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PubMed1998

The influence of (+/-)-kavain on population spikes and long-term potentiation in guinea pig hippocampal slices.

Little is known about the mechanisms of action of kava pyrones which are the pharmacological active compounds of the plant Piper methysticum Forst. We investigated the effects of the synthetic kava pyrone (+/-)-kavain on long-term potentiation (LTP) in the CA1-region of guinea pig hippocampal slices. (+/-)-Kavain reduced the amplitudes of extracellular field potential changes evoked by electrical stimulation in a concentration dependent manner. These effects were reversible. In experiments with LTP no changes were found in the presence of (+/-)-kavain. In conclusion, our findings suggest (+/-)-kavain to be an effective drug in modulating excitatory signals in the hippocampus of guinea pigs. Additionally, no alterations on synaptic plasticity in hippocampal neurons for this kava pyrone can be presumed.

Action Potentials↗
PubMed2001

Information flow from the sensorimotor cortex to muscle in humans.

OBJECTIVES: To investigate the physiologic mechanism of human electroencephalogram-electromyogram (EEG-EMG) coherence, the directed transfer function (DTF) based on a multivariate autoregressive (MVAR) model was computed. METHODS: Fifty-six channel EEG and EMG of the right abductor pollicis brevis muscle during a weak tonic contraction were recorded in 6 normal volunteers. The EEG over the left sensorimotor area and the rectified EMG were used to compute coherence and DTF. RESULTS: EEG-EMG coherence was observed at the peak frequency of 15-29 Hz (mean 18.5 Hz). The peak frequency of DTF from EEG to EMG was 12-27 Hz (mean 17.8 Hz). DTF from EEG to EMG was significantly larger than that from EMG to EEG at 19-30 and 45-50 Hz (P<0.05). CONCLUSIONS: The present findings suggest that the EEG-EMG coupling mechanism for the 19 Hz or higher frequency might differ from that for the lower frequency. Directional information flow from EEG to EMG in the former frequency range likely reflects the motor control command. The finding of the directional information flow from EEG to EMG within the gamma band indicates that 40 Hz EEG-EMG coherence is not specific to the muscle Piper rhythm which is seen only with strong contraction.

Adult↗
PubMed2001

Adverse-effect profile of kava.

The use of alternative therapies has increased substantially over the last decade, particularly for more chronic conditions such as anxiety. Among the most widely used treatments are medicinal herbs, or phytomedicines, such as kava (Piper methysticum), which has demonstrated anxiolytic activity in both animal models and clinical samples. Kava has several advantages over conventional pharmacologic treatments for anxiety--in clinical settings it has been associated with better tolerability and lack of physiologic dependence and withdrawal. However, phytomedicines are not rigorously regulated in the United States and systematically collected safety data are very limited. These issues are a leading concern regarding the safety of medicinal herbs such as kava. In this report, the safety profile for kava is provided, including findings from a study of its use in generalized anxiety disorder. Safety parameters assessed include occurrence of adverse events, withdrawal symptoms, effect on heart rate, blood pressure, laboratory assessments, and sexual function. No differences were found between kava and placebo on any of the parameters evaluated. The data support the safety of kava in treating anxiety at 280 mg kava lactones/day for 4 weeks.

Journal Article↗
PubMed1983

Trimethoprim binding to bacterial and mammalian dihydrofolate reductase: a comparison by proton and carbon-13 nuclear magnetic resonance.

The binding of trimethoprim to dihydrofolate reductase from L1210 mouse lymphoma cells has been studied by measuring the changes in chemical shift of nuclei of the ligand that accompanying binding. The 6- and 2',6'-proton chemical shifts of bound trimethoprim have been determined by transfer of saturation experiments, and the 2-carbon chemical shift has been determined by using [2-13C]trimethoprim. The changes in proton chemical shift are substantially smaller than those accompanying binding to bacterial dihydrofolate reductase [Cayley, P. J., Albrand, J. P., Feeney, J., Robert, G. C. K., Piper, E. A., & Burgen, A. S. V. (1979) Biochemistry 18, 3886]. It is shown that this difference arises largely from the fact that trimethoprim adopts different conformations when bound to mammalian and to bacterial dihydrofolate reductase. The proton chemical shifts are interpreted in terms of ring-current contributions from the two aromatic rings of trimethoprim itself and the nearby aromatic amino acid residues of the enzyme. The latter have been located by using the refined crystallographic coordinates of the Lactobacillus casei and Escherichia coli reductases in their complexes with methotrexate [Bolin, J. T., Filman, D. J., Matthews, D. A. & Kraut, J. (1982) J. Biol. Chem. 257, 13650], under the assumption that, as indicated by the 13C chemical shifts, the diaminopyrimidine ring of trimethoprim binds in the same way as does the corresponding part of methotrexate. With use of these assumptions, the conformation of trimethoprim bound to the dihydrofolate reductases from L. casei, E. coli, and L1210 cells has been calculated.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

