dihydrokavain and yangonin

Due to the widespread occurrence and spread of anthelmintic resistance, there is a need to develop new drugs against resistant parasitic nematodes of livestock animals. The Nobel Prize-winning discovery and development of the anti-parasitic drugs avermectin and artemisinin has renewed the interest in exploring natural products as anthelmintics. In the present study, we screened 7500 plant extracts for in vitro-activity against the barber's pole worm, Haemonchus contortus, a highly significant pathogen of ruminants. The anthelmintic extracts from two plants, Cryptocarya novoguineensis and Piper methysticum, were fractionated by high-performance liquid chromatography (HPLC). Subsequently, compounds were purified from fractions with significant biological activity. Four α-pyrones, namely goniothalamin (GNT), dihydrokavain (DHK), desmethoxyyangonin (DMY) and yangonin (YGN), were purified from fractions from the two plants, GNT from C. novoguineensis, and DHK, DMY and YGN (= kavalactones) from P. methysticum. The three kavalactones induced a lethal, eviscerated (Evi) phenotype in treated exsheathed third-stage larvae (xL3s), and DMY and YGN had moderate potencies (IC

Topics: Animals; Anthelmintics; Chromatography, High Pressure Liquid; Cryptocarya; Haemonchus; High-Throughput Screening Assays; Inhibitory Concentration 50; Larva; Parasitic Sensitivity Tests; Phytochemicals; Piperaceae; Plant Extracts; Pyrones

Topics: Calibration; Chromatography, High Pressure Liquid; Dietary Supplements; Kava; Lactones; Limit of Detection; Plant Roots; Pyrans; Pyrones

Topics: Chromatography, Supercritical Fluid; Kava; Lactones; Molecular Structure; Plant Roots; Pyrans; Pyrones

To examine the bioavailability of kavalactones in vitro and the possible differences in their bioavailability because of variations in either chemical structure or the method of extraction used.. Caco-2 cell monolayers were used to determine the potential bioavailability of kavalactones. Kavalactones were added to the apical layer and basolateral samples were taken over 150 min to examine the concentration diffusing across the cell monolayer. Kavalactone concentrations in these samples were determined by high pressure liquid chromatography.. Kavalactones were found to be potentially bioavailable as they all readily crossed the Caco-2 monolayers with apparent permeabilities (P(app)) increasing from 42 x 10(-6) cm/s and most exhibiting more than 70% crossing within 90 min. Not all differences in their bioavailability can be related to kavalactone structural differences as it appears that bioavailability may also be affected by co-extracted compounds. For example, the P(app) for kawain from ethanol extracts was higher than the values obtained for the same compound from water extracts or for the kavalactone alone.. While the extraction method used (ethanol or water) influences the total (but not the relative) concentrations of kavalactones, it does not markedly affect their bioavailability. Hence, any differences between an ethanolic or an aqueous extract in terms of the propensity of kava to cause liver damage is not because of differing kavalactone bioavailabilities.

Topics: Biological Availability; Biological Transport; Caco-2 Cells; Cell Membrane Permeability; Chromatography, High Pressure Liquid; Humans; Kava; Kinetics; Lactones; Models, Biological; Molecular Structure; Plant Extracts; Pyrans; Pyrones; Rhizome

Methanolic leaf and root extracts of the Hawaiian kava (Piper methysticum Forst.) cultivars, Mahakea, Nene, Purple Moi and PNG, were tested on binding affinities to CNS receptors including GABAA (GABA and benzodiazepine binding site), dopamine D2, opioid (mu and delta), serotonin (5-HT6 and 5-HT7) and histamine (H1 and H2). HPLC analysis was carried out in order to determine the amount of the main kavalactones kavain, 7,8-dihydrokavain, methysticin, 7,8-dihydromethysticin, yangonin and 5,6-demethoxyyangonin. The most potent binding inhibition was observed for leaf extracts to GABAA receptors (GABA binding site) with IC50 values of approximately 3 micrograms/ml, whereas root extracts were less active with IC50 values ranging from 5 micrograms/ml (Nene) to 87 micrograms/ml (Mahakea). Since the leaf extracts generally contained lower amounts of the kavalactones than the root extracts, there might exist additional substances responsible for these activities. Leaf extracts also inhibited binding to dopamine D2, opioid (mu and delta) and histamine (H1 and H2) receptors more potently than the corresponding root extracts with IC50 values ranging from 1 to 100 micrograms/ml vs. > or = 100 micrograms/l, respectively. Significant differences in the potential of binding inhibition were also observed between cultivars. Binding to serotonin (5-HT6 and 5-HT7) and benzodiazepine receptors was only weakly inhibited by both root and leaf extracts of all four cultivars. In conclusion, our investigation indicates that the GABAA, dopamine D2, opioid (mu and delta) and histamine (H1 and H2) receptors might be involved in the pharmacological action of kava extracts. Since the cultivars contained similar amounts of kavalactones, while their pharmacological activities differed markedly, other constituents may play a role in the observed activities. Additionally, leaves generally exhibited more potent binding inhibition than roots, therefore leaf of P. methysticum might be an interesting subject for further pharmacological studies.

Topics: Animals; Brain; Cattle; Cells, Cultured; Chromatography, High Pressure Liquid; Cricetinae; Dose-Response Relationship, Drug; Humans; In Vitro Techniques; Kava; Plant Extracts; Plant Leaves; Plant Roots; Plants, Medicinal; Pyrans; Pyrones; Rats; Rats, Inbred Strains; Rats, Wistar; Receptors, Dopamine D2; Receptors, GABA-A; Receptors, Histamine; Receptors, Opioid; Receptors, Serotonin; Semliki forest virus