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1.
Chemosphere ; 242: 125286, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31896186

RESUMO

Bisphenol-B (BPB), an analogue of bisphenol-A is used in the plastic industry. It has been found to leach from plastic containers leading to its contamination in canned food products. Moreover, it has also been detected in human samples such as sera and urine. BPB is recognized as a potential endocrine disrupting chemical owing to its estrogenic and anti-androgenic nature. Therefore, it was pertinent to study the effect of BPB exposure during the adolescence age (5-6 weeks old) in male mice. Weekly intraperitoneal injections of 5, 10 and 15% LD50 of BPB were given for 2 weeks to acute exposure groups and for 4 weeks to sub-acute exposure groups. BPB exposure induces change in enzymatic and non-enzymatic oxidative stress markers in sperm samples. DNA damage was also observed in sperm cells on acute and sub-acute exposures. Furthermore, BPB exposure led to a marked decline in sperm count and compromised sperm morphology. Computer assisted sperm analysis (CASA) revealed a significant decrease in sperm quality and progressive motility. Thus, both the acute and sub-acute exposures of adolescent male mice to BPB adversely affect the sperms' quality, functions and morphology.


Assuntos
Compostos Benzidrílicos/toxicidade , Dano ao DNA , Disruptores Endócrinos/toxicidade , Poluentes Ambientais/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Fenóis/toxicidade , Espermatozoides/efeitos dos fármacos , Fatores Etários , Animais , Humanos , Masculino , Camundongos , Oxirredução , Contagem de Espermatozoides , Espermatozoides/patologia , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda
2.
Regul Toxicol Pharmacol ; 108: 104472, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31494191

RESUMO

The OECD guideline 407 outlines the conduct of 28-day studies in rodents to detect systemic toxicity with focus on endocrine and immunotoxic effects. It was validated with the rat as preferred model species. Justification is required for other rodent species, as an increased variability is expected compared to the rat. We investigated the variability of organ weights in the mouse and compared this to data published for the rat in the validation report of test guideline 407. Furthermore, the influence of the immunotoxic model substance cyclophosphamide on spleen and thymus weights in the mouse in immunotoxicity studies (duration 28 days) is reported and discussed, an immunotoxic model substance was not included in the validation report. Historical control data were compiled for mouse studies performed according to OECD 407 and for immunotoxicity studies between 2008 and 2013 at BASF SE. For absolute weights, the coefficient of variation was determined for each study group and compared with the rat. Adrenal glands, ovaries and to lesser degree testes and prostate showed higher coefficients of variation in the mouse (most pronounced in adrenal glands in male animals: rat 5%-17%, CD1 mouse 20%-51%). Effects of cyclophosphamide were best detected measuring the thymus weight.


Assuntos
Variação Biológica Individual , Peso Corporal , Grupos Controle , Tamanho do Órgão , Testes de Toxicidade Subaguda , Glândulas Suprarrenais/anatomia & histologia , Glândulas Suprarrenais/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/anatomia & histologia , Encéfalo/efeitos dos fármacos , Ciclofosfamida/toxicidade , Feminino , Genitália/anatomia & histologia , Genitália/efeitos dos fármacos , Coração/anatomia & histologia , Coração/efeitos dos fármacos , Imunossupressores/toxicidade , Rim/anatomia & histologia , Rim/efeitos dos fármacos , Fígado/anatomia & histologia , Fígado/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Ratos , Especificidade da Espécie , Baço/anatomia & histologia , Baço/efeitos dos fármacos , Timo/anatomia & histologia , Timo/efeitos dos fármacos
3.
Nutrients ; 11(9)2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31500145

RESUMO

The objective of this study was to determine the acute (one single dose), subacute (14 days), and sub-chronic (90 days) toxicity of an aqueous virgin olive oil (VOO) extract rich in hydroxytyrosol in rats. For acute/subacute toxicity, rats were divided into three groups. The control group received distilled water (n = 9), another experimental group received a single dose of 300 mg/kg (n = 3), and a third group received one dose of 2000 mg/kg (n = 4) during 14 days. The sub-chronic study included 60rats distributed in three groups (n = 20: 10 males and 10 females) receiving daily different three doses of the VOO extract in the drinking water during 90 days: (1) 100 mg/kg, (2) 300 mg/kg, and (3) 1000 mg/kg. In parallel, a fourth additional group (n = 20: 10 males and 10 females) did not receive any extract (control group). Clinical signs, body weight, functional observations of sensory and motor reactivity, hematological and biochemical analyses, and macroscopic and microscopic histopathology were evaluated. No adverse effects were observed after the administration of the different doses of the hydroxytyrosol-rich VOO extract, which suggests that the enrichment of VOO in its phenolic compound is safe, and can be used as functional foods for the treatment of chronic degenerative diseases.


