RESUMEN

Malpighia emarginata has a high amount of vitamin C with pharmacological or food preservation potential. However, despite its wide use and application possibilities its toxicity in repeated doses and for a long time (6 months) has not yet been studied. In this context, this study aimed to evaluate the acute toxicity and repeated doses from fruits of this plant. The extract was produced with the pulp (EMe) of the lyophilized fruit and submitted to chromatographic and spectroscopic analysis (HPLC and ESI-IT-MSn). In the acute test, the EMe was administered orally and parenterally to rodents (mice and rats) for 14 days, at a dose of 2000 mg/kg. Subsequently, the repeated dose toxicity test was administered orally for 180 days at doses of 50, 300 or 1000 mg/kg. The HPLC assay revealed a high concentration of vitamin C (16.3%), and spectroscopic analyses pointed to the presence of five other polyphenolic compounds. In the acute test, the plant extract showed no apparent toxicity or lethality in rodents. The LD50 was estimated to be greater than 2000 mg/kg and falls into category 5 (low toxicity). In the repeated dose assay, there was no evidence of toxicity, and no differences were observed in water intake, food, weight development, or behavior of the animals in relation to the vehicle group (water). However, hematological and biochemical evaluations pointed out some nonconformities in the levels of cholesterol, leukocytes, and neutrophils of the male rats, but overall, these results did not reveal significant toxicity. Therefore, the Level of Unobserved Adverse Effects (NOAEL) was 1000 mg/kg. Together, the results suggest that the extract obtained from the fruits of M. emarginata does not present representative toxicity in rodents.

Asunto(s)

Frutas , Roedores , Ratas , Ratones , Animales , Frutas/toxicidad , Frutas/química , Ácido Ascórbico , Rutina , Extractos Vegetales , Agua , Pruebas de Toxicidad Aguda

RESUMEN

Toxicological studies are essential for developing novel medications in pharmaceutical industries including ayurvedic preparation. Hence, the present study is aimed to evaluate acute and 28-days repeated dose oral toxicity of anti-obesity polyherbal granules (PHG) in Sprague Dawley rats by OECD guidelines No 425 and 407, respectively. In an acute oral toxicity study, a single dose of 2 g/kg PHG was administered to rats and mortality, body weight, and clinical observations were noted for fourteen days. However, in the subacute oral toxicity study, the PHG was administered orally at doses of 0.3, 0.5 and 1 g/kg daily for 28 days to rats. Food intake and body weight were recorded weekly. On the 29th day, rats were sacrificed and subjected to haematological, biochemical, urine, necropsy, and histopathological analysis. In an acute oral toxicity study, no treatment-related, mortality, behavioral changes, and toxicity were found throughout fourteen days. Likewise, in the sub-acute toxicity study, no mortality and toxic effects were found in haematology, biochemical, urine, necropsy and histopathological analysis in rats for 28 days of treatment with PHG. Based on these results, the LD50 of PHG was found to be greater than 2 g/kg and the no-observed-adverse-effect level (NOAEL) of PHG for rats was found to be 0.5 g/kg/day. Thus, anti-obesity polyherbal granules showed a good safety profile in animal studies and can be considered an important agent for the clinical management of obesity.

---

Estudos toxicológicos são essenciais para o desenvolvimento de novos medicamentos nas indústrias farmacêuticas, incluindo a preparação aiurvédica. Assim, o presente estudo tem como objetivo avaliar a toxicidade oral aguda e de dose repetida de 28 dias de grânulos de polierva (PHG) antiobesidade em ratos Sprague Dawley pelas diretrizes da OCDE nº 425 e 407, respectivamente. Em um estudo de toxicidade oral aguda, uma dose única de 2 g/kg de PHG foi administrada a ratos, e mortalidade, peso corporal e observações clínicas foram observadas por 14 dias. No entanto, no estudo de toxicidade oral subaguda, o PHG foi administrado oralmente em doses de 0,3, 0,5 e 1 g/kg diariamente por 28 dias em ratos. A ingestão alimentar e o peso corporal foram registrados semanalmente. No 29º dia, os ratos foram sacrificados e submetidos a análises hematológicas, bioquímicas, de urina, necropsia e histopatológica. Em um estudo de toxicidade oral aguda, nenhuma mortalidade, alterações comportamentais e toxicidade relacionadas ao tratamento foram encontradas ao longo de 14 dias. Da mesma forma, no estudo de toxicidade subaguda, não foram encontrados mortalidade e efeitos tóxicos em análises hematológicas, bioquímicas, de urina, necropsia e histopatológica em ratos durante 28 dias de tratamento com PHG. Com base nesses resultados, verificou-se que a DL50 de PHG era superior a 2 g/kg e o nível de efeitos adversos não observados (NOAEL) de PHG para ratos foi de 0,5 g/kg/dia. Assim, os grânulos poliervais antiobesidade apresentaram um bom perfil de segurança em estudos com animais e podem ser considerados um importante agente para o manejo clínico da obesidade.

