kava and Chemical-and-Drug-Induced-Liver-Injury

Kava beverages are typically prepared from the root of Piper methysticum. They have been consumed among Pacific Islanders for centuries. Kava extract preparations were once used as herbal drugs to treat anxiety in Europe. Kava is also marketed as a dietary supplement in the U.S. and is gaining popularity as a recreational drink in Western countries. Recent studies suggest that kava and its key phytochemicals have anti-inflammatory and anticancer effects, in addition to the well-documented neurological benefits. While its beneficial effects are widely recognized, rare hepatotoxicity had been associated with use of certain kava preparations, but there are no validations nor consistent mechanisms. Major challenges lie in the diversity of kava products and the lack of standardization, which has produced an unmet need for quality initiatives. This review aims to provide the scientific community and consumers, as well as regulatory agencies, with a broad overview on kava use and its related research. We first provide a historical background for its different uses and then discuss the current state of the research, including its chemical composition, possible mechanisms of action, and its therapeutic potential in treating inflammatory and neurological conditions, as well as cancer. We then discuss the challenges associated with kava use and research, focusing on the need for the detailed characterization of kava components and associated risks such as its reported hepatotoxicity. Lastly, given its growing popularity in clinical and recreational use, we emphasize the urgent need for quality control and quality assurance of kava products, pharmacokinetics, absorption, distribution, metabolism, excretion, and foundational pharmacology. These are essential in order to inform research into the molecular targets, cellular mechanisms, and creative use of early stage human clinical trials for designer kava modalities to inform and guide the design and execution of future randomized placebo controlled trials to maximize kava's clinical efficacy and to minimize its risks.

Topics: Anti-Inflammatory Agents; Antineoplastic Agents, Phytogenic; Anxiety; Chemical and Drug Induced Liver Injury; Dietary Supplements; Humans; Kava; Nervous System Diseases; Nutritive Value; Phytochemicals; Phytotherapy; Plant Extracts; Quality Control

Drug-induced liver injury represents the principal cause of acute liver failure and orthotopic liver transplantation in western country. A very large number of different drugs and medicinal herbs has been associated with liver injury but just for few of them we know the process that causes liver disease. All the people which ingest a large number of drugs present a risk of developing liver injury. Diagnosis is very difficult because a specific biomarker of damage is absent and the clinical picture is common to other liver diseases. A therapeutic approach is efficacy only in few cases. When a drug-induced liver injury is suspected, cessation of the drug is the first step in their management.

Topics: Acetaminophen; Algorithms; Amoxicillin; Analgesics, Non-Narcotic; Anesthetics, Inhalation; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Halothane; Humans; Hypnotics and Sedatives; Isoniazid; Kava; Liver Failure, Acute; Risk Factors; Severity of Illness Index; Sulfonamides

Since 1998 liver injury has been assumed in some patients after the use of kava (Piper methysticum G. Forster) as an anxyolytic herbal extract, but the regulatory causality evaluation of these cases was a matter of international and scientific debate. This review critically analyzes the regulatory issues of causality assessments of patients with primarily suspected kava hepatotoxicity and suggests recommendations for minimizing regulatory risks when assessing causality in these and other related cases. The various regulatory causality approaches were based on liver unspecific assessments such as ad hoc evaluations, the WHO scale using the definitions of the WHO Collaborating Centre for International Drug Monitoring, and the Naranjo scale. Due to their liver unspecificity, however, these causality approaches are not suitable for assessing cases of primarily assumed liver related adverse reactions by drugs and herbs including kava. Major problems emerged trough the combination of regulatory inappropriate causality assessment methods with the poor data quality as presented by the regulatory agency when reassessment was done and the resulting data were heavily criticized worldwide within the scientific community. Conversely, causality of cases with primarily assumed kava hepatotoxicity is best assessed by structured, quantitative and liver specific causality algorithms such as the scale of the CIOMS (Council for International Organizations of Medical Sciences) or the main-test as its update. Future strategies should therefore focus on the implementation of structured, quantitative and liver specific causality assessment methods as regulatory standards to improve regulatory causality assessments for liver injury by drugs and herbs including kava.

Topics: Adverse Drug Reaction Reporting Systems; Anti-Anxiety Agents; Causality; Chemical and Drug Induced Liver Injury; Drug and Narcotic Control; Humans; Kava; Plant Extracts; Risk Assessment; Risk Factors; World Health Organization

Herbal hepatotoxicity by the anxiolytic kava (Piper methysticum Forst. f.) emerged unexpectedly and was observed in a few patients worldwide. Liver injury occurred after the use of traditional aqueous kava extracts in the South Pacific region and of acetonic and ethanolic extracts in Western countries in rare cases, suggesting that the solvents used play no major causative role. In this review, we discuss actual pathogenetic issues of kava hepatotoxicity with special focus on developments regarding pipermethystine, flavokavain B, and mould hepatotoxins as possible culprits. There is abundant data of in vitro cytotoxicity including apoptosis by pipermethystine and flavokavain B added to the incubation media, yet evidence is lacking of in vivo hepatotoxicity in experimental animals under conditions similar to human kava use. Furthermore, in commercial Western kava extracts, pipermethystine was not detectable and flavokavain B was present as a natural compound in amounts much too low to cause experimental liver injury. There is concern, however, that due to high temperature and humidity in the South Pacific area, kava raw material might have been contaminated by mould hepatotoxins such as aflatoxins after harvest and during storage. Whether kava hepatotoxicity may be due to aflatoxicosis or other mould hepatotoxins, requires further studies.

Topics: Aflatoxins; Chemical and Drug Induced Liver Injury; Flavonoids; Humans; Kava; Ochratoxins; Plant Preparations; Pyridones

Kava hepatotoxicity is a well described disease entity, yet there is uncertainty as to the culprit(s). In particular, there is so far no clear evidence for a causative role of kavalactones and non-kavalactone constituents, such as pipermethystine and flavokavain B, identified from kava. Therefore, novel enzymatic, analytical, toxicological, ethnobotanical and clinical studies are now required. Studies should focus on the identification of further potential hepatotoxic constituents, considering in particular possible adulterants and impurities with special reference to ochratoxin A and aflatoxins (AFs) producing Aspergillus varieties, which should be urgently assessed and published. At present, Aspergillus and other fungus species producing hepatotoxic mycotoxins have not yet been examined thoroughly as possible contaminants of some kava raw materials. Its occurence may be facilitated by high humidity, poor methods for drying procedures and insufficient storage facilities during the time after harvest. Various experimental studies are recommended using aqueous, acetonic and ethanolic kava extracts derived from different plant parts, such as peeled rhizomes and peeled roots including their peelings, and considering both noble and non-noble kava cultivars. In addition, ethnobotanical studies associated with local expertise and surveillance are required to achieve a good quality of kava as the raw material. In clinical trials of patients with anxiety disorders seeking herbal anxiolytic treatment with kava extracts, long-term safety and efficacy should be tested using traditional aqueous extracts obtained from peeled rhizomes and peeled roots of a noble kava cultivar, such as Borogu, to evaluate the risk: benefit ratio. Concomitantly, more research should be conducted on the bioavailability of kavalactones and non-kavalactones derived from aqueous kava extracts. To be on the side of caution and to ensure lack of liver injury, kava consuming inhabitants of the kava producing or importing South Pacific islands should undergo assessment of their liver function values and serum aflatoxin levels. The primary aim is to achieve a good quality of kava raw material, without the risk of adulterants and impurities including ochratoxin A and AFs, which represent the sum of aflatoxin B1, B2, G1 and G2. Although it is known that kava may naturally be contaminated with AFs, there is at present no evidence that kava hepatotoxicity might be due to aflatoxicosis. However, appro

Topics: Aflatoxins; Animals; Beverages; Chemical and Drug Induced Liver Injury; Ethnobotany; Humans; Kava; Pacific Islands; Plant Extracts; Toxicity Tests

