卡瓦胡椒提取物对经“群居-隔离-抑郁”处理后小鸡的抗焦虑作用

卡瓦胡椒Pipper methysticum提取物的抗焦虑作用是否与其总卡瓦内酯含量或其中1种或多种主要的卡瓦内酯类成分有关还不清楚。作者采用小鸡抗焦虑筛选模型——“群居-隔离-抑郁”进行了3个试验：1)4个卡瓦胡椒提取物(卡瓦内酯含量分别为12．8％、21.1％、53．2％和100．0％)或赋形剂给隔离     

药食两用植物卡瓦胡椒

卡瓦胡椒（Piper methysticum Forst）是胡椒科多年生直立灌木类药用植物，产于南太平洋诸岛，野生或栽培，根和根茎入药，有效部位为脂溶性树脂部分。卡瓦胡椒的主要药效成分是卡瓦内酯（Kavalactones）、麻醉椒碱、醉椒素（Kawain）等，能够双向调节神经递质，具有抗焦虑和抑郁、镇静催眠、局部麻醉、抗惊厥等多种作用，且未观察到药物依赖性。早在1990年，德国联邦卫生局就批准卡瓦胡椒用于治疗焦虑症，目前英国将其收入《植物药典》，美国将其收入新版《美国药典》，欧美许多国家将卡瓦胡椒列为非处方药或处方药。     

英取缔含卡瓦胡椒的食品和补充剂

从2003年1月13日起,英国取缔所有含卡瓦胡椒成分的食品和饮食补充剂。出于对卡瓦胡椒肝毒性的担心,从2001年12月开始生产商们被迫从市场上收回含卡瓦胡椒     

天然抗焦虑药卡瓦胡椒的研究进展

目前草药疗法已在世界各国比较流行。欧亚许多国家用多种草药制成补充物投入市场,并进行了大量研究;据统计,在美国大约有500万人服用各种草药制成的补充物。胡椒科植物卡瓦胡椒具有抗焦虑、镇静催眠、局部麻醉、抗惊厥等作用,且未观察到药物依赖性等优点而在欧洲和美国临床应用。1990年,德国联邦卫生局批准卡瓦胡椒治疗焦虑症。本文介绍卡瓦胡椒的化学成分、临床前药理学研究、临床研究和药物耐受性及不良反应等研究进展。     

卡瓦胡椒—南太平洋最受人崇敬的植物药

介绍了南太平洋植物药卡瓦胡椒的原植物、化学成分、药理作用和临床应用等。     

卡瓦胡椒水提取物不影响大鼠的肝功能

为研究卡瓦胡椒Piper methysticumForst.f.水提取物对肝功能的影响,作者进行了以下试验。将干燥卡瓦胡椒根于水中超声提取2次,每次20 min。提取液离心,上清液冷冻,制成干粉备用。雄性 SD 大鼠随机分为6组,4个给药组分别给予卡瓦内酯类200mg/(kg·d)(2或4周)和500 mg/(kg·d)     

卡瓦胡椒的安全性遭受质疑

继广防己和关木通导致肾毒案之后,卡瓦胡椒的安全问题再次引起了世界的关注。数十例肝毒性报告导致欧美很多国家政府采取了断然措施,或暂停销售或干脆取缔,尽管权威科学家们认为卡瓦胡椒与肝毒性间的因果关系证据不足。本文将这一事件的起因、各国政府的对策和权威专家的观点呈献给读者,旨在引起国内消费者、生产者、药品监督管理部门和医生的关注或采取应对措施。     

卡瓦胡椒的医药用途

卡瓦胡椒含有多种内酯成分,具有抗痉挛、抗颠痫、局部麻醉、抗炎及抑制真菌等多种生理药理效应。临床上用于治疗精神抑郁症、神经衰弱、多发性关节炎、疼痛、消化不良等。并可能用作毒品替代物,但无成瘾性。     

卡瓦胡椒的医药用途

卡瓦胡椒含有多种内酯成分,具有抗痉挛、抗癫痫、局部麻醉、抗炎及抑制真菌等多种生理药理效应.临床上用于治疗精神抑郁症、神经衰弱、多发性关节炎、疼痛、消化不良等.并可能用作毒品替代物,但无成瘾性.     

