Effect of ginkgo and ginger on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects

AIM: The aim of this study was to investigate the effect of two common herbal medicines, ginkgo and ginger, on the pharmacokinetics and pharmacodynamics of warfarin and the independent effect of these herbs on clotting status. METHODS: This was an open label, three-way crossover randomized study in 12 healthy male subjects, who received a single 25 mg dose of warfarin alone or after 7 days pretreatment with recommended doses of ginkgo or ginger from herbal medicine products of known quality. Dosing with ginkgo or ginger was continued for 7 days after administration of the warfarin dose. Platelet aggregation, international normalized ratio (INR) of prothrombin time, warfarin enantiomer protein binding, warfarin enantiomer concentrations in plasma and S-7-hydroxywarfarin concentration in urine were measured. Statistical comparisons were made using anova and the 90% confidence intervals (CIs) of the ratio of log transformed parameters are reported. RESULTS: INR and platelet aggregation were not affected by administration of ginkgo or ginger alone. The mean (95% CI) apparent clearances of S-warfarin after warfarin alone, with ginkgo or ginger were 189 (167-210) ml h(-1), 200 (173-227) ml h(-1) and 201 (171-231) ml h(-1), respectively. The respective apparent clearances of R-warfarin were 127 (106-149) ml h(-1), 126 (111-141) ml h(-1) and 131 (106-156) ml h(-1). The mean ratio (90% CI) of apparent clearance for S-warfarin was 1.05 (0.98-1.21) and for R-warfarin was 1.00 (0.93-1.08) when coadministered with ginkgo. The mean ratio (90% CI) of AUC(0-168) of INR was 0.93 (0.81-1.05) when coadministered with ginkgo. The mean ratio (90% CI) of apparent clearance for S-warfarin was 1.05 (0.97-1.13) and for R-warfarin was 1.02 (0.95-1.10) when coadministered with ginger. The mean ratio (90% CI) of AUC(0-168) of INR was 1.01 (0.93-1.15) when coadministered with ginger. The mean ratio (90% CI) for S-7-hydroxywarfarin urinary excretion rate was 1.07 (0.85-1.32) for ginkgo treatment, and 1.00 (0.81-1.23) for ginger coadministration suggesting these herbs did not affect CYP2C9 activity. Ginkgo and ginger did not affect the apparent volumes of distribution or protein binding of either S-warfarin or R-warfarin. CONCLUSIONS: Ginkgo and ginger at recommended doses do not significantly affect clotting status, the pharmacokinetics or pharmacodynamics of warfarin in healthy subjects.     

Alterations in cyclosporin A pharmacokinetics and metabolism during treatment with St John's wort in renal transplant patients

AIM: This study investigated the effects of St John's wort extract (SJW) on the pharmacokinetics and metabolism of the immunosuppressant cyclosporin A (CSA). METHODS: In an open-label study, 11 renal transplant patients received 600 mg SJW extract daily for 14 days in addition to their regular regimen of CSA. Blood concentrations of CSA and its metabolites AM1, AM1C, AM9, AM19, and AM4N were measured by HPLC. RESULTS: After 2 weeks of SJW coadministration, dose-corrected AUC0-12, Cmax and Ctrough values for CSA decreased significantly by 46%[geometric mean ratio baseline/SJW (95% CI): 1.83 (1.63-2.05)], 42%[1.72 (1.42-2.08)], and 41%[1.70 (1.17-2.47)], respectively. CSA doses were increased from a median of 2.7 mg day(-1) kg(-1) at baseline to 4.2 mg day(-1) kg(-1) at day 15, with the first dose adjustment required only 3 days after initiation of SJW treatment. Additionally, the metabolite pattern of CSA was substantially altered during SJW treatment. Whereas dose-corrected AUC values for AM1, AM1c and AM4N significantly decreased by 59%, 61%, and 23% compared with baseline, AUC values for AM9 and AM19 were unchanged. Following the increase in CSA dose, observed AUC and Cmax values for AM9, AM19, and AM4N increased by 20-51% and 43-90%, respectively. CONCLUSION: Administration of SJW extract to patients receiving CSA treatment resulted in a rapid and significant reduction of plasma CSA concentrations. Additionally, the substantial alterations in CSA metabolite kinetics observed may affect the toxicity profile of the drug.     

