Synthesis, in vitro, reactivity, and identification of 6-phenyl-3-hexen-2-one in human urine after kava-kava (Piper methysticum) ingestion.

This study describes the synthesis of 6 -phenyl-3-hexen-2-one, a proposed metabolite of kava-kava (kava, 'Awa, Yaqona, Piper methysticum Forst.), its reactivity with glutathione in vitro, and its isolation and identification, as its mercapturic acid adduct using LC/MS/MS, in the urine of two human subjects following their ingestion of kava. A possible metabolic pathway for the formation of this metabolite and its possible role in hepatotoxicity are also discussed.

Use of conventional and complementary health care during the transition to menopause: longitudinal results from the Study of Women's Health Across the Nation (SWAN).

OBJECTIVE: Women beginning the transition to menopause now have access to complementary and alternative therapies (CAM) that were not universally available in the past. Little is known about the association between CAM use and the use of conventional health care during menopause. We investigated the longitudinal association between use of CAM therapies and utilization of conventional health care in a large, multiethnic sample of midlife women who were enrolled in the cohort phase of the Study of Women's Health Across the Nation (SWAN). DESIGN: We used generalized estimating equations, repeated measures modeling to examine the association between CAM use and the yearly number of conventional health-care contacts, adjusting for relevant covariates, during a two-year period. CAM use was evaluated longitudinally as continuous, incident (no CAM use at baseline), sporadic, or no use during the study period. RESULTS: Relative to nonusers, continuous CAM users had more conventional health-care contacts (beta 0.14, 95% CI 0.06, 0.21). Incident users and sporadic users also showed an excess in conventional health-care contacts (beta 0.14, CI 0.06, 0.22) and (beta 0.09, CI 0.01, 0.16), respectively. Ethnicity was independently associated with health-care contacts. Relative to white women, Japanese women had fewer contacts (beta -0.18, CI -0.31, -0.05). CONCLUSIONS: Despite being a generally healthy, well-educated and high-income population with good access to health care, CAM users were using more of both conventional and alternative health-care resources than women who did not use CAM. These findings have practical implications for conventional health-care practitioners, allied health professionals and CAM practitioners.

Cocaine levels in sweat collection patches vary by location of patch placement and decline over time.

Sweat collection patches are used for drug abuse monitoring. We investigated the effect of sweat patch location (back and shoulder) on cocaine levels after controlled intravenous cocaine exposure (210 mg/70 kg) in 12 subjects (Experiment 1). Gas chromatographic-mass spectrometric analyses show cocaine and metabolites levels in Pharmchek trade mark patches were eightfold higher on the back than those on the shoulders. To assess the mechanisms for possible loss of cocaine from patches during wear, 48 sweat patches with a small amount of cocaine-d(5) (100 ng as base/patch) were placed on the backs of eight cocaine-naive volunteers for up to 72 h (Experiment 2). Drug-free patches were applied over eight of the cocaine-d(5) (100 ng) containing patches to measure loss through the patch. Cocaine levels in spiked patches declined over time (p = 0.002), with levels at 48 h postapplication 30% less than control, consistent with possible drug reabsorption. Cocaine was detectable (> 2 ng/patch, LOQ) in four of eight initially cocaine-free patches placed on top of the cocaine-containing patches, indicating transfer through the patch outer membrane. Conversion to benzoylecgonine was detectable but at low levels (< 2%). Reabsorption (back transfer), degradation or hydrolysis, and loss of cocaine to the environment may account for substantial loss of cocaine from skin sweat collection patches during patch wear.

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.

Disposition of cocaine in skin, interstitial fluid, sebum, and stratum corneum.

The aim of this study was to determine whether or not the skin acts as a reservoir for cocaine. Cocaine-d5 (1 mg/kg) was administered to five nondependent, cocaine-experienced volunteers. Skin tissue, interstitial fluid, sebum, stratum corneum, and plasma were collected for 72 h after drug administration. Cocaine and benzoylecgonine (BE) levels were determined using GC-MS. Cocaine concentrations peaked in plasma at 1 h after administration, with pharmacokinetic parameters (t(1/2), CL, Vd) also in the expected ranges. In skin, cocaine levels peaked around 1.5 h after administration and became undetectable by 6 h. A correlation was found between the plasma and skin AUC for cocaine (R = 0.99, p = 0.006, N = 4). BE was not detected in skin. In interstitial fluid (N = 4), cocaine concentrations peaked around 5 h after drug administration and were undetectable by 24 h. BE peaks varied between 2 and 24 h and were not detectable at 48 h. In sebum, cocaine levels peaked between 3 and 24 h. BE was found in three samples between 12 and 24 h. In stratum corneum, cocaine was measurable in only one sample from one subject. These findings suggest that skin does not act as a reservoir for cocaine. Rather, cocaine appears to be distributed rapidly to the skin and eliminated, following a time course similar to that of plasma.

Ethnic differences in use of complementary and alternative medicine at midlife: longitudinal results from SWAN participants.

OBJECTIVES: We estimated the prevalence and longitudinal correlates of use of complementary and alternative medicine (CAM) at midlife among participants of the Study of Women's Health Across the Nation (SWAN). METHODS: Multiple logistic regression was used to evaluate the relationship between baseline survey-reported symptoms and use of herbal, spiritual, and physical manipulation therapies 1 year later. RESULTS: Almost half of all women had used CAM in the past year. Baseline psychological symptoms were associated with subsequent use of spiritual therapies among White and Chinese women. Baseline CAM use was a major predictor of subsequent use in White, Japanese, and Chinese women. CONCLUSIONS: Baseline CAM use, rather than presence of symptoms, was the major predictor of subsequent CAM use. Premenopausal health behaviors are important determinants of choice of therapy during midlife.