Novel procedure for identification of compounds inhibitory to transcription of genes involved in mycotoxin biosynthesis.

A novel assay is described for the identification and isolation of compounds that inhibit the transcription of genes involved in mycotoxin biosynthesis. The thin-layer chromatography-based assay was used to screen plant extracts for compounds that would inhibit the expression of the beta-glucuronidase reporter gene under the control of an aflatoxin biosynthesis gene promoter in Aspergillus parasiticus. The assay was used to track purification of an inhibitory compound, cp2, from extracts of black pepper (Piper nigrum). Cp2 did not inhibit mycelial growth or the expression of the beta-tubulin gene but did inhibit aflatoxin biosynthesis at the transcriptional level. Applications of cp2 to the control of mycotoxins are discussed.

Aflatoxins↗
PubMed1999

Comparison of digestion methods for determination of trace and minor metals in plant samples.

In this paper, three dissolution methods using pressure digestion vessels (low-, medium-, and high-pressure vessels) for the determination of metals in plant samples are described. The Plackett-Burman saturated factorial design was used to identify the significant factors influencing wet ashing and to select optimized dissolution conditions. The three methods were statistically compared (on-way ANOVA) on the same sample; no significant differences were obtained. In all cases the relative standard deviation values were <3%. The digestion method based on the use of low-pressure vessels and a microwave oven was validated against CRM GBW07605 tea leaves. This method was applied to the determination of Cu, Zn, Mn, Fe, Mg, and Ca in 22 different medicinal, aromatic, and seasoning plants by flame-atomic absorption spectrometry. The concentration intervals of metal in the plants analyzed were the following: Cu, 4 (Allium sativum)-35 (Thea sinensis) microg g(-1); Zn, 7 (Piper nigrum)-90 (Betula alba) microg g(-1); Mn, 9 (Allium sativum)-939 (Caryophylus aromaticus) microg g(-1); Fe, 33 (Allium sativum)-2486 (Anethum graveolens) microg g(-1); Mg, 495 (Allium sativum)-7458 (Ocimum basilicum) microg g(-1); Ca, 386 (Allium sativum)-21500 (Ocimum basilicum) microg g(-1).

Analysis of Variance↗
PubMed2000

Influence of storage upon light-induced chlorogenic acid accumulation in potato tubers (Solanum tuberosum L.).

The influence of 2 weeks and 3 months of dark storage upon light-induced chlorogenic acid accumulation within tuber tissue of four potato cultivars and upon 5-, 4-, and 3-caffeoylquinic acid concentrations within cv. King Edward was determined. Storage period significantly affected (P < 0.05) the magnitude of the light-induced chlorogenic acid response with accumulation rates 3-4 times higher in tubers exposed to light after 2 weeks compared with those placed under light after 3 months. Comparison of chlorogenic acid concentrations in controls after 2 and 3 months of dark storage indicated that tuber chlorogenic concentrations decline during prolonged cold store at 5 degrees C. Rates of accumulation in response to light were cultivar-dependent with cv. Fianna the most light-sensitive and cv. Maris Piper relatively light-insensitive. In virtually all cases exposure to sodium and fluorescent light promoted higher rates of accumulation than did exposure to high-pressure mercury light sources. Chlorogenic acid values steadily increased over 15 days of illumination with, in the majority of cases, no indication of cessation. Light exposure increased 5-, 4-, and 3-caffeoylquinic acid accumulation rates in cv. King Edward. Irrespective of storage period and light source, ratios of 5-:4-:3-caffeoylquinic acid were ca. 85:15:0 at day 0 and 52:42:6 by day 15.

