Silexan does not cause withdrawal symptoms even when abruptly discontinued.

OBJECTIVE: Subsequent to a randomised, double-blind, double dummy clinical trial assessing the efficacy of silexan compared to placebo and paroxetine in patients suffering from generalised anxiety disorder (GAD), a 1week follow-up phase was added in order to assess possible withdrawal symptoms of silexan after abrupt discontinuation. METHODS: Participants received silexan 80 mg/d, silexan 160 mg/d, paroxetine 20 mg/d, or placebo at a ratio of 1:1:1:1. Study medication was discontinued after the 10 week active treatment phase of the original trial. Whereas paroxetine was tapered as indicated, silexan administration was discontinued abruptly. Assessment of possible withdrawal effects was done using the Physician Withdrawal Checklist questionnaire (PWC-20). RESULTS: During the 1 week down-titration phase, mean total PWC-20 scores had reduced by 0.19 in placebo, 0.23 in silexan 80, 0.65 in silexan 160, and 0.51 in paroxetine. The median change in all four groups was 0.00. In none of the treatment groups withdrawal effects occurred after discontinuation. CONCLUSIONS: Values assessed for the silexan groups indicate the absence of a dependency potential of this preparation.

Phase II trial on the effects of Silexan in patients with neurasthenia, post-traumatic stress disorder or somatization disorder.

Silexan, a novel lavender oil preparation for oral use, has been authorized in Germany for the treatment of states of restlessness during anxious mood. An open-label, exploratory trial was performed to assess the potential of the medicinal product in the treatment of restlessness caused by anxiety as related to several disorders. Outcome measures included the Symptom Checklist-90-Revised (SCL-90-R), von Zerssen's Depression Scale (D-S), the 36-item Short Form Health Survey Questionnaire (SF-36), and a sleep diary. 50 male and female patients with neurasthenia (ICD-10 F48.0), post-traumatic stress disorder (PSD; F43.1), or somatization disorder (F45.0, F45.1) were included to receive 1 × 80 mg/day Silexan over 6 weeks; 47 could be analyzed for efficacy as full analysis set. At baseline, patients suffered from restlessness (96%), depressed mood (98%), sleep disturbances (92%), or anxiety (72%). Of those, resp. 62%, resp. 57%, resp.51%, resp. 62% showed improvements during treatment (p < 0.001). For all patients, mean D-S score decreased by 32.7% and SCL-90-R Global Severity Index by 36.4% as compared to baseline, (p < 0.001), while the SF-36 Mental Health Score increased by 48.2% (p < 0.001). Waking-up frequency (p = 0.002), Waking-up duration (p < 0.001) and morning tiredness (p = 0.005) were reduced, while efficiency of sleep (p = 0.018) and mood (p = 0.03) improved. Patients suffering from neurasthenia or PSD showed comparable improvements with most outcomes. The results in this trial justify to further investigate Silexan in disorders with accompanying restlessness caused by sub-threshold anxiety. Adverse reactions, predominantly gastrointestinal complaints, were judged as mild or moderate.

Effect of Ginkgo biloba special extract EGb 761® on human cytochrome P450 activity: a cocktail interaction study in healthy volunteers.

PURPOSE: We assessed the human in vivo metabolic drug interaction profile of Ginkgo biloba extract EGb 761® with respect to the activities of major cytochrome P450 (CYP) enzymes. METHODS: A single-center, open-label, randomized, three-fold crossover, cocktail phenotyping design was applied. In random order, the following treatments were administered to 18 healthy men and women for 8 days each: placebo twice daily, EGb 761® 120 mg twice daily, and EGb 761® 240 mg in the morning and placebo in the evening. In the morning of day 8, administration was performed together with the orally administered phenotyping cocktail (enzyme, metric): 150 mg caffeine (CYP1A2, paraxanthine/caffeine plasma ratio 6-h postdose), 125 mg tolbutamide (CYP2C9, plasma concentration 24-h postdose), 20 mg omeprazole (CYP2C19, omeprazole/5-hydroxy omeprazole plasma ratio 3-h postdose), 30 mg dextromethorphan (CYP2D6, dextromethorphan/dextrorphan plasma ratio 3-h postdose), and 2 mg of midazolam (CYP3A, plasma concentration 6-h postdose). Formally, absence of a relevant interaction was assumed if the 90% confidence intervals (CIs) for EGb 761®/placebo ratios of the metrics were within the 0.70-1.43 range. RESULTS: EGb 761®/placebo ratios for phenotyping metrics were close to unity for all CYPs. Furthermore, respective CIs were within the specified margins for all ratios except CYP2C19 for EGb 761® 120 mg twice daily (90% CI 0.681-1.122) and for CYP2D6 for EGb 761® 240 mg once daily (90% CI 0.667-1.281). These findings were attributed to the intraindividual variability of the metrics used. All treatments were well tolerated. CONCLUSION: EGb 761® has no relevant effect on the in vivo activity of the major CYP enzymes in humans and therefore has no relevant potential to cause respective metabolic drug-drug interactions.