Assuntos
Azeite de Oliva/toxicidade , Álcool Feniletílico/análogos & derivados , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda , Testes de Toxicidade Subcrônica , Animais , Feminino , Masculino , Nível de Efeito Adverso não Observado , Álcool Feniletílico/toxicidade , Ratos Wistar , Medição de Risco , Fatores de Tempo
4.
BMC Complement Altern Med ; 19(1): 159, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31277639

RESUMO

BACKGROUND: Delayed gastric emptying play an important role in the pathology of functional dyspepsia. Owing to their functional attributes in alleviating the gastrointestinal disorders, single or polyherbal formulations have gained attention to treat the symptoms of functional dyspepsia. We have investigated the safety and efficacy of a novel formulation of Ferula asafoetida oleo resin and standardized Silybum marianum extract (Asdamarin). METHODS: The effect of asdamarin on delayed gastric emptying was investigated in Sprague Dawley rats using phenol red method. The acute and sub-acute oral toxicity was evaluated in wistar rats following OECD guidelines 425 and 407 respectively. The data were analyzed by one-way ANOVA using GraphPad Prism 5.0 software. RESULTS: Oral administration of Asdamarin dose-dependently improved the delay in gastric emptying as evident from the significant increase in the gastrointestinal transit time (p < 0.001). The LD50 of asdamarin was estimated to be more than 2000 mg/kg. Further, in the 28-day sub-acute toxicity study, the administration of 250, 500 and 1000 mg/kg of Asdamarin did not significantly altered the feed and water consuption, body weight change, biochemical and haematological parameters compared to control animals. Macroscopic and histopathological examination of vital organs revealed no toxic signs. CONCLUSION: The preliminary data from the present study provides the first evidence on the possible effectiveness of novel formulation of F. Asafoatida and S. marianum extracts in alleviating the associated symptoms of functional dyspepsia. The toxicity data indicated that Asdamarin can be considered safe up to 1000 mg/kg dose.


Assuntos
Dispepsia/tratamento farmacológico , Ferula/toxicidade , Esvaziamento Gástrico/efeitos dos fármacos , Cardo-Mariano/toxicidade , Animais , Avaliação Pré-Clínica de Medicamentos , Masculino , Fitoterapia , Ratos Sprague-Dawley , Ratos Wistar , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda
5.
Regul Toxicol Pharmacol ; 107: 104426, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31325534

RESUMO

Metal-organic frameworks (MOFs) nanoparticles are a class of porous crystalline materials constructed from the bonding metal ions or clusters linked with organic ligands to form frameworks. MIL-101(Cr), one of the most representative MOFs, is a three-dimensional chromium terephthalate-base porous material consisted of chromium (III)-trimers cross-linked by 1,4-benzene dicarboxylate. The present study focused on determining the safety of MIL-101(Cr) nanoparticle. The acute oral toxicity and 28-day oral toxicity in mice were investigated. An acute oral toxicity test of MIL-101(Cr) nanoparticle for female mice showed that no mortality or any significant change observed at 2000 mg/kg body weight. A dose-dependent 28-day oral toxicity evaluation of MIL-101(Cr) nanoparticle for male and female mice revealed no significant effects on mortality, feed consumption, body weight, organ weight, and behavior. Assessments of hematology, clinical biochemistry, and histopathology revealed no adverse effects in mice treated with MIL-101(Cr) nanoparticle (10-1000 mg/kg). These results suggest that MIL-101(Cr) nanoparticle has no significant acute and subacute toxicity. The no observed adverse effect level of MIL-101(Cr) nanoparticle was defined as at least 1000 mg/kg/day orally for 28 days for male and female mice.


Assuntos
Cromo/toxicidade , Estruturas Metalorgânicas/toxicidade , Nanopartículas/toxicidade , Animais , Feminino , Masculino , Camundongos Endogâmicos ICR , Nível de Efeito Adverso não Observado , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda
6.
Food Chem Toxicol ; 131: 110534, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31150781

RESUMO

Acute and subacute toxicities of the ethanol extract from Epigynum auritum (EAE) wereperformed by oral administration in pathogen-free mice. Acute toxicity study was performed at a single dose of 5000 mg/kg for 14 consecutive days, while subacute toxicity test was conducted by daily oral administration of EAE at doses of 312, 625, 1250, and 2500 mg/kg for 28 days. Acute toxicity study showed that LD50 of EAE was over 5000 mg/kg. The results of subacute toxicity showed no significant adverse effect of EAE at 312 mg/kg. Moreover, EAE exhibited toxicities to liver, spleen and kidney in mice determined by hematological, serum biochemical and histological analyses during daily oral administration of 1250 mg/kg and 2500 mg/kg EAE. The results revealed that the dose of EAE lower than 625 mg/kg can be regarded as safe.