Aqueous kava root preparations have been consumed in the South Pacific as an apparently safe ceremonial and cultural drink for centuries. However, several reports of hepatotoxicity have been linked to the consumption of kava extracts in Western countries, where mainly ethanolic or acetonic extracts are used. The mechanism of toxicity has not been established, although several theories have been put forward. The composition of the major constituents, the kava lactones, varies according to preparation method and species of kava plant, and thus, the toxicity of the individual lactones has been tested in order to establish whether a single lactone or a certain composition of lactones may be responsible for the increased prevalence of kava-induced hepatotoxicity in Western countries. However, no such conclusion has been made on the basis of current data. Inhibition or induction of the major metabolizing enzymes, which might result in drug interactions, has also gained attention, but ambiguous results have been reported. On the basis of the chemical structures of kava constituents, the formation of reactive metabolites has also been suggested as an explanation of toxicity. Furthermore, skin rash is a side effect in kava consumers, which may be indicative of the formation of reactive metabolites and covalent binding to skin proteins leading to immune-mediated responses. Reactive metabolites of kava lactones have been identified in vitro as glutathione (GSH) conjugates and in vivo as mercapturates excreted in urine. Addition of GSH to kava extracts has been shown to reduce cytotoxicity in vitro, which suggests the presence of inherently reactive constituents. Only a few studies have investigated the toxicity of the minor constituents present in kava extract, such as pipermethystine and the flavokavains, where some have been shown to display higher in vitro cytotoxicity than the lactones. To date, there remains no indisputable reason for the increased prevalence of kava-induced hepatotoxicity in Western countries.

Topics: Animals; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme System; Exanthema; Glutathione; Humans; Kava; Lactones; Plant Roots

The knowledge base of drug-induced liver injury (DILI) continues to grow each year as additional drugs are identified as hepatotoxins. There is still a need to improve our ability to predict and diagnose DILI in the preclinical and post-approval settings.. This article presents the new and updated DILI registries for 2010, including the latest information on the causes and outcomes of non-acetaminophen DILI cases in the US Acute Liver Failure Study Group database. As DILI is still largely a diagnosis of exclusion, it is appropriate that causality assessment instruments are again the subject of considerable discussion.. DILI research remains extremely active including studies aimed at being better able to identify causative agents, utilize potential biomarkers, predict who is at greatest risk of injury and manage outcomes. With respect to identifying DILI risk factors at the genetic level, the field is rapidly approaching the day where 'personalized medicine' (based on pharmacogenomics) will become a reality. A large single-center series from India reminds us that geography can influence the drugs responsible for liver injury; however, Hy's law remains universal. As our DILI knowledge continues to grow, it remains essential to keep abreast of the important changes reported each year.

Topics: Acetaminophen; Antiretroviral Therapy, Highly Active; Antitubercular Agents; Biomarkers; Catha; Chemical and Drug Induced Liver Injury; Cimicifuga; Humans; Hypoglycemic Agents; Kava; Liver; Plant Preparations; Propylthiouracil; Randomized Controlled Trials as Topic; Risk Factors

Kava is known for its recreational, ceremonial and medicinal use in the Pacific. The aqueous non-alcoholic drink of kava rhizome produces intoxicating, relaxing and soothing effects. While kava's medicinal effects receive worldwide recognition, kava-containing products came under scrutiny after over 100 reports of spontaneous adverse hepatic effects. Many mechanisms have been postulated to explain the unexpected toxicity, one being pharmacokinetic interactions between kavalactones and co-administered drugs involving cytochrome P450 enzyme system. Alcohol is often co-injested in kava hepatotoxicity cases. This review evaluates the possible hepatotoxicity mechanisms involving alcohol and kava.

Topics: Chemical and Drug Induced Liver Injury; Ethanol; Herb-Drug Interactions; Humans; Kava

Kava hepatotoxicity is a well-defined herb-induced liver injury, caused by the use of commercial anxyolytic ethanolic and acetonic kava extracts, and of traditional recreational aqueous kava extracts. The aim of this review is to elucidate possible pathogenetic factors for the development of kava-induced liver injury, considering also confounding variables. In patients with liver disease in a causal relation to kava ± comedication, confounding factors include non-adherence to therapy recommendations and comedication consisting of synthetic and herbal drugs and dietary supplements including herbal ones and herbs-kava mixtures. Various possible pathogenetic factors have to be discussed and comprise metabolic interactions with exogenous compounds at the hepatic microsomal cytochrome P450 level; genetic enzyme deficiencies; toxic constituents and metabolites derived from the kava extract including impurities and adulterations; cyclooxygenase inhibition; P-glycoprotein alterations; hepatic glutathione depletion; solvents and solubilizers of the extracts; and kava raw material of poor quality. In particular, inappropriate kava plant parts and unsuitable kava cultivars may have been used sometimes for manufacturing the kava extracts instead of the rhizome of a noble cultivar of the kava plant (Piper methysticum G. Forster). In conclusion, kava hepatotoxicity occurred independently of the extraction medium used for the kava extracts and may primarily be attributed to daily overdose, prolonged treatment and to a few kava extract batches of poor quality; by improving kava quality and adherence to therapy recommendation under avoidance of comedication, liver injury by kava should be a preventable disease, at least to a major extent.

Topics: Chemical and Drug Induced Liver Injury; Drug Interactions; Glutathione; Humans; Kava; Liver; Plants, Medicinal; Prospective Studies; Rhizome

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.

Topics: Australia; Chemical and Drug Induced Liver Injury; Europe; Humans; Kava; Liver Diseases; Phytotherapy; Plant Extracts

The removal from the marketplace of several widely prescribed drugs due to hepatotoxicity has attracted considerable attention. Now under extensive review are means by which we can better identify hepatic risk prior to federal approval. Assessment of risk-to-benefit ratios regarding a novel agent with hepatotoxicity issues (especially one for a life-threatening condition) requires considerable judgment and education on the part of prescribers and patients. The spectrum of drug-induced liver injury is broad with simulation of almost all unknown liver disorders. Drug-induced liver injuries often have a somewhat characteristic signature, as regards type of injury (hepatocellular vs cholestatic) and time of onset. The diagnosis of drug-induced liver injury is often one of exclusion with initial suspicion based on circumstantial evidence. Factors affecting susceptibility to drug-induced injury include age, sex, concomitant use of other drugs, and genetic polymorphism in metabolic pathways involved in activation or disposition of therapeutic drugs. Drug-drug interactions present particular problems in patients, often elderly, who are receiving several drugs simultaneously. Mechanisms of drug-induced liver injury are many and varied. With many drugs, intermediary products produced during metabolism are highly reactive and toxic. In these situations, the balance between the rate of production of the metabolite and the effectiveness of the drug may determine whether or not hepatic injury occurs.

Topics: Acetaminophen; Chemical and Drug Induced Liver Injury; Chromans; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Isoniazid; Kava; Liver; Male; Minocycline; Polymorphism, Genetic; Risk Assessment; Risk Factors; Thiazolidinediones; Troglitazone; Vitamin A

Before 1998, extracts of kava kava, Piper methysticum, were considered to be very safe alternatives to anxiolytic drugs and to possibly exert a wide range of other benefits. Major reviews published through the end of 2002 continued to confirm kava's safety and efficacy. Nevertheless, by January 2003 kava extracts had been banned in the entire European Union and Canada, and were subject to cautions and advisories by the US FDA as a result of 11 cases of hepatic failure leading to liver transplants, including four deaths. A total of 78 cases of hepatotoxicity reputedly linked to kava ingestion are available for review from various databases. Of these adverse events, four probably are linked to kavalactones taken alone and another 23 are potentially linked to kava intake, but also involve the concomitant ingestion of other compounds with potential hepatotoxicity. Three possible mechanisms for kavalactone hepatotoxicity are known: inhibition of cytochrome P450, reduction in liver glutathione content and, more remotely, inhibition of cyclooxygenase enzyme activity. The direct toxicity of kava extracts is quite small under any analysis, yet the potential for drug interactions and/or the potentiation of the toxicity of other compounds is large. Presently, kava toxicity appears to be "idiosyncratic." The risk-to-benefit ratio of kava extracts, nevertheless, remains good in comparison with that of other drugs used to treat anxiety.