Asunto(s)

Animales , Ratas , Ratas Sprague-Dawley , Pruebas de Toxicidad Aguda , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Obesidad

RESUMEN

Only a small number of the many medicinally important species in the genus Psidium L. have had their safety assessed. Psidium glaziovianum, a plant native to Brazil, is reported to exert antinociceptive and anti-inflammatory effects; however, there are no apparent reports of long-term safety following administering of repeated doses. The aim of this study was to examine the effects of 28-day oral of treatment at 250, 500 or 1,000 mg/kg Psidium glaziovianum essential oil (PgEO) on behavioral and physiological parameters in male and female Swiss mice. First, PgEO was chemically characterized by gas chromatography mass spectrometry (GC-MS). The following parameters were examined: motor activity, body temperature, blood glucose, urine, hematology, biochemistry, histology, and oxidative stress. Characterization of PgEO revealed 48 components which were dominated by sesquiterpenes 1,8-cineol (24.29%), α-pinene (19.73%) and ß-pinene (17.31%). Data showed that PgEO treatment in mice increased activities of antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) without markedly affecting body weight, hematological or biochemical parameters, as well as water or food consumption. Administration of PgEO in repeated daily dosages over 28 days did not significantly alter exploratory or locomotor activities. Based upon our findings, PgEO administration daily for 28 days, exhibited low toxicity and absence of effects on the nervous system. Data demonstrated that PgEO produced hypoglycemic and antioxidant actions which need to be considered in safety assessment.

Asunto(s)

Aceites Volátiles , Psidium , Ratones , Animales , Aceites Volátiles/toxicidad , Antioxidantes/farmacología , Psidium/química , Extractos Vegetales/farmacología , Hojas de la Planta/química

RESUMEN

Purpose: This study evaluated the DNA damage caused by repeated doses of xylazine-ketamine and medetomidine-ketamine anesthesia in the liver and kidneys. Methods: In this study, 60 rats were used. The rats were divided into group 1 (xylazine-ketamine), and group 2 (medetomidine-ketamine), and these anesthetic combinations were administered to the rats at repeated doses with 30-min intervals. The effects of these anesthetic agents on the tumor necrosis factor-alpha gene for DNA damage were investigated. Results: According to the gene expression results, it was observed that a single dose of xylazine-ketamine was 2.9-fold expressed, while first and second repeat doses did not show significant changes in expression levels. However, in the case of the third repetition, it was observed to be 3.8-fold overexpressed. In the case of medetomidine-ketamine administration, it was observed that a single-dose application resulted in a 1.04-fold expression, while the first and the third repeat doses showed a significant down expression. The samples from the second repeat dose administration group were found to have insignificant levels of expression. Conclusions: This study can contribute to understanding the safe anesthetic combination in research and operations in which xylazine-ketamine and medetomidine-ketamine combinations are used.

