Evaluación de la toxicidad de chalconas sintéticas con potencial anti-Leishmania en ratones BALB/c / Toxicity assessment of synthetic chalcones with antileishmanial potential in BALB/c mice

RESUMEN Objetivo: Evaluar la toxicidad de tres chalconas sintéticas administradas por vía intraperitoneal en ratones BALB/c. Materiales y métodos: La dosis letal media (DL50) se estimó por el método Up-and-Down de Dixon. La toxicidad subcrónica de las chalconas se evaluó a 20 y 40 mg/kg por 21 días. Se evaluó el efecto tóxico a nivel de comportamiento, fisiológico, bioquímico e histológico. Resultados: La chalcona 43 generó moco en las heces, daño visceral (hígado) y alteración en el coeficiente de órganos (riñón, p = 0,037 y cerebro, p = 0,008) en comparación con el grupo control. Además, en el análisis histológico se observó que esta chalcona produjo edema, inflamación y necrosis en los órganos evaluados, aunque no hubo diferencia significativa con el control. Todos los parámetros bioquímicos no difirieron significativamente entre los grupos de tratamiento a dosis de 40 mg/kg y el control. Conclusiones: La DL50 para las tres chalconas fue superior a 550 mg/kg de peso corporal. Las chalconas 40 y 42 son relativamente no tóxicas. Ambas pueden considerarse seguras para la aplicación vía intraperitoneal en ratones BALB/c y, en consecuencia, son posibles candidatas para ser usadas en el tratamiento contra las leishmaniosis.

ABSTRACT Objective: To evaluate the toxicity of three synthetic chalcones administered intraperitoneally to BALB/c mice. Materials and methods: The median lethal dose (LD50) was estimated by Dixon's Up-and-Down method. Subchronic toxicity of chalcones was evaluated at 20 and 40 mg/kg for 21 days. Behavioral, physiological, biochemical, and histological toxic effects were evaluated. Results: Chalcone 43 produced mucus in feces, visceral damage (liver) and alterations in organ coefficient (kidney, p = 0.037 and brain, p = 0.008) when compared to the control group. In addition, histological analysis showed that this chalcone produced edema, inflammation and necrosis in the evaluated organs, although there was no significant difference with the control. None of the biochemical parameters differed significantly between the treatment groups at 40 mg/kg dose and the control. Conclusions: The LD50 for all three chalcones was greater than 550 mg/kg of body weight. Chalcones 40 and 42 were found to be relatively non-toxic. Both can be considered safe for intraperitoneal application in BALB/c mice and, consequently, are potential candidates for use in the treatment of leishmaniasis.

Evaluación de la toxicidad subcrónica de la variedad colombiana de Smallanthus sonchifolius (Yacón) en ratas hembra / Subchronic toxicity evaluation of colombian variety of Smallanthus sonchifolius (Yacón) in female rats

Smallanthus sonchifolius (Yacón) es una planta usada comúnmente por largos periodos de tiempo con el fin de ayudar en el control de la diabetes y otros desordenes metabólicos, por lo que con el propósito de evaluar la toxicidad subcrónica de la variedad colombiana de esta planta, fueron tratadas 30 ratas hembra de 8 semanas de edad dividas en 6 grupos. A cada uno de ellos se administró durante 28 días una de las siguientes dosis de infusión acuosa liofilizada (500, 250 y 125 mg/kg de peso), evaluando paralelamente grupos control (positivo y negativo) e incluyendo entre ellos grupos con y sin dieta hipercalórica. Para el seguimiento del perfil metabólico de los animales, se tomaron muestras de sangre periódicamente durante el ensayo y se evaluaron los niveles séricos de: glucemia, triglicéridos, colesterol total y HDL. Además, también se realizó el control del peso, así como estudios comportamentales que incluyeron el Test de Irwin y el Test Hipocrático. Al final de estudio (28 días), se realizó el análisis anatomopatológico e histológico comparativo con el fin de detectar posibles daños tisulares. Como resultado pudo observase que el liofilizado, si bien puede tener un efecto antihiperglucemiante, no modificó significativamente el perfil lipídico. Además, a pesar de que la administración se hizo durante 28 días, no se observaron cambios comportamentales que evidencien toxicidad, pero sí pudieron observarse cambios histológicos en el tejido cardiaco como hialinización, separación y redondeo de fibras.