Pharmacokinetic modelling of the interaction between St John's wort and ciclosporin A

AIMS: St John's wort (SJW) decreases the blood concentration of ciclosporin A (CsA), which may result in allograft rejection. In addition, the time course of this interaction is not parallel with the administration of SJW. We aimed to develop a pharmacokinetic model to predict the time profile of blood CsA concentrations during and after the intake of SJW. METHODS: We developed a pharmacokinetic model incorporating turnover of detoxicating proteins, with the assumption that the amount of detoxicating proteins is in inverse proportion to the ratio of trough blood concentration to daily dose (C/D ratio) of CsA. First, we collected time profiles of blood CsA during and after the intake of SJW from the literature. Next, we analysed the relationship between D/C ratio and the daily dose of SJW at steady state. Subsequently, the developed model was simultaneously fitted to the time profiles of C/D ratios by using a nonlinear least-squares method to obtain model parameters. RESULTS: The model analysis revealed that the induction of the detoxicating proteins by SJW was saturable with an elimination rate constant of the detoxicating proteins (ke) of 4.72 month(-1). Elimination half-life of the detoxicating proteins calculated from the ke value was 4.4 days, suggesting that the dose of CsA should be carefully monitored for up to 2 weeks after the cessation of SJW intake. CONCLUSIONS: The present model may provide additional information for use in identifying optimal dosage regimens of CsA during and after the intake of SJW to prevent an adverse drug interaction between CsA and SJW.     

St John's wort (Hypericum perforatum): drug interactions and clinical outcomes

AIMS: The aim of this work is to identify the medicines which interact with the herbal remedy St John's wort (SJW), and the mechanisms responsible. METHODS: A systematic review of all the available evidence, including worldwide published literature and spontaneous case reports provided by healthcare professionals and regulatory authorities within Europe has been undertaken. RESULTS: A number of clinically significant interactions have been identified with prescribed medicines including warfarin, phenprocoumon, cyclosporin, HIV protease inhibitors, theophylline, digoxin and oral contraceptives resulting in a decrease in concentration or effect of the medicines. These interactions are probably due to the induction of cytochrome P450 isoenzymes CYP3A4, CYP2C9, CYP1A2 and the transport protein P-glycoprotein by constituent(s) in SJW. The degree of induction is unpredictable due to factors such as the variable quality and quantity of constituent(s) in SJW preparations. In addition, possible pharmacodynamic interactions with selective serotonin re-uptake inhibitors and serotonin (5-HT(1d)) receptor-agonists such as triptans used to treat migraine were identified. These interactions are associated with an increased risk of adverse reactions. CONCLUSIONS: In Sweden and the UK the potential risks to patients were judged to be significant and therefore information about the interactions was provided to health care professionals and patients. The product information of the licensed medicines involved has been amended to reflect these newly identified interactions and SJW preparations have been voluntarily labelled with appropriate warnings.     

Effect of gemfibrozil on the pharmacokinetics and pharmacodynamics of racemic warfarin in healthy subjects

AIMS: Case reports suggest that gemfobrozil can increase the anticoagulant effect of warfarin. Because gemfibrozil inhibits CYP2C9 in vitro, we studied its effects on the pharmacokinetics and pharmacodynamics of racemic warfarin. METHODS: In a randomized cross-over study, 10 healthy subjects ingested 600 mg gemfibrozil or placebo twice daily for 8 days. On day 3, they were administered a single dose of 10 mg racemic R-S-warfarin orally. The concentrations of R- and S-warfarin in plasma and thromboplastin time were monitored up to 168 h. RESULTS: Gemfibrozil decreased the mean (+/-SD) area under the plasma concentration-time curve [AUC((0-infinity))] of S-warfarin by 11%, from 19.9 +/- 5.2 mg l(-1) h to 17.6 +/- 4.7 mg l(-1) h (95% CI on the difference -3.7, -0.78; P < 0.01) and that of R-warfarin by 6% from 31.3 +/- 7.5 mg l(-1) h during the gemfibrozil phase to 29.5 +/- 6.9 mg l(-1) h during the placebo phase (95% CI -3.3, -0.33; P < 0.05). There were no significant differences in the elimination half-lives of S- or R-warfarin between the phases. Gemfibrozil did not alter the anticoagulant effect of warfarin. CONCLUSION: Unexpectedly, gemfibrozil slightly decreased the plasma concentrations of R- and S-warfarin. Displacement of warfarin from plasma albumin by gemfibrozil or its interference with the absorption of warfarin could explain the present findings. Usual therapeutic doses of gemfibrozil seem to have limited effects on the pharmacokinetics and pharmacodynamics of single dose warfarin in healthy subjects.     