卡瓦胡椒叶和根提取物的肝细胞毒性

卡瓦胡椒 Piper methysticum Forster 提取物具有广泛用途,如用其制造饮料,诱导松弛或睡眠,治疗焦虑症等多种疾病,且认为其应用是安全的。但近几年有报道记载,几例患者的肝损害与他们摄食卡瓦胡椒有关。为探讨卡瓦胡椒产生肝损害的可能作用机制,制备和分析了该植物根的甲醇和丙酮提取     

Liver toxicity and carcinogenicity in F344/N rats and B6C3F1 mice exposed to Kava Kava

Kava Kava is an herbal supplement used as an alternative to antianxiety drugs. Although some reports suggest an association of Kava Kava with hepatotoxicity , it continues to be used in the United States due to lack of toxicity characterization. In these studies F344/N rats and B6C3F1 mice were administered Kava Kava extract orally by gavage in corn oil for two weeks, thirteen weeks or two years. Results from prechronic studies administered Kava Kava at 0.125 to 2 g/kg body weight revealed dose-related increases in liver weights and incidences of hepatocellular hypertrophy. In the chronic studies, there were dose-related increases in the incidences of hepatocellular hypertrophy in rats and mice administered Kava Kava for up to 1 g/kg body weight. This was accompanied by significant increases in incidences of centrilobular fatty change. There was no treatment- related increase in carcinogenic activity in the livers of male or female rats in the chronic studies. Male mice showed a significant dose-related increase in the incidence of hepatoblastomas. In female mice, there was a significant increase in the combined incidence of hepatocellular adenoma and carcinoma in the low and mid dose groups but not in the high dose group. These findings were accompanied by several nonneoplastic hepatic lesions.     

The Kava Anxiety Depression Spectrum Study (KADSS): a randomized,placebo-controlled crossover trial using an aqueous extract of <Emphasis Type="Italic">Piper methysticum</Emphasis>

Rationale   Piper methysticum (Kava) has been withdrawn in European, British, and Canadian markets due to concerns over hepatotoxic reactions. The WHO recently recommended research into “aqueous” extracts of Kava. Objective  The objective of this study was to conduct the first documented human clinical trial assessing the anxiolytic and antidepressant efficacy of an aqueous extract of Kava. Design and participants  The Kava Anxiety Depression Spectrum Study was a 3-week placebo-controlled, double-blind crossover trial that recruited 60 adult participants with 1 month or more of elevated generalized anxiety. Five Kava tablets per day were prescribed containing 250 mg of kavalactones/day. Results  The aqueous extract of Kava reduced participants' Hamilton Anxiety Scale score in the first controlled phase by −9.9 (CI = 7.1, 12.7) vs. −0.8 (CI = −2.7, 4.3) for placebo and in the second controlled phase by −10.3 (CI = 5.8, 14.7) vs. +3.3 (CI = −6.8, 0.2). The pooled effect of Kava vs. placebo across phases was highly significant (p < 0.0001), with a substantial effect size (d = 2.24, ). Pooled analyses also revealed highly significant relative reductions in Beck Anxiety Inventory and Montgomery–Asberg Depression Rating Scale scores. The aqueous extract was found to be safe, with no serious adverse effects and no clinical hepatotoxicity. Conclusions  The aqueous Kava preparation produced significant anxiolytic and antidepressant activity and raised no safety concerns at the dose and duration studied. Kava appears equally effective in cases where anxiety is accompanied by depression. This should encourage further study and consideration of globally reintroducing aqueous rootstock extracts of Kava for the management of anxiety.     

Enhanced cognitive performance and cheerful mood by standardized extracts of Piper methysticum (Kava-kava)

The acute effects of the herbal anxiolytic Kava-kava (Piper methysticum G. Forster) on emotional reactivity and cognitive performance were investigated in a double-blind randomized placebo-controlled trial involving healthy volunteers. Subjects' reports of mood change were assessed with the state-trait-cheerfulness-inventory, which measures the three concepts of cheerfulness, seriousness and bad mood as both traits and states. Cognitive performance was examined with the Sperling partial report and the Sternberg item recognition task, which were used as an index for visual attention and short-term memory processing. The intake of a single dose of Kava extract (300 mg; p.o.) led to an increase in state cheerfulness, while the phytopharmacon did not influence state seriousness and bad mood. The mood-elevating effects of Kava were most prominent in trait cheerful subjects, indicating that trait cheerfulness moderated the drug-induced increase in cheerful mood. Furthermore, Kava improved the accuracy and the speed of performing the partial report and the item recognition task, indicative of a beneficial effect of the phytopharmacon on visual attention and short-term memory retrieval, respectively. Thus, unlike conventional benzodiazepine-type anxiolytics, which tend to impair cognitive performance and to increase the occurrence of negative affective states, Kava is a potent anxiolytic agent, which, additionally, can facilitate cognitive functioning and can increase positive affectivity related to exhilaration.     