Assuntos
Apocynaceae/química , Componentes Aéreos da Planta/química , Extratos Vegetais/toxicidade , Administração Oral , Animais , Relação Dose-Resposta a Droga , Etanol/química , Feminino , Rim/patologia , Fígado/patologia , Pulmão/patologia , Masculino , Camundongos Endogâmicos ICR , Extratos Vegetais/administração & dosagem , Extratos Vegetais/isolamento & purificação , Potássio/sangue , Sódio/sangue , Baço/patologia , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda
7.
J Ethnopharmacol ; 240: 111913, 2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31091465

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Gyejibokryeong-hwan is a traditional herbal medicine and is reported to have various pharmacological actions. Despite many reports of previous studies, there is limited scientific evidence concerning its safety and few drug-metabolism profiles to support the continued therapeutic application of Gyejibokryeong-hwan. AIM OF THE STUDY: The purpose of the present study was to investigate the acute and subacute toxicity profile of a Gyejibokryeong-hwan water extract (GBHW) in vivo, and its effects on the activities of drug-metabolizing enzymes in vitro. MATERIALS AND METHODS: Acute and subacute toxicity was evaluated by giving GBHW to rats. In a study of acute toxicity, the rats were given GBHW by single oral gavage administration at 0 and 5000 mg/kg. In a study of subacute toxicity, rats were given GBHW by oral gavage at 0, 1000, 2000, and 5000 mg/kg/day daily for 28 days. The activities of the major human microsomal cytochrome P450 (CYP450) and UDP-glucuronosyltransferase (UGT) isozymes were investigated using fluorescence- and luminescence-based enzyme assays in vitro, respectively. RESULTS: GBHW did not cause any mortality in the study of acute toxicity. In the study of subacute toxicity, GBHW at more than 2000 mg/kg/day was observed with minor changes in the absolute and relative organ weight, hematology, serum biochemistry and urinalysis parameters in rats of either sex. However, these changes were not considered to be important toxicologically. GBHW moderately inhibited the activities of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2E1, CYP3A4, and UGT1A1. CONCLUSIONS: Our present data suggest that GBHW does not cause toxicologically important adverse events at doses up to 2000 mg/kg/day in the 4-week repeated dose toxicity study and provide valuable information concerning its potential to interact with conventional medicine.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Glucuronosiltransferase/metabolismo , Extratos Vegetais/toxicidade , Animais , Feminino , Masculino , Ratos Sprague-Dawley , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda , Água/química
8.
Fitoterapia ; 136: 104161, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31048010

RESUMO

Ailanthone (AIL) has many biological activities including antimalarial, antiviral and anticancer. Our previous study also found that AIL targets p23 against castration-resistant prostate cancer. In this report, the preclinical safety of AIL was evaluated by acute toxicity, subacute toxicity and toxicokinetics in mice. In the acute toxicity study, the LD50 of AIL was 27.3 mg/kg, and severe pathological damages were mainly found in the liver and gastrointestinal tract. In the subacute toxicity study, mice were orally administered at doses of 2.5, 5 and 10 mg/kg for 28 days. The results showed the body weight of male mice in the 10 mg/kg dose group decreased, but that of female mice increased. Biochemical and histopathological analysis showed that AIL could cause steatohepatitis, splenomegaly, gastrointestinal mucosal damage and reproductive system abnormalities. In addition, AIL presented the reversible hematotoxicity. To determine the relationship between AIL toxicity and dose/exposure in vivo, toxicokinetics of AIL were carried out after a single oral dose of 15 mg/kg. The stomach was identified as the main target organ, followed by the intestine and kidney. On the basis of this study, the dose of 2.5 mg/kg had no adverse effect on mice. To sum up, this study is the first time to evaluate the systemic toxicity of AIL, which is useful for the further development of AIL.