Chlorogenic Acid↗
PubMed1998

Design and synthesis of a series of 6-substituted-2-pyridinylmethylamine derivatives as novel, high-affinity, selective agonists at 5-HT1A receptors.

A search for novel, selective agonists with high intrinsic activity at the 5-HT1A subtype of serotonin (5-HT) receptors was undertaken. Mechanistic and thermodynamic considerations led to the design of 6-substituted-2-pyridinylmethylamine as a potential 5-HT1A pharmacophore. Various adducts derived from the 6-substituted-2-pyridinylmethylamine moiety were tested for their affinity at 5-HT1A, alpha1-adrenergic, and D2-dopaminergic receptors. Compounds with high affinity for 5-HT1A receptors (pKi >/= 8) were examined for agonist properties by measuring their ability to inhibit forskolin-stimulated cAMP production in HA7 cells (i.e., HeLa cells permanently transfected with the h5-HT1A receptor gene and expressing the h5-HT1A receptor protein). Several compounds of the type aryl¿4-[(6-substituted-pyridin-2-ylmethylamino)methyl]piperidin -1-yl¿ methanone had nanomolar affinity for 5-HT1A binding sites and were more than 500-fold selective with respect to alpha1 and D2 sites. Importantly, their 5-HT1A agonist properties were demonstrated in HA7 cells where they behaved as potent inhibitors of cAMP accumulation. In particular, (3, 4-dichlorophenyl)¿4-[(6-oxazol-5-ylpyridin-2-ylmethylamin o)methyl]pip eridin-1-yl¿methanone (70) and (3, 4-dichlorophenyl)¿4-[(6-azetidinopyridin-2-ylmethylamino)met hyl]piper idin-1-yl¿methanone (36) appeared to be more potent than, and at least as efficacious as, the prototypical 5-HT1A agonist (+/-)-8-OH-DPAT. SAR studies revealed that the pyridine nitrogen atom and the nature and the position of the substituents on the pyridine ring were critically involved in the ability of the compounds to recognize and activate 5-HT1A receptors. Structural modifications of the nonpharmacophoric part of the molecule showed, however, that the entire structure was required for affinity at 5-HT1A binding sites.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1998

The strategy of Myxococcus xanthus for group cooperative behavior.

New evidence has been presented from our laboratory that the gliding bacterium, Myxococcus xanthus, does not home by chemotaxis toward a nutrient source. Our experiments, those of others, and the theory presented here combine to suggest a model, called the 'Pied Piper' model. It hypothesizes a gene that has a high mutation rate forward and back (say something in excess 10(-4) mutations per cell generation) which leads to switching between two motility states. Occasionally rare organisms become genetically, but reversibly, changed so that they move unidirectionally instead of mostly forward and back as do the bulk of the cells. When such a 'leader' cell arises, it continues to move in its original orientation, and causes a cohort of cells to move together away from the bulk of the cells. That is, in the less common mutational state it counteracts the usual tendency to just move forward and backward achieving little net movement. The assumption of a genetic element that mutates in a reversible way is suggested by numerous cases of reversible switches now known in a wide range of bacteria serving a variety of functions. A second aspect of the model is that mechanisms exist that cause cells to move in the same direction as their nearby neighbors. This process results in a regular spacing of bands of cells to form mounds in the absence of a leader. The action of C-factor, a factor-secreted by the cells which has been largely studied in the laboratory of Dale Kaiser, and extracellular fibrils, (rod-shaped protein and carbohydrate bodies) largely studied in the laboratory of Martin Dworkin, may be key elements in coordinating (or linking) the movements of neighboring cells. Based on the assumption of the absence of chemotaxis, computer simulations of pattern formation for gliding bacterial swarms and flares are consistent with observed behaviors and thus are additional evidence that chemotactic motility of the type exhibited by Escherichia coli, is not necessary for the group movements of M. xanthus. Some tests for this model are suggested.

Computer Simulation↗
PubMed2001

Interactions of aphid herbivory and nitrogen availability on the total foliar glycoalkaloid content of potato plants.

