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By submitting this manuscript, each author certifies that they have made a direct and substantial contribution to the work reported in the manuscript. In this manuscript the conception, design, investigation, acquisition of data and analysis, interpretation of data and writing of the article were conducted by author Camila Bomfim de Sá under the guidance of professors Margareth de Fátima Formiga Melo Diniz, Hilzeth de Luna Freire Pessôa and Caliandra Maria Bezerra Luna Lima, who also approved the final version of the manuscript. Professor Damião Pergentino de Sousa and his student Mayara Castro de Morais performed the production, synthesis and chemical characterization of ethyl ferulate (EF). Professor Abrahão Alves de Oliveira Filho assessed the in silico tests. PhD student Andressa Brito Lira participated in the critical review of the text for important intellectual content and assisted in the in vitro antioxidant activity and cytotoxicity tests. Kardilandia Mendes de Oliveira participated in acute oral toxicity tests evaluating the biochemical parameters. Students, Tafaela Dias and Cinthia Rodrigues Melo also assisted in the acute oral toxicity testing and preparing of slides for histopathological analysis. Pathologist Alexandre Rolim da Paz analyzed the histopathology results. EF, a phenolic compound of the large class of phenylpropanoids, is derived from ferulic acid and is produced both naturally and synthetically. Its principal pharmacological activities are: anti-inflammatory and antioxidant activity. This study aimed to investigate the in silico, in vitro and in vivo toxicity and antioxidant activity of EF. The in silico prediction showed more than 20 biological activities as well as good absorption at the biological membranes and no theoretical toxicity. However, EF presented high environmental toxicity. EF presented low hemolytic potential and exerted protective activity for the erythrocyte membrane for only blood type O. EF presented antioxidant activity against H2O2 at all concentrations and all blood types, but no effect against phenylhydrazine, being unable to prevent its oxidative effects. In the acute nonclinical toxicological trial, the treated animals presented behavioral changes (e.g., sedation). Feed intake was higher for the 2000 mg/kg group, but with no significant difference in weight change. The biochemical parameters presented no differences between treated and control animals, and the organs remained intact with no change. Thus, EF presents a low toxic profile and this study provides important information about the toxicity of this compound, suggesting future safe use.

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The ethanolic extract of the leaves of Cissampelos sympodialis showed great pharmacological potential, with inflammatory and immunomodulatory activities, however, it showed some toxicological effects. Therefore, this study aims to verify the toxicological potential of alkaloids of the genus Cissampelos through in silico methodologies, to develop a method in LC-MS/MS verifying the presence of alkaloids in the infusion and to evaluate the toxicity of the infusion of the leaves of C. sympodialis when inhaled by Swiss mice. Results in silico showed that alkaloid 93 presented high toxicological potential along with the products of its metabolism. LC-MS/MS results showed that the infusion of the leaves of this plant contained the alkaloids warifteine and methylwarifteine. Finally, the in vivo toxicological analysis of the C. sympodialis infusion showed results, both in biochemistry, organ weights and histological analysis, that the infusion of C. sympodialis leaves presents a low toxicity.

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Cissus sicyoides (Cs) has been traditionally used to treat diabetes and belongs to the family Vitaceae, and is known as "vegetable insulin". This study aimed to evaluate the acute and chronic non-clinical toxicity of hydroalcoholic extract from the leaves of Cissus sicyoides (EHA-Cs). The acute test was performed in Wistar rats, administering a single dose of 40.5 mg/kg. Behavioral parameters for pharmacological screening were observed to detect signs of Central Nervous System activity; consumption of daily food and water, and weight evaluation. After day 14, the animals were euthanized and blood samples were collected for laboratory analyses of hematological and biochemical parameters. The chronic tests were administered in doses of 4.5, 13.5 and 40.5 mg/kg. The same parameters were observed together with body temperature, glucose, exploration activity (test on the open field), and motor activity (diagnostic tests on the Rota-rod). For the group given the highest dosage during the study, histopathological examinations of vital organs were performed. For acute toxicity, there were no CNS level effects, changes in water and food consumption, or hematologic parameters. However, there was a significant decrease in weight gain for the treated females. Biochemical analyses of the treated animals presented increased levels of AST (aspartate aminotransferase) in females, uric acid levels in females and males, and amylase in males. In the chronic toxicity tests, water consumption was higher for females (at the dosages of 13.5 and 40.5 mg/kg) and for males (at 40.5 mg/kg). At the dosages of 4.5 and 13.5 mg/kg, feed consumption increased for females, while for males it decreased along with weight gain. Blood analysis presented an increase in albumin and changes in erythrocytes and hemoglobin for males (at the dose of 13.5 mg/kg). Glycemia in females (13.5 mg/kg dose) was significantly less, presenting only slight drops at the other doses. The changes were reversible in the satellite group. EHA-Cs revealed a relatively low toxicity profile (at the popular use dose), and only small changes in hematological and biochemical parameters at the dose of 13.5 mg/kg (3x the popular use dosage). In addition, EHA-Cs did not promote histological changes in vital organs such as the heart, lungs, liver and kidneys.