Topics: Animals; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Humans; Kava; Lactones; Liver; Phytotherapy; Risk Assessment

In recent years, kava kava ( Piper methysticum, Forst. f., Piperaceae) has been implicated in a number of liver failure cases. Ever since this has kept the scientific world busy. Even though, on closer inspection, the majority of the case reports are probably not connected to kava intake, hepatotoxic effects of kava cannot generally be ruled out. In this article the major theories as to the mechanism of kava hepatotoxicity are summarized. But in spite of all these hypotheses, there is still no satisfactory answer. In any case, further studies, that might hopefully restore the reputation of kava, are required.

Topics: Chemical and Drug Induced Liver Injury; Herb-Drug Interactions; Humans; Kava; Phytotherapy; Plant Extracts

In the traditional practice of Native Hawaiians, 'awa (Piper methysticum) has long been revered as a medicine, a sacred plant central to religious ceremony, and a social drink. In the late 1990s, 'awa attracted global attention as an herbal alternative to existing pharmaceuticals for reducing stress, anxiety, pain and assorted ailments. Marketed since 1994 as a dietary supplement, within seven years 'awa had earned the title of a "superstar" and quickly became one of the top eight herbal remedies in an expanding $18 billion-plus herbal remedy industry. In one study, the plant was even argued to possess chemopreventive properties, when cancer incidence and kava consumption in Pacific island communities were correlated. In 2002, however, the remedy was banned in several European countries, after case reports of liver toxicity allegedly associated with its nontraditional use surfaced. In the United States (US), the Food and Drug Administration issued a consumer advisory leading several retailers to voluntarily withdraw products containing 'awa from their shelves. These actions have sent shock waves throughout Pacific Island communities seeking to derive economic benefit from a relatively new and little-regulated industry. Moreover, they threaten the vitality of centuries of Native Hawaiian cultural practice. Clinical studies advocating both sides of the safety debate have been published, as producers, marketers and users attempt to influence government action. At the same time, issues of cultural exploitation, religious freedom, traditional practice, and native intellectual property rights are absent from the debate, leaving the future of native practice hanging in the balance. Whether or not the herb's status is restored, the situation raises critical questions: Is 'awa toxic? Or, does the poison derive from its use outside of traditional practice?

Topics: Chemical and Drug Induced Liver Injury; Commerce; Government Regulation; Hawaii; Herbal Medicine; Humans; Kava; Medicine, Traditional; United States; United States Food and Drug Administration

Kava extracts are obtained from the rhizoma of the kava shrub (Piper methysticum) and contain various pyrones which are used as herbal anxiolytic remedies for generalized anxiety syndromes of low and intermediate grades. The commonly recommended daily dose of 60-120 mg kavapyrones and the duration of the therapy of up to 3 months should not be increased without consultation of a physician and were not followed by most patients, since herbal drugs are considered by the population not only as effective but also as safe. Whereas kava extracts are well tolerated by most patients and rare side effects are rapidly reversible upon drug discontinuation, there are suspected hepatotoxic reactions reported during the last years in temporal and not necessarily causal association with a therapy with kava extracts. Almost 80 % of the patients took kavapyrones in overdose (maximally 480 mg/d) and/or for a prolonged time of more than 3 months up to 2 years. Additional risks factors include co-medication with up to 5 other chemically defined or herbal drugs with in part potentially hepatotoxic properties as well as a genetic deficiency of the hepatic microsomal cytochrome P450 2D6. Severe clinical courses with liver transplantation and possible fatal outcome occurred in 7 patients with overdose and/or long duration of the therapy with kavapyrones. Preventive measures should therefore include a dose of 120, maximally 210 mg kavapyrones per day for 1 month, maximally 2 months, as well as a prescription by a physician. Laboratory test (ALT and gamma-GT) should be done before and during the therapy, and co-medication and alcohol consumption should be avoided. With these measures the hepatotoxic risks under the treatment with kavapyrones might be minimized which are also available via internet and from abroad with possible severe consequences when taken without medical supervision.

Topics: Anti-Anxiety Agents; Chemical and Drug Induced Liver Injury; Drug Interactions; Drug Overdose; Humans; Kava; Liver Function Tests; Phytotherapy; Plant Extracts; Pyrones; Survival Analysis

Kava pyrones have been sold in Germany as OTC anxiolytics until June 2002, when all preparations with a kava pyrone content of more than 10(-4) of a homeopathic stock solution were withdrawn. Other countries in which kava pyrones have been used as anxiolytics, namely GB and the USA, have not followed suit. Kava pyrone anxiolytics have been positively reviewed by the Cochrane Collaboration; also newer German clinical studies have indicated pharmacological anxiolysis at the recommended doses. To use the first choice of treatment, psychotherapy, for all uncomplicated cases of pathological fear does not appear to be realistic. Current data about kava pyrone toxicity are unclear. Judging from the few well documented cases of kava pyrone hepatotoxicity (appr. 2 out of 36) in Germany and Switzerland, an immunologically mediated idiosyncratic mechanism appears to be most likely, especially at higher doses, whereas a direct toxic mechanism is much less likely. No direct results are available for the incidence of kava pyrone-related adverse drug effects. From spontaneously reported cases the incidences of adverse drug reactions cannot be obtained, a rough estimation indicates the incidence of hepatotoxicity to be comparable to those of benzodiazepines. Taken together, the withdrawal of kava pyrone-based anxiolytics appears to be an ill founded over-reaction given the lack of superior therapeutic alternatives. Neither the case evaluations presented by the BfArM (Bundesamt für Arzneimittel und Medizinprodukte = Federal Office for Drugs and Medical Products) nor the complete rejection of proof for therapeutic efficacy of kava pyrone anxiolytics are scientifically well founded.

Topics: Adverse Drug Reaction Reporting Systems; Anti-Anxiety Agents; Chemical and Drug Induced Liver Injury; Drug Interactions; Germany; Humans; Kava; Phytotherapy; Plant Extracts; Pyrones; United States

Kava is a perennial shrub native to some islands of the South Pacific and has been cultivated for centuries to prepare a psychoactive beverage from its rhizoma by means of extraction. Subsequently, kava extracts are commonly used as herbal anxiolytic drugs also in many other countries all over the world including European ones and the USA. Toxicological and clinical studies have shown that kava extracts are virtually devoid of toxic effects with the exception of rare hepatotoxic side effects reported in few patients. When assessed primarily by the British regulatory authority MCA but also by us, a critical analysis of the suspected cases (n = 19) in Germany reveals that only in 1 single patient a very probable causal relationship could be established between kava treatment and the development of toxic liver disease due to a positive result of an unscheduled reexposure test, whereas in another patient there might be a possible association. Out of the remaining 17 cases 12 patients were not yet assessable due to insufficient data and in 5 other cases a causal relationship was unlikely or could be excluded. The German regulatory authority might therefore well be advised to provide now additional information for those 12 patients with so far unsatisfactory data, facilitating a more appropriate assessment of causality. Nevertheless, in the meantime physicians and patients should continue to keep an eye on possible hepatotoxic side effects in the course of kava treatment, to stop the treatment alredy at first suspicion and to start with a careful diagnostic work up ruling out all other causes.

Topics: Chemical and Drug Induced Liver Injury; Humans; Kava; Liver; Plant Extracts

This paper systematically reviews the clinical evidence relating to the safety of extracts of the herbal anxiolytic kava (Piper methysticum). Literature searches were conducted in four electronic databases and the reference lists of all papers located were checked for further relevant publications. Information was also sought from the spontaneous reporting schemes of the WHO and national drug safety bodies and ten manufacturers of kava preparations were contacted. Data from short-term post-marketing surveillance studies and clinical trials suggest that adverse events are, in general, rare, mild and reversible. However, published case reports indicate that serious adverse events are possible including dermatological reactions, neurological complications and, of greatest concern, liver damage. Spontaneous reporting schemes also suggest that the most common adverse events are mild, but that serious ones occur. Controlled trials suggest that kava extracts do not impair cognitive performance and vigilance or potentiate the effects of central nervous system depressants. However, a possible interaction with benzodiazepines has been reported. It is concluded that when taken as a short-term monotherapy at recommended doses, kava extracts appear to be well tolerated by most users. Serious adverse events have been reported and further research is required to determine the nature and frequency of such events.

