabolism; D011687:Purines / Q000378:metabolism
D000981:Antiprotozoal Agents; D011073:Polyamines; D011687:Purines; D000965:Antimony