€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY***** Norton SA Ruze P Kava dermopathy. In: J Am Acad Dermatol (1994 Jul) 31(1):89-97 ISSN: 0190-9622 Kava is a psychoactive beverage used ceremonially for thousands of years by Pacific Islanders. Kava is made from the root of the pepper plant, Piper methysticum, found in Polynesia, Melanesia, and Micronesia. The beverage is a nonfermented depressant with complex neuropharmacologic properties that causes a tranquil state of intoxication. Kava also affects the skin, causing a peculiar scaly eruption. The cutaneous effects were first reported by members of Captain James Cook's Pacific expeditions, but they have never been described in dermatologic literature. Heavy kava drinkers acquire a reversible ichthyosiform eruption, kava dermopathy. The cause is unknown but may relate to interference with cholesterol metabolism. Today kava is used across the Pacific in both traditional ceremonies and informal social events. In Western nations, kava is sold as a relaxant by health food stores. This article explores the history of kava dermopathy from Cook's early reports to its presence today. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****LANCET***** Ruze P Kava-induced dermopathy: a niacin deficiency? In: Lancet (1990 Jun 16) 335(8703):1442-5 ISSN: 0140-6736 Heavy chronic consumption of kava (Piper methysticum) is associated with a pellagroid dermopathy that has been attributed to niacin deficiency. Over 200 male kava drinkers in the Tonga Islands were interviewed and examined regarding the characteristic skin changes. A scaly rash suggestive of ichthyosis and eye irritation were present in some heavy kava drinkers. 29 kava drinkers with prominent skin changes were randomised to receive either 100 mg oral nicotinamide or placebo daily for three weeks. Skin examinations and photographs showed clinical improvement in 5/15 of the nicotinamide group and 5/14 of the placebo group. These data, along with history and physical examination findings, suggest that niacin deficiency is not responsible for the rash, which is more characteristic of an acquired ichthyosis. Registry Numbers: 59-67-6 (Niacin) 98-92-0 (Niacinamide) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****ANNALES PHARMACEUTIQUES FRANCAISES***** Koch M Plat M Mehri H Saillant JP Kornowski H [Total kawalactones and dihydro-5,6 kawalactones determinations in kawa preparations (Piper methysticum Forst; Piperaceae)] Dosage des kawalactones totales et des dihydro-5,6 kawalactones dans les preparations de kawa (Piper methysticum Forst., Piperacees. In: Ann Pharm Fr (1973 Feb) 31(2):133-8 ISSN: 0003-4509 (Published in French) [No Abstract Available] €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****ARCHIVES INTERNATIONALES DE PHARMACODYNAMIE ET DE THERAPIE***** Duffield PH Jamieson DD Duffield AM Effect of aqueous and lipid-soluble extracts of kava on the conditioned avoidance response in rats. In: Arch Int Pharmacodyn Ther (1989 Sep-Oct) 301:81-90 ISSN: 0003-9780 The aqueous, pyrone-free extract from kava (Piper methysticum) and the lipid-soluble extract (kava resin) were tested for their effect on amphetamine-induced hypermotility in mice and on conditioned avoidance response behavior in rats in a shelf-jump apparatus. Both kava extracts reduced amphetamine-induced hypermotility. Aqueous kava extract in i.p. doses of 30 mg/kg to 500 mg/kg had no effect on conditioned avoidance responses. At or below 100 mg/kg i.p. kava resin also failed to modify the number of conditioned avoidance responses obtained. However, 125 mg/kg of resin significantly reduced the number of conditioned avoidance responses by 18%. Increasing the dose of kava to 150 mg/kg caused ataxia and sedation which was so marked that a modified protocol was necessary. Only a marginally greater effect on conditioned avoidance response was obtained under these conditions. The effect of kava extract was slight compared to that of the standard antipsychotic drugs chlorpromazine and haloperidol in our procedure. Registry Numbers: 300-62-9 (Amphetamine) 50-53-3 (Chlorpromazine) 52-86-8 (Haloperidol) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Jamieson DD Duffield PH Cheng D Duffield AM Comparison of the central nervous system activity of the aqueous and lipid extract of kava (Piper methysticum). In: Arch Int Pharmacodyn Ther (1989 Sep-Oct) 301:66-80 ISSN: 0003-9780 The central nervous activity of the aqueous extract of kava was examined in mice, and compared to the effect of the lipid-soluble extract. The aqueous extract caused a loss of spontaneous activity without loss of muscle tone. No hypnotic