rifampin and Leishmaniasis--Visceral

In an attempt to find an orally effective drug against kala-azar, ethambutol alone, ethambutol plus INH, INH plus rifampicin, co-trimoxazole and metronidazole were tried in the treatment of 70 patients of Indian kala-azar. Ethambutol and ethambutol plus INH were totally ineffective. INH and rifampicin were tried in 10 cases; in three there was some clinical improvement but all relapsed and were cured with sodium stibogluconate. Co-trimoxazole reduced fever in four out of 20 cases, but all relapsed within 2 months. In one case the general health was well maintained but the splenic aspirate contained a large number of parasites and there was no regression in the size of the spleen. The patient was ultimately cured with sodium stibogluconate. Metronidazole orally or intravenously was not effective. It is suggested that, as these drugs are ineffective, a search for an oral substitute to sodium stibogluconate should continue.

Topics: Antiprotozoal Agents; Drug Therapy, Combination; Ethambutol; Female; Follow-Up Studies; Humans; Isoniazid; Leishmaniasis, Visceral; Male; Metronidazole; Random Allocation; Rifampin; Trimethoprim, Sulfamethoxazole Drug Combination

6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole derivatives were initially studied for tuberculosis within a backup program for the clinical trial agent pretomanid (PA-824). Phenotypic screening of representative examples against kinetoplastid diseases unexpectedly led to the identification of DNDI-VL-2098 as a potential first-in-class drug candidate for visceral leishmaniasis (VL). Additional work was then conducted to delineate its essential structural features, aiming to improve solubility and safety without compromising activity against VL. While the 4-nitroimidazole portion was specifically required, several modifications to the aryloxy side chain were well-tolerated e.g., exchange of the linking oxygen for nitrogen (or piperazine), biaryl extension, and replacement of phenyl rings by pyridine. Several less lipophilic analogues displayed improved aqueous solubility, particularly at low pH, although stability toward liver microsomes was highly variable. Upon evaluation in a mouse model of acute Leishmania donovani infection, one phenylpyridine derivative (37) stood out, providing efficacy surpassing that of the original preclinical lead.

Topics: Animals; Antiprotozoal Agents; Antitubercular Agents; Cricetinae; Drug Repositioning; Female; High-Throughput Screening Assays; Hydrogen-Ion Concentration; Leishmania infantum; Leishmaniasis, Visceral; Mesocricetus; Mice; Mice, Inbred BALB C; Microsomes, Liver; Models, Molecular; Solubility; Structure-Activity Relationship

The aim of current research work was to develop and investigate the potential of rifampicin (RIF) loaded mannose-conjugated chitosan nanoparticulate system for selective delivery to the macrophages in the management of visceral leishmaniasis (VL). RIF loaded mannose-conjugated chitosan nanoparticles (mCNPs) were prepared and characterized for shape, size, entrapment efficiency and in vitro drug release. The in vivo bio-distribution in albino rats and ex vivo drug uptake by macrophage were also evaluated. It was observed that extent of accumulation of mCNPs in macrophage rich organs, particularly in liver and spleen, were significantly higher compared to free drug. Ex vivo uptake of mCNPs was 2.31 times higher compared to unconjugated chitosan nanoparticles (CNPs). The macrophage uptake of mCNPs was inhibited significantly on pre-incubation with 0.05 M mannose in a parallel experiment, being suggestive of receptor mediated uptake of mannosylated nanoparticles. Our results indicate that mCNPs could be a promising carrier for selective delivery of RIF to macrophages for effective management of VL.

Topics: Animals; Biological Transport; Chemical Phenomena; Chemistry, Pharmaceutical; Chitosan; Drug Carriers; Leishmaniasis, Visceral; Male; Mannose; Nanoparticles; Rats; Rifampin

Topics: Child; Drug Therapy, Combination; Female; Humans; Leishmaniasis, Visceral; Rifampin; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Administration, Oral; Child; Child, Preschool; Drug Combinations; Female; Follow-Up Studies; Humans; Leishmaniasis, Visceral; Male; Rifampin; Tablets; Trimethoprim, Sulfamethoxazole Drug Combination

Reports in the literature indicate the use of animal models for testing newer anti-leishmanial drugs in vivo. However, in certain established cell lines and macrophages in vitro models have the advantage over the in vivo system of simplicity and speed with which the results can be obtained. A simple in vitro system using peritoneal exudate macrophages of BALB/c mice infected with Leishmania donovani promastigotes has been tested for its use in determining the efficacy of several new drugs. Two well-established drugs, amphotericin B and sodium stibogluconate, as expected, could kill the intracellular parasites effectively. Two relatively new drugs not routinely used against leishmania, rifampicin and metronidazole at concentrations of 20 micrograms/ml and 10 micrograms/ml, respectively, were also able to kill the intracellular leishmania parasites effectively. Critical factors for drug testing in vitro have been elucidated: the most important being the temperature of incubation after infection.

Topics: Animals; Antiprotozoal Agents; Drug Evaluation, Preclinical; In Vitro Techniques; Leishmania donovani; Leishmaniasis, Visceral; Macrophages; Metronidazole; Mice; Mice, Inbred BALB C; Rifampin

A patient with dermal leishmaniasis subsequent to kala-azar was treated with sodium stibogluconate, but the condition did not improve. The patient was then treated with rifampin which has not been used to treat this condition in the past. All clinical features cleared spontaneously by six weeks. No overt disease was noted during the next three months. Rifampin can therefore be used to treat post-kala-azar dermal leishmaniasis when standard procedures are ineffective.

Topics: Adult; Humans; Leishmaniasis; Leishmaniasis, Visceral; Male; Rifampin; Skin