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Ivar Roots - One of the best experts on this subject based on the ideXlab platform.
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differential drug induced mrna expression of human cyp3a4 compared to cyp3a5 cyp3a7 and cyp3a43
European Journal of Pharmacology, 2003Co-Authors: Solveigh Krusekopf, Ivar Roots, Ullrich KleebergAbstract:Abstract Drug-mediated regulation of mRNA expression of all members of the cytochrome P450 3A (CYP3A) subfamily has been measured by reverse transcription–polymerase chain reaction (RT-PCR) in the human hepatocellular carcinoma cell line, HepG2. Transcriptional regulation was proved by inhibition of induction with actinomycin D. Besides the positive control dexamethasone, the H+/K+-ATPase inhibitors omeprazole, lansoprazole, pantoprazole, and rabeprazole, and the herbal antidepressant St. John's wort (Hypericum Extract) were studied. All CYP3A mRNAs were induced by dexamethasone. CYP3A4 was the only CYP3A isoform that was induced by all of the four benzimidazole derivatives, while CYP3A5, CYP3A7, and CYP3A43 were unaffected or even slightly downregulated by these drugs. St. John's wort also increased CYP3A4 mRNA exclusively, leaving CYP3A5 and CYP3A43 unaffected, whereas CYP3A7 was decreased. Depending on the inducer, expression of CYP3A4 is differently regulated from CYP3A5, CYP3A7, and CYP3A43.
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differential effects of saint john s wort Hypericum perforatum on the urinary excretion of d glucaric acid and 6β hydroxycortisol in healthy volunteers
European Journal of Clinical Pharmacology, 2002Co-Authors: Steffen Bauer, Reinhold Kerb, Andreas Johne, Elke Stormer, Jürgen Brockmöller, Ivar RootsAbstract:OBJECTIVE We investigated the effects of treatment with Saint John's wort (Hypericum perforatum) Extract on the urinary excretion of D-glucaric acid, 6beta-hydroxycortisol, and free cortisol in order to assess the effect of this Extract on the activity of hepatic xenobiotic metabolizing enzymes. METHODS Forty-eight healthy volunteers (25 male and 23 female) received a daily dose of 1800 mg Hypericum Extract for 14 days. Urinary excretion of D-glucaric acid, 6beta-hydroxycortisol, and free cortisol was measured in 24-h urine samples on the day preceding the initiation of Hypericum treatment and after 14 days of treatment. D-Glucaric acid was measured enzymatically. Cortisol and 6beta-hydroxycortisol were quantified using high-performance liquid chromatography with ultraviolet detection. RESULTS Urinary excretion of D-glucaric acid was unaffected after a 14-day treatment with Saint John's wort Extract (26.7 micromol/day vs 27.7 micromol/day; 95% confidence interval of the difference: -1.9 to 3.8). The urinary excretion of 6beta-hydroxycortisol increased from a mean baseline value of 254 microg/day to 369 microg/day (P<0.0001) indicating induction of CYP3A. While the excretion of free cortisol was unaltered, the ratio of 6beta-hydroxycortisol to free cortisol changed significantly from 9.9 at baseline to 14.3 (95% confidence interval of the difference: 2.3-6.5) after Saint John's wort treatment. CONCLUSIONS High-dose treatment with Saint John's wort Extract induced CYP3A activity in healthy volunteers as evidenced by increased 6beta-hydroxycortisol excretion. This enzyme induction most likely contributes to the decreased bioavailability observed upon co-administration of various drugs with Saint John's wort Extract. The D-glucuronic acid pathway appeared unaffected by Saint John's wort.
