A randomized, open-label clinical trial comparing the long-term effects of miltefosine and meglumine antimoniate for mucosal leishmaniasis

Abstract INTRODUCTION: The treatment of mucosal leishmaniasis (ML) is difficult due to the toxicity and route of administration of standard drugs. Miltefosine is an oral agent used for leishmaniasis treatment; however, no data exist regarding its use for ML in Brazil. In this study, we aimed to evaluate the efficacy of miltefosine for ML treatment compared to that of pentavalent antimonial in a pilot study. METHODS: We performed a randomized clinical trial with two parallel groups. The tested intervention consisted of miltefosine 1.3-2 mg/kg/day (two capsules) for 28 days or intravenous 20 mg SbV/kg/day of meglumine antimoniate (N-MA) for 30 days. The final endpoint was defined as complete healing of the lesion four years after treatment. We also analyzed an early endpoint at 90 days after treatment. RESULTS: Forty patients were included in this study: each experimental group comprised 20 patients. Applying a multivariate model in an intention-to-treat analysis, we observed that patients treated with miltefosine had a cure probability 2.08 times greater (95% confidence interval [CI] = 1.03-4.18) than those treated with N-MA at 90 days after treatment. At the final endpoint, we observed no differences in cure probability between miltefosine and N-MA (relative risk = 0.66; 95% CI = 0.33-1.32). With respect to adverse reactions, significant differences between groups were related to gastrointestinal effects, which were more frequent in the miltefosine group. CONCLUSIONS: Miltefosine may be an interesting alternative for treating ML because of its oral administration and cure rate after long-term follow-up.

Potential utility of hyperbaric oxygen therapy and propolis in enhancing the leishmanicidal activity of glucantime / A utilidade da terapia de oxigenação hiperbárica e própolis em potencializar a atividade leishmanicida do glucantime

In this study we investigated the efficacy of hyperbaric oxygen (HBO) therapy, alone or combined with the pentavalent antimonial glucantime on Leishmania amazonensis infection. In parallel, the effect of Brazilian red propolis gel (propain) alone or combined with glucantime on L. amazonensis infection was evaluated. The inhibition of the infection in macrophages treated with glucantime in combination with HBO exposition was greater than that of macrophages treated with glucantime alone or HBO alone. The susceptible mouse strain BALB/c infected in the shaved rump with L. amazonensis treated with glucantime and exposed to HBO showed: time points in the course of the disease in which lesions were smaller than those of mice treated with glucantime alone and revascularization of the skin in the lesion site; interferon-gamma (IFN-g) levels were not elevated in lymph node cells from these animals. Propain alone was not efficient against lesions, although less exudative lesions were observed in animals treated with propain alone or combined with glucantime. These results reveal the potential value of HBO and red propolis in combination with glucantime for treating cutaneous leishmaniasis and encourage further studies on the effect of more aggressive HBO, propolis and glucantime therapies on different mouse models of leishmaniasis.

Nesse trabalho foi avaliada a eficácia da terapia da oxigenação hiperbárica (HBO), aplicada em combinação ou não com o tratamento com glucantime, durante a infecção com Leishmania amazonensis. O efeito de gel da própolis vermelha de origem brasileira (propaina) aplicado em combinação ou não com o tratamento com glucantime, também foi avaliado durante infecção com esse parasita. A inibição da infecção de macrófagos tratados com glucantime em combinação com HBO foi maior que a de macrófagos tratados apenas com glucantime ou HBO. A linhagem murina susceptível, BALB/c, infectada no dorso com L. amazonensis, tratada com glucantime e exposta a HBO, mostrou durante o curso da doença, fases em que as lesões eram menores do que a de camundongos apenas tratados com glucantime; observou-se revascularização da pele da lesão e baixa produção de interferon-gama em células de linfonodos desses animais. O tratamento com propaina não foi eficiente na cura das lesões, apesar de lesões menos exsudativas serem observadas em animais tratados com propaina ou propaina combinada ao tratamento com glucantime. Os resultados demonstram que tanto HBO como a própolis vermelha em combinação com glucantime, são promissoras no tratamento da leishmaniose cutânea. Novos estudos devem ser realizados para avaliar tratamentos e outros protocolos em diferentes modelos murinos da leishmaniose.

Meglumina en series terapéuticas de 10 días en niños con leishmaniosis tegumentaria americana / Meglumine therapeutic series of 10 days in children with american tegumentary leishmaniasis

La cátedra de Medicina Tropical de la Universidad Central de Venezuela viene empleando el antimoniato de meglumina en series terapéuticas de 10 días en el tratamiento de leishmaniosis tegumentaria americana, la cual continúa como problema de salud del medio rural venezolano. Se evalúa una experiencia con una dosis de 70 mg/kg/día de meglumina en niños con la enfermendad. A los pacientes con presunción diagnóstica de leishmaniosis tegumentaria americana (clínica y antecedentes epidemiológicos) se les efectuó la prueba de leishmania, la demostración de anticuerpos flurescentes antileishmania y la visualización de amastigotes en frotis teñidos con Giemsa. Los casos identificados ingresaron al Hospital Universitario (Pediatría médica infecciosa), recibieron 70 mg/kg/día de antimoniato de meglumina en series terapéuticas de 10 días con reposo intercalados por el mismo número de días. Se incluyeron 33 niños con la enfermedad, 21 de género femenino (64%) con promedio de edad 7,12 años y predominio de escolar (70%). Del Estado Miranda procedía el 85%, una sola úlcera la tenía el 88%, localizada en miembros inferiores (49%). La Leishmanina y los anticuerpos fluorescentes antileishmania fueron positivos en todos los pacientes y el frotis para amastigotes en 45%. Dos series de antimoniato de meglumina las recibió 91% de los pacientes; una de 10 días 6%. Egresaron con cicatrizaciones de sus procesos ulcerosos y fueron evaluados durante seis meses en la consulta de endemias rurales y no se evidenciaron recaídas. La variedad cutánea localizada de la enfermedad fue la única identificada, el Estado Miranda continúa aportando la mayoría de los pacientes atendidos en medicina tropical. El antimoniato de meglumina en leishmaniosis tegumentaria americana a la dosis de 70 mg/kg/día en series terapéuticas fue tan eficaz como la anterior de 100 mg/kg/día que dejó de administrarse hace ocho años.