Extracts of kava (<Emphasis Type="Italic">Piper methysticum</Emphasis>) induce acute anxiolytic-like behavioral changes in mice

Rationale Kava has been used for centuries by Pacific Islanders for its tranquilizing and sedative effects. Recent clinical trials suggest that kava has therapeutic value for the treatment of anxiety. Demonstration of kava's anxiolytic effects in animals under controlled conditions would provide additional support for its clinical potential as an anxiolytic and would facilitate investigation of its mechanism(s) of action.Objectives This study systematically characterized the acute dosage-dependent anxiolytic and sedative effects of kava extract in well established quantitative murine behavioral assays and compared kava- and diazepam-induced behavioral changes.Methods Various doses of an ethanolic extract of kava root or diazepam were administered intraperitoneally to BALB/cByJ inbred mice. Behavioral changes were measured in the mirrored chamber avoidance assay and elevated plus-maze assay. Reduced latency to enter and increased time spent in a normally avoided environment operationally defined anxiolysis. Sedation was defined by a significant decrease in locomotor activity in a circular arena.Results Kava extract produced statistically significant dose-dependent anxiolytic-like behavioral changes in both assays of anxiolysis. ED₅₀ values for kava-induced increases in time spent inside the mirrored chamber and on the open arms of the plus maze were 125 mg/kg and 88 mg/kg, respectively. Kava extract also caused a profound decrease in locomotor activity (ED₅₀ of 172 mg/kg). Flumazenil, a competitive benzodiazepine receptor antagonist, blocked both the anxiolytic and sedative effects of diazepam, but had no effect on kava's behavioral actions.Conclusions Kava extracts produce significant murine anxiolytic-like behavioral changes and sedation that are not mediated through the benzodiazepine binding site on the GABA_A receptor complex.     

Kava hepatotoxicity: a European view

Kava was well tolerated and considered as devoid of major side effects only until 1998 when the first report of assumed kava hepatotoxicity appeared. Causality of hepatotoxicity for kava +/- comedicated drugs was evident after the use of predominantly ethanolic and acetonic kava extracts in Germany (n=7), Switzerland (n=2), United States (n=1), and Australia (n=1) as well as after aqueous extracts in New Caledonia (n=2). Compliance regarding the recommendation for daily kava dose and duration was ascertained in only a few patients, including 2 from Germany and Switzerland. Since 450 millions of daily doses of kava extracts equating to 15 millions of monthly doses were sold in Germany and Switzerland, hepatotoxicity by kava appeared to be rare--similar to other herbal remedies, dietary supplements, and synthetic drugs. Risk factors were found in most patients and include daily kava overdose, prolonged therapy, and comedication with up to 5 other herbal remedies, dietary supplements, and synthetic drugs. Kava hepatotoxicity was not reported until 1998, thus raising the question of inferior quality of the kava raw material at times of the kava boom later on. Insufficiently defined regulatory guidelines to produce kava extracts are of some concern. Open questions refer not only to kava cultivars, but also to analytical methods and definitions of extract media and contents. Future strategies should therefore focus on the solution of a standard methodology of ascertaining quality that can assure a high degree of reliability in conjunction with actions by regulators, physicians, manufacturers, and producers. A medical advisory is also recommended as part of the labelling.     

Melanogenesis stimulation in murine B16 melanoma cells by Kava (Piper methysticum) rhizome extract and kavalactones

Melanogenesis stimulation activity of aqueous ethanolic extracts obtained from several different parts of five Piper species, namely Piper longum, P. kadsura, P. methysticum, P. betle, and P. cubeba, were examined by using cultured murine B16 melanoma cells. Among them, the extract of P. methysticum rhizome (Kava) showed potent stimulatory effect on melanogenesis as well as P. nigrum leaf extract. Activity-guided fractionation of Kava extract led to the isolation of two active kavalactones, yangonin (2) and 7,8-epoxyyangonin (5), along with three inactive kavalactones, 5,6-dehydrokawain (1), (+)-kawain (3) and (+)-methysticin (4), and a glucosylsterol, daucosterin (6). 7,8-Epoxyyangonin (5) showed a significant stimulatory effect on melanogenesis in B16 melanoma cells. Yangonin (2) exhibited a weak melanogenesis stimulation activity.     

