Uso da miltefosina no tratamento clínico de cães com leishmaniose visceral: revisão de literatura / Use of miltefosin in the clinical treatment of dogs with visceral leishmaniosis / Uso de miltefosina en el tratamiento clínico de perros con leishmaniosis visceral: revisión de la literatura

A leishmaniose visceral canina é uma doença de caráter zoonótico, acometendo os seres humanos e diversas espécies de animais silvestres e domésticos. Objetivou-se com o presente estudo realizar uma revisão de literatura sobre o uso da miltefosina no tratamento clínico de cães com leishmaniose visceral. Trata- se de uma revisão de literatura, a qual foi realizada por meio de consultas à periódicos e livros presentes na biblioteca do Cesmac. Foram utilizadas bases de dados como: portal Capes, SCIELO, Google Acadêmico; pesquisa em monografias, teses e dissertações. Causada pelo protozoário Leishmania chagasi, sendo o cão doméstico o principal reservatório desse protozoário. Por representar um problema grave de saúde pública e ser considerada uma doença potencialmente fatal (quando não tratada precocemente e adequadamente), faz- se importante que o clínico esteja familiarizado com os sinais clínicos, exames complementares e principais protocolos terapêuticos, em especial a utilização da miltefosina no tratamento da leishmaniose visceral em cães. Por ser uma zoonose que causa graves problemas de saúde pública e que vem crescendo cada vez mais no Brasil, cabe aos médicos veterinários assumirem o compromisso na conscientização sobre a importância do diagnóstico precoce além de promoverem o bem-estar animal e a saúde pública.(AU)

Canine visceral leishmaniasis is a zoonotic disease, affecting humans and several species of wild and domestic animals. The objective of the present study was to carry out a literature review on the use of miltefosine in the clinical treatment of dogs with visceral leishmaniasis. This is a literature review, which was carried out through consultations with periodicals and books present in the Cesmac library. Databases such as: Capes portal, SCIELO, Google Scholar; research in monographs, theses and dissertations. Caused by the protozoan Leishmania chagasi, with the domestic dog being the main reservoir of this protozoan. As it represents a serious public health problem and is considered a potentially fatal disease (when not treated early and properly), it is important that the clinician is familiar with the clinical signs, complementary exams and main therapeutic protocols, especially the use of miltefosine in the treatment of visceral leishmaniasis in dogs. As it is a zoonosis that causes serious public health problems and that has been growing more and more in Brazil, it is up to veterinarians to make a commitment to raise awareness of the importance of early diagnosis in addition to promoting animal welfare and public health.(AU)

La leishmaniosis visceral canina es una enfermedad zoonótica que afecta a los seres humanos y a varias especies de animales salvajes y domésticos. El objetivo de este estudio fue realizar una revisión bibliográfica sobre el uso de la miltefosina en el tratamiento clínico de perros con leishmaniosis visceral. Se trata de una revisión bibliográfica, que se realizó mediante consultas a publicaciones periódicas y libros presentes en la biblioteca del Cesmac. Se utilizaron bases de datos como: portal Capes, SCIELO, Google Académico; investigación en monografías, tesis y disertaciones. Causada por el protozoo Leishmania chagasi, siendo el perro doméstico el principal reservorio de este protozoo. Dado que representa un grave problema de salud pública y se considera una enfermedad potencialmente mortal (cuando no se trata de forma temprana y adecuada), es importante que el clínico esté familiarizado con los signos clínicos, las pruebas adicionales y los principales protocolos terapéuticos, especialmente el uso de miltefosina en el tratamiento de la leishmaniosis visceral en perros. Siendo una zoonosis que causa graves problemas de salud pública y que viene creciendo cada vez más en Brasil, corresponde a los veterinarios asumir el compromiso de concienciar sobre la importancia del diagnóstico precoz y promover el bienestar animal y la salud pública.(AU)

Directrices para el tratamiento de las leishmaniasis en la región de las américas - 2 ed / Guidelines for the treatment of leishmaniasis in the region of the Americas - 2 ed