Interaction of St John's wort with low-dose oral contraceptive therapy: a randomized controlled trial

AIMS: Breakthrough bleeding or even unwanted pregnancies have been reported in women during concomitant therapy with oral contraceptives and St John's wort extract. The aim of the present study was to investigate the effects of St John's wort extract on oral contraceptive therapy with respect to ovarian activity, breakthrough bleeding episodes and the pharmacokinetics of ethinyloestradiol and 3-ketodesogestrel. METHODS: Eighteen healthy females were treated with a low-dose oral contraceptive (0.02 mg ethinyloestradiol, 0.150 mg desogestrel) alone (control cycle) or combined with 300 mg St John's wort extract given twice daily (cycle A) or three times daily (cycle B). Ovarian activity was assessed by measuring follicle maturation and serum oestradiol and progesterone concentrations. The number of breakthrough bleeding episodes and the pharmacokinetics of ethinyloestradiol and 3-ketodesogestrel were assessed under steady-state conditions. RESULTS: During concomitant administration of low-dose oral contraceptive and St John's wort, there was no significant change in follicle maturation, serum oestradiol or progesterone concentrations when compared with oral contraceptive treatment alone. However, significantly more subjects reported intracyclic bleeding during cycles A (13/17 (77%), P < 0.015) and cycle B (15/17 (88%), P < 0.001) than with oral contraceptives alone (6/17 (35%)). The AUC(0,24 h) and Cmax of ethinyloestradiol remained unchanged during all study cycles, whereas the AUC(0,24 h) and Cmax of 3-ketodesogestrel decreased significantly from 31.2 ng ml-1 h to 17.7 ng x ml-1 h (43.9%; 95% confidence interval (CI) -49.3, -38.5, P = 0.001) and from 3.6 ng x ml -1 to 3.0 ng x ml -1(17.8%; CI -29.9, -5.7, P = 0.005), respectively, during cycle A and by 41.7% (CI -47.9, -35.6; P = 0.001) and by 22.8% (CI -31.2, -13.3; P < 0.001) during cycle B respectively, compared with the control cycle. CONCLUSIONS: There was no evidence of ovulation during low-dose oral contraceptive and St John's wort extract combination therapy, but intracyclic bleeding episodes increased. Bleeding irregularities may adversely effect compliance to oral contraceptives and together with St John's wort-induced decreases in serum 3-ketodesogestrel concentrations, enhance the risk of unintended pregnancies.     

大豆异黄酮对华法林在人体内药动学和药效学的影响

目的:研究大豆异黄酮对华法林在人体内药动学和药效学的影响。方法:采用随机、单盲、双周期交叉、安慰剂对照试验设计。12名健康志愿者(男女各半)随机分为2组,连续5 wk每日分别服用大豆异黄酮胶囊(75 mg)或安慰剂1粒;d 29口服单剂量华法林5 mg;第2周期2组交叉服用安慰剂或大豆异黄酮胶囊,其余给药方案不变。按要求收集志愿者血样,分别以高效液相色谱(HPLC)法测定华法林的血药浓度以及半自动血凝仪测定常见凝血指标。结果:合用大豆异黄酮后,华法林的药动学参数c_(max)、AUC_(0～144)、AUC_(0～∞)、t_(1/2)显著增加(P<0.05),CL(F)显著域小(P<0.05),t_(max)和V_d(F)没有显著变化;华法林的药效学参数均无显著变化。单独服用大豆异黄酮4 wk后,凝血酶原时间(PT)和活化部分凝血活酶时间(APTF)无显著变化。结论:大豆异黄酮可影响华法林的药动学,但不影响华法林的药效学;单独服用大豆异黄酮4 wk对凝血功能无明显影响。     

St. John's wort (Hypericum perforatum): a review of the current pharmacological, toxicological, and clinical literature

