Pharmacokinetics of valerenic acid after single and multiple doses of valerian in older women.

Insomnia is a commonly reported clinical problem with as many as 50% of older adults reporting difficulty in falling and/or remaining asleep. Valerian (Valeriana officinalis) is a commonly used herb that has been advocated for promoting sleep. Valerenic acid is used as a marker for quantitative analysis of valerian products with evidence of pharmacological activity relevant to the hypnotic effects of valerian. The objective of this study was to determine the pharmacokinetics of valerenic acid in a group of elderly women after receiving a single nightly valerian dose and after 2 weeks of valerian dosing. There was not a statistically significant difference in the average peak concentration (C(max)), time to maximum concentration (T(max)) area under the time curve (AUC), elimination half-life (T(1/2)) and oral clearance after a single dose compared with multiple dosing. There was considerable inter- and intra-subject variability in the pharmacokinetic parameters. C(max) and AUC deceased and T(1/2) increased with increased body weight. The variability between the capsules was extremely low: 2.2%, 1.4% and 1.4%, for hydroxyvalerenic acid, acetoxyvalerenic acid and valerenic acid, respectively. In conclusion, large variability in the pharmacokinetics of valerenic acid may contribute to the inconsistencies in the effect of valerian as a sleep aid.

A randomized clinical trial of valerian fails to improve self-reported, polysomnographic, and actigraphic sleep in older women with insomnia.

OBJECTIVE: To test the effects of nightly valerian (Valeriana officinalis) extract to improve sleep of older women with insomnia. METHODS: Participants in this phase 2 randomized, double-blind, crossover controlled trial were 16 older women (mean age=69.4+/-8.1 years) with insomnia. Participants took 300 mg of concentrated valerian extract or placebo 30 min before bedtime for 2 weeks. Sleep was assessed in the laboratory by self-report and polysomnography (PSG) at baseline and again at the beginning and end of each treatment phase (total of nine nights in the laboratory) and at home by daily sleep logs and actigraphy. RESULTS: There were no statistically significant differences between valerian and placebo after a single dose or after 2 weeks of nightly dosing on any measure of sleep latency, wake after sleep onset (WASO), sleep efficiency, and self-rated sleep quality. In comparing each treatment to baseline in separate comparisons, WASO significantly increased (+17.7+/-25.6 min, p=.02) after 2 weeks of nightly valerian, but not after placebo (+6.8+/-26.4 min, NS). Side effects were minor and did not differ significantly between valerian and placebo. CONCLUSION: Valerian did not improve sleep in this sample of older women with insomnia. Findings from this study add to the scientific evidence that does not support use of valerian in the clinical management of insomnia.

Potential interactions between complementary/alternative products and conventional medicines in a Medicare population.

BACKGROUND: Despite the high prevalence of complementary and alternative medicine (CAM) product use among the elderly, little is known about the extent of concurrent CAM-conventional medicine use and the potential for adverse reactions. OBJECTIVE: To determine the prevalence of CAM product use concurrent with conventional medications, prescription and nonprescription, in a Medicare population and assess the risk for adverse interactions. METHODS: Retrospective analysis was performed on Cardiovascular Health Study interview data from 1994, 1995, 1997, and 1999. The prevalence of concurrent combinations of CAM products and conventional drugs was tabulated. The adverse interaction risks were categorized as unknown, theoretical, and significant. RESULTS: Of 5052 participants, the median age was 75, 60.2% were female, 16.6% were African American, and 83.4% were white. The percent using CAM products during the 4 time periods was 6.3%, 6.7%, 12.8%, and 15.1%. The percent using both CAM products and conventional drugs was 6.0%, 6.2%, 11.7%, and 14.4%. Of these, 294 (5.8%) individuals took combinations considered to have a significant risk for an adverse interaction. Combinations with risk were observed on 393 separate interviews. Most (379) involved a risk of bleeding due to use of ginkgo, garlic, or ginseng together with aspirin, warfarin, ticlopidine, or pentoxifylline. An additional 786 observations of combinations were considered to have some, albeit theoretical or uncertain, risk for an adverse interaction. CONCLUSIONS: Concurrent use of CAM products and conventional medicines in a Medicare population was found to be common. Research to define the risks of combining ginkgo and garlic supplements with aspirin should be of high priority.