Las leishmaniasis son enfermedades infecciosas desatendidas de gran importancia en la Región de las Américas debido a su morbilidad, mortalidad y amplia distribución geográfica. De las tres formas clínicas principales, la cutánea es la más común y la visceral es la forma más grave, ya que puede causar la muerte de hasta 90% de las personas que no reciban tratamiento. En el 2013, la Organización Panamericana de la Salud (OPS) elaboró recomendaciones para el tratamiento de las leishmaniasis en la Región de las Américas utilizando la metodología de clasificación de la valoración, la elaboración y la evaluación de las recomendaciones (GRADE, por su sigla en inglés). No obstante, dada la evidencia acumulada desde entonces, se hizo necesario revisar esas recomendaciones. En esta segunda edición se presentan las recomendaciones actualizadas sobre el tratamiento de las leishmaniasis, y se detallan los esquemas y los criterios de indicación del tratamiento en el contexto regional. Estas directrices presentan modificaciones sustanciales con respecto a la primera edición. En el caso de la leishmaniasis cutánea, se ha eliminado el ketoconazol de las opciones terapéuticas, el número de especies de Leishmania para las que hay evidencia sólida de la eficacia de la miltefosina ha aumentado de dos a cuatro y la recomendación de administrar antimoniales intralesionales ahora es fuerte. Con respecto a la leishmaniasis mucosa, se incluye una recomendación fuerte sobre el uso de antimoniales pentavalentes con o sin pentoxifilina oral. Por lo que respecta a la leishmaniasis visceral, la recomendación fuerte sobre el uso de antimoniales pentavalentes y desoxicolato de anfotericina B ahora es condicional. También hay evidencia contundente en contra del uso de miltefosina en pacientes con leishmaniasis causada por Leishmania infantum. Otros cambios importantes son el desglose de las recomendaciones según si se trata de pacientes adultos o pediátricos, la inclusión de las especies de Leishmania y, en el caso de los pacientes inmunocomprometidos, la introducción de una recomendación fuerte contra el uso de antimoniales pentavalentes. Esta segunda edición es una versión revisada de la publicación Leishmaniasis en las Américas: recomendaciones para el tratamiento: https://iris.paho.org/handle/10665.2/7704

Epidemiological aspects of visceral leishmaniasis in the municipality of Montes Claros-MG

Visceralleishmaniasis (VL), also known as 'calazar', is a serious chronic disease caused by Leishmania species from Leishmania(Leishmania) donovanicomplex, which the disease is characterized by abdominal swelling (hepatosplenomegaly) and may evolve to death in extreme cases.In this sense, the aim of our study was to assess the epidemiological profile of the cases found in Montes Claros (Minas Gerais state).A retrospective or cross-sectional study was carried out using secondary data provided by Health Information System (SINAN/HM) of Brazil from January 2010 to February 2020. Our data has shown that VL is an endemic disease in Montes Claros region, with 413 VL cases reported, 62.00% (252) male, average age ± standard deviation (years), and 93.46% (386) lived inMontes Claros city. The presence of comorbidities was observed in 13.70% (54) of the patients and in 7.26% (30). As for the evolution of the disease, 246 (59.56%) were cured, 30 (7.26%) died due to VL. Between 2010 and 2015, Glucantime®stands out, in which 46 (11.13%) patients used the drug, followed by common Amphotericin B 24 (13.48%) and liposomal Amphotericin B 38 (21.34%). In the period between 2016 and 2020, the most prevalent drug was liposomal Amphotericin B, with 71 (29.83%) patients using it, followed by Glucantime®45 (18.9%). The condition evolved to death. We conclude thatMontes Claros is still an endemic area for VL with an increased number of cases over time and a noticeable shift in patient profile towards children and young people. Joint efforts from different areas of scientific knowledge and public health services are needed to improve the effectiveness of visceral leishmaniasis surveillance and control actions. The population can contribute to this process of disease prevention and control, through educational actions in health and the environment.