effect was seen, but some analgesia was produced. The anticonvulsant effect against strychnine was very slight and there was no evidence of local anesthetic action. There was a slight anti-apomorphine effect and tetrabenazine-induced ptosis was decreased. The lipid-soluble extract (kava resin) also decreased spontaneous motility, together with a marked reduction of motor control. Hypnosis, determined by loss of righting reflex, was produced, analgesia was marked, and a local anesthetic action evident. Kava resin also decreased apomorphine-induced hyperreactivity and partially reversed tetrabenazine-induced ptosis. Kava resin produces a greater range of pharmacological actions than the aqueous extract, and the latter is orally inactive in mice and rats. The pharmacological effects of kava ingestion appear to be due to the activity of the compounds present in the lipid-soluble fraction. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****BIOMEDICAL AND ENVIRONMENTAL MASS SPECTROMETRY***** Cheng D Lidgard RO Duffield PH Duffield AM Brophy JJ Identification by methane chemical ionization gas chromatography/mass spectrometry of the products obtained by steam distillation and aqueous acid extraction of commercial Piper methysticum. In: Biomed Environ Mass Spectrom (1988 Nov) 17(5):371-6 ISSN: 0887-6134 Bornyl cinnamate has been identified as a constituent of kava resin and of the steam distillate of Piper methysticum. 5- Hydroxydihydrokawain was identified in commercial samples of P. methysticum originating from Vanuatu provided an initial aqueous extraction was employed. Commercial preparations, and fresh samples of the root of this plant from Fiji, lacked this compound. Two previously described N-cinnamoyl pyrrolidine alkaloids were also observed along with stigmasterol in kava resin from Fiji and Vanuatu. The products derived from aqueous 2 M hydrochloric acid extraction of P. methysticum were determined from methane chemical ionization gas chromatography/mass spectrometry analysis which identified a series of hydroxylated compounds (15a-d) derived from formal decarbonylation of the parent kava lactones. The products (13a-c) of dehydration of these compounds were also observed. The efficiency of kava resin extraction from plant material by water (the traditional method of preparation of the kava beverage) was typically 5-10% of that recovered by direct extraction with an organic solvent. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****EUROPEAN JOURNAL OF PHARMACOLOGY***** Gleitz J Friese J Beile A Ameri A Peters T Anticonvulsive action of (+/-)-kavain estimated from its properties on stimulated synaptosomes and Na+ channel receptor sites. In: Eur J Pharmacol (1996 Nov 7) 315(1):89-97 ISSN: 0014-2999 Kava pyrones are constituents of the intoxicating pepper (Piper methysticum Forst), which has been shown to be anticonvulsive. The question of how the excitability of neurons is affected was investigated by determining the interaction of (+/-)-kavain with epitopes (site 1, site 2) of voltage-dependent Na+ channels and the action of (+/-)-kavain on 4-aminopyridine-stimulated synaptosomes as model of repetitive firing neurons. [3H]Saxitoxin and [3H]batrachotoxin were used for radioligand-binding assays performed with synaptosomal membranes. Gultamate released from 4-aminopyridine- stimulated cerebrocortical synaptosomes and the cytosolic concentrations of Na+ and Ca2+ ([Na+]i, [Ca+]i) were detected fluorometrically by using an enzyme-linked assay, sodium-binding benzofuranisophthalate (SBFI) and Fura-2, respectively. (+/-)-Kavain failed to compete with [3H]saxitoxin up to 400 mumol/l but dose- dependently suppressed binding of [3H]batrachotoxin with an IC50 value of 88 mumol/l (Ki = 72 mumol/l) although displacement of [3H]batrachotoxin was restricted to 33% of control at 400 mumol/l (+/- )-kavain. In stimulated synaptosomes, 5 mmol/l 4-aminopyridine provoked an increase in [Na+]i and [Ca2+]i by 9 mmol/l Na+ and 235 nmol/l Ca2+. Comparable to the reduction in [3H]batrachotoxin binding, 400 mumol/l (+/-)-kavain suppressed the increase in [Na+]i and [Ca2+]i to 38 and 29% of control, respectively. Consistent with the increase in [Na+]i and [Ca2+]i, 5 mmol/l 4-aminopyridine provoked glutamate release (rate: 38 pmol/s*mg protein) which was dose- dependently diminished to 60% of control by 400 mumol/l (+/-)-kavain. KCl depolarization (40 mmol/l) provoked an increase in [Ca2+]i and glutamate release almost identical to the responses elicited by 4- aminopyridine but 400 mumol/l (+/-)-kavain suppressed only the rate of glutamate release by 9% of control. The data suggest an interaction of (+/-)-kavain with voltage-dependent Na+ and Ca2+ channels, thereby suppressing the 4-aminopyridine-induced increase in [Na+]i, [Ca2+]i and the release of endogenous glutamate. Registry Numbers: 1635-33-2 (kavain) 35523-89-8 (Saxitoxin) 504-24-5 (4-Aminopyridine) 56-86-0 (Glutamic Acid) 7440-23-5 (Sodium) 7440-70-2 (Calcium) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Backhauss C Krieglstein J Extract of kava (Piper methysticum) and its methysticin constituents protect brain tissue against ischemic damage in rodents. In: Eur J Pharmacol (1992 May 14) 215(2-3):265-9 ISSN: 0014-2999 The purpose of the present study was to test whether kava extract and its constituents kawain, dihydrokawain, methysticin, dihydromethysticin and yangonin provide protection against ischemic brain damage. To this end, we used a model of focal cerebral ischemia in mice and rats. Ischemia was induced by microbipolar coagulation of the left middle cerebral artery (MCA). To quantify the size of the lesion in mice, the area of the infarct on the brain surface was assessed planimetrically 48 h after MCA occlusion by transcardial perfusion of carbon black. In the rat model infarct volume was determined 48 h after MCA occlusion by planimetric analysis and subsequent integration of the infarct areas on serial coronal slices. Compounds were administered i.p., except the kava extract, which was administered orally. The effects of the kava extract and its constituents were compared with those produced by the typical anticonvulsant, memantine. The kava extract, methysticin and dihydromethysticin produced effects similar to those of the reference substance memantine. The kava extract (150 mg/kg, 1 h before ischemia) diminished the infarct area (P less than 0.05) in mouse brains and the infarct volume (P less than 0.05) in rat brains. Methysticin, dihydromethysticin (both 10 and 30 mg/kg, 15 min before ischemia) and memantine (20 mg/kg, 30 min before ischemia) significantly reduced the infarct area in mouse brains. All other compounds failed to produce a beneficial effect on the infarct area in mouse brains. In conclusion, the kava extract exhibited neuroprotective activity, which was probably mediated by its constituents methysticin and dihydromethysticin. Registry Numbers: 19982-08-2 (Memantine) 495-85-2 (methysticin) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****HAWAII MEDICAL JOURNAL***** Hope BE Massey DG Fournier-Massey G Hawaiian materia medica for asthma. In: Hawaii Med J (1993 Jun) 52(6):160-6 ISSN: 0017-8594 A literature search and traditional narration determined that at least 58 herbs with scientific names were commonly used by Hawaiians for asthma. Of particular note were Piper methysticum, solanum americanum, and Aleurites molucana with oral tradition singling out Sophora chrysophylla. These four therapeutic agents, especially Sophora, have scientific merit and warrant further investigation because of the recent increase in asthma mortality, their potential for improved patient compliance, minimal of side effects, and the low cost. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****JOURNAL OF CHROMATOGRAPHY***** Duffield AM Jamieson DD Lidgard RO Duffield PH Bourne DJ Identification of some human urinary metabolites of the intoxicating beverage kava. In: J Chromatogr (1989 Jul 28) 475:273-81 ISSN: 0021-9673 Methane chemical ionization (CI) gas chromatography-mass spectrometry (GC-MS) has been used to identify some of the human urinary metabolites of the kava lactones following ingestion of kava prepared by the traditional method of aqueous extraction of Piper methysticum. All seven major, and several minor, kava lactones were identified in human urine. Observed metabolic transformations include the reduction of the 3,4-double bond and/or demethylation of the 4-methoxyl group of the alpha-pyrone ring system. Demethylation of the 12-methoxy substituent in yangonin (or alternatively hydroxylation at C-12 of desmethoxyyangonin) was also recognised. This product was isolated by high-performance liquid chromatographic analysis of crude urine extracts and characterised by methane CI GC-MS. In contrast to the situation prevailing in the rat no dihydroxylated metabolites of the kava lactones, or products from ring opening of the 2-pyrone ring system, were identified in human urine. GC-MS analysis of urine can be readily utilised to determine whether donors have recently consumed kava. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****JOURNAL OF ETHNOPHARMACOLOGY***** Locher CP Burch MT Mower HF Berestecky J Davis H Van Poel B Lasure A Vanden Berghe DA Vlietinck AJ Anti-microbial activity and anti-complement activity of extracts obtained from selected Hawaiian medicinal plants. In: J Ethnopharmacol (1995 Nov 17) 49(1):23-32 ISSN: 0378-8741 Selected plants having a history of use in Polynesian traditional medicine for the treatment of infectious disease were investigated for anti-viral, anti-fungal and anti-bacterial activity in vitro. Extracts from Scaevola sericea, Psychotria hawaiiensis, Pipturus albidus and Eugenia malaccensis showed selective anti-viral activity against Herpes Simplex Virus-1 and 2 and Vesicular Stomatitis Virus. Aleurites moluccana extracts showed anti-bacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa, while Pipturus albidus and Eugenia malaccensis extracts showed growth inhibition of Staphylococcus aureus and Streptococcus pyogenes. Psychotria hawaiiensis and Solanum niger inhibited growth of the fungi Microsporum canis, Trichophyton rubrum and Epidermophyton floccosum, while Ipomoea sp., Pipturus albidus, Scaevola sericea, Eugenia malaccensis, Piper methysticum, Barringtonia asiatica and Adansonia digitata extracts showed anti-fungal activity to a lesser extent. Eugenia malaccensis was also found to inhibit the classical pathway of complement suggesting that an immunological basis for its in vivo activity was identified. This study has confirmed some of the ethnobotanical reports of Hawaiian medicinal plants having curative properties against infections using biological assays in vitro. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Singh YN Kava: an overview. In: J Ethnopharmacol (1992 Aug) 37(1):13-45 ISSN: 0378-8741 Since the first significant contact with Europeans in the 18th century, the Oceanic plant, Piper methysticum Forst. (Piperaceae) and the beverage prepared from it, both of which are called kava, have become familiar to much of the outside world through both the written and visual media. The ceremonial preparation and consumption of the beverage are probably its most conspicuous and spectacular features. Kava continues to occupy a central place in everyday life in the islands concerned, although its role has been somewhat diminished by time and outside influences. Despite the large body of literature on kava--about 800 entries are listed in a recent bibliography by Singh (1986)--there has been no comprehensive review on the subject. Earlier contributions by Keller and Klohs (1963) and Shulgin (1973) were selective in treatment and dealt primarily with chemical and pharmacological aspects. The monograph by Steinmetz (1960) remains a standard reference but understandably some of the information in it has become dated. The attention of the reader is also drawn to two excellent additions to the recent kava literature, by Lebot and Cabalion (1988) and Brunton (1989), which are, although somewhat restricted in focus, are very significant contributions to the subject. The present review paper provides an updated and a multidisciplinary overview of the subject. It was prepared on the basis of the author's personal experience--he is a native of Fiji and lived in that country for about 30 years--as well as the relevant literature listed in the Singh (1986) bibliography and some more recent publications. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY***** Schmitz D Zhang CL Chatterjee SS Heinemann U Effects of methysticin on three different models of seizure like events studied in rat hippocampal and entorhinal cortex slices. In: Naunyn Schmiedebergs Arch Pharmacol (1995 Apr) 351(4):348-55 ISSN: 0028-1298 Methysticin is one of the constituents of Piper methysticum which possesses anticonvulsant and neuroprotective properties. Its effects on different in vitro seizure models were tested using extracellular recordings in rat temporal cortex slices containing the hippocampus and the entorhinal cortex. Elevating [K+]0 induced seizure-like events with tonic and clonic electrographic phases in area CA1. Lowering [Ca2+]0 caused recurrent seizure like episodes with large negative field potential shifts. Lowering Mg2+ induced short recurrent discharges in area CA3 and CA1 while ictaform events lasting for many seconds were induced in the subiculum, entorhinal and temporal neocortex. In the hippocampus the activity stayed stable over a number of hours. In contrast, the ictaform events in the subiculum, entorhinal and temporal cortex changed their characteristics after one to two hours to late recurrent discharges. In a concentration-range from 10 to 100 microM methysticin reversibly blocked all these types of epileptiform activity. Decreases in [Ca2+]0 and associated slow field potentials evoked by repetitive stimulation of the