The experimental chemotherapy of leishmaniasis, VII

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Abstract
Using procedures described in the previous paper in this series, a number of ‘standard’ drugs used for other indications in man, as well as a range of new candidate compounds was examined for activity against infections with L. major LV39 and (a smaller number) L. mexicana amazonensis LV78 in TFW mice. A number of antimalarial agents, including trimethoprim, amopyroquine, mepacrine, mefloquine and WR 122455, showed significant activity against L. major, as did nifurtimox, diminazene aceturate and benznidazole, clindamycin, amphotericin B and erythromycin. Some were active also against L. m. amazonensis. A direct comparison with earlier results with these compounds in tissue culture is possible in only a few instances. A number of 8-aminoquinolines including several lepidines show good activity against both L. major and L. m. amazonensis by the two methods of assessment employed. Method B is considered to give more information than Method A since the latter provides only a simple score of activity. Method B gives a graphically determined estimate of the 50% and 90% suppressive doses (SD50 and SD90), an indication of drug toxicity, and a ‘Pentostam Index’. One lepidine, WR 226292, has a P.I. of over 800 for L. major and in the order of 20 for L. m. amazonensis. Generally however the 8-aminoquinolines are more active against visceral infections with ‘L. infantum LV9’ than against cutaneous infections in mice. Activity was found in a number of compounds among 68 examined, the best including diaminoquinazolines, an antimalarial pyridine (WR 113618) and an organic tin compound. An analysis of the data obtained in vivo with earlier tissue culture studies indicates a remarkably good qualitative correlation between the two systems, in spite of the fact that most compounds were examined in vivo against L. major, and in tissue culture against L. m. amazonensis. Quantitative differences in drug response are commoner between the two species than qualitative differences. An analysis is made of the type of action of the most active compounds as demonstrated in the present studies, and in earlier work with ‘L. infantum LV9′. Attention is drawn to the marked activity of dihydrofolate reductase inhibitors, as compared with the inactivity of sulphonamides and sulphones. A number of extremely potent compounds are found among the 8-aminoquinolines. Several trypanocidal agents are significantly leishmanicidal. However these groups of compounds show differing levels of activity against the individual species included in these studies, and emphasis is laid on the necessity of defining the taxonomic nature of the infecting organisms in experimental and clinical chemotherapy investigations. Suggestions are made for further lines of investigation into the metabolism of Leishmania based on the types of drugs found active against the different species. It is recommended that certain compounds should be pursued further in clinical trials in view of the good correlation that has been found so far between experimental data obtained in animal models in the hands of other investigators and ourselves. Against cutaneous infections trimethoprim, diminazene aceturate, nifurtimox, benznidazole and clindamycin justify clinical trial. Cycloguanil (possibly as the embonate) should be considered in visceral infections. Attention is drawn also to the activity in vivo of allopurinol. Further development is also indicated of certain diaminoquinazolines, WR 113618, a number of lepidines, and possibly the organic tin compound.

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