RESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Piper methysticum G. Forst, popularly known as kava, is a traditional medicinal plant native from South Pacific islands and widely used to treat anxiety, depression and stress. The psychoactive properties are related to the kavalactones, mainly kavain. AIM OF THE STUDY: To evaluate the biopharmaceutical properties of synthetic kavain and when present in kava dried extracts by means of equilibrium solubility and intestinal permeability studies in the Caco-2 cell model. MATERIALS AND METHODS: The equilibrium solubility of kavain was performed using a shake flask incubator at 37 °C in different media at physiological pH range (1.2-6.8). The intestinal permeability of kavain evaluated in Caco-2 cells in the presence and absence of the P-glycoprotein inhibitor verapamil. Kavain concentrations were determined by reversed phase high performance liquid chromatography (HPLC). RESULTS: HPLC methods were developed and fully validated for kavain quantitation. Kavain demonstrated low solubility and the pH of the aqueous media did not affect its solubility. Kavain was found to be highly permeable and efflux of kavain mediated by P-glycoprotein was not significant during intestinal permeation. CONCLUSION: The results of biopharmaceutical studies provided useful information for predicting availability of kavain from the gastrointestinal tract and this compound was ranked as BCS Class II, exhibiting dissolution rate-limited absorption.
Assuntos
Kava , Células CACO-2 , Humanos , Kava/química , Lactonas/farmacologia , Permeabilidade , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Pironas , SolubilidadeRESUMO
Piper methysticum G. Forst, popularly known as kava, is a traditional medicinal plant widely used for the treatment of anxiety and insomnia. The aim of this study was to investigate new therapeutic applications of this plant. Nociceptive response induced by heat (hot-plate) was used as pain model. Susceptibility of different strains to kava ethanolic dried extracts was evaluated by broth microdilution method. Acute oral toxicity was performed according to Organisation for Economic Cooperation and Development (OECD) guideline. Administration of kava dried extracts and kavain inhibited the nociceptive response in the hot-plate model and did not affect the time mice spent in the rota-rod apparatus. The samples showed no significant antibacterial activity, however slight antifungal activity was verified. The extracts may be considered of low oral acute toxicity. Kava extracts exhibited promising antinociceptive activity in model of nociceptive pain, which should be deeper explored as a new therapeutic application of kava.
Assuntos
Anti-Infecciosos , Kava , Analgésicos/farmacologia , Animais , Camundongos , Extratos Vegetais/farmacologia , PironasRESUMO
INTRODUCTION: Dried extracts of Piper methysticum G. Forst, also known as kava, has been widely used due to its anxiolytic and sedative properties. In order to assure the quality of these extracts, it is essential to accurately quantify kavalactones, known as the active principle. OBJECTIVES: To develop and validate an analytical method for the simultaneous quantification of six major kavalactones (kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin and demethoxyyangonin) in kava extracts, comparing multi-standards and single standard validation approaches. MATERIAL AND METHODS: Separation was performed using a C18 column, water/methanol/acetonitrile/2-propanol (66:07:09:18 v/v/v/v) and detection at 245 and 350 nm. A full method validation was performed, employing analytical standards for each compound. Commercial kava dried extracts were assayed and the results obtained using the method validated for six kavalactone standards were compared with those obtained when only kavain was used as standard. RESULTS: Baseline resolution for all kavalactones was obtained in short run time (15 min). Although the total kavalactone content varied between samples, a similar distribution profile was observed. When the method validated with all six analytical standards was compared to the calibration using only kavain standard, kavalactone contents were considerably different (from 7.57 to 36.53%). CONCLUSION: The obtained results demonstrate the importance of a validated method using individual kavalactone standards for the effective quality control of kava extracts. In a next step, the method needs to be adapted to also include flavokavin B (FKB), as an important authentication marker to distinguish between the accepted variety "noble Kava" and the toxic "two-day Kava".