Topics: Anti-Anxiety Agents; Anxiety; Chemical and Drug Induced Liver Injury; Drug Interactions; Ethanol; Humans; Kava; Myoglobinuria; Nervous System Diseases; Neuropsychological Tests; Phytotherapy; Plant Extracts; Plants, Medicinal; Product Surveillance, Postmarketing; Psychomotor Performance; Randomized Controlled Trials as Topic; Skin Diseases; Sleep

Topics: Chemical and Drug Induced Liver Injury; Humans; Kava; Liver; Liver Failure, Acute; Plant Extracts

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.. 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.. 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.. 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.. 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.. 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.

Topics: Anti-Anxiety Agents; Brazil; Chemical and Drug Induced Liver Injury; Female; Germany; Herbal Medicine; Humans; Kava; Liver Failure, Acute; Liver Transplantation; Medicine, Traditional; Middle Aged

Positive re-exposure tests are diagnostic hallmarks for hepatotoxicity.. To test validity of positive re-exposures in herb induced liver injury.. We searched Medline database for cases of herb induced liver injury with positive re-exposures and analysed 34 cases for positive re-exposure test criteria of baseline alanine aminotransferase< 5N before re-exposure, and re-exposure alanine aminotransferase ≥ 2× baseline alanine aminotransferase. Re-exposure test was negative, if baseline alanine aminotransferase< 5N combined with re-exposure alanine aminotransferase< 2× baseline alanine aminotransferase, or if baseline alanine aminotransferase≥ 5N regardless of the re-exposure alanine aminotransferase including no available re-exposure alanine aminotransferase result.. In 21/34 cases (61.8%), criteria for a positive re-exposure were fulfilled, with negative tests in 6/34 cases (17.6%) or uninterpretable ones in 7/34 cases (20.6%). Confirmed positive re-exposure tests established potential of herb induced liver injury for Aloe, Chaparral, Chinese herbal mixtures, Chinese Jin Bu Huan, Chinese Syo Saiko To, Germander, Greater Celandine, Green tea, Kava, Mistletoe, Polygonum multiflorum, and Senna, with up to 4 case reports per herb.. Among 34 cases of herb-induced liver injury with initially reported positive re-exposure tests, 61.8% of the cases actually fulfilled established test criteria and provided firm diagnoses of herb induced liver injury by various herbs.

Topics: Alanine Transaminase; Aloe; Bupleurum; Camellia sinensis; Chelidonium; Chemical and Drug Induced Liver Injury; Drugs, Chinese Herbal; Female; Humans; Kava; Male; Mistletoe; Plants, Medicinal; Polygonum; Reproducibility of Results; Senna Plant; Teucrium

Topics: Chemical and Drug Induced Liver Injury; Dietary Supplements; Food Safety; Ginkgo biloba; Hawaii; Herb-Drug Interactions; Humans; Kava; United States

The culprit of kava hepatotoxicity will continue to remain a mystery in humans, if the underlying reaction is of idiosyncratic, unpredictable, and dose-independent nature due potentially to some metabolic aberration in a few individuals emerging from kava use. In addition, kava hepatotoxicity is presently not reproducible experimentally in preclinical models, as demonstrated by studies showing whole kava extracts are not hepatotoxic. This led us to propose our 'working hypothesis' that contaminant hepatotoxins including moulds might have caused rare kava hepatotoxicity in humans. Further studies are now warranted to proof or disproof our working hypothesis, because kava hepatotoxicity possibly based on contaminant hepatotoxins could be a preventable disease. In the meantime, however, for minimizing toxicity risk in kava users, a pragmatic approach should focus on the medicinal use of an aqueous extract derived from peeled rhizomes and roots of a non-mouldy noble kava cultivar, limited to maximum 250-mg kavalactones daily for acute or intermittent use.

Topics: Chemical and Drug Induced Liver Injury; Drug Contamination; Humans; Kava; Plant Extracts

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.

Topics: Chemical and Drug Induced Liver Injury; Humans; Kava; Liver; Pacific Islands; Plant Extracts; Quality Control; Rhizome; Risk Factors

Previous studies with kava components such as kavalactones, pipermethystine and flavokavain B have demonstrated hepatotoxicity from these constituents. Regardless, there has recently been speculation that adulterants or impurities such as the mould hepatotoxin aflatoxin are a more likely cause of kava hepatotoxicity, despite a paucity of supporting evidence. Although there is limited similarity between acute kava hepatotoxicity and acute aflatoxicosis, and background levels of aflatoxin have been detected in kava samples, unless epidemiological investigations can uncover direct evidence implicating mould hepatotoxins, it remains more likely that chemical constituents of kava are the cause of the hepatotoxicity from kava.

Topics: Aflatoxins; Chemical and Drug Induced Liver Injury; Fungi; Humans; Kava

The development of alcoholic liver disease is a complex process that involves both the parenchymal and non-parenchymal cells of the liver. We examined the effect of an Ecklonia cava extract on ethanol-induced liver injury.. Isolated hepatocytes and hepatic stellate cells (HSCs) were incubated with ethanol. Ecklonia cava polyphenol (ECP) was added to the cultures that had been incubated with ethanol. Male Wistar rats were fed a diet that included 0.02% or 0.2% ECP or no ECP. For a period of 3 weeks, the animals were given drinking water containing 5% ethanol and were also treated with carbon tetrachloride (CCl4) (0.1 ml/kg of body weight).. In the cultured hepatocytes, the ECP treatment suppressed the ethanol-induced increase in cell death by maintaining intracellular glutathione (GSH) levels. In HSCs, ECP treatment suppressed the ethanol-induced increases in type I collagen and α-smooth muscle actin expression by maintaining intracellular levels of reactive oxygen species and GSH. We examined the effects of ECP on serum AST and ALT activity, as well as the progression of liver fibrosis in rats treated with ethanol and CCl4. ECP treatment suppressed plasma AST and ALT activities in the ethanol- and CCl4-treated rats. ECP treatment fully protected the rats against ethanol- and CCl4-induced liver injury.. ECP may be a candidate for preventing ethanol-induced liver injury.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Blotting, Western; Carbon Tetrachloride; Cell Proliferation; Cells, Cultured; Central Nervous System Depressants; Chemical and Drug Induced Liver Injury; Collagen Type I; Ethanol; Glutathione; Hepatic Stellate Cells; Hepatocytes; Immunoenzyme Techniques; Kava; Lipid Peroxidation; Male; Polyphenols; Protective Agents; Rats; Rats, Wistar; Reactive Oxygen Species

Liver toxicity is a side effect observed with some herbal treatments, including Piper methysticum. The possible mechanisms responsible include inflammation subsequent to activation of liver macrophages and oxidative damage. Hepatotoxicity of the pharmacologically active component of Piper methysticum (kavalactones) was tested in isolated, perfused livers from rats which were pretreated with the macrophage intoxicant gadolinium chloride. Perfusions without kavalactones in gadolinium chloride pretreated and untreated livers were included as negative controls. Serial liver lobe biopsies were collected to measure temporal changes in available (reduced) hepatic glutathione. There were no statistically significant changes in reduced glutathione over the course of perfusion in any experimental group. Liver damage was observed using electron microscopy. Hepatic sinusoids displayed extensive damage to the endothelium in kavalactone-perfused, rat livers. This damage was significantly reduced by pre-treatment with gadolinium chloride. Hence liver macrophages may be a factor in liver injury induced by Piper methysticum. Characterisation and modulation of the liver macrophage response may enable the development of strategies to avoid these hepatic side effects.

Topics: Animals; Chemical and Drug Induced Liver Injury; Gadolinium; Glutathione; Kava; Lactones; Macrophages; Male; Rats; Rats, Sprague-Dawley

The pathophysiology of kava hepatotoxicity remains inconclusive. There is circumstantial evidence for the roles of toxic metabolites, inhibition of cyclooxygenase (COX) enzymes and depletion of liver glutathione. Pharmacogenomic effects are likely, particularly for Cytochrome P450 genes. Experimental and clinical cases of hepatotoxicity show evidence of hepatitis. The question remains whether this inflammation is caused by components of kava directly, or indirectly due to the downstream effects.

