An experimental and clinical assay with ketoconazole in the treatment of Chagas disease

Abstract

Ketoconazole, an azole antifungic drug which is already in the market has also been demonstrated to be active against Trypanosoma cruzi experimental infections. In this paper we confirmed the drug effect and investigated its range of activity against different T. cruzi strains naturally resistant or susceptible to both standard drugs Nifurtimox and Benznidazole used clinically in Chagas disease. Moreover, we have shown that the association of Ketoconazole plus Lovastatin (an inhibitor of sterol synthesis), which has an antiproliferative effect against T. cruzi in vitro, failed to enhance the suppressive effect of Ketoconazole displayed when administered alone to infected mice. Finally, administration in chronic chagasic patients of Ketoconazole at doses used in the treatment of deep mycosis also failed to induce cure as demonstrated by parasitological and serological tests. The strategy of identify and test drugs which are already in the market and fortuitously are active against T. cruzi has been discussed.

A Critical Review on Chagas Disease Chemotherapy

“…1d) was administered in doses between 3.1 and 8.7 mg/kg by oral route during 51 to 96 days and cure evaluation was performed by hemoculture, conventional serology and complement-mediated lysis. The patients were monitored up to 60 months and it was observed that the drug was unable to erradicate the parasites, from 6 out of 8 patients with positive hemoculture and two others with positive serology (Brener et al 1993).…”

Activities of the Triazole Derivative SCH 56592 (Posaconazole) against Drug-Resistant Strains of the Protozoan Parasite Trypanosoma ( Schizotrypanum ) cruzi in Immunocompetent and Immunosuppressed Murine Hosts

“…Like many fungi and yeasts, T. cruzi has a strict requirement of specific endogenous sterols for cell viability and growth and is extremely sensitive to sterol biosynthesis inhibitors in vitro (13, 16, 29, 31-33, 35, 36). However, currently available sterol biosynthesis inhibitors, which are highly successful in the treatment of fungal diseases, are not powerful enough to eradicate T. cruzi from experimentally infected animals or human patients (3,18,20). Recent work from our laboratories has shown that new azole derivatives (inhibitors of fungal cytochrome P-450-dependent C 14 sterol demethylase), such as D0870 (Zeneca Pharmaceuticals) and SCH 56592 (Schering-Plough Research Institute, Kenilworth, N.J.), are capable of inducing parasitological cures in murine models of both acute and chronic Chagas' disease (13,29,30,33,34) and are the first compounds ever to display such activity.…”

In Vitro Antiproliferative Effects and Mechanism of Action of the New Triazole Derivative UR-9825 against the Protozoan Parasite Trypanosoma ( Schizotrypanum ) cruzi

“…Although T. cruzi requires specific endogenous sterols for cell viability and proliferation and thus is extremely sensitive to SBI in vitro (reviewed in references 27, 28, and 30), currently available SBI are not powerful enough to eradicate T. cruzi from experimentally infected animals or human patients (4,12,20,22). However, we have recently shown that new triazole derivatives such as D08070 (Zeneca Pharmaceuticals) and SCH 56592 (Schering-Plough), both selective inhibitors of the parasite's sterol C14␣ demethylase with high intrinsic anti-T. cruzi activity and special pharmacokinetic properties (long terminal half-lives and large volumes of distribution), are capable of inducing radical parasitological cure of both acute and chronic experimental Chagas' disease (21,28,30,34,35) (Fig.…”