antimony-sodium-gluconate and 8-aminoquinoline

The control of Leishmania infection relies primarily on chemotherapy till date. Resistance to pentavalent antimonials, which have been the recommended drugs to treat cutaneous and visceral leishmaniasis, is now widespread in Indian subcontinents. New drug formulations like amphotericin B, its lipid formulations, and miltefosine have shown great efficacy to treat leishmaniasis but their high cost and therapeutic complications limit their usefulness. In addition, irregular and inappropriate uses of these second line drugs in endemic regions like state of Bihar, India threaten resistance development in the parasite. In context to the limited drug options and unavailability of either preventive or prophylactic candidates, there is a pressing need to develop true antileishmanial drugs to reduce the disease burden of this debilitating endemic disease. Notwithstanding significant progress of leishmanial research during last few decades, identification and characterization of novel drugs and drug targets are far from satisfactory. This review will initially describe current drug regimens and later will provide an overview on few important biochemical and enzymatic machineries that could be utilized as putative drug targets for generation of true antileishmanial drugs.

Topics: Aminoquinolines; Amphotericin B; Antigens, Protozoan; Antimony Sodium Gluconate; Antiprotozoal Agents; Caspase Inhibitors; Cyclin-Dependent Kinases; Drug Discovery; Enzyme Inhibitors; Folic Acid Antagonists; Humans; Leishmaniasis; Macrophages; Microbodies; Mitogen-Activated Protein Kinase Kinases; Paromomycin; Pentamidine; Phosphorylcholine; Polyamines; Protease Inhibitors; Sterols; Sulfhydryl Compounds; Topoisomerase Inhibitors

We have compared the in vitro activity of six agents against macrophage-contained Leishmania tropica amastigotes determined by the conventional Giemsa staining procedure, with the activity determined by the semiautomated assessment of incorporation of radiolabeled uracil into the nucleic acid of the organisms. Although the mean 50% effective dose of Pentostam by Giemsa staining (4.1 micrograms/ml) was somewhat higher than that by uracil incorporation (2.8 micrograms/ml), the ED50S for the other two clinical agents (pentamidine, 0.035 versus 0.037 micrograms/ml; amphotericin B, 0.67 versus 0.70 micrograms/ml) and for three promising experimental agents (ketoconazole, 11.3 versus 11.3 micrograms/ml; the 8-aminoquinoline WR 6026, 1.6 versus 1.5 micrograms/ml formycin B, 0.018 versus 0.017 micrograms/ml) were virtually identical. The radiolabeling technique has several advantages over the Giemsa staining procedure. These include the need for relatively few macrophages, rapid and objective data generation, and viability of the test organism being measured. The successful application of the radiolabeling technique to at least six different chemical classes of compounds suggests that it would be useful for the routine assessment of antileishmanial activity in vitro.

Topics: Aminoquinolines; Amphotericin B; Antimony Sodium Gluconate; Antiprotozoal Agents; Automation; Azure Stains; Drug Evaluation, Preclinical; Formycins; Humans; In Vitro Techniques; Ketoconazole; Leishmania tropica; Macrophages; Pentamidine; Tritium; Uracil

Leishmania multiplying within either human monocyte-derived macrophages (HM) or mouse peritoneal exudate cells (PEC) have recently been shown to be susceptible to pentavalent antimony (Sb) by several investigators. The Sb susceptibilities of 5 cutaneous strains of Leishmania were compared in the 2 model systems, with infection of the macrophages initiated with either amastigotes or promastigotes. The susceptibility to Sb of amastigote-induced infections was statistically the same as the susceptibility of promastigote-induced infections for 4 strains in the PEC model, and for 3 of 4 strains in the HM model. Promastigote-induced infections with the 5th strain were non-viable in both macrophage types. The susceptibility of Leishmania to Sb within PEC was the same statistically as that of organisms within HM for amastigote-induced infections for 4 of 5 strains and for promastigote-induced infections by 3 of 4 strains. These data suggested that the susceptibilities of organisms to Sb within PEC and HM were generally comparable and that either amastigotes or viable promastigotes could be used to initiate the infection. The several technical advantages of the PEC model may make it more useful than the HM model for testing susceptibility to Sb. The modest susceptibility of some strains in both models to the peak serum amounts of antimony which may be achieved by presently recommended treatment regimes may partially explain the high current failure rate in simple cutaneous disease. The susceptibility of one strain within peritoneal cells to primaquine and WR 6026 (8-aminoquinolines), ketoconazole (an imidazole) and formycin B (an inosine analogue) was similar to that previously reported in human macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aminoquinolines; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Ascitic Fluid; Cells, Cultured; Drug Evaluation, Preclinical; Gluconates; Humans; Ketoconazole; Leishmania; Macrophages; Mice; Mice, Inbred BALB C; Monocytes; Pentamidine; Primaquine

The mechanism of action of antileishmanial compounds is poorly understood. Ultrastructural changes in Leishmania tropica within human macrophages exposed in vitro to Pentostam, pentamidine, amphotericin B, WR 6026, ketoconazole, and Formycin B were examined in these experiments. In Pentostam-treated cultures, some organisms exhibited diminished definition of mitochondrial and other membranes, while other organisms had completely disintegrated. Pentostam-exposed macrophages demonstrated loss of membrane definition in the absence of further alterations; it is therefore hypothesized that impaired macrophage membrane function may contribute towards the effect of this drug against macrophage-contained organisms. Leishmania parasites in pentamidine-treated cultures initially demonstrated swollen kinetoplasts and fragmentation of the kinetoplast DNA core. The initial observed effect of the other four drugs on the parasites was cytoplasmic condensation. These ultrastructural studies suggest that all five non-antimonial drugs may have different mechanisms of action than antimony (Pentostam) against Leishmania.

Topics: Aminoquinolines; Amphotericin B; Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Cell Membrane; Formycins; Humans; Intracellular Membranes; Ketoconazole; Leishmania; Macrophages; Organoids; Pentamidine