In vitro and in vivo experimental models for drug screening and development for Chagas disease

Abstract

Chagas disease, a neglected illness, affects nearly 12-14 million people in endemic areas of Latin America. Although the occurrence of acute cases sharply has declined due to Southern Cone Initiative efforts to control vector transmission, there still remain serious challenges, including the maintenance of sustainable public policies for Chagas disease control and the urgent need for better drugs to treat chagasic patients. Since the introduction of benznidazole and nifurtimox approximately 40 years ago, many natural and synthetic compounds have been assayed against Trypanosoma cruzi, yet only a few compounds have advanced to clinical trials. This reflects, at least in part, the lack of consensus regarding appropriate in vitro and in vivo screening protocols as well as the lack of biomarkers for treating parasitaemia. The development of more effective drugs requires (i) the identification and validation of parasite targets, (ii) compounds to be screened against the targets or the whole parasite and (iii) a panel of minimum standardised procedures to advance leading compounds to clinical trials. This third aim was the topic of the workshop entitled Experimental Models in Drug Screening and Development for Chagas Disease, held in Rio de Janeiro, Brazil, on the 25th and 26th of November 2008 by the Fiocruz Program for Research and Technological Development on Chagas Disease and Drugs for Neglected Diseases Initiative. During the meeting, the minimum steps, requirements and decision gates for the determination of the efficacy of novel drugs for T. cruzi control were evaluated by interdisciplinary experts and an in vitro and in vivo flowchart was designed to serve as a general and standardised protocol for screening potential drugs for the treatment of Chagas disease

Pharmacokinetics and Tissue Distribution of Benznidazole after Oral Administration in Mice

“…Currently, Chagas disease patients are treated with a BNZ dosage of 5 to 10 mg/kg/day, not to exceed 300 mg/day (24). On the other hand, the reference dose for treatment of mice in experimental infection with T. cruzi is 100 mg/kg/day (25). The murine model needs a higher dose of a given compound to produce the same effects as in humans (26).…”

Nitrotriazole-Based Compounds as Antichagasic Agents in a Long-Treatment In Vivo Assay

“…with each compound at 15 or 20 mg/kg/day for 20 or 40 days, beginning at the time of detection of parasitemia, which generally occurred at 4 days postinfection. A group of 15 mice was treated orally with benznidazole at 100 mg/kg/day for 20 days, which was used as the reference treatment (29), since such treatment provides a rate of cure of 55% in mice infected with the T. cruzi Y strain (27); 6 mice were maintained infected and used as untreated controls, whereas another 12 mice were maintained uninfected and used as untreated controls.…”

Ravuconazole self-emulsifying delivery system: in vitro activity against <em>Trypanosoma cruzi</em> amastigotes and in vivo toxicity

“…T. cruzi-infected animals were treated with a daily dose of 30 mg/kg of RAV in the form of free RAV (group VI) or RAV-SEDDS (group VII, 1.5 µL/g of F5, administered twice daily) received by oral gavage for 20 consecutive days, in agreement with the recommended classical protocol of experimental treatment of T. cruzi-infected mice. 5,34 The control groups received blank SEDDS (group VIII, 1.5 µL/g of F5 twice daily) or water (group IX, 2×1.5 µL/g).…”