Assuntos
Kava , Calibragem , Lactonas , Extratos Vegetais , Raízes de PlantasRESUMO
A simple and fast bioanalytical method for the quantification of kavain in mice plasma was developed using liquid chromatography (LC)-tandem mass spectrometry (MS/MS). A full method validation was performed, according to regulatory guidelines, employing isotopically labeled kavain as the internal standard (racemic-kavain-d3). For the quantification, [M+H]+ was formed using an electrospray ionization (ESI) source in the positive ion mode and multiple reaction monitoring (MRM) was employed using a quadrupole-linear ion trap (4000 QTRAP®) instrument. The monitored MRM transitions were 231.0 â 115.1 and 231.0 â 152.8 for kavain; and 234.2 â 199.2 for the internal standard. A linear response was obtained at the concentration range of 10 to 200 ng/mL with intra- and inter-day variations within the acceptable criteria for all quality control samples. After validation, the method was successfully applied for the quantification of kavain in mice plasma after oral administration of the kavain standard and Kava-kava extract. The plasma concentration over time results were applied for a pharmacokinetics study. The obtained pharmacokinetic parameters indicated a considerably higher bioavailability for kavain when Kava-kava extract was administered due to a pharmacokinetic synergism between the analyte and the other compounds present in the extract.
Assuntos
Cromatografia Líquida/métodos , Pironas/sangue , Pironas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Animais , Feminino , Kava , Limite de Detecção , Modelos Lineares , Camundongos , Extratos Vegetais , Pironas/química , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Self-medication and the belief that herbal products are free of health risks are common in Brazil. The kava (Piper methysticum), known for its anxiolytic action, has a widespread popular use. Hepatotoxicity of kava is reported, including cases of liver transplantation and death. The kava had its use prohibited or restricted in countries like Germany, France, among others. Toxicity may be related to overdosage; however, factors such as botanical characteristics of the plant, the harvesting, storage, and production process may be associated with the development of hepatotoxic substances, such as triggering idiosyncratic reactions. HYPOTHESIS: In this case, there is a suspicion that the toxicide is intrinsic to the drug; however, the possibility of adulterants and contaminants must be ruled out. STUDY DESIGN: This study reports the case of a patient who, after using the herbal kava for 52 days, evolved into acute liver failure and liver transplantation. METHODS: The data were collected directly with the patient and compared with their clinical records. Causality was determined through the RUCAM algorithm. In addition, a phytochemical analysis of the drug used was performed. RESULTS: According to the patient's report, there is no evidence of overdosage. Results from RUCAM algorithm infer causality between liver damage and the use of kava. The analysis chemical constituents did not find any possible contaminants and major changes in the active compounds. Seven months after transplantation, the patient is well and continues to be followed up by a medical team. CONCLUSION: Our investigation indicates that there was kava-induced hepatotoxicity at standard dosages. In Brazil, self-medication by herbal medicines is frequent and many patients and health professionals do not know the risks associated with their use. Diagnosing and notifying cases in which plants and herbal medicine induce liver damage is of paramount importance to increase the knowledge about DILI and to prevent or treat similar cases quickly.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Kava/efeitos adversos , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/terapia , Transplante de Fígado , Ansiolíticos/efeitos adversos , Brasil , Doença Hepática Induzida por Substâncias e Drogas/terapia , Feminino , Alemanha , Medicina Herbária , Humanos , Kava/toxicidade , Falência Hepática Aguda/etiologia , Medicina Tradicional/efeitos adversos , Pessoa de Meia-IdadeRESUMO
Angiogenesis is implicated in the development of a variety of pathological processes, most commonly cancer. It is essential for tumor growth and metastasis, making it an important cancer therapeutic target. Naturally occurring substances have led to the discovery of anticancer agents. Flavokawain B (FKB), a chalcone isolated from the root extracts of kava-kava plant, inhibits proliferation and causes apoptosis in vitro and in vivo of various cancer cell lines. The antimetastatic potential of FKB has also been suggested. In our study, we confirm the antiangiogenic action of FKB in vitro and, for the first time, demonstrate its strong antiangiogenic activity in vivo, using a zebrafish model. Our data show that FKB inhibits human brain endothelial cell (HUVEC) migration and tube formation even at very low and non-toxic concentrations. Moreover, FKB blocks angiogenesis process in zebrafish, with a dramatic reduction of subintestinal vein formation in a dose-dependent manner. Flavokawain B at the concentration of 2.5 µg/mL did not exhibit any toxic effects in zebrafish larvae and caused a markedly or complete obliteration of subintestinal vein formation. Our findings along with previously published data confirm that FKB may form the basis for creating an additional tool in the treatment of cancer and other neovascularization-related diseases. Copyright © 2017 John Wiley & Sons, Ltd.
Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Flavonoides/farmacologia , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Chalcona/farmacologia , Embrião não Mamífero/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Kava/química , Extratos Vegetais/farmacologia , Raízes de Plantas/química , Peixe-ZebraRESUMO
To evaluate in vivo the association of hypericum Hypericum perforatum, valerian Valeriana officinalis and kava Piper methysticum with analgesia by assessing their effects in reducing orofacial pain as well as the possible hepatic, hematologic and biochemical alterations induced by regular administration of these extracts. METHODS: Orofacial pain was induced in mice with the administration of 2.5% formalin in the upper lip. After 60 min, the animals were treated with saline, carbamazepine and hydroalcoholic plant extracts. The nociceptive intensity was determined by the timing at which the animal remained rubbing the injected area. To assess the hepatotoxic effect, mice were chronically treated for 25 days with saline, carbamazepine and hydroalcoholic extract. The animals were euthanized and the liver weighed, followed by a differential count of leukocytes and measurement of alanine transaminase and alkaline phosphatase. RESULTS: The evaluation of analgesic activity in phase 1 reduced the time of rubbing compared to the control by 86% 0.05 mL/10 g and 76% 0.10 mL/10 g. In phase 2, the extracts reduced rubbing time by 94% and 85%, respectively. In the evaluation of alkaline phosphatase, the groups treated with extracts at doses of 0.05 mL/10 g and 0.1 mL/10 g increased by 16.1% and 9.5% compared to the control group and a reduction of 8.5% and 9.1% in the evaluation of alanine transaminase respectively. It was demonstrated that in the differential counts showed an increase in eosinophils in the treated group with 0.05 mL/10 g. CONCLUSIONS: The use of hydroalcoholic extract of the associated plants reduced the orofacial formalin-induced pain with better results than carbamazepine, at both the neural conductor level of pain phase 1 and in inflammatory or later pain phase 2 without presenting hepatotoxicity. The observed eosinophilia is suggestive of a phenomenon called hormesis...
Assuntos
Animais , Ratos , Dor Facial , Hypericum/efeitos adversos , Kava/efeitos adversos , Transtornos da Articulação Temporomandibular , Valeriana/efeitos adversos , Analgésicos/uso terapêutico , Anestésicos/uso terapêutico , Extratos Vegetais/uso terapêutico , Fitoterapia , Plantas Medicinais , Preparações de Plantas/uso terapêuticoRESUMO
O extrato seco da raiz de Piper methysticum L. f. Forster (PIPERACEAE), a kava-kava, é usado no tratamento de diversos problemas envolvendo ansiedade como um dos sintomas. Por não causar dependência, sedação e ter ação ansiolítica, muitas pessoas têm recorrido a kava-kava para auxiliá-las no emagrecimento. Isto pode levar ao consumo indiscriminado da planta e acarretar riscos, pois todo medicamento fitoterápico deve respeitar limites de doses. Um risco na utilização de plantas medicinais é a toxicidade e, dentro deste, a mutagenicidade. Como a mutagenicidade está relacionada com a carcinogenicidade torna-se importante testar este potencial na kava-kava. Assim, o objetivo deste trabalho foi avaliar o potencial mutagênico do extrato seco da raiz de P. methysticum no sistema methG1 em Aspergillus nidulans. A linhagem utilizada foi a biA1methG1, auxotrófica para biotina e metionina. Conídios dormentes de colônias crescidas por cinco dias foram tratados com soluções da kava-kava nas concentrações de 0,35 mg mL-1 e 3,5 mg mL-1, e depois de 24h, semeados em meio seletivo contendo metionina, para análise dos sobreviventes, e sem metionina, para a análise dos mutantes. Os números de sobreviventes e mutantes dos tratamentos foram comparados aos do controle. Os resultados indicaram que o extrato da raiz da kava-kava é mutagênica, pois a freqüência de mutação dos tratamentos foi maior que da mutação espontânea, porém não ocorrendo diferença significativa entre as doses.