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decreased plasma levels of amitriptyline and its metabolites on comedication with an Extract from st john s wort Hypericum perforatum
Journal of Clinical Psychopharmacology, 2002Co-Authors: Andreas Johne, Andreas M Stadelmann, Elke Stormer, Steffen Bauer, Gudrun Scholler, Matthias Langheinrich, Jürgen Schmider, Jürgen Brockmöller, Ivar RootsAbstract:Extracts of St. John’s wort (Hypericum perforatum) became increasingly popular as easily available remedies for mild to moderate depression. Comedication with Hypericum Extract was recently shown to drastically reduce plasma concentration of ciclosporin, digoxin, and indinavir. We investigated the p
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decreased plasma levels of amitriptyline and its metabolites on comedication with an Extract from st john s wort Hypericum perforatum
Journal of Clinical Psychopharmacology, 2002Co-Authors: Andreas Johne, Andreas M Stadelmann, Elke Stormer, Steffen Bauer, Gudrun Scholler, Matthias Langheinrich, Jürgen Schmider, Jürgen Brockmöller, Ivar RootsAbstract:Extracts of St. John's wort ( Hypericum perforatum ) became increasingly popular as easily available remedies for mild to moderate depression. Comedication with Hypericum Extract was recently shown to drastically reduce plasma concentration of ciclosporin, digoxin, and indinavir. We investigated the possible interaction of Hypericum Extract LI160 with amitriptyline. Both antidepressants have a high probability of concomitant use. Twelve patients requiring amitriptyline treatment received a single dose of Hypericum Extract (900 mg) at day 1, continued by a 12-to 14-day treatment with retarded amitriptyline (75 mg twice daily). Then Hypericum (900 mg/day) was added for another 14 to 16 days. Steady-state pharmacokinetics of amitriptyline were compared before and after multiple-dose treatment with Hypericum Extract. Furthermore, comparisons were made for single-dose kinetics of Hypericum-Extract ingredients hypericin, pseudohypericin, and hyperforin between the first day of concomitant treatment and LI160 alone. Multiple-dose comedication with LI160 led to a statistically significant decrease in the area under the plasma concentration-time curve within one dosing interval of amitriptyline by 22% ( p = 0.03) and nortriptyline by 41% ( p = 0.002), as well as of all hydroxylated metabolites, except for 10-E-hydroxynortriptyline. Plasma levels of amitriptyline and hydroxylated metabolites gradually decreased, whereas nortriptyline concentrations were already markedly decreased after 3 days of cotreatment with Hypericum. Cumulative urinary amounts of amitriptyline and metabolites decreased to the same extent as plasma concentrations upon Hypericum comedication. Induction of cytochrome P-450 enzymes or drug transporters (P-glycoprotein) by St. John's wort Extract may explain this pharmacokinetic interaction. Physicians should be aware of this interaction when treating patients with amitriptyline.
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pharmacokinetic interaction of digoxin with an herbal Extract from st john s wort Hypericum perforatum
Clinical Pharmacology & Therapeutics, 1999Co-Authors: Andreas Johne, Steffen Bauer, Matthias Langheinrich, Jürgen Brockmöller, A Maurer, Ivar RootsAbstract:Objective Extracts of St John's wort (Hypericum perforatum) are widely used in the treatment of depression, often as an over-the-counter drug. In contrast to its frequent use, knowledge about the pharmacokinetics of ingredients and drug interactions of St John's wort is poor. We studied the interaction between Hypericum Extract LI160 and digoxin. Methods The pharmacokinetics of digoxin were investigated in a single-blind, placebo-controlled parallel study. After the achievement of steady state for digoxin on day 5, healthy volunteers received digoxin (0.25 mg/d) either with placebo (n = 12) or with 900 mg/d LI160 (n = 13) for another 10 days. Digoxin concentration profiles on day 5 were compared with day 6 (single-dose interaction) and day 15 (tenth day of co-medication). Results There was a highly significant combined-day-and-group effect for digoxin area under the plasma concentration–time curve [AUC(0–24); P = .0001], peak concentration in plasma (Cmax; P = .0001), and plasma drug concentration at the end of a dosing interval (P = .0003) by two-way ANOVA. No statistically significant change was observed after the first dose of Hypericum Extract [AUC(0–24) at day 6 of 18.1 ± 2.9 μg · h/L and 17.7 ± 3.0 μg · h/L, mean ± SD for placebo and Hypericum group, respectively]. However, 10 days of treatment with Hypericum Extract resulted in a decrease of digoxin AUC(0–24) by 25% (day 15, 17.2 ± 4.0 μg · h/L and 12.9 ± 2.3 μg · h/L; P = .0035). Furthermore, comparison with the parallel placebo group after multiple dosing showed a reduction in trough concentrations and Cmax of 33% (P = .0023) and 26% (P = .0095), respectively. The effect became increasingly pronounced until the tenth day of co-medication. Conclusion As with grapefruit juice, a food product, physicians should also be aware of potential drug-herb interactions. The interaction of St John's wort Extract with digoxin kinetics was time dependent. The mechanism involved may be induction of the P-glycoprotein drug transporter. Clinical Pharmacology & Therapeutics (1999) 66, 338–345; doi: 10.1053/cp.1999.v66.a101944
Siegfried Kasper - One of the best experts on this subject based on the ideXlab platform.
