In vitro antileishmanial properties of tri- and pentavalent antimonial preparations.

To better understand the antileishmanial effects of antimonial agents we synthesized complexes of tri- and pentavalent antimony with mannan. The 50% inhibitory concentrations (IC50s) of these agents, along with those of potassium antimony tartrate [Sb(III)] and sodium stibogluconate [Sb(V)], were determined for promastigotes and intramacrophage amastigotes. The trivalent antimonial agents were more potent than the pentavalent agents. Although the IC50s were 60- to more-than-600-fold higher for promastigotes than for amastigotes, similar intracellular antimony concentrations in both life forms were measured after incubation with all four drugs at their respective IC50s. Macrophages accumulated antimony during a 4-h exposure that was retained intracellularly for at least 3 days. Amastigotes inside macrophages had a higher antimony content 6 days after a single 4-h treatment than they did immediately after treatment, suggesting that macrophages serve as a reservoir for antimonial agents and prolong parasite exposure. Macrophages concentrated antimony from the medium with potassium antimony tartrate, trivalent antimony-mannan, and pentavalent antimony-mannan treatments. N-Acetylcysteine antagonized the antileishmanial effects of these three drugs against intracellular amastigotes; in contrast, it had minimal effects on the action of sodium stibogluconate.

Glucantine resistant Leishmania promastigotes are sensitive to pentostam

Diferentes amostras de leishmania foram analisadas quanto à susceptibilidade in vitro ao pentostam - uma cepa de L. (V) braziliensis considerada sensível ao glucantine, três cepas (duas L. (V) braziliensis e uma L. (L) amazonensis) consideradas naturalmente resistentes ao glucantine, uma linhagem resitente (L. (V) guyanensis) selecionada in vitro pela exposiçäo em alta concentraçäo de droga. A elevada sensibilidade destas amostras em contraposiçäo à resistência observada para a glucantine sugere existir relaçäo entre a estrutura química e a atividade destes compostos. Estes dados indicam a necessidade de uma avaliaçäo comparativa de atividade clínica do pentostam e do glucantime no tratamento da leishamniose

Glucantime resistant Leishmania promastigotes are sensitive to pentostam.

Growth inhibition in vitro tests were used to study the susceptibility to pentostam of different Leishmania strains involved in cutaneous and mucocutaneous leishmaniasis--one glucantime sensitive strain, three naturally glucantime resistant strains and one glucantime resistant line developed by in vitro drug exposure. Contrasting with the high degree of glucantime resistance, all strains were sensitive to pentostam. These differences suggest that there is some relationship between chemical structure and in vitro activity for these antimonial compounds. These data justify a clinical re-evaluation to compare therapeutic efficacy of glucantime and pentostam in the treatment of leishmaniasis.

Structural requirements for chelate antidotal efficacy in acute antimony(III) intoxication.

The LD50 for i.p. potassium antimonyl tartrate was determined to be 54.6 mg/kg in mice, with a 95% confidence range of 48.4 to 61.7 mg/kg. An examination of the antidotal efficacy of a number of different structural types of chelating agents showed that very few types were able to act as antidotes when potassium antimonyl tartrate was administered i.p. to mice at a level of 120 mg/kg. The most effective antidotes, by a substantial margin, were the water soluble vicinal dithiols: 2,3-dimercaptosuccinic acid and sodium 2.3-dimercaptopropane-1-sulfonate, with the first of these being significantly better than the second. Appreciably less effective, but still useful, was D-penicillamine. At this level of administration of antimony(III), BAL is not an effective antidote. Among other chelating agents which were also not effective at this level of antimony(III) are tartaric acid, EDTA, cysteine, sodium diethyldithiocarbamate and potassium dithiooxalate.

Penicillamine as an adjuvant to antimonial therapy of schistosomiasis: effect on liver function tests in rabbits and on antischistosomal activity.

Earlier work has shown that penicillamine reduces the acute toxicity of antimonyl potassium tartrate (APT) as well as the abnormal ECG changes it induces. In the present study, the possible protective effect of penicillamine on the hepatic toxicity of APT was investigated. Tests of liver function showed changes in the level of serum aspartate and alanine aminotransferase and of alkaline phosphatase, and in the beta-/alpha-lipoprotein ratio, in response to antimony treatment. The changes were significantly reduced by penicillamine, though the effect depended on the dose. Penicillamine was found to give the best overall protection without affecting the antischistosomal efficacy of the antimonial when a 1:2 APT/penicillamine ratio was used. The findings provide further evidence of the potential usefulness of penicillamine in the antimonial treatment of schistosomiasis.