Abstract. Smallanthus sonchifolius (Yacón) is a plant commonly used over long periods of time to help control diabetes and other metabolic disorders. To assess the sub-chronic toxicity of the Colombia variety of this plant, it was tested on 30 eight-week-old female rats, divided into six groups. For 28 days each group was administered with the following doses: three groups with lyophi­lized aqueous infusion (500 mg, 250 mg and 125 mg per kg of weight), two control groups (positive and negative) being assessed in parallel; this groups receiving hyper-caloric diet, and the last group was the general control or normal control. To monitor the animals' metabolic profile, blood samples were taken from time to time during the test period, and the serum levels of glycemia, triglycerides, total cholesterol and HDL were measured. Weight tracking was also carried out, as well as behavioral studies, including the Irwin Test and the Hippocratic Test. At the end of the study (28 days), comparative anatomo-pathological and histological analyses were performed to detect possible tissue damage. The results showed that, although the lyophilized infusion could have an antihyperglycemic effect, it did not significantly change the lipid profile. Moreover, though the infusion was administered during 28 days, it was found that it did not lead to any behavioral changes indicating toxicity, but did produce in heart tissue histological changes such as hyalinization, separation and rounding of fibers.

Toxicología subcrónica de infusión de Chenopodium ambrosioides (epazote) por administración oral en ratones NIH / Subchronic toxicology of Chenopodium ambrosioides (epazote) infusion orally administered to NIH mice

Introducción: las plantas medicinales constituyen una valiosa alternativa terapéutica y su validación científica es una necesidad. Objetivo: identificar los posibles efectos tóxicos producidos por la infusión de Chenopodium ambrosioides L. (Chenopodiaceae) sobre el modelo biológico utilizado. Métodos: para determinar la toxicidad subcrónica de la infusión se emplearon ratones albinos suizos NIH de los 2 sexos, a los que se les administró por vía oral infusiones de la especie estudiada a concentraciones de 32, 64 y 134 mg/mL por 90 días. Al mismo tiempo se realizaron observaciones clínicas diarias con el fin de identificar algún efecto tóxico posadministración de la sustancia. Después fueron sacrificados para realizar los exámenes hematológicos (hematocrito, hemoglobina, glóbulos rojos, glóbulos blancos, neutrófilos y linfocitos) y bioquímicos (alanino aminotransferasa y creatinina), así como estudios macroscópicos e histológicos de los órganos internos (riñón, hígado, pulmón e intestino). Resultados: se encontró que la infusión de Chenopodium ambrosioides a las dosis administradas no causó efectos determinantemente significativos en los parámetros toxicológicos, en el peso corporal, en hematología y química sanguínea, al igual que tampoco provocó alteraciones anatomopatológicas sobre los órganos y tejidos evaluados. Conclusiones: la infusión de Chenopodium ambrosioides bajo estas condiciones experimentales no presentó actividad tóxica.

Introduction: medicinal plants represent a valuable therapeutic alternative and their scientific validation is a must. Objectives: to determine the possible toxic effects produced by the infusion of Chenopodium ambrosioides L. (Chenopodiaceae) on the used biological model. Methods: to determine the subchronic toxicity of the infusion, NIH Swiss albino mice of both sexes were used, to which infusions from the tested species, at concentrations of 32, 64, and 134 mg/mL , were orally administered for 90 days. At the same time, daily clinical observations were performed in order to identify any toxic post-dose administration. Afterwards, they were sacrificed for conduction of hematological tests (hematocrit, hemoglobin, red blood cells, white cells, neutrophils and lymphocytes) and biochemical (alanine aminotransferase and creatinine) and macroscopic and histological studies of the internal organs (kidney, liver, lung and intestine.). Results: the infusion of Chenopodium ambrosioides at the tested doses caused neither decisively significant effects on the toxicological parameters, body weight, hematology and blood chemistry nor pathological changes on organs and tissues. Conclusions: the infusion of Chenopodium ambrosioides under our experimental conditions showed no toxic activity.

Avaliação toxicológica pré-clínica do chá das folhas de Morus nigra L. (Moraceae) / Pre-clinical toxicological evaluation of tea from the leaves of Morus nigra L. (Moraceae)

O objetivo desse estudo foi realizar um ensaio toxicológico pré-clínico para analisar a toxicidade do chá das folhas de Morus nigra L. (Moraceae). A toxicidade subcrônica do chá (CF-Mn) foi avaliada durante 30 dias por via oral em ratos. Ao grupo controle foi administrado água, para comparação. Durante o período experimental foi avaliada a presença de sinais de toxicidade, variação do peso corporal, e o consumo de líquido e alimento. Ao final do experimento o sangue dos animais foi retirado para análise de parâmetros hematológicos e bioquímicos. Não foram observados mortalidade e sinais de toxicidade indicando baixa toxicidade da planta. Não houve alterações nos parâmetros hematológicos e bioquímicos. Nas condições do estudo, o CF-Mn pode ser considerado de baixa toxicidade, pois não produziu efeitos tóxicos nos animais tratados.