RATIONALE: St. John's wort (Hypericum perforatum) has recently gained popularity as an alternative treatment for mild to moderate depression. Given the current widespread use of this herbal remedy, it is important for medical professionals to understand the potential pharmacological pathways through which Hypericum may exert an antidepressant effect. OBJECTIVES: (1) To review the current pharmacological, toxicological, and clinical literature available on Hypericum, and (2) to provide a synthesis of this information into a form that may be easily used by health care providers. METHOD: A comprehensive review of the recent scientific literature (January 1990-March 2000) was performed using the following electronic databases and reference publications: MEDLINE, The Cochrane Library, HealthSTAR, Current Contents (all editions), European Scientific Cooperative on Phytotherapy monographs, German Commission E monographs, and the Physicians' Desk Reference for Herbal Medicines, 1st edition. RESULTS: One hundred and seven (107) publications in the English language and three publications in German were included in the review. Collectively, the data suggest that therapeutic preparations of Hypericum extract appear to exert potentially significant pharmacological activity within several neurochemical systems believed to be implicated in the pathophysiology of depression. However, little information exists regarding the safety of Hypericum, including potential herb-drug interactions. CONCLUSIONS: Additional research on the pharmacological and biochemical activity of Hypericum and its several bioactive constituents is necessary to further elucidate the mode(s) of antidepressant action. Given what is currently known and unknown about the biological properties of Hypericum, those who choose to use this herb should be closely monitored by a physician.     

St John's wort extract (LI 160) in somatoform disorders: results of a placebo-controlled trial

Abstract Rationale and objective. Preliminary data have shown that St John's wort might possess some specific efficacy in patients with somatoform complaints. Therefore, the efficacy of the Hypericum extract LI 160 in patients with somatoform disorders should be studied in a double-blind placebo-controlled fashion. Methods. This was a multicentre, randomised, placebo controlled, 6-week trial comparing the efficacy of LI 160 (600 mg/day) and placebo in 151 out-patients suffering from somatization disorder (ICD-10: F45.0), undifferentiated somatoform disorder (F45.1), or somatoform autonomic dysfunctions (F45.3). The primary outcome measure was the decrease of the Hamilton Anxiety Scale, subfactor somatic anxiety (HAMA-SOM), during the trial period. Results. LI 160 was superior effective concerning the primary outcome criterion HAMA-SOM [decrease from 15.39 (SD 2.68) to 6.64 (4.32) in the Hypericum group and from 15.55 (2.94) to 11.97 (5.58) in the placebo group (statistically significant difference, P=0.001)]. This was corroborated by the result of a statistically significant superior efficacy in the outcome criteria additionally used such as Clinical Global Impression, HAMA-total score, HAMA, subscore psychic anxiety, Hamilton Depression Scale, Self-Report Symptom Inventory 90 items – revised (SCL-90-R), and SCL-90-R, subscore somatic anxiety. The efficacy of LI 160 was preserved after splitting the population in those with mild and those with severe depressive symptoms. Tolerability of LI 160 was excellent. Conclusion. The data from this trial show excellent efficacy and tolerability for LI 160 in somatoform disorders. The efficacy is independent of an existing depressive mood. This is the first study showing the efficacy of a drug in patients with somatisation disorder independent of depressive symptomatology. Electronic Publication     

Effects of St John's wort and CYP2C9 genotype on the pharmacokinetics and pharmacodynamics of gliclazide

