Effect of drugs on Trypanosoma cruzi and on its interaction with heart muscle cell in vitro

Abstract

Megazol, nifurtimox, benznidazol and allopurinol were investigated, by light and electron microscopy, for their action on T. cruzi. Both the direct effect upon amastigote and trypomastigote forms and the effect upon the interaction of heart muscle cells (HMC) with bloodstream trypomastigotes were studied. The proliferation of amastigotes in Warren medium was inhibited in a dose-dependent manner by megazol, nifurtimox and benznidazol. Treatment of amastigotes (25-50 microM/24 h) and trypomastigotes (25 microM/24h) led to several ultrastructural alterations in the parasites. These three drugs also had a potent effect on the treatment of infected heart muscle cells when added at the beginning of the interaction or after one or three days of infection. The interiorized parasites showed a similar pattern of ultrastructural alterations as observed by the direct effect on the amastigotes. The primary heart muscle cell culture proved to be a suitable model for the study of drugs on intracellular parasites. Likewise, the amastigote proliferation in axenic medium was shown to be an adequate assay for an initial trial of drugs. These parameters seem very reliable to us for a systematic investigation of the mechanism of action of new drugs.

Biological characterization of Trypanosoma cruzi strains

“…Some aspects as variations in absorption and metabolism of drug, incorporation to different infected tissues, synergic intervention of immune system as well as clinic phase of infection or morphological stage can be implicated (De Castro & De Meirelles 1987, Toledo et al 1990). However, most authors think that success of the treatment depends mainly on the strain of T. cruzi (Brener & Chiari 1967, Habekorn & Gonert 1972, Andrade et al 1975, Brener et al 1976, Andrade & Figueira 1977, Filardi & Brener 1990.…”

“…A striking feature of T. cruzi is its heterogeneity in relation to biological properties. Differences in growth rates, infectivity, tissue tropism, antigenic composition, virulence and morbility in animal models and susceptibility to immune sera and chemotherapeutic drugs have been reported in parasite isolates (Andrade et al 1975, 1985, Brener et al 1976, De Castro & De Meirelles 1987, Melo & Brener 1978, Neal & Van Bueren 1988, Roval et al 1990. In humans, a broad spectrum of clinical presentations in Chagas disease is observed, possibly reflecting the heterogeneity among T. cruzi isolates and/or genetic differences in the immune response of the host (Brener 1980).…”

In Vitro and In Vivo Activities of 1,3,4-Thiadiazole-2-Arylhydrazone Derivatives of Megazol against Trypanosoma cruzi

“…The 5-nitroimidazole megazol was shown to be highly active against T. cruzi, including strains resistant to benznidazole, in vitro and in vivo (12,17,21) and has become a core structure for the design of new leads for the treatment of Chagas disease. Megazol has been described as a scavenger of trypanothione, the cofactor for trypanothione reductase (23,42).…”

Pharmacokinetics and Tissue Distribution of Benznidazole after Oral Administration in Mice

“…The in vitro effect of BNZ is observed in both the amastigote and trypomastigote forms of T. cruzi, and it was already demonstrated the BNZ action in cells infected by the parasite (36). However, it is unclear what amount of BNZ can reach intracellular parasite forms, prevalent in chronic infection.…”