Topics: Chemical and Drug Induced Liver Injury; Humans; Inflammation; Kava

Kava-induced liver injury has been demonstrated in a few patients worldwide and appears to be caused by inappropriate quality of the kava raw material. When cases of liver disease in connection with the use of kava emerged, this was an unexpected and challenging event considering the long tradition of safe kava use. In order to prevent kava hepatotoxicity in future, a set of quality specifications as standard is essential for the preparation not only of kava drugs and kava dietary supplements in the Western world but also for traditional kava drinks in the South Pacific Islands. For all these purposes a uniform approach is required, using water based extracts from the peeled rhizomes and roots of a noble cultivar such as Borogu with at least 5 years of age at the time of harvest. Cultivated in Vanuatu for centuries, noble varieties (as defined in the Vanuatu Kava Act of December 2002) are well tolerated traditional cultivars with a good safety record. At present, Vanuatu kava legislation is inadequately enforced to meet quality issues for kava, and further efforts are required in Vanuatu, in addition to similar legislation in other kava producing South Pacific Islands. Future regulatory and commercial strategies should focus not only on the standardization of kava drugs, kava dietary supplements, and traditional kava extracts, but also on thorough surveillance during the manufacturing process to improve kava quality for safe human use. The efficacy of kava extracts to treat patients with anxiety disorders is well supported, but further clinical trials with aqueous kava extracts are necessary. We thereby propose a six-point kava solution plan: (1) use of a noble kava cultivar such as Borogu, at least 5 years old at time of harvest, (2) use of peeled and dried rhizomes and roots, (3) aqueous extraction, (4) dosage recommendation of ≤250mg kavalactones per day (for medicinal use), (5) systematic rigorous future research, and (6) a Pan Pacific quality control system enforced by strict policing. In conclusion, at different levels of responsibility, new mandatory approaches are now required to implement quality specification for international acceptance of kava as a safe and effective anxiolytic herb.

Topics: Anti-Anxiety Agents; Chemical and Drug Induced Liver Injury; Dietary Supplements; Humans; Kava; Plant Extracts; Quality Control

The use of the anxiolytic herb kava has caused toxic liver injury in Western countries and economic problems in South Pacific Islands due to tthe regulatory ban on kava. This analysis shows poor quality of kava raw material as a cause for its toxicity and suggests preventative measures by going back to the traditional use of kava for the sake of the patients and the South Pacific economy.

Topics: Anti-Anxiety Agents; Chemical and Drug Induced Liver Injury; Humans; Kava; Liver; Pacific Islands; Plants, Medicinal; Rhizome

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 2g/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 1g/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.

Topics: Animals; Carcinogenicity Tests; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Kava; Liver; Male; Mice; Mice, Inbred Strains; Rats; Rats, Inbred F344; Sex Characteristics

This paper examines the debate about the safety of kava (Piper methysticum Forst. f, Piperaceae), a plant native to Oceania, where it has a long history of traditional use. Kava became popular as an anti-anxiety treatment in Western countries in the late 1990s, but it was subsequently banned in many places due to adverse reports of liver toxicity. This paper focuses on the responses to the bans by scientists involved in kava research, contrasting their evidential culture with that employed by clinicians and regulatory officials. Cultural constructions and social negotiations of risk are shown to be context-specific, and are shaped by professional, disciplinary, and organizational factors, among others. Though the science of hepatotoxicity is uncertain enough to allow for multiple interpretations of the same data, the biomedical/clinical narrative about kava remains dominant. This case study explores the influence of these cultural, social, and political factors on the production of scientific knowledge and the assessment of benefit/risk posed by comestibles.

Topics: Anthropology; Chemical and Drug Induced Liver Injury; Ethnopharmacology; Hawaii; Herb-Drug Interactions; Herbal Medicine; Humans; Kava; Medicine, Traditional; Phytotherapy; Risk Assessment

Ingestion of the medicinal herb kava has been associated with hepatotoxicity. We aimed to compare two different quantitative methods of causality assessment of patients with assumed hepatotoxicity by the herb.. We assessed causality in 26 patients from Germany and Switzerland, using two structured quantitative analytical methods: the system of Maria and Victorino (MV) and that of the Council for International Organizations of Medical Sciences (CIOMS). In all 26 patients, regulatory ad hoc evaluation had suggested a causal relationship between liver disease and kava use.. Assessment with the MV scale resulted in no or low graded causality for kava in the 26 patients with liver disease. Causality was probable (n=1), possible (n=2), unlikely (n=7), and excluded (n=16). Causality for kava was more evident with the CIOMS scale: highly probable (n=1), probable (n=2), possible (n=6), unlikely (n=2) and excluded (n=15). However, the results of both quantitative causality assessments are not supportive for most of the regulatory ad hoc causality assessments of the 26 patients.. Grades of causality for suspected hepatotoxicity by kava were much lower when evaluated by structured quantitative causality assessment scales than by regulatory ad hoc judgements. The quantitative CIOMS scale is the preferable tool for causality assessment of spontaneous reports of hepatotoxcity involving kava.

Topics: Adult; Aged; Aged, 80 and over; Biometry; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Humans; Kava; Male; Middle Aged; Nonprescription Drugs; Phytotherapy; Time Factors

Topics: Chemical and Drug Induced Liver Injury; Commerce; Consumer Advocacy; Dietary Supplements; Drug-Related Side Effects and Adverse Reactions; Humans; Kava; Liver; Plant Extracts; Public Policy; United States; United States Food and Drug Administration; World Health Organization

Kava hepatotoxicity in 20 patients from Germany has been debated worldwide following a regulatory ad hoc causality assessment and ban of kava, an anxiolytic herbal remedy obtained from the rhizome of Piper methysticum Forster.. We assessed causality with a quantitative structured causality analysis in all 20 cases of patients with liver disease, presented by the German regulatory agency that assumed a causal relationship with the use of kava extracts.. The quantitative scale of CIOMS (Council for International Organizations of Medical Sciences) in its updated form was employed for causality assessment and quality evaluation of the regulatory data presentation.. The regulatory information is scattered and selective, and items essential for causality assessment, such as exclusion of kava independent causes, were not, or only marginally, considered by the regulator. Quantitative causality assessment for kava was possible (n=2), unlikely (n=12), or excluded (n=6), showing no concordance with the regulatory ad hoc causality evaluation.. The regulatory data regarding kava hepatotoxicity is selective and of low quality, not supportive of the regulatory proposed causality; but instead, is an explanation of the overall causality discussions of kava hepatotoxicity. We are proposing that the regulatory agency reports data in full length and reevaluates causality.

Topics: Adult; Aged; Aged, 80 and over; Causality; Chemical and Drug Induced Liver Injury; Female; Germany; Humans; Kava; Male; Middle Aged; Plant Extracts

Ethanolic and acetonic kava extracts have previously been causally related to rare hepatotoxicity observed in patients from Germany and Switzerland, but causality assessment was not performed in cases of patients having taken the traditional aqueous kava extracts of South Pacific islands or kava-herbs mixtures.. To study the possible hepatotoxicity of aqueous kava extracts of the South Pacific Islands.. Causality of hepatotoxicity by aqueous kava extracts and kava-herbs mixtures was assessed, using the updated score of the quantitative CIOMS (Council for the International Organizations of Medical Sciences).. Causality was established in five patients from New Caledonia, Australia, the United States and Germany for aqueous kava extracts and kava-herbs mixtures. A comparison with 9 patients from Germany and Switzerland with established causality of hepatotoxicity by ethanolic and acetonic kava extracts reveals that the clinical picture in all 14 patients is similar, independently whether aqueous, ethanolic and acetonic kava extracts or kava-herbs mixtures were used.. Kava hepatotoxicity occurs also with traditional aqueous kava extracts of the South Pacific islands and thereby independently from ethanol or acetone as chemical solvents, suggesting that the toxicity is linked to the kava plant itself with a possibly low quality of the used kava cultivar or kava plant part rather than to chemical solvents.