Acute uveitis: A rare adverse effect of miltefosine in the treatment of post-kala-azar dermal leishmaniasis

Abstract Post-kala-azar dermal leishmaniasis is a skin disorder occurring in 5-10% of visceral leishmaniasis patients after treatment with miltefosine,the first-line drug for this skin disorder. We reported a case of acute anterior uveitis,a rare adverse effect, experienced by a patient treated with miltefosine for post-kala-azar dermal leishmaniasis. This adverse effect developed after 15 days of miltefosine consumption, and the patient himself discontinued the treatment. The ophthalmic complication was completely resolved with antibiotics and steroid eye drops. After recovery from the ophthalmic complication, the patient was successfully treated with liposomal amphotericin B for the skin lesions.

Is splenectomy an option for multiple relapses in a child with visceral leishmaniasis? A case report

Abstract Visceral leishmaniasis (VL) is an infectious disease caused by Leishmania spp. The recurrence of the disease occurs, in general, in patients with decreased or loss of T-cell function, whether due to the use of corticosteroids, immunosuppressive disease, or another cause. In some cases, splenectomy may be a therapeutic option. However, the effectiveness of splenectomy is not well defined. This report describes the evolution of a pediatric patient with seven recurrences of VL, who relapsed post-surgery after drug therapy and splenectomy.

O probiótico Saccharomyces boulardii modula a resposta de IgG2a em camundongos expostos aos antígenos de Leishmania infantum / Probiotic Saccharomyces boulardii modulates IgG2a response in mice exposed to Leishmania infantum antigens

O objetivo do presente estudo foiavaliar os efeitos do probiótico Saccharomyces boulardii na modulação da resposta imune humoral de animais expostos a antígenos de Leishmania infantum. Para isso, 16 camundongos BALB/c foram imunizados com antígeno particulado de Leishmania infantum e divididos em dois grupos experimentais, um composto por animais suplementados e outro por animais não suplementados com o probiótico. Amostras de sangue dos animais foram colhidas semanalmente durante o período experimental e submetidas ao Ensaio da Imunoabsorbância Ligado à Enzima indireto para avaliação dos títulos de IgG totais e o perfil dos isotipos de IgG produzidos (IgG1 e IgG2a). A suplementação com o probiótico não exacerbou a produção de IgG total em comparação ao grupo controle, não havendo diferenças significativas entre os dois grupos. Porém, as soroconversões de IgG2a foram mais elevadas no grupo suplementado, no qual registrou-se um aumento de 1,46 vezes no final do experimento. Assim,a suplementação com S. boulardii foi capaz de modular a resposta de IgG2a/IgG1 nos animais expostos aos antígenos de Leishmania infantum.

The aim of the present study was to evaluate the effects of the Saccharomyces boulardii probiotic on the modulation of humoral immune response in animals exposed to Leishmania infantum antigens. For this, 16 BALB/c mice were immunized with Leishmania infantum particulate antigen and divided into two experimental groups, one consisting of supplemented animals and the other not probiotic supplemented animals. Blood samples from the animals were taken weekly during the experimental period and subjected to the Indirect Enzyme-Linked Immunosorbance Assay for evaluation of total IgG titers and the profile of the produced IgG isotypes (IgG1 and IgG2a). Probiotic supplementation did not exacerbate total IgG production compared to the control group, with no significant differences between the two groups. However, IgG2a seroconversions were higher in the supplemented group, which showed a 1.46-fold increase at the end of the experiment. Thus, supplementation with S. boulardii was able to modulate the IgG2a/IgG1 response in animals exposed to Leishmania infantum antigens.

Boletim Epidemiológico: leishmaniose visceral em Goiás no ano de 2018 / Epidemiological Bulletin: Visceral Leishmaniasis in Goiás in 2018

A Leishmaniose Visceral (LV) é uma doença negligenciada, que se mantem como um importante problema de saúde pública em todo o mundo, afetando populações economicamente vulneráveis. É uma doença de transmissão vetorial por flebotomíneos Lutzomyia (L. longipalpis e L. cruzi),sendo, portanto, uma zoonose, que tem o protozoário do gênero Leishmania como agente etiológico. Os reservatórios principais em meio urbano são os cães e em ambiente silvestre as raposas (Dusicyon vetulus e Cerdocyon thous) e os marsupiais (Didelphis albiventris). É doença de notificação compulsória devido ao quadro clínico grave causado, podendo levar a óbito quando não tratada . Os pacientes infectados podem ser assintomáticos ou apresentarem sintomas diversos, que em sua maioria se manifestam como febre, fraqueza, emagrecimento, esplenomegalia e hepatomegalia

