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Chengguo Xing - One of the best experts on this subject based on the ideXlab platform.
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Flavokawains A and B in Kava, Not Dihydromethysticin, Potentiate Acetaminophen-Induced Hepatotoxicity in C57BL/6 Mice
2016Co-Authors: Sreekanth C Narayanapillai, Pablo Leitzman, Gerard M. O’sullivan, Chengguo XingAbstract:ABSTRACT: Anxiolytic Kava products have been associated with rare but severe hepatotoxicity in humans. This adverse potential has never been captured in animal models, and the responsible compound(s) remains to be determined. The lack of such knowledge greatly hinders the preparation of a safer Kava product and limits its beneficial applications. In this study we evaluated the toxicity of Kava as a single entity or in combination with acetaminophen (APAP) in C57BL/6 mice. Kava alone revealed no adverse effects for long-term usage even at a dose of 500 mg/kg bodyweight. On the contrary a three-day Kava pretreatment potentiated APAP-induced hepatotoxicity, resulted in an increase in serum ALT and AST, and increased severity of liver lesions. Chalcone-based flavokawains A (FKA) and B (FKB) in Kava recapitulated its hepatotoxic synergism with APAP while dihydromethysticin (DHM, a representative Kavalactone and a potential lung cancer chemopreventive agent) had no such effect. These results, for the first time, demonstrate the hepatotoxic risk of Kava and it
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measuring the chemical and cytotoxic variability of commercially available Kava piper methysticum g forster
PLOS ONE, 2014Co-Authors: Amanda C Martin, Chengguo Xing, Edward Johnston, Adrian D HegemanAbstract:Formerly used world-wide as a popular botanical medicine to reduce anxiety, reports of hepatotoxicity linked to consuming Kava extracts in the late 1990s have resulted in global restrictions on Kava use and have hindered Kava-related research. Despite its presence on the United States Food and Drug Administration consumer advisory list for the past decade, export data from Kava producing countries implies that US Kava imports, which are not publicly reported, are both increasing and of a fairly high volume. We have measured the variability in extract chemical composition and cytotoxicity towards human lung adenocarcinoma A549 cancer cells of 25 commercially available Kava products. Results reveal a high level of variation in chemical content and cytotoxicity of currently available Kava products. As public interest and use of Kava products continues to increase in the United States, efforts to characterize products and expedite research of this potentially useful botanical medicine are necessary.
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flavokawains a and b in Kava not dihydromethysticin potentiate acetaminophen induced hepatotoxicity in c57bl 6 mice
Chemical Research in Toxicology, 2014Co-Authors: Sreekanth C Narayanapillai, Pablo Leitzman, Gerard M Osullivan, Chengguo XingAbstract:Anxiolytic Kava products have been associated with rare but severe hepatotoxicity in humans. This adverse potential has never been captured in animal models, and the responsible compound(s) remains to be determined. The lack of such knowledge greatly hinders the preparation of a safer Kava product and limits its beneficial applications. In this study we evaluated the toxicity of Kava as a single entity or in combination with acetaminophen (APAP) in C57BL/6 mice. Kava alone revealed no adverse effects for long-term usage even at a dose of 500 mg/kg bodyweight. On the contrary a three-day Kava pretreatment potentiated APAP-induced hepatotoxicity, resulted in an increase in serum ALT and AST, and increased severity of liver lesions. Chalcone-based flavokawains A (FKA) and B (FKB) in Kava recapitulated its hepatotoxic synergism with APAP while dihydromethysticin (DHM, a representative Kavalactone and a potential lung cancer chemopreventive agent) had no such effect. These results, for the first time, demonstr...