Assuntos
Antineoplásicos Fitogênicos/toxicidade , Fígado/efeitos dos fármacos , Neoplasias de Próstata Resistentes à Castração , Quassinas/toxicidade , Animais , Antineoplásicos Fitogênicos/farmacologia , Feminino , Masculino , Camundongos , Quassinas/farmacologia , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda , Toxicocinética
9.
Toxins (Basel) ; 11(4)2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995739

RESUMO

The toxicity and related mechanisms of aflatoxin B1 (AFB1) and aflatoxin M1 (AFM1) in the mouse kidney were studied, and the role of l-proline in alleviating kidney damage was investigated. In a 28-day toxicity mouse model, thirty mice were divided into six groups: control (without treatment), l-proline group (10 g/kg body weight (b.w.)), AFB1 group (0.5 mg/kg b.w.), AFM1 (3.5 mg/kg b.w.), AFB1 + l-proline group and AFM1 + l-proline group. Kidney index and biochemical indicators were detected, and pathological staining was observed. Using a human embryonic kidney 293 (HEK 293) cell model, cell apoptosis rate and apoptotic proteins expressions were detected. The results showed that AFB1 and AFM1 activated pathways related with oxidative stress and caused kidney injury; l-proline significantly alleviated abnormal expressions of biochemical parameters and pathological kidney damage, as well as excessive cell apoptosis in the AF-treated models. Moreover, proline dehydrogenase (PRODH) was verified to regulate the levels of l-proline and downstream apoptotic factors (Bax, Bcl-2, and cleaved Caspase-3) compared with the control (p < 0.05). In conclusion, l-proline could protect mouse kidneys from AFB1 and AFM1 through alleviating oxidative damage and decreasing downstream apoptosis, which deserves further research and development.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Aflatoxina B1/toxicidade , Aflatoxina M1/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Prolina/uso terapêutico , Substâncias Protetoras/uso terapêutico , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/patologia , Animais , Apoptose/efeitos dos fármacos , Células HEK293 , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Camundongos , Prolina/farmacologia , Prolina Oxidase/metabolismo , Substâncias Protetoras/farmacologia , Testes de Toxicidade Subaguda
10.
J Ethnopharmacol ; 238: 111852, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-30954616

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Yongdamsagan-tang, a traditional herbal formula, is used widely for the treatment of inflammatory and viral diseases. However, the safety of Yongdamsagan-tang has not been established. AIM OF THE STUDY: To evaluate the subacute toxicity of Yongdamsagan-tang water extract (YSTE) in Crl:CD Sprague Dawley rats. MATERIALS AND METHODS: We evaluated the subacute toxicity of YSTE in male and female Crl:CD Sprague Dawley rats (n = 5 per group). Rats were treated with YSTE at doses of 0, 1000, 2000 and 5000 mg/kg administered once a day by oral gavage for 4 weeks. RESULTS: There were no significant changes in mortality, body weight, food intake, serum biochemistry, or results of hematology and urinalysis after YSTE administration. However, all rats treated with 5000 mg/kg/day YSTE exhibited excessive salivation and discolored urine. Necropsy findings showed discoloration in the liver of both male (n = 1) and female (n = 3) rats treated with 5000 mg/kg/day YSTE, and an increase in the relative weights of kidney and liver was also found in male rats treated with 5000 mg/kg/day. In addition, decreases in serum creatinine, total bilirubin, alanine transaminase, and alkaline phosphatase were observed in male rats treated with 2000 or 5000 mg/kg/day YSTE. CONCLUSIONS: Abnormalities in some rats are considered to be independent of YSTE toxicity. Therefore, the results suggest that oral administration of YSTE in rats for 4 weeks is safe at doses of up to 5000 mg/kg/day.


Assuntos
Medicamentos de Ervas Chinesas/toxicidade , Administração Oral , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Animais , Bilirrubina/sangue , Creatinina/sangue , Feminino , Rim/efeitos dos fármacos , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos Sprague-Dawley , Testes de Toxicidade Subaguda
11.
Indian J Pharmacol ; 51(1): 25-30, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31031464