Visceral Leishmaniasis (VL) is a neglected disease, which remains an important public health problem worldwide, affecting economically vulnerable populations. It is a disease transmitted vector by sand flies Lutzomyia (L. longipalpis and L. cruzi), being, therefore, a zoonosis, which has the protozoan of the genus Leishmania as the etiological agent. The main reservoirs in urban areas are dogs and in the wild, foxes (Dusicyon vetulus and Cerdocyon thous) and marsupials (Didelphis albiventris). It is a notifiable disease due to the severe clinical condition caused, and it can lead to death when untreated . Infected patients may be asymptomatic or have different symptoms, most of which manifest as fever, weakness, weight loss, splenomegaly and hepatomegaly

Cost-effectiveness analysis of diagnostic-therapeutic strategies for visceral leishmaniasis in Brazil

Abstract INTRODUCTION: Visceral leishmaniasis (VL) is fatal if not diagnosed and treated. This study aimed to estimate the cost-effectiveness of diagnostic-therapeutic alternatives for VL in Brazil. METHODS: A decision model estimated the life expectancy and costs of six diagnostic-therapeutic strategies. RESULTS: IT LEISH + liposomal amphotericin B emerged the best option, presenting lower costs and higher effectiveness. DAT-LPC + liposomal amphotericin B showed an incremental cost-effectiveness ratio of US$ 326.31 per life year. CONCLUSIONS: These findings indicate the feasibility of incorporating DAT and designating liposomal amphotericin B as the first-line drug for VL in Brazil.

Visceral leishmaniasis in pregnant women from Rio Grande do Norte, Brazil: A case report and literature review

Abstract Visceral leishmaniasis (VL) in pregnant is considered rare. We present the case of a woman with 24 gestational weeks presenting fever, hepatosplenomegaly, pancytopenia, and inversion of albumin/globulin ratio. Anti-rK39 was positive and amastigotes were visualized on myelogram. Treatment with LAmB showed disease improvement. The newborn was born healthy at term, with delivery performed without complications. As VL in pregnancy can progress to death and complications for the mother-fetus binomial, inclusion of VL in the differential diagnosis of patients from endemic areas with compatible clinical picture is mandatory. Treatment with LAmB demonstrates safety and high cure rates in pregnancy.

Combination therapy with liposomal amphotericin b (ambisome), n-methylglucamine antimoniate (glucantime), and pentamidine isethionate in a refractory visceral leishmaniasis case

Abstract Visceral leishmaniasis is a systemic disease that is potentially severe and endemic in Brazil. It clinically manifests as fever, weight loss, swelling, hepatosplenomegaly, paleness, and edema. In this study, we discuss a case of a 1-year-old child diagnosed with refractory visceral leishmaniasis after being treated with liposomal amphotericin B in two distinct occasions. Considering the persistent clinical features and weak response to conventional treatment, a combination therapy with liposomal amphotericin B (ambisome), n-methylglucamine antimoniate (glucantime), and pentamidine isethionate was initiated, and response to treatment was good.

Is Visceral Leishmaniasis the same in HIV-coinfected adults?

ABSTRACT Introduction: Visceral Leishmaniasis is the most severe form of disease caused by the Leishmania donovani complex, with significant morbidity and mortality in developing countries. Worse outcomes occur among HIV-positive individuals coinfected with Leishmania. It is unclear, however, if there are significant differences on presentation between Visceral Leishmaniasis patients with or without HIV coinfection. Methods: We reviewed medical records from adult patients with Visceral Leishmaniasis treated at a reference healthcare center in Fortaleza - Ceará, Brazil, from July 2010 to December 2013. Data from HIV-coinfected patients have been abstracted and compared to non-HIV controls diagnosed with Visceral Leishmaniasis in the same period. Results: Eighty one HIV-infected patients and 365 controls were enrolled. The diagnosis in HIV patients took significantly longer, with higher recurrence and death rates. Kala-azar's classical triad (fever, constitutional symptoms and splenomegaly) was less frequently observed in Visceral Leishmaniasis-HIV patients, as well as jaundice and edema, while diarrhea was more frequent. Laboratory features included lower levels of hemoglobin, lymphocyte counts and liver enzymes, as well as higher counts of blood platelets and eosinophils. HIV-infected patients were diagnosed mainly through amastigote detection on bone marrow aspirates and treated more often with amphotericin B formulations, whereas in controls, rK39 was the main diagnostic tool and pentavalent antimony was primarily used for treatment. Conclusions: Clinical and laboratory presentation of Visceral Leishmaniasis in HIV-coinfected patients may differ from classic kala-azar, and these differences may be, in part, responsible for the delay in diagnosing and treating leishmaniasis, which might lead to worse outcomes.