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flavokawains a and b in Kava not dihydromethysticin potentiate acetaminophen induced hepatotoxicity in c57bl 6 mice
Chemical Research in Toxicology, 2014Co-Authors: Sreekanth C Narayanapillai, Pablo Leitzman, Gerard M Osullivan, Chengguo XingAbstract:Anxiolytic Kava products have been associated with rare but severe hepatotoxicity in humans. This adverse potential has never been captured in animal models, and the responsible compound(s) remains to be determined. The lack of such knowledge greatly hinders the preparation of a safer Kava product and limits its beneficial applications. In this study we evaluated the toxicity of Kava as a single entity or in combination with acetaminophen (APAP) in C57BL/6 mice. Kava alone revealed no adverse effects for long-term usage even at a dose of 500 mg/kg bodyweight. On the contrary a three-day Kava pretreatment potentiated APAP-induced hepatotoxicity, resulted in an increase in serum ALT and AST, and increased severity of liver lesions. Chalcone-based flavokawains A (FKA) and B (FKB) in Kava recapitulated its hepatotoxic synergism with APAP while dihydromethysticin (DHM, a representative Kavalactone and a potential lung cancer chemopreventive agent) had no such effect. These results, for the first time, demonstrate the hepatotoxic risk of Kava and its chalcone-based FKA and FKB in vivo and suggest that herb-drug interaction may account for the rare hepatotoxicity associated with anxiolytic Kava usage in humans.
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Kava blocks 4 methylnitrosamino 1 3 pyridyl 1 butanone induced lung tumorigenesis in association with reducing o6 methylguanine dna adduct in a j mice
Cancer Prevention Research, 2014Co-Authors: Pablo Leitzman, Sreekanth C Narayanapillai, Gerard M Osullivan, Pramod Upadhyaya, Stephen S Hecht, Silvia Balbo, Bo Zhou, Ahmad Ali Shaik, Chengguo XingAbstract:We previously reported the chemopreventive potential of Kava against 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)- and benzo(a)pyrene (BaP)-induced lung tumorigenesis in A/J mice during the initiation and postinitiation stages. In this study, we investigated the tumorigenesis-stage specificity of Kava, the potential active compounds, and the underlying mechanisms in NNK-induced lung tumorigenesis in A/J mice. In the first experiment, NNK-treated mice were given diets containing Kava at a dose of 5 mg/g of diet during different periods. Kava treatments covering the initiation stage reduced the multiplicity of lung adenomas by approximately 99%. A minimum effective dose is yet to be defined because Kava at two lower dosages (2.5 and 1.25 mg/g of diet) were equally effective as 5 mg/g of diet in completely inhibiting lung adenoma formation. Daily gavage of Kava (one before, during, and after NNK treatment) completely blocked lung adenoma formation as well. Kavalactone-enriched fraction B fully recapitulated Kava's chemopreventive efficacy, whereas Kavalactone-free fractions A and C were much less effective. Mechanistically, Kava and fraction B reduced NNK-induced DNA damage in lung tissues with a unique and preferential reduction in O(6)-methylguanine (O(6)-mG), the highly tumorigenic DNA damage by NNK, correlating and predictive of efficacy on blocking lung adenoma formation. Taken together, these results demonstrate the outstanding efficacy of Kava in preventing NNK-induced lung tumorigenesis in A/J mice with high selectivity for the initiation stage in association with the reduction of O(6)-mG adduct in DNA. They also establish the knowledge basis for the identification of the active compound(s) in Kava.
Rolf Teschke - One of the best experts on this subject based on the ideXlab platform.