RESUMO

OBJECTIVE: Bauhinia purpurea (BP) Linn. (Caesalpiniaceae) is a plant of great medicinal importance and has been used since ancient times for treating many inflammatory conditions including arthritis. This study investigates the anti-arthritic potential of the hydroalcoholic extract from the stem bark of BP. MATERIALS AND METHODS: The anti-inflammatory and anti-arthritic activity of BP at various doses was used to evaluate its anti-inflammatory activity and anti-arthritic activity. Serum of arthritic rats was collected at day 21 for detecting serum cytokines level and to evaluate the effect of BP on its serum level. Furthermore, the safety of BP was evaluated in acute (5 days) and subacute (28 days) toxicity study in rats. RESULTS: There was a significant inhibition (P < 0.01) in paw edema at a different time scale with different doses of BP (50, 100, and 200 mg/kg). BP also demonstrated dose-dependent anti-arthritic activity on all observation days (3, 7, 14, and 21). In addition, there was also a significant decrease (P < 0.01) in oxidative stress markers, circulating pro-inflammatory cytokine (tumor necrosis factor alpha from 45.91 to 37.44, interleukin-1 (IL-1) ß from 18.24 to 16.06, and IL-6 from 69.77 to 58.44) and an increase in anti-inflammatory cytokine (IL-10 from 8.07 to 12.07) levels. BP was found to be safe with an oral LD50 value of >2 g/kg in acute toxicity study and also no toxicological effect was observed in the oral subacute toxicity study. CONCLUSION: This study demonstrates that BP bark possesses anti-arthritic activity potential and confirm its folklore use in the treatment of inflammatory conditions.


Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Bauhinia , Extratos Vegetais/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Artrite Experimental/sangue , Citocinas/sangue , Edema/sangue , Edema/tratamento farmacológico , Masculino , Extratos Vegetais/farmacologia , Ratos Wistar , Testes de Toxicidade Subaguda
12.
Regul Toxicol Pharmacol ; 105: 30-35, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30922892

RESUMO

The United States Environmental Protection Agency (USEPA), as well as other international regulatory agencies, require pesticide registrants to submit toxicity data that are used to conduct ecological risk assessments. While the USEPA has required both an acute oral and sub-acute dietary test in birds, trends in the use of data from these tests over the past 20 years have suggested that the avian sub-acute dietary test generally does not contribute to risk assessment conclusions. To address this question, a retrospective analysis was conducted to evaluate 119 pesticides with publicly available ecological risk assessments that were registered into commerce between 1998 and 2017. New pesticides (i.e., registered in the United States within the past 20 years) were chosen for the retrospective analysis to show utility of these tests for modern pesticide chemistries. Risk quotient (RQ) values (a point estimate of exposure divided by a deterministic toxicity endpoint) from the avian acute oral and dietary tests, as well as risk assessment conclusions, were compared to determine which test(s) drove the risk assessment findings. The RQ values were chosen as the data point for comparison in order to assess total risk (i.e., exposure and toxicity). After comparing RQ values from avian acute oral versus sub-acute dietary tests, there was only one case in which an avian sub-acute dietary RQ was greater than the acute oral RQ. Thus, the sub-acute dietary test did not identify risk in greater than 99% (118 out of 119) of chemicals based on results that either the acute oral RQ was higher than the sub-acute dietary RQ, or both the acute oral and the subacute dietary tests did not generate an RQ value of concern. For the one exception, both the oral and sub-acute RQ values were greater than the USEPA's level of concern for endangered species. Based on the results of the retrospective analysis, it is concluded that in most cases avian risk can confidently be assessed without conducting the sub-acute dietary test.


Assuntos
Praguicidas/toxicidade , Medição de Risco/métodos , Testes de Toxicidade Aguda/métodos , Testes de Toxicidade Subaguda/métodos , Animais , Aves , Dieta , Exposição Ambiental/efeitos adversos , Estudos Retrospectivos , Estados Unidos
13.
Toxins (Basel) ; 11(2)2019 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-30736354

RESUMO

Tetrodotoxin (TTX) is one of the most potent naturally occurring neurotoxins. InitiallyTTX was associated with human food intoxications in Japan, but nowadays, concerns about thehuman health risks posed by TTX have increased in Europe after the identification of the toxin infish, marine gastropods, and bivalves captured in European waters. Even when TTX monitoring isnot currently performed in Europe, an acute oral no observable effect level (NOAEL) of 75 µg/kghas been recently established but, to date, no studies evaluating the chronic oral toxicity of TTXhave been released, even when EFSA has highlighted the need for them. Thus, in this work, thechronic effects of low oral TTX doses (below the acute lethal dose 50) were evaluated followinginternationally adopted guidelines. The results presented here demonstrate that low oral doses ofTTX have deleterious effects on renal and cardiac tissues. Moreover, alterations in bloodbiochemistry parameters, urine production, and urinalysis data were already detected at the oraldose of 75 µg/kg after the 28 days exposure. Thus, the data presented here constitute an initialapproach for the chronic evaluation of the in vivo toxicity of tetrodotoxin after its ingestion throughcontaminated fishery products.