Brote urbano de leishmaniasis en Colombia / Urban outbreak of leishmaniasis in Colombia

RESUMEN Objetivos Describir las características epidemiológicas, clínicas y el tratamiento de niños con leishmaniasis visceral en Neiva, Huila. Metodologia Se realizó un estudio descriptivo del brote de leshmaniasis visceral en niños de la zona urbana de Neiva, Huila, entre los meses de abril a junio de 2012. Resultados Se presentaron siete casos, en niños menores de cinco años, con fiebre prolongada, hepato-esplenomegalia, anemia severa y leucopenia. Cinco ingresaron con trombocitopenia severa, sin manifestaciones hemorrágicas. Seis pacientes recibieron manejo de primera línea con miltefosine, cinco presentaron fracaso terapéutico y se escalonó tratamiento a anfotericina B, de los cuales dos recibieron anfotericina liposomal y tres anfotericina deoxicolato. El principal vector identificado fue la Lutzomyia gomezi y los reservoirios indentifiacados fueron caninos. Conclusión Se describe el primer brote de leishmaniasis visceral en zona urbana, en población pediátrica sin casos de mortalidad. La mayoría de los casos con buena respuesta a Anfotericina B.(AU)

ABSTRACT Objectives To describe the epidemiology, clinical characteristics and treatment of children with visceral Leishmaniasis in Neiva- Huila, from April to June 2012. Methodology We performed a descriptive study of an outbreak of visceral leshmaniasis in children from the urban area of Neiva. Results There were seven cases in children younger than five years. All of them had prolonged fever, hepato-splenomegaly, severe anemia and leukopenia. Five were admitted with severe thrombocytopenia, without hemorrhagic manifestations. Six patients received first-line treatment with miltefosine, five of them had treatment failure requirirng therapy escalation to amphotericin B, two received liposomal amphotericin B and three deoxycholate amphotericin B. The main vector identified was the Lutzomyia gomezi and its main reservoir were canines. Conclusion We describe the first visceral leishmaniasis outbreak in children living in an urban area, with no mortality. Most of the cases had a good response to amphotericin B.(AU)

Visceral leishmaniasis and leishmaniasis-HIV coinfection: comparative study

Abstract INTRODUCTION: This study aimed to draw clinical and epidemiological comparisons between visceral leishmaniasis (VL) and VL associated with human immunodeficiency virus (HIV) infection. METHOD: Retrospective study. RESULTS: Of 473 cases of VL, 5.5% were coinfected with HIV. The highest proportion of cases of both VL and VL/HIV were found among men. A higher proportion of VL cases was seen in children aged 0-10 years, whereas coinfection was more common in those aged 18-50 years. CONCLUSIONS: VL/HIV coinfected patients presented slightly differently to and had a higher mortality rate than those with VL only.