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Kava in the treatment of generalized anxiety disorder a double blind randomized placebo controlled study
Journal of Clinical Psychopharmacology, 2013Co-Authors: Jerome Sarris, Rolf Teschke, Con Stough, Chad A Bousman, Zahra T Wahid, Greg Murray, Karen Savage, Ashley Dowell, Isaac SchweitzerAbstract:Kava (Piper methysticum) is a plant-based medicine, which has been previously shown to reduce anxiety. To date, however, no placebo-controlled trial assessing Kava in the treatment of generalized anxiety disorder (GAD) has been completed. A total of 75 participants with GAD and no comorbid mood disorder were enrolled in a 6-week double-blind trial of an aqueous extract of Kava (120/240 mg of Kavalactones per day depending on response) versus placebo. γ-Aminobutyric acid (GABA) and noradrenaline transporter polymorphisms were also analyzed as potential pharmacogenetic markers of response. Reduction in anxiety was measured using the Hamilton Anxiety Rating Scale (HAMA) as the primary outcome. Intention-to-treat analysis was performed on 58 participants who met inclusion criteria after an initial 1 week placebo run-in phase. Results revealed a significant reduction in anxiety for the Kava group compared with the placebo group with a moderate effect size (P = 0.046, Cohen d = 0.62). Among participants with moderate to severe Diagnostic and Statistical Manual of Mental Disorders-diagnosed GAD, this effect was larger (P = 0.02; d = 0.82). At conclusion of the controlled phase, 26% of the Kava group were classified as remitted (HAMA ≤ 7) compared with 6% of the placebo group (P = 0.04). Within the Kava group, GABA transporter polymorphisms rs2601126 (P = 0.021) and rs2697153 (P = 0.046) were associated with HAMA reduction. Kava was well tolerated, and aside from more headaches reported in the Kava group (P = 0.05), no other significant differences between groups occurred for any other adverse effects, nor for liver function tests. Standardized Kava may be a moderately effective short-term option for the treatment of GAD. Furthermore, specific GABA transporter polymorphisms appear to potentially modify anxiolytic response to Kava.
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contaminant hepatotoxins as culprits for Kava hepatotoxicity fact or fiction
Phytotherapy Research, 2013Co-Authors: Rolf Teschke, Jerome Sarris, Vincent LebotAbstract: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. (Resume d'auteur)
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Contaminant Hepatotoxins as Culprits for Kava Hepatotoxicity - Fact or Fiction?
Phytotherapy research : PTR, 2012Co-Authors: Rolf Teschke, Jerome Sarris, Vincent LebotAbstract: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. Copyright © 2012 John Wiley & Sons, Ltd.
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Kava hepatotoxicity in traditional and modern use the presumed pacific Kava paradox hypothesis revisited
British Journal of Clinical Pharmacology, 2012Co-Authors: Rolf Teschke, Jerome Sarris, Isaac SchweitzerAbstract: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.
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Kava and Kava hepatotoxicity requirements for novel experimental ethnobotanical and clinical studies based on a review of the evidence
Phytotherapy Research, 2011Co-Authors: Rolf Teschke, Tran Dang Xuan, Samuel X Qiu, Vincent LebotAbstract: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, appropriate studies have yet to be done and should be extended to other mould hepatotoxins, with the aim of publishing the obtained results. It is hoped that with the proposed qualifying measures, the safety of individuals consuming Kava will substantially be improved. (Resume d'auteur)
Vincent Lebot - One of the best experts on this subject based on the ideXlab platform.
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contaminant hepatotoxins as culprits for Kava hepatotoxicity fact or fiction
Phytotherapy Research, 2013Co-Authors: Rolf Teschke, Jerome Sarris, Vincent LebotAbstract: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. (Resume d'auteur)
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Contaminant Hepatotoxins as Culprits for Kava Hepatotoxicity - Fact or Fiction?
Phytotherapy research : PTR, 2012Co-Authors: Rolf Teschke, Jerome Sarris, Vincent LebotAbstract: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. Copyright © 2012 John Wiley & Sons, Ltd.
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Kava and Kava hepatotoxicity requirements for novel experimental ethnobotanical and clinical studies based on a review of the evidence
Phytotherapy Research, 2011Co-Authors: Rolf Teschke, Tran Dang Xuan, Samuel X Qiu, Vincent LebotAbstract: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, appropriate studies have yet to be done and should be extended to other mould hepatotoxins, with the aim of publishing the obtained results. It is hoped that with the proposed qualifying measures, the safety of individuals consuming Kava will substantially be improved. (Resume d'auteur)
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Proposal for a Kava quality standardization code.
