Studies on the Chemotherapy of Leishmania donovani Infections Using Compounds That Affect Trypanothione Metabolis

The hypothesis that compounds that inhibit the synthesis or interfere with the activity of trypanothione are likely to act synergistically against trypanosomatids was tested using Leishmania donovani as the target organism. Studies involved determining the efficacy of drugs and drug combinations against L. donovani growing in mice and as promastigotes and amastigotes in vitro.;The compounds tested included the antitrypanosomal drugs DL-a-difluoromethylornithine (DFMO, Eflornithine R), diminazene diaceturate (Berenil R), pentamidine (Lomidine R) (pentamidine is also recognised as antileishmanial drug), melarsonyl potassium (Trimelarsan R, Mel W R), other experimental compounds reported to have activity against trypanosomes (various nitroimidazoles and guanylhydrazones, DL-buthionine-(S,R)-sulfoximine), and also the established antileishmanial drug, sodium stibogluconate (Pentostam R). Most of these compounds were reported recently to be highly successful in the combination chemotherapy of experimental murine trypanosomiasis with central nervous system involvement.;Many of the compounds were shown to have antileishmanial activity but none of the combinations appeared to be synergistic under the conditions used. However, at high concentrations, some were more effective than the recognised antileishmanial drug sodium stibogluconate.;The antileishmanial activity of DFMO was studied in more detail using different regimens to assess the potential of the drug for treating visceral leishmaniasis and prevent relapse. DFMO showed good activity but did not give a total clearance of parasites from all tissues.;The potential of some promising drug combinations was also tested for clearing the parasites from tissues other than the liver, such as the spleen and the bone marrow. These combinations reduced significantly the number of parasites but without giving a total clearance.;An experimental compound, octyl degrol oil, which allowed a slow release of the drugs, was also investigated and the results showed a beneficial effect when it was used with sodium stibogluconate.;A number of experimental compounds with potential antitrypanosomal activity were available in limited quantities. These included DNA intercalators, platinum and rhodium drug complexes and 8-hydroxyquinolines and were tested as potential antileishmanials. The results from this study suggested that the DNA intercalators and the 8-hydroxyquinolines have antileishmanial activity and further studies evaluating these compounds would be worthwhile.