Efficacy of the triazole SCH 56592 against Leishmania amazonensis and Leishmania donovani in experimental murine cutaneous and visceral leishmaniases

Abstract

Current therapy for leishmaniasis is unsatisfactory. Efficacious and safe oral therapy would be ideal. We examined the efficacy of SCH 56592, an investigational triazole antifungal agent, against cutaneous infection with Leishmania amazonensis and visceral infection with Leishmania donovani in BALB/c mice. Mice were infected in the ear pinna and tail with L. amazonensis promastigotes and were treated with oral SCH 56592 or intraperitoneal amphotericin B for 21 days. At doses of 60 and 30 mg/kg/day, SCH 56592 was highly efficacious in treating cutaneous disease, and at a dose of 60 mg/kg/day, it was superior to amphotericin B at a dose of 1 mg/kg/day. The means of tail lesion sizes were 0.32 +/- 0.12, 0.11 +/- 0.06, 0.17 +/- 0.07, and 0.19 +/- 0.08 mm for controls, SCH 56592 at 60 and 30 mg/kg/day, and amphotericin B recipients, respectively (P = 0.0003, 0.005, and 0.01, respectively). Parasite burden in draining lymph nodes confirmed these efficacy findings. In visceral leishmaniasis due to L. donovani infection, mice treated with SCH 56592 showed a 0.5- to 1-log-unit reduction in parasite burdens in the liver and the spleen compared to untreated mice. Amphotericin B at 1 mg/kg/day was superior to SCH 56592 in the treatment of visceral infection, with a 2-log-unit reduction in parasite burdens in both the liver and spleen. These studies indicate very good activity of SCH 56592 against cutaneous leishmaniasis due to L. amazonensis infection and, to a lesser degree, against visceral leishmaniasis due to L. donovani infection in susceptible BALB/c mice.

FIG. 1

Chemical structure of amphotericin B, SCH 56592, and other currently available azoles.

FIG. 2

Graph of the efficacy of a 21-day treatment course with SCH 56592 or amphotericin B in experimental CL caused by L. amazonensis infection. Sizes of tail lesions are shown in panel A and ear pinna lesions are shown in panel B for treated and untreated control mice. Treatments were started on the 3rd day postinfection and were continued for 21 days. The ear lesion size was considered as the difference between the thicknesses of the infected and uninfected ear pinnae. The size of the tail lesion was obtained by subtracting the average tail diameter at points just rostral and caudal to the lesion site from the maximal tail diameter at the lesion site.

FIG. 3

Efficacy of a 21-day treatment course with SCH 56592 or amphotericin B in experimental CL caused by L. amazonensis. Parasite burdens in the ESLN are shown in panel A, and burdens in the ear are shown in panel B.