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.

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 =2 on item 'Improvement' of the Clinical Global Impressions (CGI) scale and a HAMD total score decrease > 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.

Efficacy of St. John's wort extract WS 5570 in acute treatment of mild depression: a reanalysis of data from controlled clinical trials.

Based on the original data from two double-blind, randomized, placebo-controlled clinical trials and the acute phase of a long-term study that investigated the antidepressant efficacy of St. John's wort extract WS 5570, we present a re-analysis of a subset of patients suffering from an acute episode of mild depression according to DSM criteria. Out of a total of more than 1,200 patients included into these trials 217 had a pre-treatment total score < or =20 points on the 17-item Hamilton Rating Scale for Depression (HAMD) and were eligible for our re-analysis. They received 600, 900, or 1,200 mg/day WS 5570 or placebo for 6 weeks. In patients treated with WS 5570 the HAMD total score decreased by averages of 10.8 (600 mg/day), 9.6 (900 mg/day), and 10.7 (1,200 mg/day) points between the pre-treatment baseline value and the end of acute treatment, compared to 6.8 points in the placebo group (p < 0.01 for all pairwise comparisons of WS 5570 against placebo). This corresponded to average relative decreases by 49-57% for WS 5570 and by 36% for placebo. The rates of responders (i.e., patients with a HAMD total score decrease > or =50%) were 73%, 64%, 71%, and 37% for WS 5570 600 mg/day, 900 mg/day and 1,200 mg/day, and placebo, respectively. At the end of acute treatment 57% of the patients treated with WS 5570 600 mg/day, 33% in the 900 mg/day group and 62% in the 1,200 mg/day group, as well as 25% in the placebo group were in remission (HAMD total score < or =7 points). The analysis shows that St. John's wort extract WS 5570 has a meaningful beneficial effect during acute treatment of patients suffering from mild depression and leads to a substantial increase in the probability of remission.

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.

OBJECTIVE: To investigate the efficacy of hypericum extract WS 5570 (St John's 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 > or = 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.

Continuation and long-term maintenance treatment with Hypericum extract WS 5570 after successful acute treatment of mild to moderate depression--rationale and study design.

Unipolar major depression is often a chronic disease that may require lifelong prophylaxis. Recovery from an acute episode is followed by 4-6 months of relapse prevention. After that, long-term maintenance treatment is administered to avoid recurrence. We present the rationale and design of an ongoing double-blind, randomized, placebo-controlled trial investigating the efficacy of Hypericum extract WS 5570 in relapse prevention in recurrent unipolar depression. An estimated sample of 425 adults with recurrent, mild to moderate major depression (ICD-10 and DSM-IV criteria), > or = 3 previous episodes (last 5 years) and a total score > or = 20 points on the 17-item Hamilton Rating Scale for Depression (HAMD) will be included. After a one-week wash out patients receive 3 x 300 mg/day WS 5570 single-blind for 6 weeks. Responders are randomized to 26 weeks of double-blind continuation treatment with 3 x 300 mg/day WS 5570 or placebo. Patients completing continuation treatment without relapse enter 52 weeks of doubleblind maintenance treatment, where those treated with WS 5570 are re-randomized to 3 x 300 mg/day WS 5570 or placebo. The primary outcome measure is the time to relapse during continuation treatment (HAMD > or = 16, clinical diagnosis of depression, or premature treatment termination for inefficacy). Hypericum extract, with its favourable tolerability profile, could be an interesting option for long-term prophylaxis. The trial was designed according to current consensus and guidance. Notably, it includes long-term prophylactic treatment with the same drug and the same therapeutic dose applied during acute treatment, uses well-defined outcome measures and provides a clear distinction between relapse and recurrence.

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.

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 3x300 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.

Therapeutic intensive seizure analysis (TISA) in presurgical evaluation of Losigamone.

OBJECTIVE: The new method TISA was used to evaluate Losigamone efficacy. METHODS: Sixteen patients with pharmacoresistant partial seizures undergoing presurgical evaluation were randomized in this double-blind, placebo-controlled, parallel-group Losigamone monotherapy study under continuous video-EEG monitoring. Duration (in s, of each seizure and each ictal sign), intensity (grade zero to three), N/24h (number of seizures and ictal signs per 24 h), D/24h (seconds per 24 h covered by seizures and ictal signs) and seizure free intervals were recorded. RESULTS: A total of 246 seizures were intensively analyzed. The duration and intensity of all seizures improved more in the active treatment group than in the placebo group. There was a statistically significant superiority in the duration of the seizure free interval in the Losigamone group. Ictal signs such as oro-alimentary automatisms and fumbling were improved during Losigamone treatment. CONCLUSION: Losigamone has a preferred inhibitory effect on propagated epileptic activity. TISA is a sensitive method for evaluation of the selective effects of AEDs.