Protection mediated by chemokine CXCL10 in BALB/c mice infected by Leishmania infantum

BACKGROUND Visceral leishmaniasis (VL) caused by Leishmania infantum is characterised by the loss of the ability of the host to generate an effective immune response. Chemokines have a direct involvement in the pathogenesis of leishmaniasis, causing a rapid change in the expression of these molecules during infection by Leishmania. OBJECTIVES Herein, it was investigated the role of CXCL10 in controlling infection by L. infantum. METHODS RAW 264.7 macrophages were infected with L. infantum in vitro and treated or not with CXCL10 (25, 50 and 100 ng/mL). Parasite load, as well as nitric oxide (NO), IL-4 and IL-10 production were assessed at 24 and 48 h after infection. In vivo, BALB/c mice were infected and treated or not with CXCL10 (5 μg/kg) at one, three and seven days of infection. Parasite load, IFN-g, IL-4, TGF-β and IL-10 were evaluated one, seven and 23 days post treatment. FINDINGS In vitro, CXCL10 reduced parasitic load, not dependent on NO, and inhibited IL-10 and IL-4 secretion. In vivo, CXCL10 was able to reduce the parasite load in both liver and spleen, four weeks after infection, representing a higher decrease in the number of parasites in these organs, also induced IFN-γ at day 23 after treatment, correlating with the decrease in parasite load, and reduced IL-10 and TGF-β. MAIN CONCLUSIONS This study suggests a partial protective role of CXCL10 against L. infantum, mediated by IFN-g, not dependent on NO, and with suppression of IL-10 and TGF-β. These data may provide information for the development of new approaches for future therapeutic interventions for VL.

The direct costs of treating human visceral leishmaniasis in Brazil

Abstract INTRODUCTION: The drugs available for visceral leishmaniasis (VL) treatment in Brazil have specific characteristics in terms of operability, effectiveness, toxicity, and cost. The aim of this study was to estimate the direct costs of therapies recommended by the Ministry of Health (MH) for VL treatment in Brazil. METHODS: The analytical perspective used was that adopted by the Brazilian Public Health System. Three drugs and four regimens were included: 1) N-methyl glucamine antimoniate intramuscularly at 20mg per kg per day for 30 days; 2) N-methyl glucamine antimoniate intravenously at 20mg per kg per day for 30 days; 3) amphotericin B deoxycholate at 1mg per kg per day for 21 days; and 4) liposomal amphotericin B at 3mg per kg per day for a 7 days treatment. RESULTS: The estimated direct costs of treatment for an adult patient using N-methylglucamine antimoniate administered via the intramuscular and intravenous routes were USD 418.52 and USD 669.40, respectively. The estimated cost of treatment with amphotericin B deoxycholate was USD 1,522.70. Finally, the estimated costs of treatment with liposomal amphotericin B were USD 659.79, and USD 11,559.15 using the price adopted by the WHO and the Drug Regulation Board, respectively. CONCLUSIONS: This analysis indicates the economic feasibility of replacing N-methyl glucamine antimoniate with liposomal amphotericin B, which allows a shorter treatment period with less toxicity compared with other treatments, provided that the purchase value used by the WHO and transferred to the MH is maintained.

Efficacy and safety of amphotericin B deoxycholate versus N-methylglucamine antimoniate in pediatric visceral leishmaniasis: an open-label, randomized, and controlled pilot trial in Brazil

ABSTRACT INTRODUCTION Despite their high toxicity, antimonials and amphotericin B deoxycholate are commonly used for treating visceral leishmaniasis (VL). Few studies showing conflictive data about their efficacy and adverse events in pediatric population are available. This study aimed to evaluate efficacy and safety of amphotericin B deoxycholate vs. that of N-methylglucamine antimoniate in treating pediatric VL in Brazil. METHODS This was a randomized, open-label, 2-arm and controlled pilot clinical trial. Treatment naïve children and adolescents with VL without signs of severe illness were treated with N-methylglucamine antimoniate (20mg/kg/day for 20 days) or amphotericin B deoxycholate (1 mg/kg/day for 14 days). All patients were diagnosed with positive direct examination and/or positive PCR for Leishmania spp. performed in bone marrow samples. The primary efficacy end-point was VL cure determined after 180 days of completion of treatment. The analysis was performed using intention-to-treat (ITT) and per protocol (PP) analyses. RESULTS In total, 101 volunteers were assessed. Efficacy was similar for both groups. The antimonial (n=51) and amphotericin B groups (n=50) had a cure rate of 94.1% and 100%, and 94% and 97.9% according to ITT and PP analyses, respectively. All patients reported adverse events (AE). Serious AE incidence was similar in both groups. Five individuals were excluded from the study because of severe adverse events. CONCLUSIONS N-methylglucamine antimoniate and amphotericin B deoxycholate have similar efficacy and adverse events rate in pediatric patients with VL.