BACKGROUND AND PURPOSE: Patients commonly take complementary medicines in conjunction with conventional drugs without clear evidence of safety or the risk of herb-drug interactions. The aim of this study was to assess potential pharmacokinetic (PK) and pharmacodynamic (PD) interactions between St John's wort and gliclazide in healthy subjects with different cytochrome P450 2C9 (CYP2C9) genotypes. EXPERIMENTAL APPROACH: A crossover controlled study was conducted in 21 healthy subjects. Each received gliclazide (80 mg) either alone or during 15 days treatment with St John's wort. The area under the plasma concentration-time curve (AUC(0-infinity)), apparent clearance (CL/F) and elimination half-life (t 1/2) of gliclazide and incremental changes in glucose and insulin AUC(0-4) were compared. CYP2C9*2 and CYP2C9*3 alleles were identified using PCR followed by restriction enzyme digestion analysis. KEY RESULTS: St John's wort significantly altered gliclazide pharmacokinetics in all except for four healthy subjects. The mean ratio and 90% confidence interval (CI) of gliclazide AUC(0-infinity) and CL/F were 0.67 (0.55-0.81) and 1.50 (1.24-1.81), respectively, after St John's wort treatment. St John's wort decreased gliclazide t (1/2), with mean ratio and 90% CI of 0.85 (0.74-0.93). There were no significant changes in glucose or insulin AUC(0-4) after St John's wort treatment and no significant differences according to CYP2C9 genotype. CONCLUSIONS AND IMPLICATIONS: Treatment with St John's wort significantly increases the apparent clearance of gliclazide which is independent of CYP2C9 genotype. People with diabetes receiving this combination should be closely monitored to evaluate possible signs of reduced efficacy.     

圣·约翰草提取物治疗轻中度抑郁症的多中心临床研究

目的：验证圣·约翰草提取物（ｎｅｕｒｏｓｔａｎ,路优泰）治疗轻中度抑郁症的疗效及安全性。方法：采用双盲、双模拟、随机、氟西汀对照、多中心的方法,以单相仰郁症或双相情感障碍的轻中度抑郁发作的抑郁症患者为入选对象．随机分为路优泰组６８例,予路优泰３００ｍｇ,ｔｉｄ,氟西汀安慰剂,ｑｄ;氟西汀组６７例,予氟西汀２０ ｍｇ,ｑｄ,路优泰安慰剂,ｔｉｄ。治疗时间均为 ６ｗｋ。疗效评定采用ＨＡＭＤ（１７项）及ＨＡＭＡ量表。安全性评价应用副反应量表（ＴＥＳＳ）、实验室检查及体检。结果：路优泰组治疗抑郁症的有效率为８３．８％,氟西汀组的有效率为８５．０％,２组之间无统计学差异。２组常见不良反应均较轻,不良反应发生率差异无统计学意义（Ｐ＞０．０５）．但路优泰组口干的发生率（１７．６％）显著低于氟西汀组（３５．８％）。结论：路优泰有良好的抗抑郁作用,疗效与氟西汀相当,不良反应轻,安全性高。     

St. John's wort significantly increased the systemic exposure and toxicity of methotrexate in rats

St. John's wort (SJW, Hypericum perforatum) is one of the popular nutraceuticals for treating depression. Methotrexate (MTX) is an immunosuppressant with narrow therapeutic window. This study investigated the effect of SJW on MTX pharmacokinetics in rats.Rats were orally given MTX alone and coadministered with 300 and 150 mg/kg of SJW, and 25 mg/kg of diclofenac, respectively. Blood was withdrawn at specific time points and serum MTX concentrations were assayed by a specific monoclonal fluorescence polarization immunoassay method.The results showed that 300 mg/kg of SJW significantly increased the AUC_0−t and C_max of MTX by 163% and 60%, respectively, and 150 mg/kg of SJW significantly increased the AUC_0−t of MTX by 55%. In addition, diclofenac enhanced the C_max of MTX by 110%. The mortality of rats treated with SJW was higher than that of controls.In conclusion, coadministration of SJW significantly increased the systemic exposure and toxicity of MTX. The combined use of MTX with SJW would need to be with caution.     

The recovery time-course of CYP3A after induction by St John's wort administration

AIMS

To examine the recovery time course of CYP3A after enzyme induction by St John''s wort administration.

METHODS

The subjects were 12 healthy men, aged 20–33 years. On the first day, they received an oral dose of midazolam 5 mg without St John''s wort (day −14). From the next day, they took St John''s wort for 14 days. On the last day of St John''s wort treatment (day 0) and 3 and 7 days after completion of St John''s wort treatment (days 3 and 7), they received the same dose of midazolam. On each day, blood samples were obtained until 8 h after midazolam administration. Plasma concentrations of midazolam were measured by HPLC. Pharmacokinetic parameters of midazolam were determined using noncompartmental analysis.