Asunto(s)

Animales , Ratas , Xilazina/administración & dosificación , ADN , Perfilación de la Expresión Génica , Anestesia , Ketamina/administración & dosificación

RESUMEN

Objective: To determine the effectiveness of vaccination against SARS-CoV-2 in preventing illness and death from COVID-19 in Córdoba, Argentina, during the period from January through June 2021. Methods: A retrospective cohort study was conducted among 1,139,458 residents of the province of Córdoba. Multiple logistic regression models were developed to describe the relationship between vaccination and the presence of SARS-CoV-2 or death from COVID-19, while taking account of comorbidities and chronic disease risk factors and adjusting for sex and age. Results: Among the general population, having received one or two doses of vaccine reduced the risk of illness by 98.8% and 99.3%, respectively, and the risk of dying by 83% and 96.5%, respectively. Among those who developed COVID-19, the probability of dying was reduced by 57% and 80%, respectively. Regarding probability of death, risk increased with age, with being male, and with obesity, arterial hypertension, and diabetes mellitus. Conclusion: Vaccination is effective and protects against the risk of getting COVID-19, developing severe disease, or dying. Having obesity, arterial hypertension, or diabetes mellitus, in descending order, increases the risk of death.

---

Objetivo: Conhecer a eficácia da vacinação contra SARS-CoV-2 para prevenir o desenvolvimento de doença e morte por COVID-19 em Córdoba, Argentina, no período de janeiro a junho de 2021. Métodos: Foi realizado um estudo de coorte retrospectivo em 1.139.458 residentes da província de Córdoba. Foram construídos modelos de regressão logística múltipla que relacionaram a vacinação à presença de SARS-CoV-2 ou morte por COVID-19, considerando comorbidades e fatores de risco para doenças crônicas e ajustando por sexo e idade. Resultados: Ter recebido uma ou duas doses da vacina na população geral reduziu o risco de adoecimento em 98,8% e 99,3%, respectivamente; e de morrer, em 83% e 96,5%, respectivamente. Naqueles que contraíram COVID-19, a probabilidade de morrer foi reduzida em 57% e 80%, respectivamente. Em relação à probabilidade de morte, o risco aumentou com o aumento da idade e para o sexo masculino, ou com a presença de obesidade, hipertensão arterial ou diabetes mellitus. Conclusão: A vacinação é efetiva e protege contra a possibilidade de contrair COVID-19, desenvolver doença grave ou morrer. A presença de obesidade, hipertensão arterial ou diabetes mellitus, em ordem decrescente, aumenta o risco de morte.

RESUMEN

Meloxicam is the non-steroidal anti-inflammatory drug most used in small animals; however, studies on genotoxicity, oxidative stress, and histopathologic alterations in cardiac tissue are limited, especially at therapeutical doses used in these animals. This study evaluated the toxic effects caused by the treatment involving repeated low at higher doses of meloxicam in mice, by genotoxicity, oxidative stress, and histopathological parameters. Mice (CF1, male) received, by gavage, meloxicam at the therapeutic dose indicated for small animals (0.1 mg/kg) and at higher doses (0.5 and 1 mg/kg) for 28 days. Later, they were euthanized for blood and organ analysis. Oxidative stress was analyzed by the plasma ferric reduction capacity (FRAP) and catalase, and genotoxicity, by the comet assay and the micronucleus test. Heart, liver, lung, and kidney tissues were analyzed by the histology, and stomach and duodenum were analyzed with a magnifying glass. The relative weight of organs did not present significant alterations. However, congestion of duodenum vessels was observed at the three tested doses and caused hyperemia of stomach mucosa at 1 mg/kg. In the heart histology there was a reduction in the number of cardiomyocytes, accompanied by an increase in cell diameter (possible cell hypertrophy) dose-dependent. The highest tested dose of meloxicam also increased the DNA damage index, without alterations in the micronucleus test. Meloxicam did not affect the catalase activity but increased the FRAP (1 mg/kg). Meloxicam at the dose prescribed for small animals could potentially cause cardiac histopathologic alterations and genotoxic effects.