Echinacea alkylamides inhibit interleukin-2 production by Jurkat T cells.

Alkylamides present in Echinacea species have reported immunomodulatory actions, yet their direct effects on T lymphocytes, key mediators of antiviral immunity, are poorly understood. We hypothesized that constituents present in ethanolic extracts of Echinacea species exert direct immunomodulatory effects on human Jurkat T cells. Modulation of IL-2 production by submaximally stimulated Jurkat cells was determined in response to treatment with extracts prepared from dried aerial parts of Echinacea purpurea. Cells were treated with the extracts, with alkylamides or caffeic acid derivatives isolated from Echinacea species, or with corresponding ethanol vehicle, in the absence or presence of phytohemagglutinin and phorbal ester. E. purpurea extracted in a solvent mixture of 95:5 ethanol/water dose-dependently inhibited IL-2 production. This IL-2 inhibitory activity correlated with the presence of alkylamides but not caffeic acid derivatives, as determined by high performance liquid chromatography/electrospray ionization-mass spectrometry analysis. Simultaneous measurement of secreted IL-2 by ELISA and cell viability by the XTT assay showed that the 95:5 ethanol/water extract of E. purpurea was both IL-2 suppressive and cytotoxic at 50 and 100 microg/mL. Lower concentrations from 6.25 to 25 microg/mL significantly decreased IL-2 production but not cell viability. Alkylamides at concentrations found in a 50 microg/mL extract decreased IL-2 production by approximately 50%. Two Echinacea-derived alkylamides significantly depressed IL-2 production but not cell viability in a dose-dependent manner. Thus, alkylamides present in E. purpurea suppress the ability of activated Jurkat T cells to produce IL-2 independently of direct, cytotoxic effects.

Ginkgo biloba: evaluation of CYP2C9 drug interactions in vitro and in vivo.

Ginkgo biloba extract is one of the most widely used herbal products in the United States. However, bleeding episodes in patients taking Ginkgo biloba and warfarin have been documented. Therefore, in vitro and in vivo inhibition studies were done to ascertain the influence of ginkgo on CYP2C9, the P-450 isozyme responsible for the metabolism of the most potent warfarin enantiomer, (S)-warfarin. Ginkgo extract inhibited human liver microsomal CYP2C9 with an apparent Ki=14.8 microg/mL, and the inhibition was increased by acid hydrolysis (apparent Ki=9.1 microg/mL). Two open-label, crossover pharmacokinetic studies in healthy subjects were performed using tolbutamide and diclofenac as probe CYP2C9 substrates. In contrast to the in vitro inhibition of CYP2C9, no interactions between Ginkgo biloba extract and CYP2C9 probe substrates were observed in vivo as evidenced by the lack of effect on the steady-state pharmacokinetics of diclofenac or on the urinary metabolic ratio of tolbutamide.

Pharmacokinetics of valerenic acid after administration of valerian in healthy subjects.

OBJECTIVES: To describe the pharmacokinetics of valerenic acid in a group of healthy adults after a single oral dose of valerian using a newly developed sensitive assay for serum concentrations of valerenic acid, a commonly used marker for qualitative and quantitative analysis of valerian root and valerian products. STUDY DESIGN: Six healthy adults (22-61 years, five men, one female) received a single 600 mg dose of valerian at 08:00. Blood samples were collected for 8 h after administration. Valerenic acid was extracted from serum and measured using a LC/MS/MS method developed in our laboratory. RESULTS: The maximum serum concentration of valerenic acid for five of the six subjects occurred between 1 and 2 h ranging from 0.9 to 2.3 ng/mL. Valerenic acid serum concentrations were measurable for at least 5 h after the valerian dose. One subject showed a peak plasma value at 1 h and a second peak at 5 h. The elimination half-life (T(1/2)) for valerenic acid was 1.1 +/- 0.6 h. The area under the concentration time curve (AUC) as a measure of valerenic acid exposure was variable (4.80 +/- 2.96 microg/mL. h) and not correlated with subject's age or weight. CONCLUSIONS: Assuming that valerenic acid serum concentrations correlate with the pharmacological activity of valerian, the timing of the valerenic acid peak concentration is consistent with the standard dosage recommendation to take valerian 30 min to 2 h before bedtime. Ongoing studies are evaluating the relationship between valerenic acid serum concentrations and objective measures of sleep in patients.

