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

Brener, Z.; Cançado, J. R.; Galvão, Lúcia Maria da Cunha; Luz, Zélia Maria Profeta da; Filardi, Leny de Sousa; Pereira, M. E. S.; Santos, Luiz Mauro T.; Cançado, Catarina B.

doi:10.1590/s0074-02761993000100023

Cited by 81 publications

(46 citation statements)

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“…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).…”

Section: Ketoconazolementioning

confidence: 99%

A Critical Review on Chagas Disease Chemotherapy

Coura¹,

Castro

2002

Mem. Inst. Oswaldo Cruz

845

444

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Section: Ketoconazolementioning

confidence: 99%

A Critical Review on Chagas Disease Chemotherapy

Coura¹,

Castro

2002

Mem. Inst. Oswaldo Cruz

845

444

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“…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.…”

mentioning

confidence: 99%

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

Molina

Martins‐Filho²,

Brener³

et al. 2000

Antimicrob Agents Chemother

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182

143

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We have studied the in vivo activity of the new experimental triazole derivative SCH 56592 (posaconazole) against a variety of strains of the protozoan parasite Trypanosoma (Schizotrypanum) cruzi, the causative agent of Chagas' disease, in both immunocompetent and immunosuppressed murine hosts. The T. cruzi strains used in the study were previously characterized as susceptible (CL), partially resistant (Y), or highly resistant (Colombiana, SC-28, and VL-10) to the drugs currently in clinical use, nifurtimox and benznidazole. Furthermore, all strains are completely resistant to conventional antifungal azoles, such as ketoconazole. In the first study, acute infections with the CL, Y, and Colombiana strains in both normal and cyclophosphamide-immunosuppressed mice were treated orally, starting 4 days postinfection (p.i.), for 20 consecutive daily doses. The results indicated that in immunocompetent animals SCH 56592 at 20 mg/kg of body weight/day provided protection (80 to 90%) against death caused by all strains, a level comparable or superior to that provided by the optimal dose of benznidazole (100 mg/kg/day). Evaluation of parasitological cure revealed that SCH 56592 was able to cure 90 to 100% of the surviving animals infected with the CL and Y strains and 50% of those which received the benznidazole-and nifurtimox-resistant Colombiana strain. Immunosuppression markedly reduced the mean survival time of untreated mice infected with any of the strains, but this was not observed for the groups which received SCH 56592 at 20 mg/kg/day or benznidazole at 100 mg/kg/day. However, the overall cure rates were higher for animals treated with SCH 56592 than among those treated with benznidazole. The results were confirmed in a second study, using the same model but a longer (43-dose) treatment period. Finally, a model for the chronic disease in which oral treatment was started 120 days p.i. and consisted of 20 daily consecutive doses was investigated. The results showed that SCH 56592 at 20 mg/kg/day was able to induce a statistically significant increase in survival of animals infected with all strains, while benznidazole at 100 mg/kg/day was able to increase survival only in animals infected with the Colombiana strain. Moreover, the triazole was able to induce parasitological cures in 50 to 60% of surviving animals, irrespective of the infecting strain, while no cures were obtained with benznidazole. Taken together, the results demonstrate that SCH 56592 has in vivo trypanocidal activity, even against T. cruzi strains naturally resistant to nitrofurans, nitroimidazoles, and conventional antifungal azoles, and that this activity is retained to a large extent in immunosuppressed hosts.Chemotherapy of Chagas' disease (American trypanosomiasis), a parasitic disease caused by the kinetoplastid protozoan Trypanosoma (Schizotrypanum) cruzi which afflicts 16 to 18 million people in Latin America, remains an enormous scientific and social challenge, as the drugs currently available, nitrofurans (nifurtimox; Bayer) and nitroimi...

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“…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.…”

mentioning

confidence: 99%

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

Urbina

Lira

Visbal

et al. 2000

Antimicrob Agents Chemother

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We describe the in vitro antiproliferative effects of the new triazole derivative UR-9825 against the protozoan parasite Trypanosoma (Schizotrypanum) cruzi, the causative agent of Chagas' disease in Latin America. The compound was found to be extremely active against the cultured (epimastigote) form of the parasite, equivalent to that present in the reduviid vector, with a MIC of 30 nM, a concentration 33-fold lower than that required with the reference compound ketoconazole. At that MIC, growth arrest coincided with depletion of the parasite's 4,14-desmethyl endogenous sterols (ergosterol, 24-ethylcholesta-5,7,22-trien-3b-ol, and precursors) and their replacement by methylated sterols (lanosterol, 24-methylenedihydrolanosterol, and obtusifoliol), as revealed by high-resolution gas chromatography coupled with mass spectrometry. This indicated that the primary mechanism of action of UR-9825 was inhibition of the parasite's sterol C14␣ demethylase, as seen with other azole derivatives. The phospholipid composition of growth-arrested epimastigotes was also altered, when compared to controls, with a significant increase in the content of phosphatidylethanolamine and phosphatidylserine and a concomitant reduction of the content of phosphatidylcholine. The clinically relevant intracellular amastigote form, grown in cultured Vero cells at 37°C, was even more sensitive to UR-9825, with a MIC of 10 nM, comparable to that for ketoconazole. The results showed that UR-9825 is among the most potent azole derivatives tested against this parasite and support in vivo studies with this compound.The largest parasitic disease burden on the American continent is Chagas' disease, caused by the kinetoplastid protozoon Trypanosoma (Schizotrypanum) cruzi, with 16 to 18 million people infected and an estimated annual loss of 2.7 disability-adjusted years (41). The parasite develops intracellularly in its mammalian hosts, leading to severe tissue damage, particularly in the heart and gastrointestinal tract, which, coupled with intense inflammatory reactions, underlies the pathogenesis of the disease (1, 5). Although Ͼ90% of those infected survive the initial acute phase, 30 to 40% of individuals with chronic T. cruzi infection will develop, over years or decades, irreversible heart and gastrointestinal lesions which are frequently lethal (1,6,23,25). Current chemotherapeutic approaches for the treatment of this condition, based on nitrofurans and nitroimidazoles, are unsatisfactory due to limited efficacy, particularly for the prevalent chronic form of the disease, and frequent toxic side effects (8,10,23,25). Recently, great advances have been made in the control of both vectorial and transfusional transmission of the disease, particularly through the Southern Cone and Andean Initiatives (41). However, transmission continues in other parts of the continent and the problem of those already infected, most of them in the undetermined chronic phase, remains a challenge (8,28,29).Sterol biosynthesis inhibitors (SBI) are currently the most ad...

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

Cited by 81 publications

References 0 publications

A Critical Review on Chagas Disease Chemotherapy

A Critical Review on Chagas Disease Chemotherapy

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

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

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