Asunto(s)

Daño del ADN , Corazón , Animales , Ensayo Cometa , Hígado , Masculino , Meloxicam/toxicidad , Ratones , Pruebas de Micronúcleos

RESUMEN

RESUMEN Objetivo. Conocer la efectividad de la vacunación contra SARS-CoV-2 para prevenir el desarrollo de enfermedad y muerte por COVID-19 en Córdoba, Argentina, en el periodo enero-junio de 2021. Métodos. Se llevó a cabo un estudio de cohorte retrospectivo en 1 139 458 residentes en la provincia de Córdoba. Se construyeron modelos de regresión logística múltiple que relacionaron la vacunación con la infección por SARS-CoV-2 o la muerte por COVID-19, considerando comorbilidades y factores de riesgo de enfermedades crónicas y ajustando por sexo y edad. Resultados. El haber recibido una o dos dosis de vacuna en la población general redujo el riesgo de enfermar un 98,8% y 99,3%, respectivamente; y de morir un 83% y 96,5%, respectivamente. En quienes contrajeron COVID-19, la probabilidad de morir se redujo en 57% y 80%, respectivamente. En cuanto a la probabilidad de muerte, el riesgo aumentó a medida que aumentaba la edad y con la pertenencia al sexo masculino o la presencia de obesidad, hipertensión arterial o diabetes mellitus. Conclusión. La vacunación es efectiva y protege contra la posibilidad de contraer COVID-19, desarrollar enfermedad grave o morir. Presentar obesidad, hipertensión arterial o diabetes mellitus, en orden decreciente, aumentan el riesgo de morir.

---

ABSTRACT Objective. To determine the effectiveness of vaccination against SARS-CoV-2 in preventing illness and death from COVID-19 in Córdoba, Argentina, during the period from January through June 2021. Methods. A retrospective cohort study was conducted among 1,139,458 residents of the province of Córdoba. Multiple logistic regression models were developed to describe the relationship between vaccination and the presence of SARS-CoV-2 or death from COVID-19, while taking account of comorbidities and chronic disease risk factors and adjusting for sex and age. Results. Among the general population, having received one or two doses of vaccine reduced the risk of illness by 98.8% and 99.3%, respectively, and the risk of dying by 83% and 96.5%, respectively. Among those who developed COVID-19, the probability of dying was reduced by 57% and 80%, respectively. Regarding probability of death, risk increased with age, with being male, and with obesity, arterial hypertension, and diabetes mellitus. Conclusion. Vaccination is effective and protects against the risk of getting COVID-19, developing severe disease, or dying. Having obesity, arterial hypertension, or diabetes mellitus, in descending order, increases the risk of death.

---

RESUMO Objetivo. Conhecer a eficácia da vacinação contra SARS-CoV-2 para prevenir o desenvolvimento de doença e morte por COVID-19 em Córdoba, Argentina, no período de janeiro a junho de 2021. Métodos. Foi realizado um estudo de coorte retrospectivo em 1.139.458 residentes da província de Córdoba. Foram construídos modelos de regressão logística múltipla que relacionaram a vacinação à presença de SARS-CoV-2 ou morte por COVID-19, considerando comorbidades e fatores de risco para doenças crônicas e ajustando por sexo e idade. Resultados. Ter recebido uma ou duas doses da vacina na população geral reduziu o risco de adoecimento em 98,8% e 99,3%, respectivamente; e de morrer, em 83% e 96,5%, respectivamente. Naqueles que contraíram COVID-19, a probabilidade de morrer foi reduzida em 57% e 80%, respectivamente. Em relação à probabilidade de morte, o risco aumentou com o aumento da idade e para o sexo masculino, ou com a presença de obesidade, hipertensão arterial ou diabetes mellitus. Conclusão. A vacinação é efetiva e protege contra a possibilidade de contrair COVID-19, desenvolver doença grave ou morrer. A presença de obesidade, hipertensão arterial ou diabetes mellitus, em ordem decrescente, aumenta o risco de morte.

RESUMEN

Modified titanium dioxide (m-TiO2NPs) is a novel photocatalytic nanomaterial. Its level of toxicity was evaluated to be used in photodynamic treatment for cervical cancer. In the toxicity studies (Irwin test, acute and repeated doses (10 days)), female albino Swiss Webster (CFW) mice, 28 days old were used; the m-TiO2NPs was administered in single 300, 600 and 5,000 mg/kg of body weight (b.w) doses injected in the peritoneal zone. No adverse events or mortality were produced. Daily intraperitoneal doses of 300 and 600 mg/kg b.w every 24 h for 10 days did not produce adverse effects or mortality. There were no abnormal clinical signs or behavioral changes (neurological or physiological) in any of the mice. All organs exhibited normal architecture, and histological studies determined that m-TiO2NPs does not produce changes in the cells or tissues. Based on the test results, it is concluded that the m-TiO2NPs has not a toxic effect in doses equal to or less than 5,000 mg/kg b.w.

