In Vitro and In Vivo Antileishmanial Activity of Thioridazine.

INTRODUCTION: Leishmaniasis is a neglected disease with high prevalence and incidence in tropical and subtropical areas. Existing drugs are limited due to cost, toxicity, declining efficacy and unavailability in endemic places. Drug repurposing has established as an efficient way for the discovery of drugs for a variety of diseases. PURPOSE: The objective of the present work was testing the antileishmanial activity of thioridazine, an antipsychotic agent with demonstrated effect against other intracellular pathogens. METHODS: The cytotoxicity for mouse peritoneal macrophages as well as the activity against Leishmania amazonensis, Leishmania mexicana and Leishmania major promastigotes and intracellular amastigotes, as well as in a mouse model of cutaneous leishmaniasis, were assessed. RESULTS: Thioridazine inhibited the in vitro proliferation of promastigotes (50% inhibitory concentration-IC50-values in the range of 0.73 µM to 3.8 µM against L. amazonensis, L. mexicana and L. major) and intracellular amastigotes (IC50 values of 1.27 µM to 4.4 µM for the same species). In contrast, in mouse peritoneal macrophages, the 50% cytotoxic concentration was 24.0 ± 1.89 µM. Thioridazine inhibited the growth of cutaneous lesions and reduced the number of parasites in the infected tissue of mice. The dose of thioridazine that inhibited lesion development by 50% compared to controls was 23.3 ± 3.1 mg/kg and in terms of parasite load, it was 11.1 ± 0.97 mg/kg. CONCLUSIONS: Thioridazine was effective against the promastigote and intracellular amastigote stages of three Leishmania species and in a mouse model of cutaneous leishmaniasis, supporting the potential repurposing of this drug as an antileishmanial agent.

Amphotericin B is usually underdosed in the treatment of experimental cutaneous leishmaniasis / La anfotericina B normalmente es subdosificada en el tratamiento de la leishmaniasis cutánea experimental

Introduction: Amphotericin B is an effective drug for the treatment of the different clinical forms of leishmaniasis. However, there are reports of its ineffectiveness in animals experimentally infected withLeishmaniaspp. That is why, the objective of the present work was to evaluate the balance of activity-toxicity at amphotericin B doses over 1 mg/kg, so that its use as a positive control antileishmanial drug were adequate. Method: BALB/c mice were experimentally infected withL. amazonensisand treated with amphotericin B by intraperitoneal route at doses from 5 mg/kg to 12.5 mg/kg, beginning 21 days after infection. The size of the lesions and the body weight of the mice were measured for eleven weeks after the commencement of treatment. The number of parasites was also determined three days after the end of treatment. Results: Amphotericin B at 5 mg/kg retarded lesions growth but neither reduced lesion size nor the parasite load at lesion site. Doses of 7.5 mg/kg to 10 mg/kg, every 48 h for 14 days (7 doses) caused a significant reduction of lesion size and parasite load without evident loss of body weight and without signs of toxicity. Amphotericin B at 12.5 mg/kg was more effective but produced unacceptable toxicity. Conclusions: The results support the use of amphotericin B as a positive control drug in BALB/c mice experimentally infected withL. amazonensisat doses of 7.5 mg/kg to 10 mg/kg to achieve an effect comparable to that observed in clinical practice. (AU)

Introducción: La anfotericina B es un fármaco eficaz para el tratamiento de las distintas formas de leishmaniosis. Sin embargo, existen informes sobre su ineficacia en animales de laboratorio infectados experimentalmente conLeishmaniaspp.Es por ello que el objetivo del presente trabajo fue evaluar el balance de actividad-toxicidad a dosis de Anfotericina B superiores a 1 mg/kg, de modo que su uso como fármaco leishmanicida control positivo sea adecuado. Método: Se infectaron experimentalmente ratones BALB/c conL. amazonensisy se trataron con anfotericina B por vía intraperitoneal a dosis desde 5 mg/kg hasta 12,5 mg/kg, comenzando 21 días después de la infección. Durante once semanas a partir del comienzo del tratamiento se evaluó el tamaño de las lesiones y el peso corporal de los ratones. Tres días después de concluido el tratamiento se determinó el número de parásitos en las lesiones. Resultados: La anfotericina B a 5 mg/kg retrasó el crecimiento de las lesiones, pero no redujo su tamaño ni disminuyó significativamente el número de parásitos en la lesión. Dosis de 7,5 mg/kg a 10 mg/kg, cada 48 h durante 14 días (7 dosis) causaron una reducción significativa del tamaño de la lesión y de la carga parasitaria sin pérdida manifiesta de peso corporal y sin signos de toxicidad. La anfotericina B a 12,5 mg/kg fue más eficaz, pero produjo una toxicidad inaceptable. Conclusiones: Los resultados avalan el uso de la anfotericina B como control positivo en ratones BALB/c infectados experimentalmente conL. amazonensisen dosis de 7,5 mg/kg a 10 mg/kg para lograr un efecto comparable al observado en la práctica clínica. (AU)

Enfermedad de Chagas: El desenlace de un conflicto entre el Parásito y el Sistema Inmunitario / Chagas’ Disease: the outcome of a conflict between the Parasite and the Immune System

Transcurridos más de cien años de su descubrimiento, la patogénesis de la enfermedad de Chagas sigue siendo un tema controvertido. Durante décadas se ha dado mayor relevancia a las consecuencias de la respuesta inmunitaria, hasta el punto de estar considerada como una enfermedad autoinmune. El mimetismo molecular entre antígenos del parásito y del hospedador, la diseminación de epitopos y la activación policlonal son algunos de los mecanismos que explicarían el carácter autoinmune de la enfermedad. Sin embargo, en los últimos años, el interés vuelve a centrarse en el parásito. La utilización de técnicas más sensibles no sólo ha puesto en evidencia su presencia en tejidos, sino que se ha demostrado que existe una correlación entre inflamación y antígenos y/o ADN parasitario. En base a ello, sin descartar la importancia de la respuesta inmune, la necesidad de que persista el parásito está inclinando la balanza hacia consideración como enfermedad parasitaria. Este artículo resume y analiza la participación del parásito, del sistema inmune, así como la influencia de otros factores, como cambios microvasculares o alteraciones neurogénicas, en la patogénesis de una enfermedad que apasiona a parasitólogos e inmunólogos(AU)

Chagas' disease was described more than one hundred years ago, but its pathogenesis remains controversial. For several decades it has been considered as an autoimmune disease. Molecular mimicry responsible for anti-parasite-responses that "cross react" with self-molecules in Trypanosoma cruzi-infected host, epitopes dissemination and polyclonal activation support the autoimmune etiology of the disease. However, in the last years, parasites have been detected in tissues of hosts with chronic infections by using more sensitive techniques and also a correlation among inflammation and parasite antigens and/or DNA has been demonstrated. So, rather than discarding the autoimmune hypothesis, Chagas' disease is considered as a parasite-induced disorder. This review resumes and analyzes the role of the persistence of parasites, the autoimmunity, as well as other factors possibly involved as microvascular changes and neurogenic alterations, in such a disease that interest both parasitologists and immunologists(AU)