Assuntos
Cardiotoxicidade , Coração/efeitos dos fármacos , Rim/efeitos dos fármacos , Tetrodotoxina/toxicidade , Administração Oral , Animais , Feminino , Camundongos , Testes de Toxicidade Subaguda
14.
J Ethnopharmacol ; 236: 42-49, 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-30771517

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Tetrapleura tetrapteura Taub. is a leguminous multipurpose tree (Fabaceae) indigenous to tropical Africa. Fruits, seeds and stem bark infusions or decoctions of Tetrapleura tetrapteura Taub. are used to treat many diseases, such as gastric ulcer, rheumatism, malaria, hypertension and hyperlipidemia. AIM OF THE STUDY: This work was conducted to evaluate the acute and sub-acute toxicity of the aqueous extract of Tetrapleura tetrapteura Taub. (AETT) stem barks. MATERIALS AND METHODS: For the study of acute toxicity, single oral doses of 2000 mg/kg and 5000 mg/kg of AETT were administrated to male and female Balb/c mice, followed by observation of mice for 14 days. In the study of sub-acute toxicity, 48 albino wistar rats of both genders were randomly divided into six groups of 8 animals and they were daily and orally administrated for twenty eight days. The animal's test groups and satellite test group were administrated with the extract (AETT) at the doses of 100, 200 and 400 mg/kg and 400 mg/kg respectively. On the 29th day, the satellite group (control 2 and satellite 400 mg/kg) were observed during two more weeks. General behavior changes, mortality, body weight of animal, water and food intake were recorded during the study period. At the end of each treatment period, biochemical and hematological parameters were measured and histological examinations of liver and kidneys sections performed. RESULTS: Up to 5000 mg/kg single dose administration of AETT for fourteen days registered no death animal. In sub-acute study, no mortality was recorded in various experimental groups. Significant reductions in body weight, water and food intake were recorded in all treated animals. Relative weights of liver, kidneys, stomach, spleen, lungs, and heart of treated animals remained unchanged. Significant increases in the number of platelets as well as in serum ALAT level were recorded in rats, treated with 400 mg/kg of AETT. Female rat liver histology showed, at a higher dose of AETT, a slight congestion of portal vein. CONCLUSION: AETT is safe after therapeutic (200 mg/kg) or acute administration. Higher dose (400 mg/kg) administered for longer period showed signs of liver toxicity.


Assuntos
Casca de Planta/química , Extratos Vegetais/toxicidade , Caules de Planta/química , Tetrapleura/química , Animais , Rim/efeitos dos fármacos , Dose Letal Mediana , Fígado/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Extratos Vegetais/isolamento & purificação , Ratos Wistar , Testes de Toxicidade , Testes de Toxicidade Subaguda
15.
Drug Dev Ind Pharm ; 45(5): 839-851, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30702966

RESUMO

BACKGROUND: Multiple sclerosis (MS) is one of the most severe autoimmune disorder of the central nervous system (CNS). OBJECTIVE: The present research work was aimed to formulate and investigate teriflunomide (TFM)-loaded intranasal (i.n.) nanostructured lipid carriers (NLC) for the treatment of multiple sclerosis (MS). METHODS: The TFM-loaded NLC (TFM-NLC) nanoparticles were prepared by melt emulsification ultrasonication method using biodegradable and biocompatible polymers. The Box-Behnken statistical design was applied to optimize the formulation. The optimized NLC formulation was subjected to evaluate for particle size, entrapment efficiency (%), in vitro and ex vivo permeation. The safety and efficacy of optimized formulations were demonstrated using pharmacodynamic, subacute toxicity and hepatotoxicity data. RESULTS: Experimental data demonstrated that optimized NLC formulation (F17) showed significant size (99.82 ± 1.36 nm), zeta potential (-22.29 ± 1.8 mV) and % entrapment efficiency (83.39 ± 1.24%). Alternatively, ex vivo permeation of TFM mucoadhesive NLC (TFM-MNLC) and TFM-NLC was observed 830 ± 7.6 and 651 ± 9.8 µg/cm2, respectively. Whereas, TFM-MNLC shows around 2.0-folds more Jss than the TFM-NLC. Finally, TFM-MNLC (i.n.) formulation produced the rapid remyelination in cuprizone-treated animals and decreases the number of entries in open compartment of EPM when compared with negative control and TFM-NLC (oral) animals. Simultaneously, the nanoformulation did not reflect any gross changes in hepatic biomarkers and subacute toxicity when compared with control. CONCLUSIONS: Hence it can be inferred that the nose-to-brain delivery of TFM-MNLC can be considered as effective and safe delivery for brain disorders.