Buparvaquone nanostructured lipid carrier development: physicochemical and in vitro leishmanicidal performances / Desenvolvimento de carreadores lipídicos nanoestruturados contendo buparvaquona: caracterização físico-química e avaliação da atividade leishmanicida in vitro

Leishmaniases is a group of diseases caused by parasites of the genus Leishmania. The estimated number of deaths from visceral leishmaniases ranges from 20,000 to 50,000 annually. The most common treatment over the past 60 years has been pentavalent antimonials. Besides the doubtful effectiveness, they present several disadvantages such as the need for parenteral administration, large doses, long treatment, severe toxicity and parasite resistance. Buparvaquone (BPQ), a drug used for veterinary treatment of theileriosis, showed promising activity against Leishmania spp. However, due to its low aqueous solubility and bioavailability, it has failed in in vivo tests. The use of nanotechnologies has the potential to overcome these drawbacks due to the following advantages: increase in drug water-solubility, increase in therapeutic efficacy and treatment toxicity reduction. Therefore, the present work aimed the development, optimization, physical-chemical evaluation and in vitro performances of nanostructured lipid carriers (NLC) for BPQ encapsulation. The NLC preparation was performed by high pressure homogenization, and surface response and factorial design were applied to formulation optimization. In vitro dissolution profiles were evaluated in phosphate buffer pH 7.4 with tween 80 0.07% w/v or sodium dodecyl sulfate 1% w/v and simulated body fluid pH 7.4. Cytotoxicity was evaluated in mouse peritoneal macrophages and leishmanicidal activity in L. infantum amastigotes. Six optimized NCL were prepared and they showed solubility improvement from 1.5- fold to 611-fold when compared with free BPQ, depending on the formulation and medium. Dissolution profiles showed the NLC formulation suitability for BPQ regarding oral administration, the release could reach 83.29% of a 4mg dose in 30 minutes for formulation of 175.1 nm, while the free drug could be dissolved only 2.89% of the same dose after 4 hours. Moreover, formulation of 230.7 nm showed 81.42% of drug release in in phosphate buffer pH 7.4 with dodecyl sulfate 1.0% w/v after 30 minutes, while BPQ did not dissolved. Cytotoxicity assay showed the safety of all formulations. The iv CC50 values were close to 500 µM, while the IC50 against amastigotes was only 456.5 nM for free BPQ. Developed NLCs showed an increase in IC50 from 2.0 to 3.1-fold when compared to free drug in the in vitro leishmanicidal evaluation. Therefore, the NLC containing BPQ are a promising alternative for the treatment of leishmaniases as oral and parenteral drug dosage forms. Additionally, they have a potential use for lymphatic targeted drug delivery, which can be an innovative approach for this neglected disease.