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Phenolic compounds, among them isopropyl caffeate, possess antioxidant potential, but not without toxicity and/or adverse effects. The present study aimed to evaluate the antioxidant activity and toxicity of isopropyl caffeate through in silico, in vitro and in vivo testing. The results showed that isopropyl caffeate presents no significant theoretical risk of toxicity, with likely moderate bioactivity: GPCR binding, ion channel modulation, nuclear receptor binding, and enzyme inhibition. Isopropyl caffeate induced hemolysis only at the concentrations of 500 and 1000 µg/ml. We observed types A and O erythrocyte protection from osmotic stress, no oxidation of erythrocytes, and even sequestrator and antioxidant behavior. However, moderate toxicity, according to the classification of GHS, was demonstrated through depressant effects on the central nervous system, though there was no influence on water and food consumption or on weight gain, and it did present possible hepatoprotection. We conclude that the effects induced by isopropyl caffeate are due to its antioxidant activity, capable of preventing production of free radicals and oxidative stress, a promising molecule with pharmacological potential.

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Cissampelos sympodialis is a plant in northeastern Brazil used by the populace for treating respiratory diseases. Several studies have shown that ethanol leaf extracts have immunomodulatory and anti-inflammatory activities. Infusions are widely used, popular, and an ancient technique in traditional medicine, using hot water alone as the means of extraction. This study aimed to investigate acute toxicological potential of leaf infusions of Cissampelos sympodialis, when applied orally at a dose of 2000mg/kg to Rattus norvegicus, combined with an in silico study of 117 alkaloids present in the Cissampelos genus; five (5) of which were determined to have high toxicity (21, 8, 93, 32 and 88), and five (5) having both low toxicity (57, 77, 28, 25 and 67) and low liver metabolism. The in vivo toxicological evaluation showed that male water consumption decreased, and the feed intake decreased in both sexes. Yet, the figures as to change in weight gain of the animals were not statistically sufficient. As for the biochemical parameters, there was an increase in urea, and decreases in uric acid and AST in males. In females, there was a decrease in albumin and globulin which consequently leads to a total protein decrease. Despite biochemical changes suggestive of kidney damage, the histological sections revealed no kidney or liver changes. The results therefore indicate that despite presenting alkaloids which may be toxic, the genus Cissampelos, or leaf infusions of Cissampelos sympodialis, when applied orally at a dose of 2000mg/kg present low toxicity.

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ABSTRACTCissampelos sympodialis Eichler, Menispermaceae, is widely used by Indian tribes and folk medicine to treat various inflammatory disorders, including asthma. Clinical toxicological trials were made with the tea of C. sympodialis, a medicinal plant. The study took place at Lauro Wanderley Hospital/UFPB-PB, where seventeen healthy volunteers were chosen, among those six men and eleven women who orally ingested, during four weeks uninterruptedly, 150 ml of the tea, once a day. Before the first ingestion and after the last one, the participants were subjected to clinical and laboratorial tests for their overall conditions in order to analyze the toxicity of the plant. The results demonstrated that the volunteers neither experience clinical nor laboratorial alterations, as well as no significant adverse effects, apart from little change detected in their hematological tests. Nevertheless, none demonstrated any pathological conditions, just alterations of the normal human being physiology. Therefore, it is concluded that these data complement that obtained during pre-clinical studies and confirm a low toxicity of this plant.