RESUMEN

Purpose: A vaccine composition based on the extracellular domain of the human epidermal growth factor receptor 1 (HER1-ECD) and the combination of VSSP (very small size proteoliposomes) and Montanide ISA 51 adjuvants when used by intramuscular route, demonstrated promising results in preclinical studies. However, in order to avoid potential adverse events due to the use of Montanide, it is proposed to modify the vaccine formulation by using VSSP (very small size proteoliposomes) adjuvant alone, and to evaluate the quality of subcutaneously induced immune response. This study aimed to assess the immunotoxicological effects of HER1 vaccine in Cercopithecus aethiops.Materials and methods: Fifteen monkeys were randomized into four groups: Negative Control (Tris/NaCl, s.c.), Positive Control (200 µg HER1-ECD/VSSP/Montanide ISA-51 VG, i.m), Low Dose (200 µg HER1-ECD/VSSP/Tris NaCl, s.c.) and High Dose (800 µg HER1-ECD/VSSP/Tris NaCl, s.c). All monkeys received 7 doses and were daily inspected for clinical signs. Body weight, rectal temperature, cardiac and respiratory rates were measured during the study, and electrocardiographical and ophthalmological studies were performed. Humoral and cellular immune response and clinical pathology parameters were analyzed.Results: Animal's survival in the study was 100% (n = 15). Administration site reactions were observed in the Positive Control animals (n = 4). HER1 vaccine administered subcutaneously (High Dose Group) achieved good IgG antibody titers although lower than the Positive Control group, but with higher ability to inhibit HER1 phosphorylation. Conclusions: This suggests that the alternative of eliminating the use of Montanide in the HER1 vaccine preparation and the using subcutaneous route is feasible.

Asunto(s)

Vacunas contra el Cáncer/farmacología , Animales , Vacunas contra el Cáncer/efectos adversos , Chlorocebus aethiops , Evaluación Preclínica de Medicamentos , Receptores ErbB/efectos adversos , Receptores ErbB/farmacología , Femenino , Inyecciones Subcutáneas , Masculino

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Pilosocereus gounellei is a plant found in the Brazilian Caatinga and is popular due to its traditional uses in the treatment of inflammation. The present study was conducted to investigate the sub-acute toxicity of the saline extract from the stem of P. gounellei. AIM OF THE STUDY: To evaluate the 28-day oral toxicity (through behavioral, biochemical, hematological, and morphological analysis) and the antipyretic activity of the extract in mice. MATERIALS AND METHODS: A single oral dose (250, 500, and 1000 mg/kg) was administered daily over 28 consecutive days to male and female mice. Body weight, food and water intake, blood biochemical and hematological parameters, and urine composition were recorded. Histopathological examinations of the liver, kidney, spleen, lungs, and heart were performed and oxidative stress in the organs was evaluated by lipid peroxidation, superoxide dismutase (SOD), catalase (CAT), and nitrite analysis. The antipyretic effect of the 500 mg/kg dose was assessed using a yeast-induced pyrexia model. RESULTS: Oral administration of the extract over 28 days did not affect body weight gain, food and water consumption, body temperature, and hematological parameters in male and female mice. Blood glucose, total cholesterol, and triglyceride levels in male and female mice were reduced. Protein in the urine and histological alterations in both the liver and lungs were detected in male and female mice treated with the highest dose of the extract. SOD levels in the liver and the spleen increased significantly in both sexes, whereas lipid peroxidation decreased in the spleen of male mice. The extract also exerted an antipyretic effect after the first 60 min of the evaluation until the end of the observation duration (180 min). CONCLUSION: The saline extract from the stem of P. gounellei did not present significant toxic effects over 28 consecutive days and demonstrated antipyretic activity when administered orally. Moreover, the results suggest that the extract has potential hypoglycemic and hypolipidemic effects. Future studies are needed to investigate its pharmacological potential.

