Efficacies of KY62 against Leishmania amazonensis and Leishmania donovani in experimental murine cutaneous leishmaniasis and visceral leishmaniasis

Abstract

Current therapy for leishmaniasis is unsatisfactory because parenteral antimonial salts and pentamidine are associated with significant toxicity and failure rates. We examined the efficacy of KY62, a new, water-soluble, polyene antifungal, against cutaneous infection with Leishmania amazonensis and against visceral infection with Leishmania donovani in susceptible BALB/c mice. Mice were infected with L. amazonensis promastigotes in the ear pinna and in the tail and were treated with KY62 or amphotericin B. The cutaneous lesions showed a remarkable response to therapy with KY62 at a dose of 30 mg per kg of body weight per day. At this dose, the efficacy of KY62 was equivalent to or better than that of amphotericin B at 1 to 5 mg/kg/day. Mice infected intravenously with 10(7) L. donovani promastigotes and treated with KY62 showed a 4-log reduction in the parasite burden in the liver and spleen compared to untreated mice. These studies indicate potent activity of KY62 against experimental cutaneous leishmaniasis caused by L. amazoniensis and against experimental visceral leishmaniasis caused by L. donovani.

FIG. 1

Chemical structure of KY62 and amphotericin B.

FIG. 2

Efficacy of a 14-day treatment course with KY62 (30 mg/kg/day) or amphotericin B (1 mg/kg/day) in experimental cutaneous leishmaniasis caused by L. amazonensis. Sizes of ear pinna lesions (A) and tail lesions (B) in the treated and untreated control mice are shown. Treatments were started on the third day postinfection and continued for 14 days. The ear lesion size was considered the difference between the thicknesses of the infected and uninfected ear pinna. The size of the tail lesion was obtained by subtracting the average of the measurements of the tail diameter at points just rostral and caudal to the lesion site from the maximal tail diameter at the lesion site.

FIG. 3

Wright’s stain of sections of an ear lesion in the control (A) and KY62-treated (B) mice. The section from the control mouse shows a predominance of the large, foamy macrophages with abundant amastigotes (arrow), whereas the section from the treated mouse shows a more lymphocytic predominance (arrow) and a markedly reduced number of amastigotes. Magnification, ×40 (for both panels).

FIG. 4

Efficacy of a 7-day treatment course with various doses of KY62 or with amphotericin B (5 mg/kg/day) in experimental cutaneous leishmaniasis caused by L. amazonensis. Sizes of ear pinna lesions (A) and tail lesions (B) are shown. Treatments were started on the third day postinfection and continued for 7 days. Lesions were measured as described in the legend to Fig. 2.

FIG. 5

Efficacy of a prolonged treatment course with KY62 (15 mg/kg/day) in experimental cutaneous leishmaniasis caused by L. amazonensis. Sizes of ear pinna lesions (A) and tail lesions (B) in the KY62-treated and control mice are shown. Treatments were started on the third day postinfection and continued for 28 days. Lesions were measured as described in the legend to Fig. 2.