Food and Chemical Toxicology, 2011Co-Authors: Rolf Teschke, Vincent LebotAbstract: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.
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Kava hepatotoxicity solution a six point plan for new Kava standardization
Phytomedicine, 2011Co-Authors: Rolf Teschke, Jerome Sarris, Vincent LebotAbstract: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.
Jerome Sarris - One of the best experts on this subject based on the ideXlab platform.
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Kava in the treatment of generalized anxiety disorder a double blind randomized placebo controlled study
Journal of Clinical Psychopharmacology, 2013Co-Authors: Jerome Sarris, Rolf Teschke, Con Stough, Chad A Bousman, Zahra T Wahid, Greg Murray, Karen Savage, Ashley Dowell, Isaac SchweitzerAbstract:Kava (Piper methysticum) is a plant-based medicine, which has been previously shown to reduce anxiety. To date, however, no placebo-controlled trial assessing Kava in the treatment of generalized anxiety disorder (GAD) has been completed. A total of 75 participants with GAD and no comorbid mood disorder were enrolled in a 6-week double-blind trial of an aqueous extract of Kava (120/240 mg of Kavalactones per day depending on response) versus placebo. γ-Aminobutyric acid (GABA) and noradrenaline transporter polymorphisms were also analyzed as potential pharmacogenetic markers of response. Reduction in anxiety was measured using the Hamilton Anxiety Rating Scale (HAMA) as the primary outcome. Intention-to-treat analysis was performed on 58 participants who met inclusion criteria after an initial 1 week placebo run-in phase. Results revealed a significant reduction in anxiety for the Kava group compared with the placebo group with a moderate effect size (P = 0.046, Cohen d = 0.62). Among participants with moderate to severe Diagnostic and Statistical Manual of Mental Disorders-diagnosed GAD, this effect was larger (P = 0.02; d = 0.82). At conclusion of the controlled phase, 26% of the Kava group were classified as remitted (HAMA ≤ 7) compared with 6% of the placebo group (P = 0.04). Within the Kava group, GABA transporter polymorphisms rs2601126 (P = 0.021) and rs2697153 (P = 0.046) were associated with HAMA reduction. Kava was well tolerated, and aside from more headaches reported in the Kava group (P = 0.05), no other significant differences between groups occurred for any other adverse effects, nor for liver function tests. Standardized Kava may be a moderately effective short-term option for the treatment of GAD. Furthermore, specific GABA transporter polymorphisms appear to potentially modify anxiolytic response to Kava.
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contaminant hepatotoxins as culprits for Kava hepatotoxicity fact or fiction
Phytotherapy Research, 2013Co-Authors: Rolf Teschke, Jerome Sarris, Vincent LebotAbstract: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. (Resume d'auteur)
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Contaminant Hepatotoxins as Culprits for Kava Hepatotoxicity - Fact or Fiction?
Phytotherapy research : PTR, 2012Co-Authors: Rolf Teschke, Jerome Sarris, Vincent LebotAbstract: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. Copyright © 2012 John Wiley & Sons, Ltd.
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Kava hepatotoxicity in traditional and modern use the presumed pacific Kava paradox hypothesis revisited
British Journal of Clinical Pharmacology, 2012Co-Authors: Rolf Teschke, Jerome Sarris, Isaac SchweitzerAbstract: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.