Asunto(s)

Antipiréticos/farmacología , Cactaceae/química , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Administración Oral , Animales , Antipiréticos/administración & dosificación , Antipiréticos/aislamiento & purificación , Glucemia/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Fiebre/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/aislamiento & purificación , Hipoglucemiantes/farmacología , Hipolipemiantes/administración & dosificación , Hipolipemiantes/aislamiento & purificación , Hipolipemiantes/farmacología , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratones , Extractos Vegetales/administración & dosificación , Extractos Vegetales/toxicidad , Superóxido Dismutasa/metabolismo , Factores de Tiempo , Pruebas de Toxicidad Subcrónica

RESUMEN

BACKGROUND: Species of Valeriana show sedative, hypnotic, anxiolytic, antidepressant and anti-inflammatory properties, which are associated with valepotriates. However, data about toxicity and safety of these compounds are still limited. The aim of this study was to investigate the toxicity of a valepotriate-enriched fraction (VAL) from Valeriana glechomifolia Meyer based on the Organization for Economic Cooperation and Development (OECD) guidelines 423 and 407. METHODS: In the acute study, CF1 mice were treated with a single dose of VAL (2000 mg/kg, p.o.) and observed for 14 days. In the repeated dose study, CF1 mice received single daily doses of VAL (30, 150 or 300 mg/kg, p.o.) or vehicle for 28 days. These doses were chosen based on previous results by our group and according to Guideline 407- OECD. RESULTS: The acute study allowed to classify VAL in the hazard category 5. The repeat-dose study has shown that VAL 300 mg/kg delayed weight gain and reduced food consumption in the first week, probably due to transient sedative effects. The other doses had no effect on animals' ponderal evolution. At the end of the treatment, all groups had equal body weight and food consumption. None of the doses altered any behavioral, urinary, biochemical, hematological, anatomic or histological parameters. CONCLUSION: A valepotriate-enriched fraction from Valeriana glechomifolia presents relatively low oral acute toxicity and does not induce evident toxicity after oral repeated treatment (at least up to 300 mg/kg) in mice.

Asunto(s)

Iridoides/toxicidad , Extractos Vegetales/toxicidad , Valeriana , Administración Oral , Animales , Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Masculino , Ratones , Pruebas de Toxicidad Aguda , Pruebas de Toxicidad Subaguda

RESUMEN

Neoflavonoids, which are classified as 4-arylcoumarin (neoflavone), 3,4-dihydro-4-arylcoumarin and neoflavene, have been the subject of a number of studies with respect to their therapeutic potential and, despite promising in vitro, ex vivo and in vivo pharmacological activities, there is a lack of studies demonstrating their toxicological properties. Therefore, this study aims to evaluate the acute (14 days) and repeated-dose (28 days) toxicity of synthetic neoflavonoid 7-acetoxy-4-aryl-3,4-dihydrocoumarin in Swiss mice through parameters related to changes in body weight, food and water intake, hematological and biochemical parameters. Toxicity studies using acute doses (300 and 2000 mg/kg) and repeated doses (250, 500 and 1000 mg/kg) orally were carried out as per Organization for Economic Co-operation and Development (OECD) guidelines 423 and 407, respectively. Based on the results of this study, treatment with 7-acetoxy-4-aryl-3,4-dihydrocoumarin was found to not cause clinical adverse symptoms and mortality in any animal used in the acute and repeated-dose toxicity study. In addition, no significant changes were observed in body weight and internal organs, food and water intake, hematological and biochemical parameters, compared to control group. Therefore, these results provide an initial understanding regarding the toxicity profile of 7-acetoxy-4-aryl-3,4-dihydrocoumarin, which can be considered a neoflavonoid with toxicity seen at doses higher than 2000 mg/kg in Swiss mice.