In plant growth room (PGR) and open-air pot (OAP) experiments, potato cvs King Edward and Maris Piper were grown under two nitrogen levels or two different nitrogen release patterns. Plants were subjected to infestation by peach potato aphids Myzus persicae (Homoptera: Aphididae). Total glycoalkaloid (GA) levels were measured in the foliage of both infested and non-infested plants, before, during and after aphid infestation. In the PGR experiment, aphid infestation reduced the amounts of total GAs in both cultivars. This reduction is attributed to the sugar deficiency induced in the plants owing to the dense aphid colonization. Results from the OAP experiment showed a temporal increase of GAs produced by potato cv. King Edward plants subjected to aphid infestation. Elevated amounts of nitrogen in the nutrient solutions (PGR experiment) reduced total GAs, while no differences were observed between manure and fertilizer treated plants (OAP experiment). It is concluded that the source of available nitrogen does not affect foliar GA synthesis in potatoes, and as a consequence, does not affect its endogenous chemical defense against insect herbivory. The case for insect-induced chemical defense mechanisms as triggered by low rates of aphid infestation is discussed.

Adaptation, Physiological↗
PubMed2003

Saccade and cognitive function in chronic kava users.

Kava is an extract from the Piper methysticum Forst. f. plant that has been consumed in the Pacific islands for millennia and more recently, among indigenous populations, in northern Australia and throughout the Western world as an herbal medicine. Through alterations on neuronal excitation, kava induces muscle relaxation, anasthesia, and has anxiolytic properties. There have been several isolated reports of psychotic syndromes, severe choreoathetosis and possible seizures following kava use. However, there is no conclusive evidence that kava interferes with normal cognitive processes. We tested a group of current, ex, and nonkava users among an indigenous population in northern Australia, using saccade and cognitive tests that have proven cross-cultural validity and are sensitive to subtle disruptions of the brain arising from substance abuse or neuropsychiatric illness. Despite collecting data from among the heaviest reported kava drinkers in the world, we found no impairment in cognitive or saccade function in individuals who were currently heavy kava users (and had been for up to 18 years), nor was there any impairment in individuals who had been heavy kava users in the past but had abstained for longer than 6 months. Current and ex-kava users showed a higher rate of kava dermopathy, lower body mass index, lowered blood lymphocytes and, in addition, current kava users showed elevated liver enzymes. While there has recently been increasing concern about potentially fatal liver damage attributed to kava use, we have found no evidence of brain dysfunction in heavy and long-term kava users.

Adolescent↗
PubMed2000

Antimicrobial agents from plants: antibacterial activity of plant volatile oils.

The volatile oils of black pepper [Piper nigrum L. (Piperaceae)], clove [Syzygium aromaticum (L.) Merr. & Perry (Myrtaceae)], geranium [Pelargonium graveolens L'Herit (Geraniaceae)], nutmeg [Myristica fragrans Houtt. (Myristicaceae), oregano [Origanum vulgare ssp. hirtum (Link) Letsw. (Lamiaceae)] and thyme [Thymus vulgaris L. (Lamiaceae)] were assessed for antibacterial activity against 25 different genera of bacteria. These included animal and plant pathogens, food poisoning and spoilage bacteria. The volatile oils exhibited considerable inhibitory effects against all the organisms under test while their major components demonstrated various degrees of growth inhibition.

Animals↗
PubMed2002

The neurobehavioural effects of kava.

OBJECTIVE: This review considers the context in which kava is used, together with its underlying psychopharmacological mechanisms, to investigate the neurobehavioural effects associated with kava use. METHOD: We conducted a systematic search using the computerized databases MEDLINE, OVID and PsychLIT for all articles containing any of the following words: kava, kavain, kawa and Piper methysticum. In the opinion of the authors, all articles from this collection containing data that could inform the neurological and cognitive sequelae of kava use were included for the purpose of this review. RESULTS: The use of kava occurs among indigenous populations in the South Pacific and in northern Australia, while also being used throughout the western world as a herbal medicine. Animal studies show that kava lactones alter neuronal excitation through direct interactions with voltage-dependent ion channels, giving rise to kava's muscle relaxant, anaesthetic, anxiolytic and anticonvulsive properties. Several isolated cases of psychotic and severe dystonic reactions following kava use suggest that kava also has psychoactive properties, yet there is no conclusive evidence that kava interferes with normal cognitive processes. CONCLUSIONS: Kava is effective in the treatment of tension and anxiety. There may be risk-factors for severe motor and psychiatric responses to kava use, although these are not well-understood. Given the increasingly widespread use of kava, further investigation is necessary to gain an understanding of its immediate neuropsychiatric effects and long-term cognitive effects.