The Tropical Medicine Department of the Universidad Central de Venezuela employs the meglumine pentavalent antimonial in series of 10 days of treatment for American Tegumentary Leishmaniosis, which continues being a health problem in the Venezuelan rural areas. We are reporting a clinical experience of treatment in children at a dose of 70 mg/kg/day. Patients with diagnostic suspición of American Tegumentary Leishmaniosis (clinical and epidemiologic antecedents) who attended the Rural Endemics Clinic at the Instituto de Medicina Tropical of the Universidad Central de Venezuela and to the Medical Infectious Pediatrics Service at the Hospital Universitario de Caracas (HUC), were tested for leishmanine, fluorescent antileishmania antibodies and for the presence of amastigotes of the parasite in smear for apposition from the ulcer that were treated by the Giemsa method. Patients hospitalized at the Medical Infectious Pediatric Service (Hospital Universitario de Caracas) received 70 mg/kg/day of meglumine pentavalent antimonial during 10 days, a rest period of 10 days without treatment and, if 20 days after ulcers were unhealed, was administred a new 10 days meglumine pentavalent antimonial series. We included 33 children with the disease with a mean age of 7,12 years, 70% in school age and 30% preschool children, and 21 (64%) were girls. The 85% of patients came from Miranda`s state, 88% had only ulcer and in 49% of them the lesions where localized in the legs. The apposition smear showed Leishmania amastigotes in 45% od cases. One series of treatment was given to 91% of cases, two children received two series and one three. At discharge from the hospital all ulcers were healed and follow-up control for a 6 months period showed no relapses. The cutaneous localized from was the clinical form of presentation in the children studied. The great majority of patients that assits to the Tropical Medicine Institute come from the Miranda`s state area...

Two cases of visceral leishmaniasis in Colombia resistant to meglumine antimonial treatment / Dois casos de leishmaniose visceral da Colômbia, resistentes ao tratamento com antimoniato de meglumina

Visceral leishmaniasis (VL) affects over 500 000 people worldwide each year. The disease occurs in the Mediterranean basin, Central and South America and is caused by Leishmania infantum (syn L. chagasi). VL is an endemic disease in Colombia, particularly along the Caribbean coast and the Magdalena River Valley and 90% of VL cases occur in children under the age of five. The first line of treatment is chemotherapy with pentavalent antimonial compounds, including sodium stibogluconate (Pentostam®) and meglumine antimoniate (Glucantime®). These compounds are the ones most used in Colombia, at a dose of 20 mg/kg/day for 28 days. Nevertheless resistance of L. infantum to pentavalent antimonials is becoming an important problem. No cases of VL resistant to pentavalent antimonial compounds have previously been reported from Colombia. This report describes the two cases of VL resistance to antimonial compounds in a girl and a boy who did not respond to previous treatment with Pentacarinat® and Glucantime® regimens but were treated successfully with liposomal amphotericin B. Based on our findings, we recommend liposomal amphotericin B as the first line of treatment for VL due to its low toxicity, shorter administration period and the low price obtained by WHO.

A leishmaniose visceral (VL) afeta aproximadamente 500000 pessoas anualmente no mundo. A doença ocorre no mediterrâneo, na América Central e na América do Sul, sendo causada por Leishmania infantum (syn. L. chagasi). Na Colômbia VL é uma doença endêmica, presente no litoral do Caribe e no Vale do rio Magdalena sendo que 90% de casos de VL ocorrem em crianças menores de cinco anos. O principal tratamento é a quimioterapia com compostos de antimoniais pentavalentes, incluindo stibogluconato de sódio (Pentostam®) e antimoniato de meglumina (Glucantime®). Estes compostos são os mais usados na Colômbia em dosagem de 20 mg/kg/dia durante 28 dias. Entretanto, a resistência de L. infantum aos antimoniais pentavalentes está se tornando problema importante. Na Colômbia não existiam relatos de casos de VL resistentes aos antimoniais pentavalentes. Este trabalho descreve os dois primeiros casos colombianos de VL resistentes aos compostos antimoniais em uma menina e um menino, que foram tratados com regime de Pentamidina e Glucantime®, e demonstra o sucesso obtido no tratamento com anfotericina B liposomal. Em conclusão, sugerimos como primeira opção de tratamento a anfotericina B liposomal porque é altamente efetiva no tratamento da VL, dada sua baixa toxicidade, curtos períodos de administração e o baixo preço obtido pela organização Médicos Sem Fronteiras.