Asunto(s)

Cumarinas/toxicidad , Animales , Artemia/efectos de los fármacos , Femenino , Masculino , Ratones , Pruebas de Toxicidad Aguda , Pruebas de Toxicidad Subaguda

RESUMEN

1,8-cineole (eucalyptol) is widely used as an excipient in the pharmaceutical industry and as a food flavoring agent, thus providing significant potential for human exposure to the compound. We investigated the preclinical toxicity and reproductive toxicity of 1,8-cineole (CIN). In the repeated-doses toxicity study for 50 days, CIN (100, 500 or 1000 mg/kg) did not produce any signs of toxicity or deaths, but affected body weight gain during the first week of treatment. The hematological and biochemical profiles did not show significant differences except for increase in the MCV, platelet and urea levels or reduction in MCHC, MPV and alkaline phosphatase. Histopathological analysis showed weak changes in the lungs, liver, kidneys and uterus. In the reproductive toxicity, CIN (250, 500 or 1000 mg/kg) produced a reduction in body weight in pregnant rats treated during the pre-implantation or organogenesis periods. The highest doses induced a reduction in the mass of fetuses (pre-implantation) and dead fetuses (both periods) of pregnant rats. The results indicate that the treatment by repeated-doses showed occasional alterations in rats of both sexes. However, provide evidence that possibly 1,8-cineole presents maternal and fetal toxicity. This requires more detailed investigation to better characterize the toxic effects of this compound.

Asunto(s)

Antiinfecciosos/toxicidad , Ciclohexanoles/toxicidad , Feto/efectos de los fármacos , Exposición Materna/efectos adversos , Monoterpenos/toxicidad , Reproducción/efectos de los fármacos , Pruebas de Toxicidad/métodos , Animales , Peso Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Eucaliptol , Femenino , Humanos , Masculino , Tamaño de los Órganos/efectos de los fármacos , Embarazo , Ratas , Ratas Wistar

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Casearia sylvestris S.w (Salicaceae) is catalogued by the Brazilian Unified Health System as a plant of interest for the Brazilian population with the purpose of treating inflammatory disorders, such as pain and gastrointestinal disorders based on the folk use and some literature about efficacy; however, no toxicological studies concerned the safety of extract fluid of this plant have been reported. AIM OF THE STUDY: The present study was carried out to evaluate the acute and subchronic toxicity of the hydroethanolic extract fluid (FE) obtained from leaves of C. sylvestris in Wistar rats. MATERIALS AND METHODS: In the acute toxicity test three female Wistar rats were treated with a single dose of FE (2000 mg/kg) administered by oral gavage and observed for 14 days in order to identify signs of toxicity or death. In subchronic toxicity study animals received, by daily gavage three doses 60, 120 and 240 mg/kg of the FE of the plant for 28 and 90 days. The animals were observed daily for clinical signs and mortality. Body weight and food consumption were measured weekly and at the end of treatment were analysed hematological, biochemical and histopathological parameters. Also was analysed the cellularity of bone marrow and spleen. Moreover, phytochemical analysis by HPLC-PDA-ESI(+)/MS and CG/MS/EI was carried out to qualify the constituents of the extract. RESULTS: The results of acute study indicated that the LD50 is higher than 2000 mg/kg and at 28 and 90 day oral toxicity showed that there were no toxic effects detected in any of the parameters evaluated: body weight and relative organ weight, general behavioral changes, haematological and biochemical parameters and histopathological examination. The analysis by HPLC-PDA-ESI(+)/MS and CG/MS/EI identified the flavonoids rutin, quercetin and luteolin and also chlorogenic on the extract. CONCLUSION: Based on this study the hydroethanolic fluid extract of C. sylvestris could be safe even when used over a long period for therapeutic uses proposed by the Brazilian Unified Health System.