The aim of this study was to carry out a pre-clinical toxicological assay to analyze the toxicity of tea from the leaves of Morus nigra L. (Moraceae). The subchronic toxicity of this tea (CF-Mn) was orally evaluated during 30 days in rats. The control group was given water for comparison. During the experimental period, signs of toxicity, body weight variation, and water and food consumption were assessed. At the end of the experiment, the blood of animals was removed for analysis of hematological and biochemical parameters. No mortality and no toxicity signs were observed, indicating low toxicity of the plant. There was no alteration in the hematological and biochemical parameters. Under the study conditions, CF-Mn can be considered of low toxicity since it did not produce toxic effects in treated animals.

Subchronic and acute preclinic toxicity and some pharmacological effects of the water extract from leaves of Petiveria alliacea (Phytolaccaceae)

We tested the effects of the aqueous extract of Petiveria alliacea leaves on acute and sub-chronic toxicity, hematocrit and blood glucose level and intestinal motility of male albino NGP mice of 20 to 25 g mean weight. Treatments were in all cases doses of 1,000 and 2,000 mg/kg animal weight and a control treatment with 0.5 ml distilled water, using 10 animals per treatment and administered orally every day (5 days per week). Experimental periods were 18 and 70 days for acute and sub chronic toxicity, respectively. No mortality nor any toxicity signs could be observed. A slight but significant increase in the glucose levels during the first three weeks was observed with the 1,000 mg/kg dose but not for the higher 2,000 mg/kg dose. After administering the doses once after a starving period of six hours, no significant differences in intestinal motility could be found.

Se evaluaron los efectos del estracto acuoso de las hojas de Petiveria alliacea, en la toxicidad aguda y toxicidad subcrónica, hematocritos, niveles de glucosa en la sangre y motilidad intestinal del ratón macho albino NGP, con un peso promedio de 20 a 25g. En todos los casos los tratamientos fueron dosis de 1 000 y 2 000 mg/kg de peso del animal y un tratamiento control con 0.5 ml de agua destilada, usando 10 animales por tratamiento y administrado oralmente cinco días por semana. Los períodos experimentales fueron de 18 y 70 días para toxicidad aguda y toxicidad subcrónica, respectivamente. No se observaron signos de mortalidad ni de toxidad en ambas pruebas. Con la dosis de 1 000 mg/kg hubo un leve pero significativo incremento en los niveles de glucosa durante las primeras tres semanas, pero no con la dosis más alta de 2 000 mg/ kg. Después de administrar las dosis luego de un período de hambre de seis horas, no se encontraron diferencias significativas en la motilidad intestinal.

Avaliação da toxicidade subcrônica do extrato bruto seco de Anacardium occidentale Linn em cães / Evaluation of the subchronic toxicity of the crude dry extract of Anacardium occidentale Linn in dogs

A busca de novos medicamentos tem levado ao desenvolvimento de novos fármacos que sejam eficientes e destituídos de toxicidade. Uma das fronteiras nessas pesquisas são os medicamentos fitoterápicos. No Brasil, a Agência Nacional de Vigilância Sanitária (ANVISA) regulariza essas pesquisas e padroniza os procedimentos. A Resolução da Diretoria Colegiada (RDC) 48/2004, por exemplo, regulariza o registro de fitoterápicos. O Anacardium occidentale Linn está entre as plantas mais estudadas, devido às ações antibiótica e antiinflamatória de seus metabólitos secundários, principalmente taninos. Esta planta também possui a capacidade de impedir a formação da placa bacteriana bucal. Diante dessas ações, formas farmacêuticas acabadas (cremes e géis) foram desenvolvidas a partir do extrato bruto seco (EBS) das cascas do caule do A. occidentale Linn para registro de um novo fitomedicamento. Entretanto, testes pré-clínicos e clínicos devem ser feitos de acordo com a lei vigente. O presente trabalho avaliou a toxicidade subcrônica do EBS em cães sem raça definida (SRD). Os testes revelaram apenas hepatotoxicidade transitória demonstrada pela elevação dos níveis da alanina transaminase (ALT) e aspartato transaminase (AST).

Research on new medicaments has led to the development of efficient and non-toxic drugs. In Brazil, the Agência Nacional de Vigilância Sanitária (National Department of Sanitary Supervision - ANVISA) regularizes and standardizes the procedure. Anacardium occidentale is amongst the most researched plants, due to the antibiotics and antinflammatory properties of its secondary metabolites, mainly tannins and flavonoids. Furthermore, it prevents the dental plaque formation. On account of these actions, finished pharmaceutical forms (creams and gels) were developed from the crude dry extract (CDE) of A. occidentale Linn stem rinds, in order to register a new form. However, pre-clinical and clinical assays can be made in accordance with the effective law. The present work evaluated the subchronic toxicity of the CDE in dogs of indefinite pedigree. Data showed an increase of alanine transaminase (ALT) and aspartate transaminase (AST) levels, which may indicate transitory hepatotoxicity.