Assuntos
Crotonatos/administração & dosagem , Portadores de Fármacos/química , Esclerose Múltipla/tratamento farmacológico , Toluidinas/administração & dosagem , Adesividade , Administração Intranasal , Administração Oral , Animais , Materiais Biocompatíveis/química , Biomarcadores/metabolismo , Crotonatos/farmacocinética , Cuprizona/toxicidade , Modelos Animais de Doenças , Liberação Controlada de Fármacos , Humanos , Lipídeos/química , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Esclerose Múltipla/induzido quimicamente , Nanopartículas/química , Mucosa Nasal/metabolismo , Tamanho da Partícula , Polímeros/química , Ratos , Ratos Wistar , Ovinos , Toluidinas/farmacocinética , Testes de Toxicidade Subaguda
16.
Regul Toxicol Pharmacol ; 102: 90-94, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30611818

RESUMO

Increased concerns about ensuring food safety motivated the exploration of insects as an alternative protein source. It has been reported that Tenebrio molitor (TM) and Pachymerus nucleorum (PN) larvae are great protein and lipid sources with considerable concentrations of unsaturated fatty acids. Nevertheless, little attention has been given to the safety of using these edible insects. This study presents the acute and subacute (28 days) toxicological profile of the oil extracted from TM and PN larvae. The TM and PN larvae have all essential amino acids and the oils extracted from them fostered a considerable reduction in cholesterol and glucose levels of the treated rats. The experiments suggested that the TM and PN oils have low toxicity since it did not cause any lethality as well as no changes in hematological parameters.


Assuntos
Besouros , Larva , Óleos/toxicidade , Aminoácidos/análise , Animais , Feminino , Inocuidade dos Alimentos , Humanos , Ratos Wistar , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda
17.
Regul Toxicol Pharmacol ; 102: 79-89, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30611819

RESUMO

Intra-articular (IA) injection of hyaluronic acid (HA) in combination with nonsteroidal anti-inflammatory drugs, such as ketorolac (KL), have been clinically investigated to provide more rapid and profound pain relief in patients with osteoarthritis. However, its safety, local tolerance, and potential for pharmacokinetic interaction have not been assessed. In this study, the pharmacokinetics and toxicity of a combination of HA and KL were evaluated in normal rats following four-week repeated-dose injection. Rats received HA or KL alone at 4 mg/kg or 16 mg/kg, respectively, or HA/KL combination at 4/4 mg/kg, 4/8 mg/kg, or 4/16 mg/kg on a weekly basis. The rats exhibited temporal, reversible changes in hematology, serum chemistry, and urinalysis caused primarily by KL treatment. No deleterious effects were observed on the joint following repeated IA HA/KL administration, which showed only minimal to mild levels of temporary inflammatory changes in synovial membrane. The plasma KL level following IA injection rose as fast as that of intra-muscular injection, with no alteration with the co-administered HA. In conclusion, repeated IA administration of HA/KL combination was tolerated well in normal rats, encouraging future studies of IA injection of HA/KL combination on osteoarthritis-induced animal models and even patients.


Assuntos
Anti-Inflamatórios não Esteroides , Ácido Hialurônico , Cetorolaco , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/toxicidade , Combinação de Medicamentos , Interações Medicamentosas , Feminino , Ácido Hialurônico/farmacocinética , Ácido Hialurônico/toxicidade , Injeções Intra-Articulares , Cetorolaco/farmacocinética , Cetorolaco/toxicidade , Masculino , Ratos Wistar , Caracteres Sexuais , Testes de Toxicidade Subaguda
18.
J Ethnopharmacol ; 230: 109-116, 2019 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-30381238

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Piper cernuum Vell (Piperaceae) is a native species from Atlantic rain forest, popularly known as pariparoba. Its leaves have been commonly used by rural and urban communities from State of São Paulo, Brazil, to treat pain (orally and topically), and hepatic and renal complications. AIM OF THE STUDY: In this study we evaluated the acute and sub-acute toxicity, genotoxicity and mutagenicity of hydroalcoholic extract obtained from P. cernuum leaf using in vivo and in vitro methods. MATERIAL AND METHODS: In the acute toxicity study, mice were orally treated with P. cernuum extract (2000 mg/kg, p.o.). General behavior and mortality were observed for up to 14 days. In the sub-acute toxicity study, P. cernuum extract was given orally as a single administration to the rats at doses of 50 or 250 mg/kg/day, for 28 days. General behavior, body weight, biochemical and hematological parameters, organ coefficients and pathological morphology were analyzed. The P. cernuum mutagenicity was evaluated using mammalian cell micronucleus assay. Additionally, in vitro toxicity profile of the extract was assessed through cytotoxicity, hemolytic activity, and genotoxicity assay. RESULTS: Data from comet assay demonstrates that high concentrations of P. cernuum extract induce genotoxicity. However, no evidence of hemolytic, cytotoxic or mutagenicity activity was found. In addition, the acute and sub-acute toxicity studies did not show significant changes in body weight, general behavior, hematology and biochemical parameters, organ weight and liver and kidney histopathological analysis. CONCLUSIONS: Together, the results herein obtained indicate that P. cernuum leaves extract did not present significant toxicity when administered to male or female rats. Additionally, no significant alteration in hematological, biochemical and morphological parameters were observed. Data obtained in vitro shows that extract did not present cytotoxicity and mutagenicity. However, the extract induces in vitro genotoxicity, but in high concentration. Further studies are necessary to evaluate the safety of long-term exposure to P. cernuum leaves extract added to in vivo genotoxicity.


