Cure of Short- and Long-Term Experimental Chagas' Disease Using D0870

Abstract

Chagas' disease, a protozoan infection by the kinetoplastid Trypanosoma cruzi, constitutes a major public health problem in Latin America. With the use of mouse models of both short- and long-term forms of the disease, the efficacy of D0870, a bis-triazole derivative, was tested. D0870 was able to prevent death and induced parasitological cure in 70 to 90 percent of animals, in both the short- and long-term disease. In contrast, currently used drugs such as nifurtimox or ketoconazole prolonged survival but did not induce significant curing effects. D0870 may be useful in the treatment of human long-term Chagas' disease, a condition that is currently incurable.

Sterol 14α-demethylase cytochrome P450 (CYP51), a P450 in all biological kingdoms

“…They coordinate to the heme iron through a basic nitrogen and inhibit activity preventing substrate binding and metabolism. Azoles play a pivotal role in the treatment of systemic and dermal mycoses [61] and have been found effective to cure murine models of leishmaniases and Chagas disease [62][63][64]. Azoles are less toxic than other antifungal and anti-trypanosomal drugs, inexpensive and broadly available, yet have several disadvantages.…”

Ergosterol biosynthesis and drug development for Chagas disease

“…However, over the past 15 years, new triazole derivatives, e.g., D0870 (Zeneca Pharmaceuticals) and posaconazole (POS; SCH 56592; Schering-Plough Research Institute, SPRI) (Fig. 1), which are potent and selective inhibitors of fungal and protozoan cytochrome P-450-dependent CYP51, have been found to induce radical parasitological cure in murine models of acute and chronic Chagas disease (Urbina et al 1996, Urbina 2002, Urbina & Docampo 2003. These were the first compounds reported to display curative activity in both forms of the disease.…”

Update on Chagas' disease in Mexico

“…9 Their efficacy is also limited to the acute phase of the infection, and it is highly variable so that there is still controversial evidence that patients really benefit from such treatments. 10 A variety of new drugs is thus currently under development, [20][21][22][23][24] and some appear to show promise. However, additional studies are necessary and it will be some time before new treatments become available.…”