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Neurocognitive effects of Kava (Piper methysticum): a systematic review
Human psychopharmacology, 2011Co-Authors: E. Laporte, Jerome Sarris, Con Stough, Andrew ScholeyAbstract:Rationale Kava (Piper methysticum) elicits dose-dependent psychotropic effects and thus may potentially deleteriously affect cognitive performance. Clinical trials have assessed the effects of Kava on cognition, however, to our knowledge no systematic review has been conducted in this area. Objective To systematically review the effects of Kava on cognition, providing an analysis of the individual study's methodological quality, results and effect sizes. Methods A systematic review was conducted of publications up to June 15th 2010, using the electronic databases MEDLINE, PsychINFO, CINAHL, Web of Science and The Cochrane Library. The search criteria involved Kava and cognition related terms, e.g. memory and attention. Results Ten human clinical trials met inclusion criteria (acute n = 7, chronic n = 3). One acute study found that Kava significantly improved visual attention and working memory processes while another found that Kava increased body sway. One chronic study found that Kava significantly impaired visual attention during high-cognitive demand. Potential enhanced cognition may be attributed to the ability of Kava to inhibit re-uptake of noradrenaline in the pre-frontal cortex, while increased body sway may be due to GABA pathway modulation. Conclusions The majority of evidence suggests that Kava has no replicated significant negative effects on cognition. Copyright © 2011 John Wiley & Sons, Ltd.
Gerard M Osullivan - One of the best experts on this subject based on the ideXlab platform.
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flavokawains a and b in Kava not dihydromethysticin potentiate acetaminophen induced hepatotoxicity in c57bl 6 mice
Chemical Research in Toxicology, 2014Co-Authors: Sreekanth C Narayanapillai, Pablo Leitzman, Gerard M Osullivan, Chengguo XingAbstract:Anxiolytic Kava products have been associated with rare but severe hepatotoxicity in humans. This adverse potential has never been captured in animal models, and the responsible compound(s) remains to be determined. The lack of such knowledge greatly hinders the preparation of a safer Kava product and limits its beneficial applications. In this study we evaluated the toxicity of Kava as a single entity or in combination with acetaminophen (APAP) in C57BL/6 mice. Kava alone revealed no adverse effects for long-term usage even at a dose of 500 mg/kg bodyweight. On the contrary a three-day Kava pretreatment potentiated APAP-induced hepatotoxicity, resulted in an increase in serum ALT and AST, and increased severity of liver lesions. Chalcone-based flavokawains A (FKA) and B (FKB) in Kava recapitulated its hepatotoxic synergism with APAP while dihydromethysticin (DHM, a representative Kavalactone and a potential lung cancer chemopreventive agent) had no such effect. These results, for the first time, demonstr...
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flavokawains a and b in Kava not dihydromethysticin potentiate acetaminophen induced hepatotoxicity in c57bl 6 mice
Chemical Research in Toxicology, 2014Co-Authors: Sreekanth C Narayanapillai, Pablo Leitzman, Gerard M Osullivan, Chengguo XingAbstract:Anxiolytic Kava products have been associated with rare but severe hepatotoxicity in humans. This adverse potential has never been captured in animal models, and the responsible compound(s) remains to be determined. The lack of such knowledge greatly hinders the preparation of a safer Kava product and limits its beneficial applications. In this study we evaluated the toxicity of Kava as a single entity or in combination with acetaminophen (APAP) in C57BL/6 mice. Kava alone revealed no adverse effects for long-term usage even at a dose of 500 mg/kg bodyweight. On the contrary a three-day Kava pretreatment potentiated APAP-induced hepatotoxicity, resulted in an increase in serum ALT and AST, and increased severity of liver lesions. Chalcone-based flavokawains A (FKA) and B (FKB) in Kava recapitulated its hepatotoxic synergism with APAP while dihydromethysticin (DHM, a representative Kavalactone and a potential lung cancer chemopreventive agent) had no such effect. These results, for the first time, demonstrate the hepatotoxic risk of Kava and its chalcone-based FKA and FKB in vivo and suggest that herb-drug interaction may account for the rare hepatotoxicity associated with anxiolytic Kava usage in humans.
