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Objetivo: este estudio pretende realizar una comparación de la eficacia y los posibles efectos adversos asociados al uso de Miltefosina y Glucantime para el tratamiento de la leishmaniasis cutánea (LC) en niños. Método: se realizó una revisión sistemática de ensayos clínicos y estudios de cohortes, que evaluaran tratamientos de la LC en niños (≤12 años). Se efectuaron búsquedas estructuradas en PubMed, EMBASE, Cochrane, LILACS, Web of Science y SciELO. No se aplicaron restricciones en cuanto a etnia, país, sexo o año de publicación. Los idiomas se limitaron a inglés, español y portugués. Dos revisores independientes revisaron los artículos, extrajeron los datos y evaluaron el riesgo de sesgo. Se realizó un resumen cuantitativo de los estudios incluidos. Resultados: encontramos un total de 747 registros, que incluían 3 ensayos clínicos aleatorizados (ECA) y 1 estudio no aleatorizado. La mayoría de los artículos excluidos en la revisión de texto completo no informaban de los resultados por separado para los niños. En la LC americana (LCA), 4 estudios evaluaron la Miltefosina y el Glucantime. Su eficacia varió del 55,8 al 82,7 % y del 55 al 68,9 %, respectivamente. Conclusiones: en esta revisión sistémica y metaanálisis encontramos que la Miltefosina es mejor opción de tratamiento sistémico para CL en términos de curación clínica y menor efecto adverso al Glucantime administrado de forma sistémica, sin embargo, estas diferencias no fueron significativas.

Objective: this study aims to perform a comparison of the efficacy and potential adverse effects associated with the use of Miltefosine and Glucantime for the treatment of cutaneous leishmaniasis (CL) in children. Method: a systematic review of clinical trials and cohort studies evaluating treatments for CL in children (≤12 years) was conducted. Structured searches were performed in PubMed, EMBASE, Cochrane, LILACS, Web of Science, and SciELO. No restrictions were applied regarding ethnicity, country, gender, or year of publication. Languages were limited to English, Spanish, and Portuguese. Two independent reviewers screened articles, extracted data, and assessed the risk of bias. A quantitative summary of included studies was performed. Results: a total of 747 records were found, including 3 randomized clinical trials (RCTs) and 1 non-randomized study. Most articles excluded in the full-text review did not report results separately for children. In American CL (ACL), 4 studies evaluated Miltefosine and Glucantime. Their efficacy ranged from 55.8 to 82.7 % and from 55 to 68.9 %, respectively. Conclusions: in this systematic review and meta-analysis, we found that Miltefosine is a better systemic treatment option for CL in terms of clinical cure and fewer adverse effects compared to Glucantime administered systemically; however, these differences were not significant.

Objetivo: este estudo tem como objetivo realizar uma comparação da eficácia e dos possíveis efeitos adversos associados ao uso de Miltefosina e Glucantime para o tratamento da leishmaniose cutânea (LC) em crianças. Método: foi realizado uma revisão sistemática de ensaios clínicos e estudos de coorte que avaliaram tratamentos para LC em crianças (≤12 anos). Foram realizadas buscas estruturadas no PubMed, EMBASE, Cochrane, LILACS, Web of Science e SciELO. Não houve restrições quanto à etnia, país, sexo ou ano de publicação. Os idiomas foram limitados a inglês, espanhol e português. Dois revisores independentes revisaram os artigos, extraíram os dados e avaliaram o risco de viés. Foi feito um resumo quantitativo dos estudos incluídos. Resultados: encontramos um total de 747 registros, incluindo 3 ensaios clínicos randomizados (ECR) e 1 estudo não randomizado. A maioria dos artigos excluídos na revisão em texto completo não relatava resultados separados para crianças. Na LC americana (LCA), 4 estudos avaliaram Miltefosina e Glucantime. Sua eficácia variou de 55,8% a 82,7% e de 55% a 68,9%, respectivamente. Conclusões: nesta revisão sistemática e meta-análise, encontramos que a Miltefosina é uma melhor opção de tratamento sistêmico para LC em termos de cura clínica e menos efeitos adversos em comparação com o Glucantime administrado de forma sistêmica; no entanto, essas diferenças não foram significativas.

