Kavalactones

This next example involves the well-known plant kawa. A psychoactive beverage made from the roots of this plant is used widely in the islands of the southwestern Pacific Ocean either for ritualistic or routine consumption. Kava is the common name for Piper methysticum Forst. f. from which several compounds responsible for the pharmacological activity have been isolated and identified. Representative structures of the family of styrylpyrones, commonly called kavalactones, are given in Fig. 6.6. The compounds are based upon a carbon skeleton consisting of a styryl function (C C ) attached to a six-membered lactone ring. The fundamental compound, kawain, is shown as structure [547]. Structural variants include... 

Shore, J. S. and Christ, C. M. 1992. Variation in cyanogenesis within and among populations and species ofTumem section Canaligerae (Tumeraceae). Biochem. Syst. Ecol. 20 9-15. Simeoni, P. and Lehot, V. 2002. Identification of factors determining kavalactone content and chemotype in Kava (Piper methysticum Forst. f). Biochem. Syst. Ecol. 30 413 24. 

Kava Kavalactones Facilitation of GABA binding Inhibition of Nan-, Ca2-i- channels Inhibits NE uptake MAO inhibition Inhibits TXA2 synthesis... 

The pharmacologically active chemicals most studied from the kava plant are collectively called kavapyrones or kavalactones (referred to here as kavalactones) (figure 6.5). Some of the principal kavaactones are kavain, dihydrokavain, yangonin, 11-methoxy-yangonin, methysticin, and dihydromethysticin (Lebot et al. 1997 Boonen et al. 1997). The concentrations of kavalactones vary across different parts of the plant kavain and dimethoxyyangonin are more concentrated in the rootstalk, but dihy-... 

Neither an acute dose of dihydromethysticin (100 mg/kg) or chronic doses of ( )-kavain altered levels of dopamine, serotonin, or their metabolites in the striatum and cortex of rats (Boonen et al. 1998). However, kavalactones have complex and mixed effects on monoamine levels in the nucleus accumbens, depending both on which kavapyrone was... 

The functional significance of thromboxane A2 inhibition by kava is not certain. More needs to be understood about the functions of prostaglandins in the CNS, but given the inhibition of GABAA by thromboxane A2, kava s suppression of thromboxane A2 synthesis could conceivably contribute to its anxiolytic and sedative effects. More research is needed to determine if this mechanism of action is physiologically significant at normal kavalactone concentrations. 

Pharmacological effects of kavalactones are estimated to occur at plasma concentrations of 50-150 pM/L (Kretzschmar and Meyer 1968). Kavalactones peripherally administered quickly gain access to the CNS (Keled-... 

Baum SS, Hill R, Rommelspacher H. (1998). Effect of kava extract and individual kavalactones on neurotransmitter levels in the nucleus accumbens of rats. Prog Neuropsychopharmacol Biol Psychiatry. 22(7) 1105-20. 

Boonen G, Beck MA, Haberlein H. (1997). Contribution to the quantitative and enantioselective determination of kavalactones by high-performance liquid chromatography on ChiraSpher NT material. J Chromatogr B Biomed Sci Appl. 702(1-2) 240-44. 

Boonen G, Ferger B, Kuschinsky K, Haberlein H. (1998). In vivo effects of the kavalactones (+)-dihydromethysticin and (H-/-)-kavain on dopamine, 3,4-dihydroxyphenylacetic acid, serotonin and 5-hydroxyindoleacetic acid levels in striatal and cortical brain regions. Planta Med. 64(6) 507-10. Boonen G, Haberlein H. (1998). Influence of genuine kavalactone enantiomers on the GABA-A binding site. Planta Med. 64(6) 504-6. 

Of particular concern is that this inconsistency in product and active constituent occurs even within the same batch. As part of a clinical study with St. John s wort. Hall et al. analyzed 10 capsules of St. John s wort from the same lot (lot 13207) and found the mean total weight to be 444 mg (4.6% CV) versus 300 mg as stated on the label. In addition, the dosage form was supposed to be standardized to contain 900 pg of hypericin, but the mean content was found to be 840 pg (6.6% CV). There was also variability of the hyperforin content (mean 11 mg and 5.7 /o CV), which was not stated on the label (21). Our experience (Lam YWF, unpublished data) with two random capsules from one batch of kava-kava also showed the same extent of undesirable variance the total content of the pharmacologically active kavalactone was 47.3 mg in one capsule and 39.4 mg in the second one. 

Matthews JM, Etheridge AS, Black SR. Inhibition of human cytochrome P450 activities by kava extract and kavalactones. Drug Metab Dispos 2002 30 1153-1157. 

Extracts of the kava root contain both lipophilic and hydrophilic components. The active constituents of kava are referred to as kavalactones or kavapyrones. The active enolides and dienolides are thought to be kawain (kavain), methysticin, and yangonin. 

One of the kavalactones, kavain, has in vitro cyclooxygenase-inhibiting activity. The potential for antiplatelet and anti-inflammatory effects needs further study. 

Kava has been shown to alter uterine tone in vitro and should be avoided during pregnancy. Kavalactones are soluble and excreted into breast milk. Women who are nursing should avoid kava. 

Fifty to 70 milligrams of purified kavalactones three times daily appears to be the optimal antianxiety dosage. This is equivalent to 100-250 mg of dried kava root extract three times daily. 

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