Topics: Adolescent; Chemical and Drug Induced Liver Injury; Female; Humans; Kava; Liver; Middle Aged; Necrosis; Pacific Islands; Plant Extracts; Plants, Medicinal; Solvents; United States

Hepatotoxicity has been previously suspected by national regulatory agencies in 26 patients in causal relationship with the treatment by kava extracts commonly used as herbal anxiolytic drugs.. A quantitative causality assessment was undertaken using the system of the Council for International Organizations of Medical Sciences, scale of objective probability scoring.. Causality was unassessable, unrelated, or excluded in 16 patients owing to lack of temporal association and causes independent of kava or comedicated drugs. Low Council for International Organizations of Medical Sciences scores additionally resulted in excluded or unlikely causality assessments (n=2), leaving a total of eight patients with various degrees of causality for kava +/- comedicated drugs. Only one out of these eight patients adhered to the regulatory recommendations regarding both daily dose (

Topics: Adult; Aged; Aged, 80 and over; Anti-Anxiety Agents; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Female; Humans; Kava; Male; Middle Aged; Patient Compliance; Phytotherapy; Plant Extracts; Prognosis; Risk Factors; Severity of Illness Index; Young Adult

The pyridone alkaloid pipermethystine has been considered to be responsible for alleged hepatoxicity of Kava products. Investigation of a series of retain samples of finished products from the German market and self-produced extracts from root and stem material of Piper methysticum clearly showed that pipermethystine (1) is absent from all root and retain samples and extracts, with a limit of quantification of 45 ppm. As a positive control, leaves of P. methysticum showed an amount of 0.2% of 1. Thus, if there is any hepatotoxicity, compound 1 should not be the responsible constituent in the case reports with ethanolic extracts produced in Germany.

Topics: Alkaloids; Chemical and Drug Induced Liver Injury; Chromatography, Thin Layer; Gas Chromatography-Mass Spectrometry; Kava; Mass Spectrometry; Plant Extracts; Plant Leaves; Plant Roots; Plant Stems; Pyridones; Spectrometry, Mass, Electrospray Ionization

Kava, like a number of herbals, has been associated with causing liver damage based on limited evidence. In contrast, the present study found that in rats, 3 mo feedings of two types of kava extracts (an acetone extract and an ethanol extract of the Samoan kava cultivar Ava Laau) at three different doses (31.25, 62.5 and 133 mg/kg diet) produced no liver injury based on serum markers of liver damage (sorbitol dehydrogenase activities, bile acid concentrations, and beta-glucuronidase activities) and serum lipid peroxide readings. In fact, for some measurements and some kava doses, the injury marker readings were below control values. Moreover, for these same parameters, kava feeding did not enhance the effects of the hepatotoxin galacatosamine (500 mg/kg ip); some kava doses even showed modest protection against liver injury. Liver histology analysis showed no signs of kava causing or enhancing liver injury. Thus, this study does not support the concept that kava produces or aggravates liver injury.

Topics: Acetone; Animals; Bile Acids and Salts; Biomarkers; Chemical and Drug Induced Liver Injury; Diet; Dose-Response Relationship, Drug; Drug Synergism; Ethanol; Galactosamine; Glucuronidase; Kava; L-Iditol 2-Dehydrogenase; Lipid Peroxides; Liver; Liver Function Tests; Male; Plant Extracts; Rats; Rats, Sprague-Dawley; Solvents

Topics: Chemical and Drug Induced Liver Injury; Drug Monitoring; Humans; Kava; Plant Extracts

Kava (Piper methysticum) extract products have been implicated in a number of severe hepatotoxicity cases. However, systematic toxicological studies regarding kava consumption have not been reported. In this study, 6 major kavalactones and different solvent fractions of kava roots, leaves, and stem peelings were evaluated for their mutagenic potential. None of the kavalactones was found to be positive in the experimental concentration ranges tested by the umu test (a sensitive test for point mutations). However, among the different solvent fractions, the n-butanol fraction of kava leaves was positive. Further investigations using bioassay-directed isolation and analysis indicated that 2 C-glycoside flavonoid compounds accounted for the positive mutagenic results. Two isolated compounds were identified as 2''-O-rhamnosylvitexin and schaftoside by NMR and MS techniques.

Topics: Animals; Biological Assay; Chemical and Drug Induced Liver Injury; Flavonoids; Glycosides; Kava; Monosaccharides; Mutagenicity Tests; Plant Extracts; Plant Leaves; Plant Roots; Plant Stems; Point Mutation; Rats; Rats, Sprague-Dawley; Salmonella typhimurium

In recent years, Kava kava (Piper methysticum, Forst. f., Piperaceae), a folkloric beverage and popular herbal remedy, has been implicated in a number of liver failure cases. Many hypotheses as to the mechanism of its hepatotoxicity, for example interactions with other co-ingested medication, have been postulated. This present study investigated whether pharmacokinetic interactions between kava constituents and alcohol via alcohol dehydrogenase (ADH) inhibition by individual kavalactones might explain its claimed hepatotoxic effects. Four kavalactones, (+/-)-kavain, methysticin, yangonin and desmethoxyyangonin, fail to inhibit ADH in vitro at 1, 10 or 100 microM concentrations.

Topics: Alcohol Dehydrogenase; Alcohol Drinking; Chemical and Drug Induced Liver Injury; Herb-Drug Interactions; Kava; Lactones; Plant Extracts; Pyrans; Pyrazoles; Pyrones; Spectrophotometry

Kava (Piper methysticum), a perennial shrub native to the South Pacific islands, has been used to relieve anxiety. Recently, several cases of severe hepatotoxicity have been reported from the consumption of dietary supplements containing kava. It is unclear whether the kava constituents, kavalactones, are responsible for the associated hepatotoxicity. To investigate the key components responsible for the liver toxicity, bioassay-guided fractionation was carried out in this study. Kava roots, leaves, and stem peelings were extracted with methanol, and the resulting residues were subjected to partition with a different polarity of solvents (hexane, ethyl acetate, n-butanol, and water) for evaluation of their cytotoxicity on HepG2 cells based on the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and lactate dehydrogenase and aspartate aminotransferase enzyme leakage assays. Organic solvent fractions displayed a much stronger cytotoxicity than water fractions for all parts of kava. The hexane fraction of the root exhibited stronger cytotoxic effects than fractions of root extracted with other solvents or extracts from the other parts of kava. Further investigations using bioassay-directed isolation and analysis of the hexane fraction indicated that the compound responsible for the cytotoxicity was flavokavain B. The identity of the compound was confirmed by (1)H and (13) C NMR and MS techniques.

Topics: Aspartate Aminotransferases; Cell Line; Chemical and Drug Induced Liver Injury; Flavonoids; Kava; L-Lactate Dehydrogenase; Methanol; Plant Extracts; Plant Leaves; Plant Roots; Plant Stems; Solvents

In an otherwise healthy 48-year-old female patient, acute hepatitis with transaminase increase (GOT up to 613 U/l, GPT up to 752 U/l), inconspicuous hepatitis serology findings, negative autoantibody status and negative virus serology was observed after a 10-week long intake of kava-kava (1-3 x 200 mg/day) and St John's Wort (1 x 425 mg/day). Biopsy of the liver showed lobular and portal necroinflammatory activity without indication of cirrhosis.. Due to these findings with proven T-cell activity (lymphocyte typing, neopterin determination) as well as the aetiopathology, this form of hepatitis with histological characteristics of a nutritive/medicinal toxic origin was classified as induced immunologic idiosyncratic hepatitis, possibly in terms of an antibody-negative autoimmune hepatitis.. Discontinuation of the existing medication and simultaneous onset of immunosuppressive combination therapy of cortisone, azathioprine and ursodeoxycholic acid resulted in normalisation of the liver parameters within a period of two months.. On the one hand, it appears that simultaneous intake of St John's Wort possibly potentiates the toxicity of kavapyrones. On the other hand, an immune-mediated mechanism, induced by kava-kava, cannot be completely excluded in the present case. It must be stressed that in patients with autoimmune hepatitis, precise history of medication intake should also be available.

