Activity of the Novel Immunomodulatory Compound Tucaresol against Experimental Visceral Leishmaniasis

Abstract

Tucaresol, a novel immunomodulator, was inactive against Leishmania donovani amastigotes in both peritoneal and bone marrow macrophages in vitro at concentrations between 100 and 1 M, with toxicity to macrophages and parasites at 300 M. However, against L. donovani in BALB/c mice at doses between 80 and 1.25 mg/kg of body weight administered once daily by the oral route during days 7 to 11 of infection, an optimal dose of 5 mg/kg produced a 43.8 to 62.4% suppression of liver amastigotes, with significantly reduced activity at the extremes of the dose range. This response was not related to levels of infection. No interaction with the standard pentavalent antimonial sodium stibogluconate (Pentostam) was observed during this period of infection. The optimum dose of 5 mg/kg was ineffective when administered during the first week of infection and was most effective against the liver infection when administered during weeks 2 to 3 of infection (42.3 to 46.8% inhibition) and against the splenic infection when administered during week 6 of infection (59.5% inhibition). The optimum dose of tucaresol against L. donovani in C57BL/6 mice was 5 mg/kg, which produced a 40.8 to 48.7% suppression of liver amastigotes when administered in a range of 80 to 1.25 mg/kg during days 7 to 11 of infection. The drug had no activity against L. donovani infections in C.B-17 scid mice when the same regimen was used.

In Vitro Susceptibilities of Leishmania donovani Promastigote and Amastigote Stages to Antileishmanial Reference Drugs: Practical Relevance of Stage-Specific Differences

“…The latter phenomenon has been shown to occur frequently with clinical field isolates during their adaptation to in vitro culture and will affect the outcome of in vitro Sb resistance determinations (L. Maes, unpublished data). Overall, the results obtained in the present study are within the range of published IC 50 s for L. donovani strain L82 (10,14,30,35): IC 50 s of 4.8 to 34.5 g Sb V /ml were reported for sodium stibogluconate against intracellular amastigotes; miltefosine exhibited IC 50 s of 0.18 to 13.6 M on promastigotes and 2.8 to 5.8 M on intracellular amastigotes, while amphotericin B showed IC 50 s of 0.003 to 0.15 M and 0.026 to 0.076 g/ml against promastigotes and intracellular amastigotes, respectively.…”

Inhibition of Fumarate Reductase in Leishmania major and L. donovani by Chalcones

“…Some efforts have been devoted to searching for new antileishmanial drugs during the past 2 decades (2,6,15,21,22,25,30,33,38). One of the strategies for development of new antileishmanial drugs is to identify some unique enzymes, which exist only in the parasite and play important role in energy metabolism, as targets, and then to find or design inhibitors of these enzymes.…”

“…This resistance occurred in 5 to 70% of patients in some areas of endemicity (28, 36). There is, therefore, a great and urgent need for the development of new, effective, and safe drugs for the treatment of leishmaniasis.A number of investigations to explore potential antileishmanial drugs have been carried out during the last 2 decades (2,6,15,21,22,25,30,33,38). We have previously reported that chalcones have potent antileishmanial and antimalarial activities and might be developed into a new class of antileishmanial drugs (7-10, 39).…”

“…A number of investigations to explore potential antileishmanial drugs have been carried out during the last 2 decades (2,6,15,21,22,25,30,33,38). We have previously reported that chalcones have potent antileishmanial and antimalarial activities and might be developed into a new class of antileishmanial drugs (7)(8)(9)(10)39).…”

Clinical and Experimental Advances in Treatment of Visceral Leishmaniasis

“…In the L. major model, prophylactic costimulation, including engaging the CD40 ligand and CD40 pathway by anti-CD40 injection, promotes Th1-cell responses and control over infection (61). The effect of the oral agent tucaresol in visceral infection also probably reflects T-cell costimulation (161).…”