Drug interaction potential of soy extract and Panax ginseng.

To determine if soy extract or Panax ginseng increases the urinary excretion of the 6-beta-hydroxycortisol/cortisol ratio as a marker of cytochrome P450 (CYP) 3A enzyme induction, subjects received a soy extract containing 50 mg isoflavones twice daily (n = 20) or Panax ginseng 100 mg standardized to 4% ginsenosides twice daily (n = 20) for 14 days. Neither Panax ginseng nor soy extract significantly altered the urinary 6-beta-OH-cortisol/cortisol ratio, suggesting that unlike St. John's wort, they are not CYP3A inducers. Studies in vitro using human liver microsomes were performed to determine the effect of soy extract on probe substrates of CYP and UDP glucuronosyltransferase (UGT). Unhydrolyzed soy extract produced very little inhibition of CYP1A2, CYP2A6, and CYP2D6 and a trend of activation of CYP3A4. Hydrolyzed soy extract showed inhibition of all of the CYPs tested, particularly CYP2C9 and CYP3A4. UGT2B15 was the only UGT significantly inhibited. Even though both soy extract and ginseng have been shown to activate CYP3A4 in vitro, there is a lack of an in vitro correlation with the in vivo effects.

Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease.

OBJECTIVE: There is currently uncertainty as to the best treatment for patients with recurrent episodes of Clostridium difficile disease (RCDD). Our objective was to evaluate the success of treatment strategies in a cohort of 163 RCDD patients. METHODS: Data were used from patients who had participated in the placebo arm in two national referral clinical trials evaluating a new combination treatment. Patients with active RCCD were enrolled, prescribed either vancomycin or metronidazole, and randomized to either the investigational biological or a placebo. All patients were observed for at least 2 months for a subsequent episode of RCCD. RESULTS: Of the 163 cases, 44.8% recurred. A tapering course of vancomycin resulted in significantly fewer recurrences (31%, p = 0.01), as did pulsed dosing of vancomycin (14.3%, p = 0.02). A trend (p = 0.09) for a lower recurrence frequency was observed for high-dose (> or =2 g/day) vancomycin and low-dose (< or =1 g/day) metronidazole. Vancomycin was significantly more effective in clearing C. difficile culture and/or toxin by the end of therapy than metronidazole (89% vs 59%, respectively; p < 0.001). CONCLUSIONS: These data show that tapered or pulsed dosing regimens of vancomycin may result in a significantly better cure of RCDD. The persistence of C. difficile spores suggests that additional strategies to restore the normal colonic microflora may also be beneficial.

Update on natural product--drug interactions.

The interactions of natural products with drugs are discussed. Interactions between natural products and drugs are based on the same pharmacokinetic and pharmacodynamic principles as drug-drug interactions. Clinically important interactions appear to involve effects on drug metabolism via cytochrome P-450 isoenzymes, impairment of hepatic or renal function, and other possible mechanisms. Natural products that have been reported to interact with drugs in humans include coenzyme Q10, dong quai, ephedra, Ginkgo biloba, ginseng, glucosamine sulfate, ipriflavone, melatonin, and St. John's wort. In many cases, more research is needed to confirm these interactions and to determine whether other natural products may also interact with drugs. To effectively counsel patients about interactions involving natural products, pharmacists should be familiar with the most commonly used products and have access to information on more obscure products. In view of the less than stringent provisions of the Dietary Supplement Health and Education Act, pharmacists should consult reliable, independent sources of information on natural products rather than rely on literature provided by manufacturers. Pharmacists should recommend only those products that are manufactured to high quality-control standards. Natural products can interact with drugs and with other natural products by the same mechanisms as drugs.