Topics: Alanine Transaminase; Aspartate Aminotransferases; Biopsy; Chemical and Drug Induced Liver Injury; Drug Synergism; Female; Hepatitis, Autoimmune; Humans; Hypericum; Immunosuppressive Agents; Kava; Liver; Middle Aged; Plant Preparations

Topics: Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Hepatitis, Autoimmune; Humans; Hypericum; Kava; Phytotherapy; Plant Extracts; Transaminases

Topics: Animals; Chemical and Drug Induced Liver Injury; Hepatitis, Autoimmune; Humans; Hypericum; Kava; Plant Preparations

Topics: Chemical and Drug Induced Liver Injury; Hepatitis, Autoimmune; Humans; Hypericum; Kava; Phytotherapy; Plant Preparations

Topics: Chemical and Drug Induced Liver Injury; Hepatitis, Autoimmune; Humans; Hypericum; Kava; Plant Preparations; Pyrones

This study describes the synthesis of 6 -phenyl-3-hexen-2-one, a proposed metabolite of kava-kava (kava, 'Awa, Yaqona, Piper methysticum Forst.), its reactivity with glutathione in vitro, and its isolation and identification, as its mercapturic acid adduct using LC/MS/MS, in the urine of two human subjects following their ingestion of kava. A possible metabolic pathway for the formation of this metabolite and its possible role in hepatotoxicity are also discussed.

Topics: Administration, Oral; Beverages; Chemical and Drug Induced Liver Injury; Humans; Kava; Lactones; Liver; Phytotherapy; Plant Extracts; Plant Roots

In early 2002, the FDA and Health Canada issued federal advisories that people should discontinue taking the herbal antianxiolitic kava kava, until further information regarding safety and potential for liver damage were determined. We conducted a field study 2 months following the advisories in Toronto, Canada to determine whether kava kava continued to be recommended to consumers at retail health food stores. Eight participants asked employees at all stores what was recommended for anxiety and whether the products were safe. Twenty-two of 34 stores recommended kava kava, 9 of which mentioned safety concerns. Physicians should be aware that federal advisories may not affect sales of unsafe products.

Topics: Anxiety; Chemical and Drug Induced Liver Injury; Commerce; Consumer Product Safety; Humans; Kava; Ontario; Phytotherapy; Plant Preparations

Topics: Adolescent; Chemical and Drug Induced Liver Injury; Dietary Supplements; Female; Germany; Humans; Kava; Liver Transplantation; Middle Aged; Switzerland; United States

Topics: Chemical and Drug Induced Liver Injury; Europe; Humans; Kava; Pacific Islands; Plant Preparations; United States

Following reports of liver toxicity, including liver failure, associated with extracts from the Pacific islands plant kava (Piper methysticum), these have been banned from sale as a herbal anxiolytic in many Western countries, to the detriment of Pacific island economies. Pacific Islanders have used kava extensively for centuries, without recognised liver toxicity. However, the population is small, and there has been no systematic evaluation of possible liver damage. For both economic and public health reasons, it is important to determine if kava is inherently hepatotoxic, and what the mechanisms of toxicity are. Such research could lead to safer kava extracts for sale in Western countries, or identification of a subpopulation who should not consume kava.

Topics: Australia; Chemical and Drug Induced Liver Injury; Europe; Herbal Medicine; Humans; Internationality; Kava; Liver; Pacific Islands; Plant Preparations; Technology, Pharmaceutical

Herbal preparations are available widely and regarded generally by the public as harmless remedies for a variety of medical ailments. We report a case of acute hepatitis associated with the use of kava kava, derived from the root of the pepper plant, Piper methysticum. It is used in the United States as an antianxiety and sedative agent.. A previously healthy 14-year-old female was admitted to the hospital with hepatic failure. Initial therapy, including plasmapheresis, was unsuccessful and she deteriorated. She ultimately required a liver transplant and now remains well. The liver biopsy showed hepatocellular necrosis consistent with chemical hepatitis. A work-up for alternative causes of liver failure was negative. The patient gave a history of taking a kava kava-containing product for four months. The use of kava kava and liver failure, is supported by kava kava use, a negative work-up for alternative causes of liver failure, and histological changes in the liver.. Health care professionals need to be aware of the possibility of kava kava-induced hepatotoxicity. The toxicity of these alternative remedies emphasizes the importance of surveillance programs and quality control in the manufacture of these products. Clinicians must remain aware of the toxic potential of herbal products and always inquire about their intake in cases of unexplained liver injury.

Topics: Adolescent; Chemical and Drug Induced Liver Injury; Female; Hepatocytes; Humans; Kava; Liver; Liver Function Tests; Liver Transplantation

Topics: Animals; Anti-Anxiety Agents; Chemical and Drug Induced Liver Injury; Glutathione; Humans; Kava; Liver Failure; Plant Extracts

Botanical drugs are widely used and often contain highly active compounds. Kava root (Piper methysticum rhizoma), used frequently in Europe as a remedy against anxiety, contains kavapyrones with sedative effects. Seven case reports suggested the development of hepatitis after the intake of Kava.. We analyzed 29 novel cases of hepatitis along with Kava ingestion which occurred between 1990 and 2002 in addition to the seven already published case reports using a clinical diagnostic scale established for adverse hepatic drug reactions.. Hepatic necrosis or cholestatic hepatitis were noticed with both alcoholic and acetonic Kava extracts. The majority of the 29 patients and the additional seven published reports were women (27 females, nine males). Both the cumulative dose and the latency to when the hepatotoxic reaction emerged were highly variable. Nine patients developed fulminant liver failure, of which eight patients underwent liver transplantation. Three patients died, two following unsuccessful liver transplantation and one without. In all other patients, a complete recovery was noticed after the withdrawal of Kava. Pathophysiologically, both immunoallergic and idiosyncratic factors may be responsible.. The present report emphasizes the potentially severe hepatotoxicity of Kava which has recently led to the retraction of Kava-containing drugs by the pharmacovigilance authorities in Germany.

Topics: Acute Disease; Adult; Aged; Anti-Anxiety Agents; Chemical and Drug Induced Liver Injury; Female; Germany; Humans; Kava; Liver; Liver Failure; Male; Middle Aged; Product Surveillance, Postmarketing

Topics: Chemical and Drug Induced Liver Injury; France; Humans; Kava; Liver Cirrhosis; Liver Failure; Product Surveillance, Postmarketing

Topics: Anti-Anxiety Agents; Chemical and Drug Induced Liver Injury; Humans; Kava; Phytotherapy; Risk Factors

The use of potentially hepatotoxic herbal and dietary supplements is highly prevalent in the fulminant hepatic failure (FHF) patient population at our institution, and this subgroup of patients has a worse prognosis.. Retrospective case series. Settings An adult tertiary care university hospital and a Veterans Affairs hospital in Oregon.. All patients referred to the liver transplantation service for FHF from January 2001 through October 2002 (N = 20). We defined FHF as onset of encephalopathy within 8 weeks of onset of jaundice in the absence of preexisting liver disease. All patients underwent investigation for potential causes of liver injury. Potentially hepatotoxic supplements were defined as those with previously published reports of hepatic injury related to their use.. Ten patients (50%) were recent or active users of potentially hepatotoxic supplements or herbs; 10 had no history of supplement use. In the supplement group, 7 patients (35%) had no other identified cause for hepatic failure. Six patients in the supplement group and 2 patients in the nonsupplement group underwent orthotopic liver transplantation. Five patients in each group died. There were no significant differences in transplantation rate (P =.07) or survival (P>.99) between groups. Supplement use alone accounted for the most cases of FHF during this period, exceeding acetaminophen toxicity and viral hepatitis.. Herbal and dietary supplements were potential hepatotoxins in a high proportion of patients with FHF at our institution. Enhanced public awareness of the potential hepatotoxicity of these commonly used agents and increased regulatory oversight of their use is strongly urged.