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efficacy and tolerability of Hypericum Extract for the treatment of mild to moderate depression
European Neuropsychopharmacology, 2010Co-Authors: Siegfried Kasper, Bruno Forti, Filippo Caraci, Filippo Drago, Eugenio AgugliaAbstract:Depression is a common condition in the community with a significant impact on affected individuals, their relatives and society. Many patients with depression do not seek treatment and are often concerned about the possible adverse effects of antidepressant drugs. Extract of Hypericum perforatum (St. John's wort) has long been recognized as a treatment for depression. Several published trials and meta-analyses have demonstrated the efficacy and tolerability of Hypericum Extract for mild to moderate depression. Recent comparative trials of Hypericum Extract and other antidepressants, including selective serotonin reuptake inhibitors (SSRIs), provide support for Hypericum Extract efficacy. However, since the constituents of Hypericum Extract differ between the individual manufacturers, the efficacy cannot be extrapolated from one Extract to another. In this review, WS 5572, LI 160, WS 5570 and ZE 117 Hypericum Extracts have been shown to be significantly more effective than placebo with at least similar efficacy and better tolerability compared to standard antidepressant drugs.
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continuation and long term maintenance treatment with Hypericum Extract ws 5570 after recovery from an acute episode of moderate depression a double blind randomized placebo controlled long term trial
European Neuropsychopharmacology, 2008Co-Authors: Siegfried Kasper, Hans-peter Volz, Angelika Dienel, H J Moller, Meinhard KieserAbstract:The efficacy and safety of Hypericum Extract WS 5570 in preventing relapse during 6 months' continuation treatment and 12 months' long-term maintenance treatment after recovery from an episode of recurrent depression were investigated in a double-blind, placebo controlled multicenter trial. Adult out-patients with a recurrent episode of moderate major depression, a 17-item Hamilton Depression Rating Scale (HAMD) total score > or =20 and > or =3 previous episodes in 5 years participated. After 6 weeks of single-blind treatment with 3 x 300 mg/day WS 5570 patients with score or =50% versus baseline were randomized to 3 x 300 mg/day WS 5570 or placebo for 26 weeks. 426 patients were evaluated for efficacy. Relapse rates during continuation treatment were 51/282 (18.1%) for WS 5570 and 37/144 (25.7%) for placebo. Average time to relapse was 177+/-2.8 and 163+/-4.4 days for WS 5570 and placebo, respectively (time-to-event analysis; p=0.034; alpha=0.025 one-sided). Patients treated with WS 5570 showed more favorable HAMD and Beck Depression Inventory time courses and greater over-all improvement (CGI) than those randomized to placebo. In long-term maintenance treatment a pronounced prophylactic effect of WS 5570 was observed in patients with an early onset of depression as well as in those with a high degree of chronicity. Adverse event rates under WS 5570 were comparable to placebo. WS 5570 showed a beneficial effect in preventing relapse after recovery from acute depression. Tolerability in continuation and long-term maintenance treatment was on the placebo level.
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cluster analysis of symptoms during antidepressant treatment with Hypericum Extract in mildly to moderately depressed out patients a meta analysis of data from three randomized placebo controlled trials
Psychopharmacology, 2002Co-Authors: Siegfried Kasper, Angelika DienelAbstract:Abstract Rationale. Although Extracts from Hypericum have long played a major role in the treatment of mild to moderate depression, information pertaining to the drug's therapeutic profile is sparse. Objectives. To investigate whether the administration of the Hypericum Extract has a selective effect on particular signs and symptoms of depression as opposed to a more general acceleration of recovery. Methods. A meta-analysis was performed on the original data of three double-blind, randomized multicenter trials, during which 544 out-patients suffering from mild to moderate depression according to DSM-IV criteria received 3×300 mg/day Hypericum Extract (WS® 5570 or WS® 5572) or placebo over a double-blind treatment period of 6 weeks. The primary outcome measure for treatment efficacy in the original trials was the change in the total score of the Hamilton Rating Scale for Depression (HAMD, 17-item version) between baseline and treatment end. The relationship between the symptoms of depression represented by the items of the HAMD was assessed by means of cluster analysis and individual item analysis. Results. Two clusters of items were identified which were stable in several independent subsets of the full data set. While cluster 1 (HAMD items 1, 2, 3, 7, 8, 12, 13, 14, 16) was interpreted to represent the core symptoms of depression (including somatic aspects), cluster 2 (items 4, 5, 6, 9, 10, 11, 15, 17) was primarily composed of items assessing depression-related anxiety and insomnia. In both clusters, Hypericum Extract reduced the symptoms of depression more effectively than placebo. However, the herbal drug was particularly effective in the core symptoms of the disorder. Conclusions. The results indicate that Hypericum Extract accelerated the recovery from depression in a rather general manner, by influencing all investigated signs and symptoms of the disease. The drug's therapeutic profile was thus found to be similar to the profile of selective serotonin reuptake inhibitors.