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Introdução: A Dioclea grandiflora, conhecido como Mucunã de caroço,atua sobre o Sistema Nervoso Central, doenças da próstata e pedrasnos rins. Objetivo: Realizar estudo toxicológico não clínico agudo, emratos, com base na Instrução Normativa nº4, de 18 de junho de 2014da Agência Nacional de Vigilância Sanitária (ANVISA). Material eMétodos: Foram utilizados ratos Wistar, ambos os sexos, dose 2000mg/kg, via oral, do extrato etanólico bruto de Dioclea grandifloraadministrado a um grupo tratado e um grupo controle (veículo). Apósa administração, os parâmetros de comportamento foi observado por30, 60, 90, 120, 180 e 240 minutos, consumo de ração e água,parâmetros hematológicos e bioquímicos. O número de sobreviventescontabilizados para determinar a DL50. Resultados: Houve aumentoestatisticamente significativo no consumo de água (Controle:160,4±5,85; Tratado: 201,3±8,55) e ração das fêmeas (Controle:95,98±3,02; Tratado: 113,1±2,42) e aumento estatisticamentesignificativo no consumo de água (Controle: 236,7±6,43; Tratado:267,5±8,72) e ração dos machos (Controle: 152,4±2,51; Tratado:177,64,15). Aumento estatisticamente significativo na albumina dosmachos (Controle: 3,2±0,08; Tratado: 3,6±0,08), nas fêmeas reduziuestatisticamente significativo a fosfatase alcalina (Controle:198,5±18,81; Tratado: 99,97±16,02) , proteína total (Controle:7,85±0,09; Tratado: 6,85±0,24) e globulinas (Controle: 4,28±0,14;Tratado: 3,27±0,27). Diminuiu estatisticamente significativo o númerode hemácias nas fêmeas (Controle: 10,18±0,28; Tratado: 9,62±0,18).Conclusão: De acordo com os resultados a DL50 foi superior à dosetestada, porém são necessários estudos toxicológicos de longa duraçãopara atestar a segurança de seu uso...

Introduction: Dioclea grandiflora, known as Mucunã de caroço, acts onthe central nervous system, and against prostate disease and kidneystones. Objective: To perform a nonclinical acute toxicology study inrats following the Normative Instruction #4 as of June 18th 2014 of theNational Health Surveillance Agency (ANVISA). Material and Methods:Wistar rats of both sexes were used in the study. A dose of 2000 mg/kg of Dioclea grandiflora ethanolic extract was administered orally tothe test group. A control group using only the vehicle was also included.Then behavioral parameters were monitored for 30, 60, 90, 120, 180,and 240 minutes after feed and water intake, along with hematologicaland biochemical parameters. The number of survivors was recordedto determine the LD50. Results: There was a statistically significantincrease in water (Control: 160.4 ± 5.85; Treated: 201.3 ± 8.55), andfeed intake (Control: 95.98 ± 3.02; Treated: 113.1 ± 2.42) for femalerats; and a statistically significant increase in water (Control: 236.7 ±6.43; Treated: 267.5 ± 8.72) and feed intake (Control: 152.4 ± 2.51;Treated: 177.6 ± 4.15) for males. A statistically significant increase inalbumin levels was observed for males (Control: 3.2 ± 0.08; Treated:3.6 ± 0.08), and a decrease in alkaline phosphatase (Control: 198.5 ±18.81; Treated: 99.97 ± 16.02), total protein (Control: 7.85 ± 0.09;Treated: 6.85 ± 0.24) and globulin (Control: 4.28 ± 0.14; Treated: 3.27± 0.27) was found for females. Also, in females the number of redblood cells was found to be significantly reduced (Control: 10.18 ±0.28; Treated: 9.62 ± 0.18). Conclusion: According to the results, theLD50 value found was higher than that of the tested dose. Howeverlong-term toxicology studies are needed to further prove the safetyof the extract...

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Objetivo: Este trabalho teve como objetivo estabelecer valores de referência de parâmetros bioquímicos e hematológicos de roedores provenientes do Biotério Professor Thomas George do Laboratório de Tecnologia Farmacêutica (LTF) da Universidade Federal da Paraíba(UFPB). Metodologia: Avaliaram-se o perfil hematológico,hemograma, contagem de plaquetas, e a determinação bioquímica de vários constituintes plasmáticos: glicose, uréia,creatinina, colesterol total, triglicerídeos, ácido úrico,proteínas totais e frações, fosfatase alcalina, transaminases,sódio, potássio, cálcio e magnésio. Foram utilizados ratos Wistar albinos e camundongos Swiss, adultos, pesando 150a 350g e 15 a 35g, respectivamente, totalizando 40 para cada espécie animal (20 machos e 20 fêmeas). Resultados:Algumas variações foram detectadas entre os valores obtidos nos animais investigados e os parâmetros da literatura. Nos ratos, observaram-se valores inferiores para leucócitos e eosinófilos, e para camundongos obtiveram-se valores elevados para plaquetas, AST, ALT, fosfatase alcalina, globulina, íons cálcio e magnésio, em comparação com dados na literatura. Conclusão: Portanto, é importante oconhecimento e a divulgação dos valores de parâmetros fisiológicos dos animais de experimentação, considerando que podem exibir variações influenciadas por vários fatores que devem ser levados em consideração nas pesquisas experimentais, como sexo, linhagem e genótipo.