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Canine visceral leishmaniasis is an endemic zoonosis in Brazil. Dogs are the main hosts in urban environments. The treatment has gained popularity since the Brazilian government authorized miltefosine for canine treatment. The aim of this study was to investigate the clinical and parasitological impact of short-term treatment with miltefosine and allopurinol, alone and in combination. We evaluated the ability of pharmacotherapy to reduce clinical signs of disease, antibody levels using the indirect fluorescence antibody test (IFAT) and skin parasite load via qPCR after 28 days of treatment. The therapeutic protocols promoted a significant decline in clinical signs and in the skin parasite load in dogs (p < 0.01). We observed a moderate correlation between the skin parasite load and the clinical score in all three treatment groups (r > 0.5) Antibody levels did not decrease in this short period. It was concluded that the treatment with allopurinol reduced the number of parasites in the skin of dogs with visceral leishmaniasis in the short term. However, its efficiency is potentiated when associated with miltefosine.(AU)

A leishmaniose visceral canina é uma zoonose endêmica no Brasil. Os cães são os principais hospedeiros em ambientes urbanos. O tratamento ganhou popularidade desde que o governo brasileiro autorizou a miltefosina para tratamento canino. O objetivo deste estudo foi investigar o impacto clínico e parasitológico do tratamento a curto prazo com miltefosina e alopurinol, isoladamente e/ou em combinação. Foi avaliada a capacidade da farmacoterapia em reduzir os sinais clínicos da doença e também os níveis de anticorpos, usando-se o teste de anticorpos de fluorescência indireta (RIFI) e a carga parasitária na pele, via qPCR, após 28 dias de tratamento. Os protocolos terapêuticos promoveram declínio significativo dos sinais clínicos e da carga parasitária na pele dos cães (p < 0,01). Foi observada uma correlação moderada entre a carga parasitária da pele e o escore clínico em todos os três grupos de tratamento (r > 0,5). Já os níveis de anticorpos não diminuíram nesse curto período. Concluiu-se que o tratamento com alopurinol, em curto prazo, reduziu a quantidade de parasitos na pele dos cães com leishmaniose visceral. No entanto, sua eficiência é potencializada quando associada a miltefosina.(AU)

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Background: Canine visceral leishmaniasis (CVL) is a parasitic disease of high lethality caused by the protozoan Leishmania infantum in Brazil and is often related to splenomegaly. However, splenic nodules in dogs, although frequent, have not previously been reported as associated with CVL, but with neoplastic diseases. Considering that most dogs infected are oligosymptomatic or asymptomatic and that splenic nodules are common to other diseases, it is prudent to differentially diagnose CVL in view of its high zoonotic potential and lethality. The objective of the study was to describe a case of splenomegaly with splenic nodules associated with CVL in an asymptomatic dog treated with 2% miltefosina. Case: A 5-year-old male Rottweiler with 41 kg, with a history of inappetence, apathy and weight loss was referred to the Veterinary Medicine School Clinic of the Cesmac University Center, Maceió, AL, Brazil. However, during palpation a slight increase in the spleen was noted. Hematological, hemoparasite, biochemical and abdominal ultrasonographic examinations were requested to clarify the clinical suspicion of hemoparasitosis. The hematological and biochemical results respectively showed the following: normocytic normochromic anemia, hyperproteinemia and thrombocytopenia, in addition to hypoalbuminemia, with elevated total protein levels. The test for hemoparasites was negative. Ultrasonography showed mixed echogenicity suggestive of nodules. The rapid test for Ehrlichia, Anaplasma and L. infantum was performed. It was positive only for L. infantum. ELISA, IFAT and qPCR tests were performed to confirm the result. The test showed a cutoff result of 0.371 for ELISA, positive for RIFI at a cut-off of 1:40 and qPCR with less than 1 fg and with amplification above 36 cycles. In view of these results, treatment with 2% miltefosine at a dose of 1 mL/ 10 kg was started once a day, after feeding, for 28 days. The animal was monitored throughout treatment and re-evaluated every 10 days for 30 days, showing signs of clinical development, presenting satisfactory results. Discussion: Canine splenomegaly can be associated with a variety of disease possibilities. In asymptomatic canine visceral leishmaniasis (CanL), the slight increase in spleen and the presence of splenic nodules may lead to a false diagnosis. Splenic nodules may be associated with dogs of advanced age and may be due to lymphoid nodular hyperplasia, which causes nodules with echogenicity, hyperechoic regions with well demarcated irregularity, with centralized hypoechoic areas and an absence of hematological and biochemical alterations. The cause of splenomegaly associated with nodules may be difficult to diagnose and require much time and effort. Therefore, diseases such as visceral leishmaniasis of high lethality must be the priority in differential diagnosis in endemic areas in order to minimize the risk of transmission. In addition to allowing an early intervention aiming at good animal health results and preventive measures, such as the use of repellent collars that reduce the risk of phlebotomo infection. The differential diagnosis of CVL is necessary in endemic areas, even in asymptomatic dogs that may present splenic alterations suggestive of other diseases. Treatment with 2% miltefosine was shown to be, in this case, effective at reducing the splenic nodules and a good alternative for the quality of life of the animal.(AU)