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st john s wort Extract li 160 in somatoform disorders results of a placebo controlled trial
Psychopharmacology, 2002Co-Authors: Hans-peter Volz, Siegfried Kasper, H Murck, Hans-jürgen MöllerAbstract: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.
Meinhard Kieser - One of the best experts on this subject based on the ideXlab platform.
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continuation and long term maintenance treatment with Hypericum Extract ws 5570 after recovery from an acute episode of moderate depression a double blind randomized placebo controlled long term trial
European Neuropsychopharmacology, 2008Co-Authors: Siegfried Kasper, Hans-peter Volz, Angelika Dienel, H J Moller, Meinhard KieserAbstract:The efficacy and safety of Hypericum Extract WS 5570 in preventing relapse during 6 months' continuation treatment and 12 months' long-term maintenance treatment after recovery from an episode of recurrent depression were investigated in a double-blind, placebo controlled multicenter trial. Adult out-patients with a recurrent episode of moderate major depression, a 17-item Hamilton Depression Rating Scale (HAMD) total score > or =20 and > or =3 previous episodes in 5 years participated. After 6 weeks of single-blind treatment with 3 x 300 mg/day WS 5570 patients with score or =50% versus baseline were randomized to 3 x 300 mg/day WS 5570 or placebo for 26 weeks. 426 patients were evaluated for efficacy. Relapse rates during continuation treatment were 51/282 (18.1%) for WS 5570 and 37/144 (25.7%) for placebo. Average time to relapse was 177+/-2.8 and 163+/-4.4 days for WS 5570 and placebo, respectively (time-to-event analysis; p=0.034; alpha=0.025 one-sided). Patients treated with WS 5570 showed more favorable HAMD and Beck Depression Inventory time courses and greater over-all improvement (CGI) than those randomized to placebo. In long-term maintenance treatment a pronounced prophylactic effect of WS 5570 was observed in patients with an early onset of depression as well as in those with a high degree of chronicity. Adverse event rates under WS 5570 were comparable to placebo. WS 5570 showed a beneficial effect in preventing relapse after recovery from acute depression. Tolerability in continuation and long-term maintenance treatment was on the placebo level.
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comparison of Hypericum Extract ws 5570 and paroxetine in ongoing treatment after recovery from an episode of moderate to severe depression results from a randomized multicenter study
Pharmacopsychiatry, 2006Co-Authors: Iongeorge Anghelescu, Ralf Kohnen, Armin Szegedi, S Klement, Meinhard KieserAbstract:Objective: To test and compare the efficacy and safety of Hypericum Extract WS® 5570 to paroxetine, a potent SSRI, in patients suffering from moderate or severe depression according to DSM-IV criteria. Methods: In a multicenter, randomized, double-blind phase III study, the changes in moderate to severe major depression [DSM-IV; 17-item Hamilton Depression Rating Scale (HAM-D total >22)] after an acute treatment with Hypericum Extract WS® 5570 or paroxetine were analyzed in a 16-week continuation phase for relapse prevention. Patients with a HAM-D total score decrease of ≥50% during the 6 weeks of acute treatment were asked to continue the treatment for another 4 months. One-hundred and thirty-three adult out-patients who received maintenance doses of 900 (n=33) or 1800 mg/d (n=38) of WS® 5570 and 20 (n=28) or 40 mg/d (n=34) of paroxetine, respectively, were included. The relevant dosage was already fixed during the acute treatment. Results: Between baseline of the acute phase and end of continuation treatment the HAM-D total score decreased from 25.3±2.5 (mean±SD) to 4.3±6.2 points for WS" 5570 and from 25.3 ± 2.6 to 5.2±5.5 points for paroxetine (p=0.49, two-sided t-test; median relative decrease: 92.0 and 85.5 %, respectively). During maintenance treatment alone (day 154 - day 42), 61.6% of the patients randomized to WS® 5570 and 54.6% treated with paroxetine showed an additional reduction (p=0.59) with respect to the HAM-D total score. Remission (HAM-D endpoint total score below 8) occurred in 81.6 % (31 patients) of the patients for WS® 5570 and in 71.4% (30 patients) for paroxetine (p = 0.29). Three patients in the WS® 5570 group and 2 patients in the paroxetine group showed a HAM-D increase >5 points during continuation treatment. In the continuation phase there were 0.006 adverse events per day of exposure for WS® 5570 and 0.007 events for paroxetine. Conclusion: This study showed that WS® 5570 and paroxetine were similarly effective in preventing relapse in a continuation treatment after recovery from an episode of moderate to severe depression and point therefore to an important alternative treatment option for long-term relapse-prevention.
