Treatment of kala-azar in Brazil with Amphocil (amphotericin B cholesterol dispersion) for 5 days.

We have treated 10 patients suffering from kala-azar in Brazil with Amphocil (amphotericin B cholesterol dispersion) at a dose of 2 mg/kg/d for 5 d, following an earlier study in which this dosage for 7 d was found to cure all of 9 patients, with no relapse during 12 months. In the present study, all patients demonstrated initial resolution of disease. Parasites were absent upon bone marrow re-aspiration 2 weeks after therapy; no spleen extended beyond the costal margin 2 months after therapy; white blood cell counts, platelet counts, and serum levels of albumin rapidly returned to normal. Although one patient relapsed at 5 months, 8 of the other 9 patients had spleens of normal size (undetectable on deep palpation) at 12 months after therapy. Fever, sometimes accompanied by increased respiratory rate, occurred on the first day of drug infusion in 8 of 10 patients and was more severe in patients < 6 years old. Pre-medication with a non-steroidal anti-inflammatory agent (diclofenac potassium) before the next 4 infusions protected against this side effect in 5 of 6 patients. The results of this and our previous study suggest that the most appropriate regimen of Amphocil for kala-azar is 2 mg/kg/d for 7 d, with pre-medication each day, in patients aged > 5 years.

Activity of amphotericin B cholesterol dispersion (Amphocil) in experimental visceral leishmaniasis.

Standard therapy of human visceral leishmaniasis with parenteral pentavalent antimonial agents is generally curative but has the disadvantages of a 28-day treatment course, occasional treatment failures, and toxicity. The antifungal and antileishmanial agent amphotericin B has been complexed with lipids to develop a less toxic formulation of amphotericin B. Because lipid particles are phagocytized by the reticuloendothelial system, lipid-associated amphotericin B should be concentrated in infected macrophages and be very effective against visceral leishmaniasis. One formulation, amphotericin B cholesterol dispersion (ABCD) (Amphocil), was tested for antileishmanial activity in Leishmania donovani-infected hamsters. In the first experiment, hamsters were infected, administered with the drug 3 days later, and then sacrificed after a further 4 days. ABCD (dose needed to suppress 99% of hepatic parasites compared with controls [SD (99)], 0.4 mg/kg of body weight) was 15 times as effective as conventional amphotericin B [SD (99), 6.0 mg/kg]. Pentavalent antimony in the form of meglumine antimonate had an SD (84) of 416 mg/kg. In a second experiment in which animals were allowed to become more heavily infected, the drug was administered 10 days after infection and the animals were sacrificed after a further 2, 7, or 11 days. ABCD was approximately four times as active as conventional amphotericin B. These experiments suggest that ABCD is at least four times as active as conventional amphotericin B against visceral leishmaniasis and that clinical trials are warranted.

Treatment of Brazilian kala-azar with a short course of amphocil (amphotericin B cholesterol dispersion).

Amphotericin B is an effective but toxic antileishmanial agent. Lipid-encapsulated amphotericin B should have a high therapeutic index for visceral leishmaniasis because reticuloendothelial cells, the sole site in which Leishmania is found, will phagocytize and concentrate the complex. Amphotericin B cholesterol dispersion (Amphocil; 2 mg/[kg.d] intravenously) was administered to 10 Brazilians with kala-azar for 10 days (cohort 1) and to 10 Brazilians with kala-azar for 7 days (cohort 2). All patients were successfully treated: 19 of the 20 patients were without visible parasites in the bone marrow; the mean time to afebrility was 4.2 days; spleen size regressed by a mean of 79% 2 months after therapy; and no patient had clinical or laboratory abnormalities by the end of 6-12 months of follow-up. Side effects were fever and chills accompanied by respiratory distress, but not nephrotoxicity, in children < 3 years of age.