stratum radiatum or the alveus remained almost unaffected by methysticin. A paired pulse stimulus paradigm used to test for effects of methysticin on synaptically evoked transient field potentials in normal medium revealed interference with mechanisms involved in frequency potentiation. While responses to alvear stimulation were largely unaffected, the responses to a paired pulse stimulus to stratum radiatum were depressed over the whole range of tested stimulus intervals. The findings suggest that methysticin has effects on different patterns of epileptiform activity possibly by interfering with processes responsible for frequency potentiation. Registry Numbers: 495-85-2 (methysticin) 7439-95-4 (Magnesium) 7440-09-7 (Potassium) 7440-70-2 (Calcium) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****NEUROPHARMACOLOGY***** Gleitz J Beile A Peters T (+/-)-Kavain inhibits veratridine-activated voltage-dependent Na(+)- channels in synaptosomes prepared from rat cerebral cortex. In: Neuropharmacology (1995 Sep) 34(9):1133-8 ISSN: 0028-3908 Kava pyrones are pharmacologically active compounds extracted from Piper methysticum Forst. Because kava pyrones were characterized by their anticonvulsive, analgesic and centrally muscle relaxing action, we investigated the influence of (+/-)-kavain, a synthetic kava pyrone, on veratridine-stimulated increase in intrasynaptosomal Na+ concentration ([Na+]i) of rat cerebrocortical synaptosomes. [Na+]i was measured spectrofluorometrically employing SBFI as Na+ sensitive fluorescence dye. Veratridine (5 mumol/I) enhanced basal [Na+]i 6.6- fold from 11.3 to 74.1 mmol/l Na+. Incubation of synaptosomes for 100 sec with (+/-)-kavain was sufficient to reduce dose dependently the stimulated increase of [Na+]i with an IC50 value of 86.0 mumol/l, and almost complete inhibition of Na(+)-channels was attained with 400 mumol/l) reduced veratridine-elevated [Na+]i to 30.4% and 7.9% of control whereas the centrally acting muscle relaxant mephenesin (400 mumol/l) was without any effect. Postapplication of 400 mumol/l (+/-)- kavain or 10 mumol/l TTX immediately diminished veratridine-elevated [Na+]i to nearly basal levels with a half life time of 69.7 and 41.8 sec, respectively. To study the influence of (+/-)-kavain on non stimulated synaptosomes, an increase in [Na+]i was induced by 200 mumol/l ouabain, which enhanced [Na+]i hyperbolically with an initial rate of 18.4 mmol Na+/l min. Preincubation of synaptosomes with 400 mumol/l (+/-)-kavain or 10 mumol/l TTX partly prevented Na(+)-influx for both compounds to the same extent of about 57% of control. The presented data indicate a fast and specific inhibition of voltage- dependent Na(+)-channels by (+/-)-kavain. Registry Numbers: 1635-33-2 (kavain) 71-62-5 (Veratridine) 7440-23-5 (Sodium) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****NEUROPSYCHOBIOLOGY***** Munte TF Heinze HJ Matzke M Steitz J Effects of oxazepam and an extract of kava roots (Piper methysticum) on event-related potentials in a word recognition task. In: Neuropsychobiology (1993) 27(1):46-53 ISSN: 0302-282X Twelve healthy volunteers were tested in a double-blind crossover study to assess the effects of oxazepam and an extract of kava roots (Piper methysticum) on behavior and event-related potentials (ERPs) in a recognition memory task. The subjects' task was to identify within a list of visually presented words those that were shown for the first time and those that were being repeated. The repeated words were associated with an increased positivity beginning approximately 250 ms poststimulus. Oxazepam led to a reduction of a negative component in the 250-500 ms range for both old and new words and to a reduction of the old/new difference in the ERP associated with a significantly worse recognition rate. Kava on the other hand showed a slightly increased recognition rate and a larger ERP difference between old and new words. Registry Numbers: 604-75-1 (Oxazepam) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****PHARMACOLOGY AND TOXICOLOGY***** Davies LP Drew CA Duffield P Johnston GA Jamieson DD Kava pyrones and resin: studies on GABAA, GABAB and benzodiazepine binding sites in rodent brain. In: Pharmacol Toxicol (1992 Aug) 71(2):120-6 ISSN: 0901-9928 Kava, an intoxicating beverage prepared from the pepper plant Piper methysticum, is widely consumed by the indigenous peoples in the islands of the South Pacific. As the first of a series of studies on the neuropharmacological interactions of kava with CNS receptors we tested purified pyrones and kava resin for activity on GABA and benzodiazepine binding sites in rat and mouse brain