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acute treatment of moderate to severe depression with Hypericum Extract ws 5570 st john s wort randomised controlled double blind non inferiority trial versus paroxetine
BMJ, 2005Co-Authors: Armin Szegedi, Ralf Kohnen, Angelika Dienel, Meinhard KieserAbstract:Abstract Objective To investigate the efficacy of Hypericum Extract WS 5570 (St John9s wort) compared with paroxetine in patients with moderate to severe major depression. Design Randomised double blind, double dummy, reference controlled, multicentre non-inferiority trial. Setting 21 psychiatric primary care practices in Germany. Participants 251 adult outpatients with acute major depression with total score ≥ 22 on the 17 item Hamilton depression scale. Interventions 900 mg/day Hypericum Extract WS 5570 three times a day or 20 mg paroxetine once a day for six weeks. In initial non-responders doses were increased to 1800 mg/day Hypericum or 40 mg/day paroxetine after two weeks. Main outcome measures Change in score on Hamilton depression scale from baseline to day 42 (primary outcome). Secondary measures were change in scores on Montgomery-Asberg depression rating scale, clinical global impressions, and Beck depression inventory. Results The Hamilton depression total score decreased by mean 14.4 (SD 8.8) points, corresponding to 56.6% (SD 34.3%) of the baseline value, in the Hypericum group and by 11.4 (SD 8.6) points (44.8% (SD 33.5%) of baseline value) in the paroxetine group (intention to treat analysis; similar results were observed in the per protocol analysis). The intention to treat analysis (lower one sided 97.5% confidence limit 1.5 points for the difference Hypericum minus paroxetine) and the per protocol analysis (lower confidence limit 0.7 points) showed non-inferiority of Hypericum and statistical superiority over paroxetine. The lower limits in both cases exceeded the pre-specified non-inferiority margin of −2.5 points and the superiority margin of 0. The incidence of adverse events was 0.035 and 0.060 events per day of exposure for Hypericum and paroxetine, respectively. Conclusions In the treatment of moderate to severe major depression, Hypericum Extract WS 5570 is at least as effective as paroxetine and is better tolerated.
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efficacy and tolerability of Hypericum Extract ws 5572 versus placebo in mildly to moderately depressed patients a randomized double blind multicenter clinical trial
Pharmacopsychiatry, 2001Co-Authors: R Kalb, R D Trautmannsponsel, Meinhard KieserAbstract:We have investigated the antidepressant efficacy and safety of Hypericum perforatum (St. John's wort) Extract WS5572 in a double-blind, placebo-controlled multicenter clinical trial. 72 patients (WS 5572: 37, placebo: 35) with a diagnosis of mild to moderate major depressive disorder (according to DSM-IV criteria) were randomized in 42 days of treatment with either 300 mg WS5572 t.i.d. or placebo. The primary efficacy variable was the change of the 17-item Hamilton Depression Scale (HAMD) total score between baseline and double-blind treatment. The study was conducted with an adaptive interim analysis, which led to early stopping because convincing treatment efficacy could already be demonstrated. Group differences in favor of WS 5572 were descriptively apparent as early as day 7 of randomized treatment and were statistically significant at days 28 (p = 0.011) and day 42 (p < 0.001). Between baseline and treatment end, the HAMD total score decreased from 19.7 +/- 3.4 to 8.9 +/- 4.3 points in the Hypericum group and from 20.1 +/- 2.6 to 14.4 +/- 6.8 points in the placebo group (mean +/- SD). Responder rates were consistently higher in the Hypericum group. Comparable group differences in favor of WS 5572 were also found for von Zerssen's Depression Scale (D-S; self-rating), Clinical Global Impressions (CGI) and a global patient's self-assessment (GPA). Tolerability was very good in both groups, with no adverse drug reactions and no clinically relevant changes in safety parameters. The results indicate that Hypericum Extract WS 5572 is an effective and well-tolerated drug for the treatment of mild to moderate major depressive disorder.
Jürgen Brockmöller - One of the best experts on this subject based on the ideXlab platform.
