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No abstract

This trial provides evidence of the efficacy of paromomycin-gentamicin and paromomycin alone for ulcerative L. major disease. (Funded by the Department of the Army; ClinicalTrials.gov number, NCT00606580.).

The antiprotozoal compound 1,5-di(4-amidinophenoxy)pentane (pentamidine) and 36 of its analogs were screened for in vitro activity against Leishmania mexicana amazonensis clone 669 C4S (MHOM/BR/73/M2269) and Plasmodium falciparum clones W2 (Indochina HI/CDC) and D6 (Sierra Leone I/CDC). Pentamidine and each of the analogs tested exhibited activity in vitro against L. m. amazonensis and P. falciparum. The pentamidine analogs were more effective against the P. falciparum clones than against L. m. amazonensis. P. falciparum was extremely susceptible to these compounds, with 50% inhibitory concentrations as low as 0.03 FpM. While none of the analogs exhibited marked improvement in antileishmanial activity compared with pentamidine, 12 of the pentamidine analogs showed activity approximately equal to or greater than that of the parent compound. From the promising activity exhibited by the pentamidine analogs in this in vitro study and their potential for reduced toxicity relative to the parent drug, pentamidine-related compounds hold promise as new agents for the treatment of protozoal infections.The efficacy of aromatic diamidines in the treatment of protozoal diseases was first recognized in the 1930s by investigators searching for agents with therapeutic activity against African trypanosomiasis (14). Early clinical trials examining the activities of pentamidine, propamidine, and stilbamidine revealed that these and other aromatic diamidines are effective against the early stages of African trypanosomiasis (6,7,13,14) and against leishmaniasis (11,15,22). Although they are not clinically used in the treatment of malaria, the antiplasmodial activity of aromatic diamidines in monkeys infected with Plasmodium knowlesi was demonstrated during the 1940s (1, 4).Aromatic diamidines not only have antiprotozoal activity but also exhibit activity against bacteria (3), fungi (3), viruses (21), and tumors (12). In the past, their use has mainly been confined to the treatment of protozoal diseases, for which they were first developed. Pentamidine continues to be used in the treatment of the Gambian form of African trypanosomiasis and against antimony-resistant leishmaniasis (17). Pentamidine was first shown to be active against the opportunistic pathogen Pneumocystis carinii in 1958 (10), and in the United States, this compound is primarily used to treat P. carinii pneumonia in patients with the acquired immune deficiency syndrome. The toxicity and side effects associated with the use of pentamidine in the treatment of P. carinii pneumonia in acquired immune deficiency syndrome patients have led to extensive investigations to identify a derivative of pentamidine which is more active against P. carinii pneumonia and less toxic than the parent drug.To this end, over 50 analogs of pentamidine have been synthesized in our laboratory and have been examined for in vivo efficacy against P. carinii in the rat model of disease (10a, 18, 19). The design of more-potent analogs of pentamidine against P. carinii pneumonia has been hampered ...

The current evidence-base for recommendations on the treatment of cutaneous leishmaniasis (CL) is generally weak. Systematic reviews have pointed to a general lack of standardization of methods for the conduct and analysis of clinical trials of CL, compounded with poor overall quality of several trials. For CL, there is a specific need for methodologies which can be applied generally, while allowing the flexibility needed to cover the diverse forms of the disease. This paper intends to provide clinical investigators with guidance for the design, conduct, analysis and report of clinical trials of treatments for CL, including the definition of measurable, reproducible and clinically-meaningful outcomes. Having unified criteria will help strengthen evidence, optimize investments, and enhance the capacity for high-quality trials. The limited resources available for CL have to be concentrated in clinical studies of excellence that meet international quality standards.