Leishmanioses são um grupo de doenças causadas por parasitas do gênero Leishmania. O número estimado de óbitos por leishmaniose visceral varia entre 20.000 e 50.000 por ano. O tratamento mais comum nos últimos 60 anos tem sido os antimônios pentavalentes. Além da eficácia duvidosa, eles apresentam várias desvantagens, como a necessidade de administração parenteral, altas doses, tratamento prolongado, toxicidade severa e resistência parasitária. Buparvaquona (BPQ), um fármaco usado para tratamento veterinário da teileriose, mostrou atividade promissora contra Leishmania donovani. No entanto, devido à sua baixa solubilidade e biodisponibilidade aquosa, falhou em testes in vivo. O uso das nanotecnologias tem o potencial de superar esses obstáculos devido às seguintes vantagens: aumento da solubilidade em água, aumento da eficácia terapêutica e redução da toxicidade do tratamento. Portanto, o presente trabalho objetivou o desenvolvimento, otimização, avaliação físico-química e avaliação do desempenho in vitro de carreadores lipídicos nanoestruturados (NLC) para o encapsulação da BPQ. A preparação do NLC foi realizada por homogeneização de alta pressão e superfície de resposta e planejamento fatorial foram aplicados à otimização das formulações. Os perfis de dissolução in vitro foram avaliados em tampão fosfato pH 7.4 com tween 80 a 0.07% p/v ou dodecilsulfato de sódio 1.0% p/v e fluido corporal simulado pH 7.4. A citotoxicidade foi avaliada em macrófagos peritoneais de camundongos e atividade leishmanicida em amastigotas de L. infantum. Foram preparados quatro NCL otimizados e mostraram melhora da solubilidade de 1,5 a 611 vezes quando comparado com a BPQ livre, dependendo da formulação e do meio. Os perfis de dissolução mostraram a adequação da formulação NLC para BPQ em relação à administração oral. A dissolução pode atingir 83,29% de uma dose de 4.0 mg em 30 minutos para a formulação de 175,1 nm, enquanto o fármaco livre dissolveu apenas vi 2,89% da mesma dose após 4 horas. Além disso, a formulação de 230,7 nm mostrou 81,42% de liberação do fármaco em tampão fosfato pH 7.4 com dodecil sulfato de sódio 1.0% p/v após 30 minutos, enquanto o BPQ não se dissolveu. O teste de citotoxicidade mostrou a segurança de todas as formulações. Os valores CC50 foram próximos de 500 µM, enquanto o IC50 em amastigotas foi de apenas 456,5 nM para BPQ livre. Os NLC desenvolvidos mostraram um aumento no IC50 de 2,0 a 3,1 vezes quando comparado ao;fármaco livre na avaliação leishmanicida in vitro. Logo, as NLC contendo BPQ são uma alternativa promissora para o tratamento de leishmanioses como formas farmacêuticas oral e parenteral. Além disso, eles têm um uso potencial para a sítio-específico ao sistema linfático, o que pode ser uma abordagem inovadora para esta doença negligenciada.

Percepções da população e de profissionais de saúde sobre a leishmaniose visceral / Perceptions of the population and health professionals regarding visceral leishmaniasis

Resumo O presente estudo buscou, a partir do referencial teórico metodológico da pesquisa qualitativa, investigar a percepção, sobre a leishmaniose visceral (LV), de atores sociais diretamente envolvidos com a prevenção e controle da doença. A partir da realização de 38 entrevistas semiestruturadas com moradores e grupo focal com 18 agentes de saúde, de município endêmico para LV, foram coletados depoimentos que, tratados pela Análise de Conteúdo, evidenciaram lacunas, desafios e perspectivas do controle e prevenção da doença. A população associava a LV ao cão, reconhecia sua corresponsabilidade no enfrentamento da doença e demandava informação. Os agentes de saúde identificavam o saneamento ambiental como fator imprescindível para prevenção da LV. Entre as lacunas observamos fragilidade nas informações sobre a doença e culpabilização do indivíduo pela não adesão a medidas, sobretudo, de manejo ambiental. Provavelmente, abordagens que destaquem o papel do ambiente como promotor de saúde, em detrimento da prescrição pontual de medidas ambientais específicas contra LV, constitui perspectiva de superação dessas lacunas. Entendemos que o principal desafio para o fortalecimento da prevenção e controle seja a construção participativa e dialógica dessas abordagens entre profissionais de saúde e população.

Abstract Based on theoretical qualitative research reference methodology, this study sought to investigate the perception of visceral leishmaniasis (VL) by social actors directly involved in the prevention and control of the disease. Thirty-eight semi-structured interviews were conducted with residents, focus groups were staged with 18 health workers in an endemic VL area and depositions were collected, which after being processed by content analysis revealed shortcomings and challenges. The population associated VL with dogs, acknowledged their co-responsibility in tackling the disease and demanded information. Health workers identified environmental sanitation as an essential factor for VL prevention. Among the shortcomings, the lack of information about the disease and culpability of the individual because of non-adherence to prevention measures were observed, especially environmental management. Probably, approaches emphasizing the role of the environment as a health promotion agent and the timely definition of specific environmental measures against VL, constitute a prospect for overcoming these shortcomings. The consensus is that the main challenge for enhancing the prevention and control might be the participatory and dialogical construction of these approaches between health professionals and the population.