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Kava blocks 4 methylnitrosamino 1 3 pyridyl 1 butanone induced lung tumorigenesis in association with reducing o6 methylguanine dna adduct in a j mice
Cancer Prevention Research, 2014Co-Authors: Pablo Leitzman, Sreekanth C Narayanapillai, Gerard M Osullivan, Pramod Upadhyaya, Stephen S Hecht, Silvia Balbo, Bo Zhou, Ahmad Ali Shaik, Chengguo XingAbstract:We previously reported the chemopreventive potential of Kava against 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)- and benzo(a)pyrene (BaP)-induced lung tumorigenesis in A/J mice during the initiation and postinitiation stages. In this study, we investigated the tumorigenesis-stage specificity of Kava, the potential active compounds, and the underlying mechanisms in NNK-induced lung tumorigenesis in A/J mice. In the first experiment, NNK-treated mice were given diets containing Kava at a dose of 5 mg/g of diet during different periods. Kava treatments covering the initiation stage reduced the multiplicity of lung adenomas by approximately 99%. A minimum effective dose is yet to be defined because Kava at two lower dosages (2.5 and 1.25 mg/g of diet) were equally effective as 5 mg/g of diet in completely inhibiting lung adenoma formation. Daily gavage of Kava (one before, during, and after NNK treatment) completely blocked lung adenoma formation as well. Kavalactone-enriched fraction B fully recapitulated Kava's chemopreventive efficacy, whereas Kavalactone-free fractions A and C were much less effective. Mechanistically, Kava and fraction B reduced NNK-induced DNA damage in lung tissues with a unique and preferential reduction in O(6)-methylguanine (O(6)-mG), the highly tumorigenic DNA damage by NNK, correlating and predictive of efficacy on blocking lung adenoma formation. Taken together, these results demonstrate the outstanding efficacy of Kava in preventing NNK-induced lung tumorigenesis in A/J mice with high selectivity for the initiation stage in association with the reduction of O(6)-mG adduct in DNA. They also establish the knowledge basis for the identification of the active compound(s) in Kava.
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chemopreventive effect of Kava on 4 methylnitrosamino 1 3 pyridyl 1 butanone plus benzo a pyrene induced lung tumorigenesis in a j mice
Cancer Prevention Research, 2008Co-Authors: Thomas E Johnson, Gerard M Osullivan, Fekadu Kassie, Mesfin Negia, Timothy Hanson, Pramod Upadhyaya, Peter P Ruvolo, Stephen S Hecht, Chengguo XingAbstract:Lung cancer is the leading cause of cancer death, and chemoprevention is a potential strategy to help control this disease. Epidemiologic survey indicates that Kava may be chemopreventive for lung cancer, but there is a concern about its potential hepatotoxicity. In this study, we evaluated whether oral Kava could prevent 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) plus benzo[a]pyrene (B[a]P)-induced lung tumorigenesis in A/J mice. We also studied the effect of Kava to liver. At a dose of 10 mg/g diet, 30-week Kava treatment (8 weeks concurrent with NNK and B[a]P treatment followed by 22 weeks post-carcinogen treatment) effectively reduced lung tumor multiplicity by 56%. Kava also reduced lung tumor multiplicity by 47% when administered concurrently with NNK and B[a]P for 8 weeks. Perhaps most importantly, Kava reduced lung tumor multiplicity by 49% when administered after the final NNK and B[a]P treatment. These results show for the first time the chemopreventive potential of Kava against lung tumorigenesis. Mechanistically, Kava inhibited proliferation and enhanced apoptosis in lung tumors, as shown by a reduction in proliferating cell nuclear antigen (PCNA), an increase in caspase-3, and cleavage of poly(ADP-ribose) polymerase (PARP). Kava treatment also inhibited the activation of nuclear factor kappaBNF-kappaB, a potential upstream mechanism of Kava chemoprevention. Although not rigorously evaluated in this study, our preliminary data were not suggestive of hepatotoxicity. Based on these results, further studies are warranted to explore the chemopreventive potential and safety of Kava.