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differential effects of saint john s wort Hypericum perforatum on the urinary excretion of d glucaric acid and 6β hydroxycortisol in healthy volunteers
European Journal of Clinical Pharmacology, 2002Co-Authors: Steffen Bauer, Reinhold Kerb, Andreas Johne, Elke Stormer, Jürgen Brockmöller, Ivar RootsAbstract:OBJECTIVE We investigated the effects of treatment with Saint John's wort (Hypericum perforatum) Extract on the urinary excretion of D-glucaric acid, 6beta-hydroxycortisol, and free cortisol in order to assess the effect of this Extract on the activity of hepatic xenobiotic metabolizing enzymes. METHODS Forty-eight healthy volunteers (25 male and 23 female) received a daily dose of 1800 mg Hypericum Extract for 14 days. Urinary excretion of D-glucaric acid, 6beta-hydroxycortisol, and free cortisol was measured in 24-h urine samples on the day preceding the initiation of Hypericum treatment and after 14 days of treatment. D-Glucaric acid was measured enzymatically. Cortisol and 6beta-hydroxycortisol were quantified using high-performance liquid chromatography with ultraviolet detection. RESULTS Urinary excretion of D-glucaric acid was unaffected after a 14-day treatment with Saint John's wort Extract (26.7 micromol/day vs 27.7 micromol/day; 95% confidence interval of the difference: -1.9 to 3.8). The urinary excretion of 6beta-hydroxycortisol increased from a mean baseline value of 254 microg/day to 369 microg/day (P<0.0001) indicating induction of CYP3A. While the excretion of free cortisol was unaltered, the ratio of 6beta-hydroxycortisol to free cortisol changed significantly from 9.9 at baseline to 14.3 (95% confidence interval of the difference: 2.3-6.5) after Saint John's wort treatment. CONCLUSIONS High-dose treatment with Saint John's wort Extract induced CYP3A activity in healthy volunteers as evidenced by increased 6beta-hydroxycortisol excretion. This enzyme induction most likely contributes to the decreased bioavailability observed upon co-administration of various drugs with Saint John's wort Extract. The D-glucuronic acid pathway appeared unaffected by Saint John's wort.
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decreased plasma levels of amitriptyline and its metabolites on comedication with an Extract from st john s wort Hypericum perforatum
Journal of Clinical Psychopharmacology, 2002Co-Authors: Andreas Johne, Andreas M Stadelmann, Elke Stormer, Steffen Bauer, Gudrun Scholler, Matthias Langheinrich, Jürgen Schmider, Jürgen Brockmöller, Ivar RootsAbstract:Extracts of St. John’s wort (Hypericum perforatum) became increasingly popular as easily available remedies for mild to moderate depression. Comedication with Hypericum Extract was recently shown to drastically reduce plasma concentration of ciclosporin, digoxin, and indinavir. We investigated the p
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decreased plasma levels of amitriptyline and its metabolites on comedication with an Extract from st john s wort Hypericum perforatum
Journal of Clinical Psychopharmacology, 2002Co-Authors: Andreas Johne, Andreas M Stadelmann, Elke Stormer, Steffen Bauer, Gudrun Scholler, Matthias Langheinrich, Jürgen Schmider, Jürgen Brockmöller, Ivar RootsAbstract:Extracts of St. John's wort ( Hypericum perforatum ) became increasingly popular as easily available remedies for mild to moderate depression. Comedication with Hypericum Extract was recently shown to drastically reduce plasma concentration of ciclosporin, digoxin, and indinavir. We investigated the possible interaction of Hypericum Extract LI160 with amitriptyline. Both antidepressants have a high probability of concomitant use. Twelve patients requiring amitriptyline treatment received a single dose of Hypericum Extract (900 mg) at day 1, continued by a 12-to 14-day treatment with retarded amitriptyline (75 mg twice daily). Then Hypericum (900 mg/day) was added for another 14 to 16 days. Steady-state pharmacokinetics of amitriptyline were compared before and after multiple-dose treatment with Hypericum Extract. Furthermore, comparisons were made for single-dose kinetics of Hypericum-Extract ingredients hypericin, pseudohypericin, and hyperforin between the first day of concomitant treatment and LI160 alone. Multiple-dose comedication with LI160 led to a statistically significant decrease in the area under the plasma concentration-time curve within one dosing interval of amitriptyline by 22% ( p = 0.03) and nortriptyline by 41% ( p = 0.002), as well as of all hydroxylated metabolites, except for 10-E-hydroxynortriptyline. Plasma levels of amitriptyline and hydroxylated metabolites gradually decreased, whereas nortriptyline concentrations were already markedly decreased after 3 days of cotreatment with Hypericum. Cumulative urinary amounts of amitriptyline and metabolites decreased to the same extent as plasma concentrations upon Hypericum comedication. Induction of cytochrome P-450 enzymes or drug transporters (P-glycoprotein) by St. John's wort Extract may explain this pharmacokinetic interaction. Physicians should be aware of this interaction when treating patients with amitriptyline.