The dry root extract of Piper methysticum L. f. Forster (Piperaceae), kava-kava, is used as to treat several health problems involving anxiety symptoms. As it causes no addiction, it can be applied as a sedative and anxiolytic. Many people have been relying on kava-kava as an auxiliary treatment. This can lead to an indiscriminate plant consumption and lead to risks, because all phytotherapic medications must observe dosage limits. One risk in the folk medicinal plant use is toxicity, and within it, mutagenicity. As mutagenicity is closely related to carcinogenicity, it is important to test the kava-kava mutagenicity potential. Thus, the purpose of this work was to test the mutagenicity of the dry root extract of P. methysticum in the methG1 system of Aspergillus nidulans. The bia1methG1 lineage, which is auxotrophic for biotine and methione, was used. Conidia from five-day-old colonies were collected and treated with kava-kava solutions at 0.35 mg mL-1 and 3.5 mg mL-1 concentrations and, after 24h, they were planted in selective growth medium with and without methione, in order to analyze the survivors and mutants, respectively. The number of survivors and mutants analyzed under effect of the treatments was compared with the control. The results indicated that the kava-kava dry root extract is mutagenic, since the mutation frequency of the treatments was higher than spontaneous mutation, however, there were no differences between the doses tested.
Assuntos
Kava/efeitos adversos , Mutagênicos/análise , Aspergillus nidulans/isolamento & purificação , Extratos Vegetais , Raízes de PlantasRESUMO
Kava is an anxiolytic herbal medicine used in the treatment of sleep and anxiety disorders. Some cases of kava-induced hepatotoxicity have been reported in the literature leading to its banishment in most countries worldwide. Clinically, the spectrum ranged from transient elevations of liver enzyme levels to fulminant liver failure and death. Liver transplantation was performed in a few cases. This paper provides a review of the currently available literature on kava-related toxic hepatitis which may result from its use, discusses the possible mechanisms for the potentially severe hepatotoxicity and describes some features which must be considered when adverse liver effects seem to be associated to kava administration. In conclusion, the incidence of kava toxicity on the liver remains to be investigated; however, some concerns before or during kava use are important, due to the possibility of severe liver dysfunction.
Kava é um fitoterápico ansiolítico usado no tratamento da insônia e da ansiedade. Alguns casos de hepatotoxicidade induzida pela kava foram relatados na literatura, levando à proibição do seu uso em muitos países. Clinicamente, o espectro dessas alterações variou de elevações transitórias das enzimas hepáticas, até à falência hepática fulminante e morte. Em alguns casos, realizou-se transplante hepático. Este artigo revisa a literatura atual sobre a hepatite tóxica provavelmente relacionada à kava, discute os possíveis mecanismos responsáveis pela hepatotoxicidade potencialmente grave e descreve alguns aspectos que devem ser considerados quando eventos adversos hepáticos pareçam ser relacionados à administração dessa substância. Conclui-se que a possível toxicidade hepática pela kava ainda deve ser investigada e que algumas medidas antes e durante o seu uso são importantes, dada a possibilidade de disfunção hepática grave.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Kava , Piperaceae/toxicidadeRESUMO
A utilização de produtos naturais na medicina popular é milenar e persiste até os dias atuais. Entretanto, a idéia de que estes produtos são isentos de toxicidade torna o uso de medicamentos fitoterápicos cada vez maior e indiscriminado. Este trabalho trata de uma revisão sobre as interações que podem ocorrer com a utilização concomitante de Hypericum perforatum L. (erva de são joão) e Piper methysticum F. (kava-kava) com fármacos, podendo levar a sérios efeitos tóxicos, incluindo a fatalidade.
Natural products in popular medicine have been used for hundreds of years and persists nowadays. However, the idea that these products are exempted of toxicity turns the use of herbs to be larger and indiscriminate. This work is a review of interactions that can happen with concomitant use of Hypericum perforatum L. (St. John's wort) and Piper methysticum F. (kava-kava) with medicines that can result in serious toxicological effects including fate.