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Resumen Introducción: La diversidad de las formas clínicas de la leishmaniasis del Nuevo Mundo (desde formas cutáneas localizadas a diseminadas o formas mucosas) causada por especies del subgénero Viannia podría inferir en la eficacia de los tratamientos tópicos. El objetivo del presente trabajo fue determinar las características de la leishmaniasis cutánea producida por infecciones con Leishmania (V.) braziliensis y L.(V.) panamensis en ratones BALB/c y la eficacia de un mismo tratamiento tópico. Materiales y métodos: Después de la infección con cada una de las especies se realizó seguimiento de las lesiones determinando su tamaño (mm ) y características macroscópicas, cada siete días por 150 días. Las características histopatológicas (en lesiones y órganos) fueron determinadas 70, 106 y 150 días post-infección y la eficacia de un tratamiento tópico (cura de lesión y parasitológica) fue determinada después del tratamiento con un gel de miltefosina aplicado una vez al día por 20 días sobre las lesiones. Resultados: Se observó un aumento del tamaño de las lesiones en ambos grupos de ratones, sin embargo, un mayor tamaño de las lesiones e intensidad de la respuesta inflamatoria con menos alteraciones epidérmicas fue encontrada en los ratones infectados con L. (V.) braziliensis. En ningún grupo se encontraron parásitos en órganos (nódulos, bazo e hígado) ni diferencias en la efectividad del tratamiento tópico utilizado. Conclusión: La eficacia del tratamiento tópico utilizado no fue afectada por las diferencias macro y microscópicas encontradas en la leishmaniasis producida por las dos especies de Leishmania evaluadas.

Abstract Introduction: The efficacy of topical treatments could be affected by the diversity of clinical forms (localized or disseminated cutaneous forms, mucosal forms) of New World-leishmaniasis caused by species of Leishmania from the subgenus Viannia. The aim of this study was to determine the cutaneous leishmaniasis features produced after infection with Leishmania (V.) braziliensis and L. (V.) panamensis in BALB/c mice and to determine the efficacy of one topical treatment. Materials and methods: Cutaneous leishmaniasis lesions were followed up after infection determining their lesion-size (mm2) and other macroscopic characteristics every 7 days for 150 days. Histopathological patterns (in lesions and organs) were determined 70, 106 and 150 days post-infection and the efficacy (lesion and parasitological cure) of miltefosine gel applied topical once a day for 20 days was determined. Results: An increase of size-lesions was observed in both groups of mice, however, a higher lesion- size and inflammatory response but lower epidermal changes were observed in L. (V.) braziliensis compared with L. (V.) panamensis infected ones. No parasites were observed in organs (nodules, spleen and liver) and no differences were observed in the effectiveness of the used topical treatment. Conclusion: The efficacy of the topical treatment used was not affected by the macro and microscopic differences produced after infection by the two Leishmania species evaluated.

