In vitro and in vivo activities of ravuconazole on Trypanosoma cruzi, the causative agent of Chagas disease

Antitrypanosomal Treatment with Benznidazole Is Superior to Posaconazole Regimens in Mouse Models of Chagas Disease

“…However, this readout does not allow conclusive determination of radical parasitological cure in patients. Recent clinical testing of posaconazole and the ravuconazole prodrug E1224 in Chagas disease patients did not yield favorable treatment outcomes despite predictions from preclinical in vivo data (8,9,(33)(34)(35). In both trials, the fraction of treated patients who experienced long-term parasitemia suppression/PCR negativity (as determined by qPCR) was low and inferior to that achieved with benznidazole.…”

Ergosterol biosynthesis and drug development for Chagas disease

“…However, its very short half-life in the mouse (< 0.5 h) precluded in vivo studies in this animal model, but work in a canine model has demonstrated that the compound exhibits curative activity against established infections of the virulent Y strain of T. cruzi with very low toxicity, although drug resistance was encountered with the Berenice-78 strain (Guedes et al 2004). Finally, ravuconazole has also been shown to be very active against T. cruzi in vitro, but its in vivo activity in mice was limited, most likely due to inadequate pharmacokinetic properties in this animal model (terminal half-life of 4.5 h) (Urbina et al 2003b). Similarly, the activity of ravuconazole in a canine model of acute Chagas disease was found to be suppressive, not curative, a result that was again attributed to the relatively short half-life of the compound in dogs (8.8 h) (MT Bahia & JA Urbina, unpublished observations).…”

“…1), such as TAK-187 (Takeda Chemical Company) (Urbina et al 2003c, Corrales et al 2005, UR-9825 (Uriach & Company) (Urbina et al 2000, Guedes et al 2004) and ravuconazole (ER-30346, Eisai Co.; BMS 207,147; Bristol-Myers Squibb) (Urbina et al 2003b) also exhibit trypanocidal activity in vitro and in vivo. TAK-187 is a long-lasting triazole derivative with broad-spectrum antifungal activity, which also possesses very potent anti-T. cruzi activity in vitro and is capable of curing both acute and chronic infections in murine hosts even when the infecting strain is resistant to nitrofuran and nitroimidazole (Urbina et al 2003c).…”

Design, structure–activity relationship and in vivo efficacy of piperazine analogues of fenarimol as inhibitors of Trypanosoma cruzi

“…[11][12][13][14] More active second generation antifungals posaconazole and a ravuconazole pro-drug are the first compounds to enter clinical trials for the treatment of Chagas disease in more than 40 years. Other compounds targeting T. cruzi CYP51 include the tipifarnib series, [15][16][17][18] dialkyl imidazoles, 19 LP10, 20 and indomethacin amides, 21 with current hit generation efforts potentially fueling further research.…”