Adult↗
PubMed2002

Kavain attenuates vascular contractility through inhibition of calcium channels.

Kavain is a biologically active compound from the Oceanic plant Piper methysticum (kava). Traditional medicinal uses of the kava root are many. Kava is increasingly being utilized by Western societies for its anxiolytic effects. Recent reports indicate that kavain blocks ion channels in neural tissue, relaxes precontracted ileum, and relaxes precontracted airway. Thus, we investigated the potential ability of this plant-derived compound to alter vascular smooth muscle function. Thoracic aortae were isolated from Sprague-Dawley rat and cut into 4 mm rings. Rings were placed in tissue baths and suspended from force-displacement transducers for the measurement of isometric tension. In a dose-dependent manner, kavain (10(-6) M to 10(-3) M) was found to relax aortic rings precontracted with phenylephrine (PE). This response was not dependent on functional endothelium. In addition, kavain pretreatment (3 x 10(-5) M or 3 x 10(-4) M) attenuated vascular smooth muscle contraction evoked by PE. However, kavain failed to attenuate PE-mediated contraction in calcium (Ca(++))-free buffer, indicating that intracellular signaling processes were likely not affected. Also, kavain did attenuate the contraction elicited by administration of Ca(++) to depolarized tissue. Interestingly, in rings pre-treated with the selective L-type Ca(++) channel blocker nifedipine, kavain-mediated relaxation was inhibited. Lastly, in rings selectively contracted with an L-type calcium channel activator, kavain elicited dose-dependent (and ultimately complete) relaxation. These data strongly suggest that kavain impairs vascular smooth muscle contraction, likely through inhibition of Ca(++) channels.

Animals↗
PubMed2003

[Kava, kavapyrones and toxic liver injury].

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.

Anti-Anxiety Agents↗
PubMed2003

Aqueous kava extracts do not affect liver function tests in rats.

Kava ( Piper methysticum Forst. f., Piperaceae), prepared as the traditional aqueous infusion, was tested in the rat for possible effects on liver function tests. Extracts were administered in daily dosages of 200 or 500 mg of the active kavalactones/kg for two or four weeks. Sera were assayed for four enzymes that are markers of liver toxicity and liver homogenates for malondialdehyde formation that indicates changes in lipid peroxidation. The data showed that none of the enzymes, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase, nor malondialdehyde were elevated, in fact in some cases they were significantly reduced, suggesting the lack of a toxic effect by kava on the liver.

Alanine Transaminase↗
PubMed2004

Kava Hepatotoxicity: Are we any closer to the truth?

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.

Chemical and Drug Induced Liver Injury↗
PubMed2004

Kava does not display metabolic toxicity in a homogeneous cellular assay.

To determine whether kava (Kava kava, 'Awa, Yaqona, Piper methysticum Forst.), the popular herbal product associated recently with possible human hepatotoxicity, is bioactivated by cytochrome P450 enzymes to cytotoxic metabolites, three kava lactones (methysticin, yangonin, and desmethoxyyangonin) and an ethanolic extract of dried kava root were incubated over time in culture with MCL-5 cells, a human lymphoblastoid cell line that has been stably transfected with five human P450's (CYP 1A1, 1A2, 2A6, 2E1, and 3A4) and human epoxide hydrolase. Incubations were performed concurrently with a control cell line (cH2) that is derived from the same parental line as MCL-5, but transfected with two empty vectors. The kava compounds displayed varying degrees of toxicity (IC (50) values ranged from 50 to > 100 microM) to the MCL-5 and cH2 cell lines; however, both cell lines were equally sensitive to the test compounds. These results suggest that the parent compound for each of the four test compounds was primarily responsible for the observed cell toxicity and that CYP 1A1, 1A2, 2A6, 2E1, and 3A4 or epoxide hydroxylase did not appear to be involved. Thus, in vitro kava does not appear to be activated to toxic metabolites by enzymes known to be important in metabolic toxicity.

Cell Line↗