RESULTS

Apparent oral clearance of midazolam was significantly increased after St John''s wort administration from 65.3 ± 8.4 l h⁻¹ (day −14) to 86.8 ± 17.3 l h⁻¹ (day 0). It returned to the control level 7 days after the completion of St John''s wort (day 7, 59.7 ± 3.8 l h⁻¹). No significant difference in the elimination half-life between the four periods of the study was observed. The changes in apparent oral clearance after St John''s wort discontinuation indicated that CYP3A activity recovers from enzyme induction with an estimated half-life of 46.2 h.

CONCLUSIONS

CYP3A activity induced by St John''s wort administration progressively returns to the basal level after approximately 1 week. This finding may provide useful information to avoid clinically significant interactions of St John''s wort with CYP3A substrates.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• St John''s wort causes the induction of CYP3A. Little is known about how long the effect remains after cessation of St John''s wort.

WHAT THIS STUDY ADDS

• The in vivo CYP3A activity returns progressively to the basal level approximately 1 week after cessation of St John''s wort administration

     

Analysis and stability of the constituents of St. John's wort oils prepared with different methods

St. John's wort is a medicinal plant with a long history of use in traditional medicine all over Europe. Traditional preparations and in particular the infused oil from SJW flowers remains one of the most popular and curative topical remedy against ulcerations and burns. The presence of the characteristic polyprenylated acylphloroglucinol derivatives, namely hyperforin and analogs are instead related to the oil's therapeutic activity. Indeed, it is well known that hyperforin has a potent antibacterial activity.

In this study we tried to rationalize the production system of the oily preparation in order to obtain the highest concentration and stability of phloroglucinols. Five different samples of SJW oils were evaluated by HPLC-DAD-MS analysis to verify the variability and stability of the constituents according to the following factors: different harvesting time, fresh or dried plant material, use of sunlight or heating systems during extraction. The stability of these oils during 1 year was also tested.     

In vitro receptor screening of pure constituents of St. John's wort reveals novel interactions with a number of GPCRs

RATIONALE: Hypericum perforatum L. (St. John's wort; SJW) is one of the leading psychotherapeutic phytomedicines and great effort has been devoted to clarifying its mechanism of action. OBJECTIVE: We have undertaken a comprehensive analysis of several pure compounds isolated from the crude extract to gain further insight into the molecular actions of various substituents of SJW. METHODS: We characterized the in vitro pharmacology of the naphthodianthrones hypericin and pseudohypericin, the phloroglucinol derivative hyperforin, and several flavonoids at 42 biogenic amine receptors and transporters using the resources of the National Institute of Mental Health Psychoactive Drug Screening Program. RESULTS: The biflavonoid amentoflavone significantly inhibited binding at serotonin (5-HT(1D), 5-HT(2C)), D(3)-dopamine, delta-opiate, and benzodiazepine receptors. The naphthodianthrone hypericin had significant activity at D(3)- and D(4)-dopamine receptors and beta-adrenergic receptors. With the exception of the D(1)-dopamine receptor, the phloroglucinol derivative hyperforin was less active than other SJW constituents tested on all screened receptors. CONCLUSION: Our present in vitro data clearly show that several pure substances in SJW are potential CNS psychoactive agents and may contribute to the antidepressant efficacy of the plant in a complex manner. Our data also reveal novel and heretofore unexpected interactions of pure compounds in SJW at a number of GPCRs, transporters, and ion channels. We hypothesize that additive or synergistic actions of different single compounds may be responsible for the antidepressant efficacy of SJW. These results and this general approach may impact our understanding of phytomedicines in general and H. perforatum specifically.     

Effects of fesoterodine on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers

AIMS

To confirm the lack of an interaction of fesoterodine 8 mg with warfarin pharmacokinetics and pharmacodynamics in healthy adults.

METHODS

In this open-label, two-treatment, crossover study, subjects (n = 14) aged 20–41 years with normal prothrombin time (PT) and International Normalized Ratio (INR) were randomized to receive a single dose of warfarin 25 mg alone in one period and fesoterodine 8 mg once daily on days 1–9 with a single dose of warfarin 25 mg co-administered on day 3 in the other period. There was a 10-day washout between treatments. Pharmacokinetic endpoints were area under the plasma concentration–time curve from time 0 to infinity (AUC(0,∞)), maximum plasma concentration (C_max), AUC from time 0 to the time of the last quantifiable concentration (AUC(0,last)), time to C_max (t_max), and half-life (t_1/2) for S- and R-warfarin. Pharmacodynamic endpoints were area under the INR-time curve (AUC_INR), maximum INR (INR_max), area under the PT-time curve (AUC_PT) and maximum PT (PT_max).

