tak-187 and Chagas-Disease

The current situation regarding specific chemotherapy for Chagas disease (American trypanosomiasis), and new developments in this field, are reviewed. Despite previous controversy on the autoimmune origin of Chagas disease pathology, available knowledge supports the notion that this condition should be treated as a parasitic, not an autoimmune, disease. Currently available drugs (nitrofurans and nitroimidazoles) are active in acute or short-term chronic infections, but have very low antiparasitic activity against the prevalent chronic form of the disease, and toxic side-effects are frequently encountered. The nitroimidazole benznidazole has also shown significant activity in the treatment of reactivated Trypanosoma cruzi infections in patients with acquired immune deficiency syndrome and in other immunosuppressed patients with underlying chronic Chagas disease. Although the etiological agent, T. (Schizotrypanum) cruzi, requires specific endogenous sterols for cell viability and proliferation, the currently available antifungal sterol biosynthesis inhibitors are not powerful enough to induce parasitological cures of human or experimental infections. However, new triazole antifungal compounds, which are potent inhibitors of the sterol C14alpha demethylase of the parasite and have special pharmacokinetic properties, are capable of inducing parasitological cures in murine models of both acute and chronic Chagas disease. They are currently the most advanced candidates for clinical trials in patients with Chagas disease. Other potential chemotherapeutic agents against T. cruzi currently in development include antiproliferative lysophospholipid analogs (already in clinical trials as the first oral treatment for visceral leishmaniasis), cysteine proteinase (cruzipain) inhibitors, and compounds that interfere with purine salvage and inositol metabolism.

Topics: Chagas Disease; Cysteine Proteinase Inhibitors; Humans; Quinazolines; Triazoles

We carried out a comparative study of benznidazole and TAK-187, a long-lasting ergosterol biosynthesis inhibitor, with a murine model of Chagas' disease. The results indicated that TAK-187 was more effective than benznidazole in preventing Trypanosoma cruzi-induced cardiac damage in experimental animals.

Topics: Acute Disease; Animals; Chagas Cardiomyopathy; Chagas Disease; Disease Models, Animal; Ergosterol; Male; Mice; Nitroimidazoles; Triazoles; Trypanocidal Agents; Trypanosoma cruzi

We investigated the activity of TAK-187, an experimental antifungal triazole with a long terminal half-life in several experimental animals, against Trypanosoma cruzi. In vitro studies showed that the minimal inhibitory concentration (MIC) against the (extracellular) epimastigote form was 0.3-1 microM, while the corresponding concentration against clinically relevant intracellular amastigotes was 1 nM. At the MIC the endogenous epimastigote C4,14-desmethyl sterols were replaced by di- and tri-methylated sterols, supporting the notion that the primary target of TAK-187 is the parasite's sterol C14alpha demethylase. We investigated the in vivo activity of the compound in a murine model of acute Chagas disease, using T. cruzi strains with different susceptibilities to the drugs currently used clinically (nitrofurans and nitroimidazoles). It was found that TAK-187 given orally at 20 mg/kg induced complete protection against death and high levels (60-100%) of parasitological cures, independently of the infecting strain and even when administered every other day (e.o.d.), consistent with its long terminal half-life in mice. Other experiments, using longer treatment periods were carried out in both acute and chronic models of the disease and showed that TAK-187 given at 10-20 mg/kg e.o.d. induced 80-100% survival with 80-100% of parasitological cures of survivors in both models. No toxic side effects were observed in any of the experimental protocols. TAK-187 is a potent anti-T. cruzi compound with trypanocidal activity in vivo and should be considered for further studies as a potential specific treatment of human Chagas disease.

Topics: Acute Disease; Animals; Chagas Disease; Chronic Disease; Dose-Response Relationship, Drug; Drug Resistance; Female; Mice; Triazoles; Trypanocidal Agents