Objective: The objective of the present study was to establish reference values for the biochemical and hematological parameters of rodents from the Professor Thomas George animal laboratory of the Pharmaceutical Technology Laboratory, Federal University of Paraíba. Methodology: The parameters evaluated consisted of hematological profile withfull blood and platelet counts, as well as serum components including glucose, urea, creatinine, total cholesterol, triglycerides, uric acid, total protein and protein fractions, alkaline phosphatase, transaminases, sodium, potassium, calcium and magnesium. Adult albino Wistar rats and Swissmice (20 males and 20 females of each species), weighing150-350 grams and 15-35 grams, respectively, were used inthe study. Results: Variations were detected between values obtained in the animals and parameters established in theliterature. In rats, leukocyte and eosinophile counts werelower, while in mice, platelet counts, AST, ALT, alkalinephosphatase, globulin, calcium and magnesium levels werehigher compared to data published in the literature. Conclusion: In conclusion, the physiological parameters of experimental animals should be well established and made available in view of the variations that may exist as a result of various factors such as sex, lineage and geno type of the rodents that must be taken into consideration in experimental studies.

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Este trabalho teve como objetivo a avaliação da toxicidade aguda do extrato etanólico (EE) de partes aéreas de Jatropha gossypiifolia L., espécie vegetal muito usada na medicina popular, apesar de ser catalogada como planta tóxica. Ratos Wistar foram tratados por via oral com doses únicas do extrato (1,2 g/kg; 1,8 g/kg; 2,7 g/kg; 4,0 g/kg e 5,0 g/kg) e observados por 14 dias. Os principais sinais de toxicidade encontrados, em alguns animais, foram: ptose palpebral, perda de peso e paralisia do trem posterior. Outras alterações significativas ocorreram apenas em machos tratados com a dose de 5 g/kg: aumento dos níveis sangüíneos de creatinina, AST, sódio e potássio; diminuição dos níveis de uréia e albumina; leucopenia, além de discretas alterações na coloração e consistência de vísceras. A dose letal mediana (DL50) foi superior a 4,0 g/kg para machos e maior do que 5,0 g/kg para fêmeas. Estes resultados indicam uma toxicidade aguda oral relativamente baixa; contudo, ressaltam a necessidade da realização de estudos toxicológicos de longa duração com o EE de J. gossypiifolia L.

The aim of this work was the assessment of acute oral toxicity of the ethanol extract (EE) of the aerial parts of Jatropha gossypiifolia L. This plant is used in folk medicine despite its classification as a toxic plant. Wistar rats were treated per oralis with single doses of EE [1.2 g/kg; 1.8 g/kg; 2.7 g/kg; 4.0 g/kg and 5.0 g/kg (w.b.)] and observed for 14 days. The most important signs of toxicity were: ptosis; reduction of body weight and hindlimb paralysis. Other sgnificant alterations occurred only in males treated with 5.0 g/kg (w.b.): increase of creatinine, AST, sodium and potassium seric levels; reduction of urea and albumin; leukopenia and small alterations in color and consistence of viscera. The LD50 value was higher than 4.0 g/kg (w.b.) for males and higher than 5.0 g/kg (w.b) for females. These results indicate a low oral acute toxicity, in relative terms, however it shows the importance of long-term toxicological studies of the EE from J. gossypiifolia.

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Foram realizados determinações hematológicas (hemograma e contagem de plaquetas) e bioquímicas (glicose, uréia, creatinina, colesterol total, triglicerídeos, ácido úrico, proteínas totais e frações, fosfatase alcalina, transaminases, sódio, potássio, cálcio e magnésio) em camundongos Swiss e ratos Wistar, mantidos no Biotério do Laboratório de Tecnologia Farmacêutica da Universidade Federal da Paraíba. Para a obtenção desses parâmetros foi utlizado sangue obtido pela sangria do plexo braquial. Foram detectadas variações nos valores obtidos entre os animais machos e fêmeas investigados; também ficou evidenciado que existem diferenças nos parâmetros obtidos por outros autores.

Swiss mice and Wistar rats, maintained in the Bioterium of the Laboratory of Pharmaceutics Technology/UFPB, were analysed through haematological (hemogram and platelets) and biochemistry (glucose, urea, creatinine, total cholesterol, triglycerides, uric acid, total proteins and fractions, alkaline phosphatase, transaminases, sodium, potassium, calcium and magnesium) determinations. The blood analysed was obtained from the brachial plexus bloodletting. It was detected that there are variations in the parameters among males and females investigated and so in relation to the values obtained from other searchers.

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