Asunto(s)

Casearia , Extractos Vegetales/toxicidad , Animales , Brasil , Femenino , Dosificación Letal Mediana , Masculino , Programas Nacionales de Salud , Hojas de la Planta , Plantas Medicinales , Ratas Wistar , Pruebas de Toxicidad Aguda , Pruebas de Toxicidad Subcrónica

RESUMEN

Polymeric nanocarriers have shown great promise as delivery systems. An alternative strategy has been to explore new delivery routes, such as intradermal (i.d.), that can be used for vaccines and patch-based drug delivery. Despite their many advantages, there are few toxicity studies, especially in vivo. We report a safety assessment of biodegradable poly(ɛ-caprolactone) lipid-core nanocapsules (LNC) with a mean size of 245±10nm following single and repeated intradermal injections to Wistar rats. Suspensions were prepared by interfacial deposition of polymer. The animals (n=6/group) received a single-dose of saline solution (1.2ml/kg) or LNC (7.2×10(12)LNC/kg), or repeated-doses of two controls, saline solution or Tween 80 (0.9ml/kg), or three different concentrations of LNC (1.8, 3.6, and 5.4×10(12)LNC/kg) for 28 consecutive days. Clinical and physiological signs and mortality were observed. Samples of urine, blood, and tissue were used to perform toxicological evaluation. There were no clinical signs of toxicity or mortality, but there was a slight decrease in the relative body weights in the Tween 80-treated group (p<0.01) after repeated administration. No histopathological alterations were observed in tissues or significant changes in blood and urinary biomarkers for tissue damage. Mild alterations in white blood cells count with increases in granulocytes in the Tween-80 group (p<0.05) were found. Genotoxicity was evaluated through the comet assay, and no statistical difference was observed among the groups. Therefore, we conclude that, under the conditions of these experiments, biodegradable LNC did not present appreciable toxicity after 28 consecutive days of intradermal administration and is promising for its future application in vaccines and patch-based devices for enhancing the delivery of drugs.

Asunto(s)

Nanocápsulas/administración & dosificación , Nanocápsulas/efectos adversos , Polímeros/administración & dosificación , Polímeros/análisis , Animales , Caproatos/administración & dosificación , Caproatos/efectos adversos , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/efectos adversos , Sistemas de Liberación de Medicamentos/métodos , Granulocitos/efectos de los fármacos , Inyecciones Intradérmicas/métodos , Lactonas/administración & dosificación , Lactonas/efectos adversos , Lípidos/administración & dosificación , Lípidos/efectos adversos , Masculino , Tamaño de la Partícula , Polisorbatos/administración & dosificación , Polisorbatos/efectos adversos , Ratas , Ratas Wistar , Suspensiones/administración & dosificación , Suspensiones/efectos adversos

RESUMEN

El extracto acuoso de Cecropia peltata es elaborado a partir de la planta denominada comúnmente yagruma o guarumo en Cuba. Este se emplea en la elaboración de tabletas con acción broncodilatadora. A la planta se le atribuyen propiedades antiasmáticas, antiblenorrágicas, analgésicas y cicatrizantes por solo citar algunas. El ensayo se realizó para evaluar las características tóxicas del extracto acuoso y sus efectos tóxicos en ratas. Se administró por vía oral, una dosis de 1000 mg de sólidos totales/kg de peso corporal durante 28 días. Los animales se observaron diariamente para detectar signos de toxicidad. Al finalizar el tratamiento se realizaron exámenes de hematología, de química sanguínea y la necropsia, para hacer el examen anatomopatológico e histopatológico correspondiente. Se pudo concluir que no se afectaron los indicadores hematológicos y de química sanguínea por causa del extracto ensayado. Tampoco hubo afectaciones en el peso corporal y el consumo de alimento. Los resultados obtenidos con el análisis histopatológico corroboraron todo lo antes expuesto.

---

The aqueous extract of Cecropia peltata is made from a plant commonly called yagruma or guarumo in Cuba. This extract is used in the manufacture of tablets with bronchodilator action. This plant has antiasthmatic, antiblennorrheal, analgesic, and healing effects, among others. The assay was carried out to assess the toxic features of this aqueous extract and its toxic effects in rats. An oral dose of 1000 mg of total solids/kg of body weight was administered for 28 days. The animals were daily observed to detect signs of toxicity. At the end of the treatment hematology and blood chemistry tests were done and necropsy was performed to make the corresponding anatomopathological and histopathological examination. No affectations were reported in body weight and food consumption. The results attained by the histopathological examination confirmed all the above.