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pharmacokinetic interaction of digoxin with an herbal Extract from st john s wort Hypericum perforatum
Clinical Pharmacology & Therapeutics, 1999Co-Authors: Andreas Johne, Steffen Bauer, Matthias Langheinrich, Jürgen Brockmöller, A Maurer, Ivar RootsAbstract:Objective Extracts of St John's wort (Hypericum perforatum) are widely used in the treatment of depression, often as an over-the-counter drug. In contrast to its frequent use, knowledge about the pharmacokinetics of ingredients and drug interactions of St John's wort is poor. We studied the interaction between Hypericum Extract LI160 and digoxin. Methods The pharmacokinetics of digoxin were investigated in a single-blind, placebo-controlled parallel study. After the achievement of steady state for digoxin on day 5, healthy volunteers received digoxin (0.25 mg/d) either with placebo (n = 12) or with 900 mg/d LI160 (n = 13) for another 10 days. Digoxin concentration profiles on day 5 were compared with day 6 (single-dose interaction) and day 15 (tenth day of co-medication). Results There was a highly significant combined-day-and-group effect for digoxin area under the plasma concentration–time curve [AUC(0–24); P = .0001], peak concentration in plasma (Cmax; P = .0001), and plasma drug concentration at the end of a dosing interval (P = .0003) by two-way ANOVA. No statistically significant change was observed after the first dose of Hypericum Extract [AUC(0–24) at day 6 of 18.1 ± 2.9 μg · h/L and 17.7 ± 3.0 μg · h/L, mean ± SD for placebo and Hypericum group, respectively]. However, 10 days of treatment with Hypericum Extract resulted in a decrease of digoxin AUC(0–24) by 25% (day 15, 17.2 ± 4.0 μg · h/L and 12.9 ± 2.3 μg · h/L; P = .0035). Furthermore, comparison with the parallel placebo group after multiple dosing showed a reduction in trough concentrations and Cmax of 33% (P = .0023) and 26% (P = .0095), respectively. The effect became increasingly pronounced until the tenth day of co-medication. Conclusion As with grapefruit juice, a food product, physicians should also be aware of potential drug-herb interactions. The interaction of St John's wort Extract with digoxin kinetics was time dependent. The mechanism involved may be induction of the P-glycoprotein drug transporter. Clinical Pharmacology & Therapeutics (1999) 66, 338–345; doi: 10.1053/cp.1999.v66.a101944
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hypericin and pseudohypericin pharmacokinetics and effects on photosensitivity in humans
Pharmacopsychiatry, 1997Co-Authors: Jürgen Brockmöller, Reinhold Kerb, Steffen Bauer, T Reum, W D Hubner, Ivar RootsAbstract:Extracts of St. John's wort (Hypericum perforatum) are used in treatment of depression. They contain various substances with the naphthodianthrones hypericin and pseudohypericin as characteristic ingredients. These compounds were shown to cause phototoxicity in cell culture and in animals. A placebo-controlled randomized clinical trial with monitoring of hypericin and pseudohypericin plasma concentration was performed to evaluate the increase in dermal photosensitivity in humans after application of high dose Hypericum Extracts. The study was divided into a single dose and a multiple dose part. In the single dose period, each of 13 volunteers received in a double blind fourfold complete crossover design, either placebo, or 900, 1800 or 3600 mg of a standardized Hypericum Extract (LI 160) containing zero, 2.81, 5.62 and 11.25 mg of total hypericin (total hypericin is the sum of hypericin and pseudohypericin). Maximum total hypericin plasma concentrations were observed about 4 h after dosage and were 0, 0.028, 0.061 and 0.159 mg/L, respectively. Before and 4 h after drug intake, the subjects were exposed at small areas of their back to increasing doses of solar simulated irradiation (SSI, with combined ultraviolet A, UV-A, and UV-B light) and another part was exposed to selective UV-A light irradiation. Minimal erythema dose was determined 5, 20 and 68 h after irradiation. Comparison of SSI sensitivity without and with Hypericum Extract did not show and difference and there was no dose-related trend in light sensitivity. Sensitivity to selective UV-A light was increased only after the highest dose from a minimal tanning dose of 10.8 J/ cm2 (mean) after placebo to 8.7 J/cm2 after 3600 mg Extract with marginal statistical significance (p = 0.03 by one sided paired t-test). There was no correlation between