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No Brasil, mudanças epidemiológicas são observadas na LV, com um aumento da incidência, da taxa de letalidade, da urbanização e disseminação para novas áreas, da presença de novos reservatórios.

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No Brasil, mudanças epidemiológicas são observadas na LV, com um aumento da incidência, da taxa de letalidade, da urbanização e disseminação para novas áreas, da presença de novos reservatórios.

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Introducción: los liposomas ultradeformables de miltefosina (LUD-MIL) constituyen una opción para el tratamiento tópico en leishmaniasis cutánea penetrando los estratos de la piel hasta la dermis, sitio donde habita el parásito. Objetivo: diseñar LUD-MIL y determinar su actividad contra L. (Viannia) panamensis y L. (V.) braziliensis y la permeación en piel humana. Métodos: los LUD-MIL, liposomas convencionales de fosfatidilcolina (LConv) y LUD-MIL-fluorescente (LUD-MIL-Fluo) fueron preparados por el método de rehidratación de película lipídica. Se caracterizaron fisicoquímicamente y se determinaron: la liberación en membrana semisintéticas, la retención en las capas de la piel y la permeación en piel humana. La citotoxicidad en THP-1 fue determinada por el ensayo colorimétrico de MTT y la actividad en promastigotes y amastigotes intracelulares por recuento microscópico. Resultados: el tamaño, índice de polidispersión, potencial Z y concentración de fosfolípidos de los LUD-MIL fue de 100,7 nm, 0,147, -12,0 mV y 53,24 mM respectivamente. El flujo de MIL a través de la membrana fue mayor con LUD-MIL que con MIL-libre. El tratamiento con LUD-MIL indujo menor acumulación de la MIL en el estrato corneo y mayor permeación que el tratamiento con MIL libre. Los LUD-MIL y los LConv-MIL mantuvieron la actividad de la MIL en los parásitos y células. Los LUD-MIL fueron más tóxicos para las células que los LConv y la MIL y más activos en amastigotes intracelulares de L. (V.) braziliensis. Conclusión: los LUD-MIL preparados conservaron la actividad anti-Leishmania de la MIL y permitieron la liberación del compuesto en membranas y piel humana. Ensayos en modelos experimentales de leishmaniasis cutánea para evaluar la actividad de estas formulaciones son urgentes de realizar(AU)

Introduction: miltefosine ultradeformable liposomes (MIL-LUD) are an option for the topical treatment of cutaneous leishmaniasis penetrating the skin layers to the dermis where the parasite inhabits. Objective: to design MIL-LUD and determine their in vitro activity against L. (Viannia) panamensis and L. (V.) braziliensis and to determine human skin permeation. Methods: MIL-LUD, phosphatidylcholine liposomes (MIL-LConv) and fluorescent MIL-LUD (MIL-LUD-Fluo) were prepared by lipid film rehydration method. They were physicochemically characterized to determine drug release in semisynthetic membrane, retention in skin layers and permeation on human skin membranes. Cytotoxicity in THP-1 was determined by the MTT colorimetric test and activity in promastigotes and intracellular amastigotes by microscopic counting. Results: the size, the polydispersion index, the Zeta potential and phospholipid content were 100.7 nm, 0.147, -12.0mV and 53.24mM, respectively for MIL-LUD. MIL flow through the semisynthetic membrane was greater with MIL-LUD than MIL-free treatment. MIL-LUD treatment induced lower MIL accumulation in the stratum corneum and increased permeation than MIL free treatment. The MIL-LUD and MIL-Conv maintained MIL activity in parasites and cells. The MIL-LUD was more toxic to cells than MIL-Conv and more active against intracellular amastigotes of L. (V.) braziliensis. Conclusion: prepared LUD -MIL retained the anti-leishmanial activity of the MIL and allowed the compound release in human skin and membranes. Testing of experimental cutaneous leishmaniasis models to evaluate the activity of these formulations are urgently needed(AU)