Kava hepatotoxicity in traditional and modern use: the presumed Pacific kava paradox hypothesis revisited

Kava, a Pacific herb consumed worldwide for medicinal, recreational and cultural purposes, has been associated with rare hepatotoxicity, and there is currently a critical need to determine this causation. The previously proposed Pacific kava paradox was based on the theory that kava hepatotoxicity was not observed following use of traditional aqueous extracts in the Pacific region, but was restricted to use of Western acetonic and ethanolic extracts. Subsequent cases analyzed by the World Health Organization and published case reports revealed that traditional aqueous extracts used in New Caledonia, Australia, the USA and Germany may also be hepatotoxic; thus, there is no longer a basis to sustain the previously proposed Pacific kava paradox. It appears that the primary cause of toxicity may reside in the time before the preparation of the various kava extracts, possibly attributed to poor quality of the raw material caused by mould hepatotoxins. Rigorous testing of kava raw material is urgently advised, in addition to Pan-Pacific kava manufacturing quality standards.     

Acute effects of kava, alone or in combination with alcohol, on subjective measures of impairment and intoxication and on cognitive performance

Kava (Piper methysticum) and alcohol were administered either separately or in combination to human subjects. Self-reports of their levels of impairment and intoxication were collected, and performance skills on a number of cognitive and visuomotor tests were determined, before and three times after consumption of the experimental drink. Kava alone had no effect on reported condition. In contrast, alcohol produced marked changes in each of the five subjective measures, all of which were in the direction of lowered ability. The combination of these two substances produced even larger negative changes on these measures. In the cognitive tests, kava produced a decrement in performance on Digit Symbol Coding. Alcohol produced a significant decrease in performance on a divided attention test, which was almost entirely on the peripheral, discontinuous component of the test. The combination of kava and alcohol produced an even greater decrease in performance on this test, and in the same component. The present findings suggest that kava alone has little effect on reported condition and cognitive performance, but appears to potentiate both perceived and measured impairment when combined with alcohol.     

Evaluation of commercial kava extracts and kavalactone standards for mutagenicity and toxicity using the mammalian cell gene mutation assay in L5178Y mouse lymphoma cells.

Kava (Piper methysticum) is a member of the pepper family and has been cultivated by South Pacific islanders for centuries and used as a social and ceremonial drink. Traditionally, kava extracts are prepared by grinding or chewing the rhizome and mixing with water and coconut milk. The active constituents of kava are a group of approximately 18 compounds collectively referred to as kavalactones or kava pyrones. Kawain, dihydrokawain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin are the six major kavalactones. Kava beverages and other preparations are known to be anxiolytic and are used for anxiety disorders. Dietary supplements containing the root of the kava shrub have been implicated in several cases of liver toxicity in humans, including several who required liver transplants after using kava supplements. In order to study the toxicity and mutagenicity, two commercial samples of kava, Kaviar and KavaPure, and the six pure kavalactones including both D-kawain and DL-kawain, were evaluated in L5178Y mouse lymphoma cells. Neither the kava samples nor the kavalactones induced a mutagenic response in the L5178Y mouse lymphoma mutation assay with the addition of human liver S9 activation.     

Proposal for a Kava Quality Standardization Code

Rare cases of hepatotoxicity emerged with the use of kava drugs and dietary supplements prepared from rhizomes and roots of the South Pacific plant kava (Piper methysticum). Their psychoactive, anxiolytic, relaxing, and recreational ingredients are the kavalactones kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin, but there is little evidence that these kavalactones or the non-kavalactones pipermethystine and flavokavain B are the culprits of the adverse hepatic reactions. It rather appears that poor quality of the kava material was responsible for the liver toxicity. Analysis of existing kava quality standardizations with focus on chemical, agricultural, manufacturing, nutritional, regulatory, and legislation backgrounds showed major shortcomings that could easily explain quality problems. We therefore suggest a uniform, internationally accepted device for kava quality standardizations that are in the interest of the consumers because of safety reasons and will meet the expectations of kava farmers, pharmaceutical manufacturers, regulators of agencies, and legislators. The initial step resides in the establishment of Pan-Pacific kava quality legislation as an important part of the proposed Kava Quality Standardization Code. In conclusion, a sophisticated approach to establish kava quality standardizations is needed for safe human use of kava as relaxing traditional beverages, the anxiolytic drugs, and recreational dietary supplements.