Topics: Adult; Benzofurans; Benzopyrans; Caffeine; Chemical and Drug Induced Liver Injury; Dietary Supplements; Diiodothyronines; Drug Combinations; Ephedra sinica; Female; Humans; Kava; Larrea; Liver Failure; Liver Transplantation; Male; Middle Aged; Phenylpropanolamine; Plant Preparations; Prevalence; Retrospective Studies; Yohimbine

Traditional aqueous kava extracts were the most probable cause of hepatitis in two patients presenting with markedly elevated transaminases and hyperbilirubinaemia. A consequent survey of 27 heavy kava drinkers in New Caledonia showed elevated gamma glutamyl transferase in 23/27 and minimally elevated transaminases in 8/27. We conclude that not only commercially available, but also traditionally prepared kava extracts may rarely cause liver injury. The increased activity of gamma glutamyl transferase in heavy kava consumers in the presence of normal or minimally elevated transaminases is probably not a sign of liver injury, but rather reflects an induction of CYP450 enzymes.

Topics: Adult; Chemical and Drug Induced Liver Injury; Female; gamma-Glutamyltransferase; Humans; Kava; Male; Middle Aged; Phytotherapy; Plant Extracts; Transaminases

Kava-kava is a traditional beverage of the South Pacific islanders and has had centuries of use without major side effects. Standardised extracts of kava-kava produced in Europe have led to many serious health problems and even to death. The extraction process (aqueous vs. acetone in the two types of preparations) is responsible for the difference in toxicity as extraction of glutathione in addition to the kava lactones is important to provide protection against hepatotoxicity. The Michael reaction between glutathione and kava lactones, resulting in opening of the lactone ring, reduces the side effects of the kava kava extracts. This protective activity was demonstrated using Acanthamoebae castellanii in which 100% cell death occurred with 100 mg ml(-1) kava lactones alone, and 40% cell death with a mixture of 100 mg ml (-1)glutathione and 100 mg ml (-1) kava lactones. A comparison of kava lactone toxicity with other pharmaceutical products is discussed and recommendations made for safe usage of kava-kava products

Topics: Acanthamoeba; Animals; Cell Survival; Chemical and Drug Induced Liver Injury; Drug Interactions; Glutathione; Humans; Kava; Lactones; Plant Extracts; Plant Roots; Plant Stems; Pyrones; Tissue Distribution

January 2002, Health Canada issued an advisory, followed by a ban in August 2002, on the sale of herbal kava. One month after the advisory, 22 (67%) of 33 health food stores approached were selling kava. Two months after the ban, 17 (57%) of 30 stores continued to sell kava. These findings demonstrate that health food stores may need to be better informed about the sale of restricted natural health products.

Topics: Canada; Chemical and Drug Induced Liver Injury; Commerce; Consumer Product Safety; Humans; Kava; Phytotherapy; Plant Preparations

Topics: Anxiety; Canada; Chemical and Drug Induced Liver Injury; Commerce; Consumer Product Safety; Humans; Kava; Phytotherapy; Plant Preparations

Hepatic toxicity from manufactured herbal remedies that contain kava lactones has been reported in Europe, North America, and Australia. There is no evidence for serious liver damage in kava-using populations in Pacific Island societies or in Indigenous Australians who have used aqueous kava extracts. This article presents evidence that liver function changes in users of aqueous kava extracts appear to be reversible. Data from one Arnhem Land community [Northern Territory (NT), Australia] with 340 indigenous people older than 15 years of age in 2000 are used.. This study was a cross-sectional study with 98 participants, 36 of whom had never used kava. Among 62 kava users, 23 had discontinued kava at least 1 year before the study. Continuing users had not used kava for 1 to 2 months (n = 10) or 1 to 2 weeks previously (n = 15). Some (n = 14) had used kava within the previous 24 hr. Liver function tests were compared across these groups, taking into account differences due to age, sex, alcohol, and other substance use.. The average quantity of kava powder consumed was 118 g/week, and median duration of use was 12 years (range, 1-18 years). Kava usage levels were less than one-half of those found in previous studies. More recent kava use was independently associated with higher levels of liver enzymes gamma-glutamyl transferase (GGT) (p < 0.001) and alkaline phosphatase (ALP) (p < 0.001), but not with alanine aminotransferase or bilirubin, which were not elevated. In those who were not heavy alcohol users, only those who used kava within the previous 24 hr showed GGT levels higher than nonusers (p < 0.001), whereas higher ALP levels occurred only in those who last used kava 1 to 2 weeks (p = 0.015) and 24 hr previously (p = 0.005).. Liver function changes in users of aqueous kava extracts at these moderate levels of consumption appear to be reversible and begin to return to baseline after 1 to 2 weeks abstinence from kava. No evidence for irreversible liver damage has been found.

Topics: Adult; Alkaline Phosphatase; Australia; Beverages; Chemical and Drug Induced Liver Injury; Data Collection; Drug Interactions; Female; gamma-Glutamyltransferase; Humans; Kava; Liver Function Tests; Male; Native Hawaiian or Other Pacific Islander; Plant Extracts; Smoking; Substance-Related Disorders

Topics: Chemical and Drug Induced Liver Injury; Evidence-Based Medicine; Germany; Herbal Medicine; Humans; Kava; Legislation, Drug; Phytotherapy; Plant Extracts; Societies, Medical

Topics: Chemical and Drug Induced Liver Injury; Dietary Supplements; Echinacea; Glucosamine; Herbal Medicine; Kava; Legislation, Drug; Melatonin; United States; United States Food and Drug Administration

Since 1999, health-care professionals in Germany, Switzerland, and the United States have reported the occurrence of severe hepatic toxicity possibly associated with the consumption of products containing kava (i.e., kava kava or Piper methysticum). A total of 11 patients who used kava products had liver failure and underwent subsequent liver transplantation. On March 25, 2002, in response to five such case reports (four in Europe and one in the United States), the Food and Drug Administration (FDA) issued a consumer advisory and subsequently completed an investigation already underway of a similar U.S. case. This report presents the investigation of the two U.S. cases of liver failure associated with kava-containing dietary supplement products and summarizes the European cases. FDA continues to advise consumers and health-care providers about the potential risk associated with the use of kava-containing products.

Topics: Adolescent; Chemical and Drug Induced Liver Injury; Dietary Supplements; Female; Germany; Humans; Kava; Liver Transplantation; Middle Aged; Switzerland; United States

Topics: Chemical and Drug Induced Liver Injury; Humans; Kava

Topics: Anxiety Disorders; Chemical and Drug Induced Liver Injury; Drug Interactions; Humans; Kava

Topics: Chemical and Drug Induced Liver Injury; Consumer Product Safety; Humans; Kava; Phytotherapy; United States; United States Food and Drug Administration

Topics: Anxiety; Chemical and Drug Induced Liver Injury; Humans; Kava; Phytotherapy

Topics: Adolescent; Chemical and Drug Induced Liver Injury; Female; Humans; Kava; Liver Failure

Topics: Adult; Chemical and Drug Induced Liver Injury; Female; Humans; Kava; Lactones; Materia Medica; Nonprescription Drugs; Plants, Medicinal; Risk Factors

Two unrelated women, aged 39 and 42 years, had been admitted (at different times) to hospital because of "recurrence of an aetiologically uncertain acute hepatitis". Both patients had a history of acute hepatitis with GPT concentration of 796 and 755 U/l, respectively. Each of them had experienced recurrences of hepatitis, each of them preceded by taking herbal remedies as alternative medication, containing kava or common (or lesser) celandine, respectively. In each patient physical examination had been unremarkable.. Maximal values of GPT in the two patients were 422 and 350 U/l, respectively. Viral, autoimmune and metabolic causes of the hepatitis were excluded. In each of them liver biopsy revealed the picture of acute necrotizing hepatitis.. As it was suspected that the hepatitis was medication-induced, the intake of the mentioned herbal preparations was stopped. The liver function tests quickly became normal.. In view of the rapid response to their withdrawal, a causal connection between intake of the herbal preparations and the recurrences of acute hepatitis is the most likely explanation in both cases.

Topics: Acute Disease; Adult; Alanine Transaminase; Anti-Anxiety Agents; Chemical and Drug Induced Liver Injury; Female; Humans; Kava; Necrosis; Papaver; Plant Extracts; Plants, Medicinal; Recurrence