Public / private partnership: developing an oral treatment for visceral leishmaniasis.

PIP: The phase III clinical trials of a new oral treatment, miltefosine, for visceral leishmaniasis are being conducted in Bihar, India, by the Training in Tropical Diseases and ASTA Medica. Other drugs used to combat this disease were administered through injection or infusion. Pentostam causes serious side effects, such as mortality in 2-5% and toxicity in 10-15% of the patients, while pentamidine, the second-line treatment, causes mortality in 7-9% and toxicity in 60%, including diabetes. Amphotericin B, considered to be the most effective and expensive treatment, causes severe rigor, fever and sometimes anaphylaxis. Miltefosine, on the other hand, will be cheaper than the rest of the treatments. Moreover, compliance has been good and earlier trials showed an overall cure rate of 90%. The only major disadvantage is its effect on the fetus; thus it cannot be used as mass outpatient treatment and will need to be monitored all the time.^ieng

Electrophoretic investigation of some dehydrogenases in Leishmania amastigotes.

Amastigotes of Leishmania mexicana mexicana and of Leishmania donovani were grown in mouse peritoneal macrophages and dog sarcoma cells in culture. Polyacrylamide gel disc electrophoresis of amastigote-infected tissue cultures failed to detect parasite lactate dehydrogenase and malate dehydrogenase, although the presence of glucose-6-phosphate dehydrogenase was indicated.

The experimental chemotherapy of leishmaniasis. II. The activity in tissue culture of some antiparasitic and antimicrobial compounds in clinical use.

A variety of compounds used in the treatment of parasitic or bacterial infections in man, including leishmaniasis itself, were examined for their activity against three lines of Leishmania in tissue culture. The organisms used were L. mexicana mexicana, L. tropical major and L. donovani; they were grown in dog sarcoma and hamster peritoneal exudate cell lines. Leishmanicidal activity was observed in a number of compounds currently in clinical use for the treatment of one or other form of leishmaniasis. Cycloguanil, nifurtimox, amphotericin B and monomycin were effective but pentamidine showed poor activity. In each case marked differences were observed in the level of response in the different parasite lines. Organic antimonials were most active when anmastigotes were exposed to them prior to entry of the parasites into host cells. This suggests that such compounds may exert an effect on amastigotes during their brief extracellular transit from one host cell to another in vivo. A number of antimalarials showed good to moderate leishmanicidal action, particularly against L. mexicana and L.t. major. Several schistosomicidal agents also possessed leishmanicidal properties. The commonly used broad spectrum antibiotics showed little if any activity. In discusssion a comparison is drawn between data published on the action of some of these drugs against L.t. major in mice and our observations with the same strain and L. mexicana in tissue culture. A remarkably good agreement is found for most of the compounds examined. General agreement is also noted between these data and reports of clinical trials although it is not possible to draw too many conclusions because of the failure in most clinical studies to make an accurate identification of the causative Leishmania. It is concluded that, although the tissue culture model is not to be considered as ideal and can probably be improved, data obtained by its use do bear relevance to the action compounds in vivo, and the model may be use in the screening of drugs for leishmanicidal activity.

The experimental chemotherapy of leishmaniasis. I: Techniques for the study of drug action in tissue culture.

Three lines of Leishmania have been grown successfully in tissue culture. L. mexicana mexicana, L.tropica major and L. donovani develop readily as amastigotes in dog sarcoma cells, and in a hamster peritoneal exudate cell line. The procedures used for cultivating both host cells and parasites are described, as are the methods employed for studying the senitivity of the parasites and hosts to drugs. It is concluded that the use of a tissue culture system is a valid way of determining the baseline sensitivity of a Leishmania to chemotherapy and the limitations of the technique are discussed. Illustrative data are presented of the response of two Leishmania species to amphotericin B and to a quinine analogue. L. mexicana mexicana is highly sensitive to amphotericin B and the response is shown to be consistent in duplicate experiments. L. mexicana mexicana and L. donovani are shown to have a different innate sensitivity to the quinine analogue.