Antiproliferative Effects of △<sup>24(25)</sup> Sterol Methyl Transferase Inhibitors on <i>Trypanosoma (Schizotrypanum) cruzi</i>: In vitro and in vivo Studies

4区 · 医学

Article

作者: Piras, Romano ; Payares, Gilberto ; Vivas, Julio ; Lazardi, Keyla ; Molina, Judith ; Urbina, Julio A. ; Piras, Marta M.

We have studied the antiproliferative effects of two sterol analogs previously reported as potent inhibitors of delta 24(25) sterol methyl transferase (E.C. 2.1.1.43) of yeasts and fungi on epimastigotes and amastigotes on Trypanosoma (Schizotrypanum) cruzi, the causative agents of Chagas disease, as well as its chemotherapeutic effects in a murine model of the disease. On the epimastigote form proliferating in liver infusion tryptose medium at 28 degrees C 22,26-azasterol (AZA), a cholestanol analog with a 6-membered aza ring as a side chain produced a dose-dependent reduction of the growth rate up to 3 microM, but at 10 microM complete growth arest and cell lysis took place after 120-144 h. For 24(R,S),25-epiminolanosterol (EIL), complete growth arrest and lysis took place with 6 microM. In both cases the antiproliferative effects were potentiated by the simultaneous incubation of the epimastigotes with inhibitors of sterol C-14 alpha-demethylase such as ketoconazole or SDZ 89,485, as indicated by concave isobolograms and fractional inhibitory concentrations ranging from 0.11 to 0.46. Analysis of the sterol composition in control and treated cells by thin-layer and capillary gas-liquid chromatography coupled to mass spectrometry showed that growth inhibition correlated with the complete disappearance of the native endogenous sterols of the parasite (ergosterol and 24-ethyl analogs) and the accumulation of 24-desalkyl sterols. Against the clinically relevant amastigote form proliferating inside cultured Vero cells at 37 degrees C, AZA eradicated the parasite of 100 nM, while the corresponding concentration for EIL was 300 nM. Synergic effects of both inhibitors when combined with ketoconazole against this form of the parasite was demonstrated using a three-dimensional analytic method which allowed the identification of optimal drug concentrations. Finally, it was found that daily oral administration of AZA at 50 mg/kg/day for a total of 43 doses to mice infected with a lethal inoculum of T. cruzi allowed survival of all treated animals 25 days after infection, while all control (untreated) animals were dead at this point of time. Increased survival correlated with a 90% reduction in parasitemia in the treated animals. The antiparasitic effects of the azasterol were potentiated in combined treatments with ketoconazole. This is the first report of a successful application of a sterol methyl transferase inhibitor as a chemotherapeutic agent in a protozoal infection.

1990-01-01·Antimicrobial Agents and Chemotherapy2区 · 医学

Comparison of fluconazole and SDZ89-485 for therapy of experimental murine coccidioidomycosis

2区 · 医学

Article

作者: Kirkland, T ; Fierer, J ; Finley, F

We infected mice with arthroconidia of Coccidioides immitis by intraperitoneal injection and 48 h later treated them with either oral fluconazole or SDZ89-485, a new triazole. Both drugs completely inhibited fungal growth when administered at a dose of 50 mg/kg of body weight twice a day, but only SDZ89-485 was fully inhibitory at a dose of 5 mg/kg twice a day. In a second experiment, treatment with SDZ89-485 was delayed until 8 days after infection to allow infection to be well established before treatment. Both 5 and 50 mg/kg twice a day were effective regimens, which establishes that SDZ89-485 has activity against spherules in vivo. Mice that received fluconazole (50 mg/kg twice a day) had a peak level in blood of 60 micrograms/ml 1 h after a dose, but no measurable amount was found after 12 h. SDZ89-485 was more slowly absorbed, reaching a peak level in blood of 14 micrograms/ml at 12 to 15 h after a dose of 50 mg/kg. We conclude that SDZ89-485 is more effective than fluconazole as treatment for experimental systemic coccidioidomycosis in mice, even though fluconazole achieves higher peak levels in blood.

1990-01-01·Medical Mycology

Biochemical model of action and enantiomeric selectivity of SDZ 89-485, a new triazole antimycotic

Article

作者: Ryder, N S

SDZ 89-485, a new triazole antimycotic agent, potently inhibited ergosterol biosynthesis in cells of Candida. Trichophyton and Aspergillus. Biosynthesis was measured both by incorporation of radiolabelled acetate and also by methylation of the sterol side chain. Inhibition was accompanied by accumulation of radiolabel in 4,4-dimethylsterols and to a lesser extent in the 4-methylsterols, consistent with inhibition of lanosterol 14-demethylation. No other steps were affected. Ergosterol biosynthesis in the mycelial growth form of Candida albicans was about twice as sensitive to the drug as that in the yeast form. Inhibition by SDZ 89-485 was qualitatively and quantitatively similar to that shown by other systemically active azoles (ketoconazole, itraconazole, ICI 195,739) in Candida cells and cell-free preparations. Rat liver cell-free cholesterol biosynthesis was much less sensitive to inhibition by SDZ 89-485 than was the equivalent Candida system (selectivity ratio of about 300). In contrast to miconazole and econazole, SDZ 89-485 had no uncoupling effect on respiration in C. albicans cells. The structure of SDZ 89-485 contains an asymmetric centre, the drug being the (-)(R) enantiomer. The (+)(S) enantiomer 89-486, which is antifungally much less effective, was at least 10-fold less active than SDZ 89-485 as an ergosterol biosynthesis inhibitor in all test systems employed. The difference between the two enantiomers appears to reside in stereo-selectivity at the level of interaction with the demethylase enzyme.

100 项与 SDZ-89-485 相关的药物交易

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