Assuntos
Piper , Extratos Vegetais/toxicidade , Animais , Sobrevivência Celular/efeitos dos fármacos , Ensaio Cometa , Eritrócitos/efeitos dos fármacos , Feminino , Hemólise/efeitos dos fármacos , Células Hep G2 , Humanos , Masculino , Testes para Micronúcleos , Folhas de Planta , Ratos Wistar , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda
19.
Physiol Res ; 68(1): 67-74, 2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30433801

RESUMO

Current study evaluated the synergistic potential of propolis and vitamin E against sub-acute toxicity of aluminum chloride on different biochemical parameters and liver histology. Swiss albino mice (n=42) were randomly divided into seven groups. Group I received 0.2 ml of 0.9 % saline solution, Group II received Propolis (50 mg/kg b.w.), Group III received vitamin E (150 mg/kg b.w.), Group IV received AlCl(3) 50 mg/kg b.w., Group V received AlCl(3) + Propolis, Group VI received AlCl(3) + vitamin E and Group VII received AlCl(3) + propolis + vitamin E. Blood and tissue samples were collected after 7 and 21 days. The body weight of the animals significantly increased in all groups except Group IV. The concentration of serum high density lipoprotein significantly decreased in Group IV and increased in Group V, VI and VII. The level of aspartate aminotransferase, alanine transferase, alkaline phosphatase, triglycerides, total cholesterol, and low density lipoprotein significantly increased in AlCl(3) treated group and increased in Group V, VI and VII. Tissue sections were processed and stained by hematoxylin and eosin. Group II showed cellular necrosis. Group V, VI showed decreased number of vacuolization, sinusoidal spacing and macrophage cell infiltration. Group VI showed less degenerative changes in the third week. Vitamin E and propolis in combination with Al provides more protection against AlCl(3) induced toxicity.


Assuntos
Cloreto de Alumínio/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Fígado/efeitos dos fármacos , Própole/administração & dosagem , Testes de Toxicidade Subaguda/métodos , Vitamina E/administração & dosagem , Animais , Doença Hepática Induzida por Substâncias e Drogas/patologia , Sinergismo Farmacológico , Fígado/patologia , Camundongos , Própole/isolamento & purificação , Distribuição Aleatória
20.
Regul Toxicol Pharmacol ; 101: 71-78, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30465803

RESUMO

Gallic acid is a phenolic acid ubiquitously present in numerous medicinal plants and food beverages. Gallic acid is also a potent anti-oxidant phytochemical possessing numerous medicinal potentials against various ailments such as diabetes, hypercholesterolemia and other life-threatening diseases including malignancy. Present study was aimed to evaluate acute and sub-acute toxicity of gallic acid in albino mice. The primary aim of the study was to investigate gallic acid prompted PPAR-α/γ activation associated adverse events. Acute toxicity of gallic acid was determined in albino mice and 28-days sub-acute toxicity study was carried out in male and female albino mice at three dose levels, 100, 300 and 900 mg/kg/day, p.o. LD50 of gallic acid was found to be greater than 2000 mg/kg in mice. Hematological investigation did not show any alteration in transaminases and other blood homeostasis parameters. Gross necropsy showed non-significant alteration upon gallic acid administration. Histopathological finding suggested no significant alteration in tissue histology with slight fatty cells in bone marrow indicating non-significant bone marrow suppression, also no obvious effect was observed on hematological parameters. High dose of gallic acid (900 mg/kg/day) for 28 days did not produce any significant alteration in morphological and behavioral parameters. Histopathological finding also supports safety of gallic acid in mice.


Assuntos
Ácido Gálico/toxicidade , Animais , Feminino , Dose Letal Mediana , Masculino , Camundongos , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda
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