total hypericin plasma concentrations and photosensitivity. In the multiple dose part, 50 volunteers received 600 mg Hypericum Extract t.i.d. with a daily dose of 5.6 mg of total hypericin. Comparison of UV light sensitivity before dosing with day 15 of treatment showed a slightly increased SSI sensitivity expressed by decrease of the MED from 0.17 to 0.16 J/cm2 (p = 0.005 by Wilcoxon test), and similarly, sensitivity to UV-A light increased (the mean tanning dose decreased from 9.9 to 7.8 J/cm2, p < 0.0001). This increase in cutaneous light sensitivity could be compensated by reducing irradiation time by 21%. Doses used in this study were higher than typical doses in current commercial preparations. In spite of these high doses in the double blind single dose part, frequency of side effects was equal to placebo medication and UV light sensitivity was not or only marginally increased. The study does not, however, exclude phototoxic reactions with doses above 11.25 mg of total hypericin and plasma levels above 100 micrograms/L. Furthermore, phototoxicity may be different after application of pure hypericin, since some constituents in the plant Extract may exhibit protective effects.
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efficacy of Hypericum Extract ws 5570 compared with paroxetine in patients with a moderate major depressive episode a subgroup analysis
European Psychiatry, 2017Co-Authors: Edith Holsboertrachsler, Erich Seifritz, Martin HatzingerAbstract:Introduction Various studies showed the efficacy and tolerability of WS® 5570 (Hyperiplant® Rx, Dr. Willmar Schwabe GmbH & Co. KG) for the treatment of acute mild-to moderate depression. Beneficial effects of WS® 5570 have been also shown in patients with moderate-to-severe depression. Objectives/aims We present a subgroup analysis of a double blind, randomised trial to compare the therapeutic efficacy of WS® 5570 with paroxetine in patients suffering from a major depressive episode with moderate symptom intensity. This analysis on moderately depressed patients treated with WS® 5570 tries to support the hypothesis that WS® 5570 is an effective remedy in patients with major depression and moderate symptom intensity. Methods Moderate depression was defined by a baseline Hamilton Depression Rating Scale (HAM-D) total score between 22 and 25. Sixty-four patients received, after a single blind placebo run-in phase of 3–7 days, either 3 × 300 mg/day WS® 5570 or 20 mg/day paroxetine for six weeks. The change of the HAM-D total score was used to describe the efficacy of WS® 5570 compared with paroxetine in the subgroup of patients with moderate depression. Results The reduction of the HAM-D total score was significantly more pronounced in patients treated with 3 × 300 mg/day WS® 5570 compared to 20 mg/day paroxetine. After six weeks, responder (87.1%) and remission rates (60.6%) to WS® 5570 were significantly higher than to paroxetine (71%/42.4%). Conclusions After six weeks, patients treated with WS® 5570 showed a higher reduction in depression severity score and yielded greater response and remission rates compared with patients treated with paroxetine.
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efficacy of Hypericum Extract ws 5570 compared with paroxetine in patients with a moderate major depressive episode a subgroup analysis
International Journal of Psychiatry in Clinical Practice, 2016Co-Authors: Erich Seifritz, Martin Hatzinger, Edith HolsboertrachslerAbstract:AbstractObjectives: efficacy and tolerability of WS® 5570 for the treatment of acute mild-to-moderate depression, has been demonstrated in various studies. Here, we present a subgroup analysis of a double blind, randomised trial to compare the therapeutic efficacy of WS® 5570 with paroxetine in patients suffering from a major depressive episode with moderate symptom intensity.Methods: moderate depression was defined by a baseline Hamilton Depression Rating Scale (HAM-D) total score between 22 and 25. Patients received, after a single blind placebo run-in phase of 3–7 d, either 3 × 300 mg/d WS® 5570 or 20 mg/d paroxetine for six weeks. The change of the HAM-D total score was used to describe the efficacy of WS® 5570 compared with paroxetine in the subgroup of patients with moderate depression.Results: the reductions of the HAM-D total score were significantly more pronounced in patients treated with 3 × 300 mg/d WS® 5570 compared to 20 mg/d paroxetine.Conclusions: patients treated with WS® 5570 not only sh...