Until now, there has been no effective treatment for the long-term, chronic form of Chagas disease, which kills up to one-third of those infected, usually by heart failure. However, two Howard Hughes Medical Institute (HHMI) international research scholars have now found that in mice, a compound called TAK-187 is significantly more effective than the current standard of care - the drug benznidazole - in preventing T. cruzi-induced cardiac damage. Julio Urbina from theVenezuelan Institute for Scientific Research and Miguel Angel Basombrío from the National University of Salta and colleagues report their findings in the April issue of the journal Antimicrobial Agents and Chemotherapy.
Benznidazole, a drug used to treat acute, recent Chagas infections, often has toxic side effects and does not work once the disease has entered its chronic phase. As an alternative, Urbina, Basombrío, and colleagues tested TAK-187, a compound that prevents T.cruzi from producing a member of the steroid family called ergosterol, which is essential to the parasite's life cycle. The compound is currently in development as a systemic antifungal agent, but the results of the current study suggest that drugs of this type, which inhibit ergosterol synthesis, could be a "superior alternative to currently available therapy in the management of chronic Chagas disease," Urbina and Basombrío write in their report.
The scientists infected a group of mice with T.cruzi, then treated those mice with either TAK-187, benznidazole, or nothing at all. While both drugs completely eliminated T.cruzi from the blood of infected animals, the researchers found that TAK-187 was much more effective at preventing cardiac and skeletal inflammation and tissue damage, with no toxic side effects. Cardiac and skeletal damage occur in chronic Chagas infection, causing crippling and death.
Importantly, TAK-187 was effective at a dose that was both 10 times lower and administered less frequently than that of benznidazole. The researchers think this may be because the new compound is eliminated more slowly than benznidazole from the tr5eated animals and is also more resistant to metabolism by the mammalian host.
The latest study confirms results published in 2003 by Urbina and colleagues in the International Journal of Antimicrobial Agents, when they found TAK-187 effective against drug-resistant strains of T.cruzi.
"These results, together with the previous publication, are very promising," said Roberto Docampo, a professor at the Center for Tropical and Emerging Global Diseases at University of Georgia. "The results strongly support the view that a more efficient treatment for Chagas disease could be available." But Louis Kirchhoff, a professor at University of Iowa, questions whether the drug is effective enough. "TAK-187 suppresses T-cruzi," he said. "What we are looking for is a compound that wipes out the parasite."
Urbina and colleagues now plan clinical trials to determine the safety and efficacy of TAK-187 in patients with Chagas disease. "We must now examine the safety and effectiveness of therapeutic doses of this drug and determine the optimal administration schedule, the treatment duration, and its possible combination with other drugs," said Basombrío, who started studying the disease 28 years ago because it is so prevalent in his homeland of Argentina.
Takeda Chemical Company, the largest pharmaceutical manufacturer in Japan, has patented TAK-187 as a systemic antifungal agent. "The clinical development of this compound as an anti-T-cruzi agent in humans will depend on legal and economic agreements with Takeda, which are being sought through the World Health Organization," said Urbina.
The Venezuelan started doing basic research on Chagas disease 25 years ago, concerned by the neglect of this tropical disease by the pharmaceutical industry and most academic research centers in Latin America and throughout the world. "Only one percent of the new drugs introduced to the market in the last 25 years were developed to treat [tropical] diseases, despite the enormous unmet need for such compounds," he said. "Only 10 percent of current global health research is directed to address the medical needs of 90 percent of the human population."