RESUMO
A Kava kava ( Piper methysticum Forst), pertencente à família das Piperaceae, é utilizada para diminuir a ansiedade e medo e tratar distúrbios comportamentais. É um fitoterápico utilizado em vários países, entretanto pouco se sabe, sobre seus efeitos no desenvolvimento embrionário. O presente trabalho avaliou o possível efeito teratogênico da formulação fitoterápica contendo Piper methysticum Forst durante o período de organogênese em ratas Wistar. As ratas foram tratadas com 0mg.kg 1 (controle), 5mg.kg 1 ; 35mg.kg 1 e 50mg.kg 1 da preparação fitoterápica, por via oral, do 6 ao 21 dia de prenhez. Os resultados revelaram ausência de toxicidade sistêmica e reprodutiva nas variáveis avaliadas, fundamentados pela ausência de alterações no desenvolvimento ponderal, consumos de ração e água, na massa relativa dos órgãos, nas reabsorções embrionárias, na massa corporal, na vitalidade, no número de fetos por progenitora e nas alterações macroscópicas externas e esqueléticas dos fetos. Adicionalmente as enzimas alanina aminotrasferase (ALT) e fosfatase alcalina (FA) foram determinadas no soro das ratas tratadas, para avaliar o possível efeito hepatotóxico da preparação fitoterápica. Não houve alteração das enzimas ALT e FA, bem como alterações histopatólógicas do fígado das ratas, não confirmando a hepatotoxicidade. Conclui-se que o fitoterápico kava kava, nas doses testadas, não
RESUMO
A Kava kava ( Piper methysticum Forst), pertencente à família das Piperaceae, é utilizada para diminuir a ansiedade e medo e tratar distúrbios comportamentais. É um fitoterápico utilizado em vários países, entretanto pouco se sabe, sobre seus efeitos no desenvolvimento embrionário. O presente trabalho avaliou o possível efeito teratogênico da formulação fitoterápica contendo Piper methysticum Forst durante o período de organogênese em ratas Wistar. As ratas foram tratadas com 0mg.kg 1 (controle), 5mg.kg 1 ; 35mg.kg 1 e 50mg.kg 1 da preparação fitoterápica, por via oral, do 6 ao 21 dia de prenhez. Os resultados revelaram ausência de toxicidade sistêmica e reprodutiva nas variáveis avaliadas, fundamentados pela ausência de alterações no desenvolvimento ponderal, consumos de ração e água, na massa relativa dos órgãos, nas reabsorções embrionárias, na massa corporal, na vitalidade, no número de fetos por progenitora e nas alterações macroscópicas externas e esqueléticas dos fetos. Adicionalmente as enzimas alanina aminotrasferase (ALT) e fosfatase alcalina (FA) foram determinadas no soro das ratas tratadas, para avaliar o possível efeito hepatotóxico da preparação fitoterápica. Não houve alteração das enzimas ALT e FA, bem como alterações histopatólógicas do fígado das ratas, não confirmando a hepatotoxicidade. Conclui-se que o fitoterápico kava kava, nas doses testadas, não
RESUMO
A Kava kava ( Piper methysticum Forst), pertencente à família das Piperaceae, é utilizada para diminuir a ansiedade e medo e tratar distúrbios comportamentais. É um fitoterápico utilizado em vários países, entretanto pouco se sabe, sobre seus efeitos no desenvolvimento embrionário. O presente trabalho avaliou o possível efeito teratogênico da formulação fitoterápica contendo Piper methysticum Forst durante o período de organogênese em ratas Wistar. As ratas foram tratadas com 0mg.kg 1 (controle), 5mg.kg 1 ; 35mg.kg 1 e 50mg.kg 1 da preparação fitoterápica, por via oral, do 6 ao 21 dia de prenhez. Os resultados revelaram ausência de toxicidade sistêmica e reprodutiva nas variáveis avaliadas, fundamentados pela ausência de alterações no desenvolvimento ponderal, consumos de ração e água, na massa relativa dos órgãos, nas reabsorções embrionárias, na massa corporal, na vitalidade, no número de fetos por progenitora e nas alterações macroscópicas externas e esqueléticas dos fetos. Adicionalmente as enzimas alanina aminotrasferase (ALT) e fosfatase alcalina (FA) foram determinadas no soro das ratas tratadas, para avaliar o possível efeito hepatotóxico da preparação fitoterápica. Não houve alteração das enzimas ALT e FA, bem como alterações histopatólógicas do fígado das ratas, não confirmando a hepatotoxicidade. Conclui-se que o fitoterápico kava kava, nas doses testadas, não