Biochemical and ultrastructural alterations produced by miconazole and econazole in Trypanosoma cruzi

Parasitological cure of Chagas disease: is it possible? Is it relevant?

“…Sterol biosynthesis inhibitors (SBI) have been found to be particularly useful, as endogenous sterols are essential for survival in these pathogenic organisms; these compounds are in most cases orally active, have broad spectrum of activity and very low toxicity (Ryder & Mieth 1992, Mercer 1993, Vanden Bossche 1995. T. cruzi has also an absolute requirement of specific endogenous sterols for cell viability and proliferation and is extremely sensitive to sterol biosynthesis inhibitors (SBI) in vitro (Docampo et al 1981, Beach et al 1986, Goad et al 1989, Urbina et al 1988, 1993, 1996b; thus, the sterol biosynthesis pathway in this organism is a valid chemotherapeutic target (Urbina 1997). Nevertheless, currently available SBI's, such as ketoconazole and itraconazole, have been shown to be unable to eradicate T. cruzi from experimentally infected animals or human patients (McCabe 1988, Moreira et al 1992, Brener et al 1993, although a recent report from Chile claims a high level (>50%) of parasitological cures in chronic patients treated with itraconazole (Apt et al 1998).…”

Structural Insights into Inhibition of Sterol 14α-Demethylase in the Human Pathogen Trypanosoma cruzi

“…In addition to blocking ergosterol production, antifungal azoles cause accu-mulation of toxic methylated sterol precursors, leading to pathogen growth arrest and cell death (16). The antiparasitic effect of antifungal azoles on TC has been observed by several investigators (17)(18)(19)(20)(21)(22); yet, only recently, the antifungal drug posaconazole, proven to be capable of producing a parasitological cure in a mouse model of the chronic stage of Chagas disease, has been reported to be entering clinical trials in June 2010 (23).…”

“…Posaconazole is a highly potent broad spectrum antifungal drug, approved by the U.S. Food and Drug Administration in 2006 as salvage therapy for invasive fungal infections in immunocompromised patients (15,17,24). The disadvantages of this drug include its cost and severe adverse side effects, especially gastrointestinal problems, because the drug is produced only in an orally available form.…”

Contributions of Ultrastructural Studies to the Cell Biology of Trypanosmatids: Targets for Anti-Parasitic Drugs

“…2A). No alterations in mitochondrion structure have been described in T. cruzi after incubation in the presence of miconazole or econazole [47].…”

“…Docampo et al showed that treatment of T. cruzi with miconazole and econazole caused enhanced response of the parasite to the lectins WGA (wheat germ agglutinin) and PHA (phytohemagglutinin) [47]. Treatment of T. cruzi with suramin, a symmetrical polysulfonated derivative of urea used in the prophylactic treatment of human trypanosomiasis in Africa, caused increased activity of a Mg 2+ ecto-ATPase and the FRA antigen and redistribution of negative surface charges.…”