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El tratamiento convencional para la leishmaniasis tegumentaria es el antimoniato de meglumina, el cual presenta falla terapéutica creciente, producción de efectos adversos graves, y necesidad de administración parenteral, justificando la búsqueda de alternativas terapéuticas. Presentamos aquí los resultados preliminares de un ensayo clínico de fase II en pacientes con leishmaniasis mucosa, en el que se comparó la eficacia de miltefosina por vía oral con respecto a la del compuesto antimonial. La evaluación de la respuesta a los tratamientos se realizó mediante un seguimiento con videofibroscopia nasofaríngea, utilizándose un score de gravedad de lesiones mucosas para aplicar en cada momento del seguimiento de los pacientes. No se encontraron hasta ahora diferencias significativas entre el número de pacientes curados con miltefosina o con la quimioterapia convencional. Los resultados favorables de este trabajo sugieren que miltefosina podría constituir una alternativa terapéutica efectiva y segura en la región.

The conventional treatment for tegumentary leishmaniasis is meglumine antimoniate, which needs parenteral administration, has increased therapeutic failure, and produces serious adverse effects, justifying the search for therapeutic alternatives. We report here the preliminary results of a phase II clinical trial in patients with mucosal leishmaniasis, in which the efficacy of oral miltefosine versus the antimonial compound was assessed. The evaluation of response to the treatment was performed by monitoring with nasopharyngeal video-fibroscopy, using a score of mucosal injury severity for patients at each follow-up point. We found no significant differences so far between the number of patients cured with miltefosine or conventional chemotherapy. The favorable results of this study suggest that miltefosine could be an effective and safe oral therapeutic alternative in the region.

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El tratamiento convencional para la leishmaniasis tegumentaria es el antimoniato de meglumina, el cual presenta falla terapéutica creciente, producción de efectos adversos graves, y necesidad de administración parenteral, justificando la búsqueda de alternativas terapéuticas. Presentamos aquí los resultados preliminares de un ensayo clínico de fase II en pacientes con leishmaniasis mucosa, en el que se comparó la eficacia de miltefosina por vía oral con respecto a la del compuesto antimonial. La evaluación de la respuesta a los tratamientos se realizó mediante un seguimiento con videofibroscopia nasofaríngea, utilizándose un score de gravedad de lesiones mucosas para aplicar en cada momento del seguimiento de los pacientes. No se encontraron hasta ahora diferencias significativas entre el número de pacientes curados con miltefosina o con la quimioterapia convencional. Los resultados favorables de este trabajo sugieren que miltefosina podría constituir una alternativa terapéutica efectiva y segura en la región.(AU)

The conventional treatment for tegumentary leishmaniasis is meglumine antimoniate, which needs parenteral administration, has increased therapeutic failure, and produces serious adverse effects, justifying the search for therapeutic alternatives. We report here the preliminary results of a phase II clinical trial in patients with mucosal leishmaniasis, in which the efficacy of oral miltefosine versus the antimonial compound was assessed. The evaluation of response to the treatment was performed by monitoring with nasopharyngeal video-fibroscopy, using a score of mucosal injury severity for patients at each follow-up point. We found no significant differences so far between the number of patients cured with miltefosine or conventional chemotherapy. The favorable results of this study suggest that miltefosine could be an effective and safe oral therapeutic alternative in the region.(AU)

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Vinte e cinco camundongos infectados com Leishmania amazonensis foram tratados com antimoniato de N-metil glucamina e miltefosina oral. Critérios: medidas das patas, pesquisa de amastigotas e culturas após-tratamento. Miltefosina: 2,43mm e glucamina 3,46mm (p=0,05). Miltefosina: esfregaços e culturas negativos. Glucamina: 2 esfregaços positivos e culturas positivas (p<0,05). Concluímos que miltefosina foi semelhante à glucamina.

Twenty-five mice were infected with Leishmania amazonensis and treated with glucamine and oral miltefosine. The criteria used were pad measurements and investigations of amastigotes and cultures after treatment. Measurements: miltefosine 2.43 mm and glucamine 3.46 mm (p: 0.05). Miltefosine smears and cultures were negative. Glucamine produced two positive smears and the cultures were positive (p < 0.05). Miltefosine was similar to or better than glucamine.

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