RESULTS

Across all pharmacokinetic and pharmacodynamic comparisons, the point estimates of treatment ratio (warfarin co-administered with fesoterodine vs. warfarin alone) were 92–100%. The 90% confidence intervals for the ratios of the adjusted geometric means were contained within (80%, 125%). There were no clinically relevant changes in laboratory tests, vital signs or ECG recordings.

CONCLUSIONS

The pharmacokinetics and pharmacodynamics of warfarin 25 mg in healthy adults are unaffected by fesoterodine 8 mg. Concomitant administration of fesoterodine and warfarin was well tolerated.     

The effects of St John's wort extract on heart rate variability,cognitive function and quantitative EEG: a comparison with amitriptyline and placebo in healthy men

AIMS: To compare the effects of multiple dosing with St John's wort (Hypericum perforatum) extract and amitriptyline on heart rate variability, cognitive function and quantitative EEG (qEEG) with placebo in healthy humans. METHODS: A randomized, double-blind, cross over study of 12 healthy male volunteers. Subjects orally received capsules with 255-285 mg St John's wort extract (900 micro g hypericin content), 25 mg amitriptyline and placebo three times daily for periods of 14 days each with at least 14 days between. The doses of amitriptyline and St John's wort extract are comparable with respect to their antidepressant activity. Compliance was confirmed by coadministration of 10 mg of riboflavin with each capsule and detection of urinary vitamin B2 on treatment day 11 with high performance liquid chromatography. Measurements of heart rate variability, psychometric tests and qEEG were performed before start of medication and repeatedly on the last treatment day. RESULTS: St John's wort extract did not affect heart rate variability (HRV) whereas amitripytline significantly decreased it: the difference in the percentage number of adjacent RR intervals> 50 ms (pNN50) was 8.6 (-2.6, 19.9; mean; 95% confidence interval) between St John's wort extract and placebo and -17.6 (-24.7, -10.4) between amitriptyline and placebo. Neither St John's wort extract nor amitriptyline had an influence on cognitive performance such as choice reaction, psychomotor coordination, short-term memory and responsiveness to distractive stimuli. Amitriptyline but not St John's wort extract decreased self rated activity (P < 0.05). Both drugs caused significant qEEG changes. St John's wort extract increased theta power density. Amitriptyline increased theta as well as fast alpha power density. CONCLUSIONS: Multiple doses of St John's wort extract do not affect heart rate variability nor cognitive function. Chronic administration of amitriptyline causes a decrement of HRV and subjective sedation but it does not impair cognitive performance.     

Effect of the oral renin inhibitor aliskiren on the pharmacokinetics and pharmacodynamics of a single dose of warfarin in healthy subjects

AIMS: To investigate the effects of aliskiren, an oral renin inhibitor, on the pharmacokinetics and pharmacodynamics of warfarin. METHODS: In a single-blind, placebo-controlled, randomized, two-period crossover study, 15 healthy male and female subjects received a single oral dose of 25 mg racemic warfarin twice, once in the morning of the 8th day of treatment with 150 mg aliskiren and once at the same time point during treatment with placebo. Blood samples were collected for the measurement of prothrombin time (PT) and activated thromboplastin time (aPTT) and for determination of plasma concentrations of (R)- and (S)-warfarin. RESULTS: Aliskiren treatment had no effect on the blood coagulation parameters (PT, INR and aPTT). The ratios of least square means (90% CI) of pharmacokinetic parameters in the presence and absence of aliskiren for (R)- and (S)-warfarin were Cmax 0.89 (0.82, 0.96) and 0.88 (0.80, 0.97), AUC(0, infinity) 1.00 (0.94, 1.07) and 1.06 (0.96, 1.16) and t(1/2) 0.99 (0.92, 1.07) and 1.05 (0.96, 1.14). CONCLUSIONS: Multiple doses of aliskiren had no detectable effect on the pharmacokinetics or pharmacodynamics of a single dose of warfarin in healthy subjects.