membranes. Only weak activity was observed on GABAA binding sites in washed synaptosomal membranes prepared from rat brain and this was abolished by extraction of the membranes with Triton X-100, suggesting that lipid soluble components were involved. No effects were observed on GABAB binding sites in rat brain membranes in vitro. Kava resin and pyrones exerted some weak effects on benzodiazepine binding in vitro but this did not correlate with pharmacological activity. In addition, in ex vivo studies, no effects were observed on [3H]diazepam binding to brain membranes prepared from mice in which selected kava constituents were injected intraperitoneally, whereas similarly administered diazepam (5 mg/kg) inhibited [3H]diazepam binding by greater than 95%. Similar lack of activity was observed in in vivo binding studies; injection of kava resin failed to influence the CNS binding of the benzodiazepine-receptor ligand [3H]Ro15-1788 injected into mice prior to sacrifice. The pharmacological activities of kava resin and pyrones do not appear to be explained by any significant interaction with GABA or benzodiazepine binding sites. Registry Numbers: 12794-10-4 (benzodiazepine) 56-12-2 (GABA) 78755-81-4 (Flumazenil) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****PLANTA MEDICA***** Gleitz J Beile A Wilkens P Ameri A Peters T Antithrombotic action of the kava pyrone (+)-kavain prepared from Piper methysticum on human platelets. In: Planta Med (1997 Feb) 63(1):27-30 ISSN: 0032-0943 (+)-Kavain, a 4-methoxy-alpha-pyrone prepared from Piper methysticum Forst. (Piperaceae), was investigated regarding its assumed antithrombotic action on human platelets which was deduced from its ability to suppress arachidonic acid (AA)-induced aggregation, exocytosis of ATP, and inhibition of cyclooxygenase (COX) and thromboxane synthase (TXS) activity, the latter two effects being estimated from the generation of prostaglandin E2 (PGE2) and thromboxane A2 (TXA2), respectively. Exogenously applied AA (100 mumol/l) provoked a 90% aggregation of platelets, the release of 14 pmol ATP, and the formation of either 220 pg TXA2 or 43 pg PGE2, each parameter being related to 10(6) platelets. An application of (+)- kavain 5 min before AA, dose-dependently diminished aggregation, ATP- release, and the synthesis of TXA2 and PGE2 with IC50 values of 78, 115, 71, and 86 mumol/l, respectively. The similarity of the IC50 values suggest an inhibition of COX by (+)-kavain as primary target, thus suppressing the generation of TXA2 which induces aggregation of platelets and exocytosis of ATP by its binding on TXA2-receptors. Registry Numbers: EC 5.3.99.5 (Thromboxane Synthetase) 1635-33-2 (kavain) 363-24-6 (Dinoprostone) 57576-52-0 (Thromboxane A2) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****PSYCHOPHARMACOLOGY***** Jussofie A Schmiz A Hiemke C Kavapyrone enriched extract from Piper methysticum as modulator of the GABA binding site in different regions of rat brain. In: Psychopharmacology (Berl) (1994 Dec) 116(4):469-74 ISSN: 0033-3158 Regional differences in the modulation of [3H] muscimol binding to GABAA receptor complexes by kavapyrones, compounds of the rhizome of the plant Piper methysticum which possess sedative activity, were demonstrated using membrane fractions obtained from target brain centers of kavapyrone action: hippocampus (HIP), amygdala (AMY) and medulla oblongata (MED), and from brain centers outside the main kavapyrone effects as frontal cortex (FC) and cerebellum (CER). The kava extract enhanced the binding of [3H] muscimol in a concentration- dependent manner with maximal potentiation of 358% over control in HIP followed by AMY and MED (main target brain centers). Minimal stimulation was observed in CER followed by FC. In contrast, apart from CER, the potency of kavapyrones was similar in the brain areas investigated with EC50 values ranging between 200 and 300 microM kavapyrones. Scatchard analysis revealed that the observed effects of kavapyrones were due to an increase in the number of binding sites (Bmax), rather than to a change in affinity. At a kavapyrone concentration of 500 microM the order of enhancement in Bmax was HIP = AMY > MED > FC > CER. When kavapyrones are included together with pentobarbital or HPO the two classes of compounds produced a more than additive, i.e., synergetic effect on [3H] muscimol binding. Our findings suggest that one way kavapyrones might mediate sedative effects in vivo is through effects on GABAA receptor binding. Registry Numbers: 2763-96-4 (Muscimol) 439-14-5 (Diazepam) 76-74-4 (Pentobarbital) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€