Losigamone add-on therapy in partial epilepsy: a placebo-controlled study.

OBJECTIVES: To evaluate the efficacy and tolerability of losigamone (LSG). PATIENTS AND METHODS: Double-blind, placebo-controlled add-on study with 3x500 mg LSG/die for the treatment of chronic partial seizures in 203 patients (99 treated with LSG, 104 on placebo). RESULTS: The median percent change of seizures was 14.9% (LSG) versus 6.7% (placebo) (P=0.004). Seizure frequency was decreased by more than 50% in 22.3% (LSG) and 14.6% (placebo) of patients (P=0.13). Mean percent change of seizures was best in patients with only one additional anticonvulsant drug (LSG versus placebo, P=0.004). Adverse events (usually CNS-related side effects of mild to moderate intensity) were reported in 59.6% (LSG) and 37.5% (placebo) of patients. CONCLUSIONS: LSG proved to be an effective and well tolerated anticonvulsant drug for the treatment of chronic partial seizures.

Clinical significance of hyperforin for the efficacy of Hypericum extracts on depressive disorders of different severities.

In a randomized, double-blind, placebo-controlled, multicenter study, the clinical efficacy and safety of two different extracts of St. John's wort were investigated in 147 male and female out-patients suffering from mild or moderate depression according to DSM-IV criteria. Fifty-six (38.1%) of them had an initial total score ≥ 22 points on the Hamilton Rating Scale for Depression (HAMD, 17-item version). Following a placebo run-in period of three to seven days, the patients were randomized to one of three treatment groups: During the 42-day treatment period, they received 3×1 tablet of either placebo, Hypericum extract WS 5573 (300mg, with a content of 0.5% hyperforin), or Hypericum extract WS 5572 (300 mg, with a content of 5% hyperforin). The manufacturing process for both Hypericum preparations was identical, they only differed with regard to their content of hyperforin. Efficacy regarding depressive symptoms was assessed on days 0, 7,14,28, and 42. The last observation of patients withdrawn from the trial prematurely was carried forward. At the end of the treatment period (day 42), the patients receiving WS 5572 (5% hyperforin) exhibited the largest HAMD reduction versus day 0 (10.3 ± 4.6 points; mean ± SD), followed by the WS 5573 group (0.5% hyperforin; HAMD reduction 8.5 ± 6.1 points) and the placebo group (7.9 ± 5.2 points). The monotonie trend was significant (Jonckheere-Terpstra test; p = 0.017). In patients with an initial HAMD total score ≥ 22, the HAMD reduction was even by 16.5% larger than in the total study group receiving WS 5572. More severely depressed patients treated with WS 5573, however, showed a 22.4% lower reduction of the HAMD total score than the entire WS 5573 treatment group. In patients with HAMD ≥ 22, WS 5572 showed a 53.8% larger HAMD reduction than placebo, whereas WS 5573 was not relevantly different from the placebo level. The mean HAMD reductions, treatment end versus baseline, for the more severely depressed patients were 12.0 (3.7) points, 6.6 (7.7) points and 7.8 (5.4) points [mean (SD)] for WS 5S72, WS 5573 and placebo, respectively. The results of a responder analysis support these findings. The data point to a dose-response relationship between the antidepressant efficacy of Hypericum extract and its hyperforin content. The extract with a higher content of hyperforin was particularly effective in patients who were more severely depressed.

Pharmacokinetics of losigamone, a new antiepileptic drug, in healthy male volunteers.

Losigamone (AO-33), a new potential antiepileptic drug, was tested in 52 healthy male volunteers in 4 placebo-controlled phase I studies. In study 1 single doses of 100, 200, 300, 500, 700, and 1,000 mg losigamone were given as a fast releasing capsule to 12 subjects. The pharmacokinetics of losigamone measured after administration of 100, 300, and 700 mg was linear. Clearance and t1/2 were about 350 ml/min and 4 h, respectively, the Cmax values of 0.7, 1.7, and 4.4 micrograms/ml were reached after 2.5 h. In study 2,500 mg losigamone were given as a fast release capsule for 6 days (t.i.d.) to 12 subjects. There was a small but statistically significant decrease for the AUC but no change in t1/2, Cmax or tmax comparing single dose kinetics on day 1 and 8. There appeared to be no change in caffeine clearance on days 1 and 9. Study 2 was repeated in 20 volunteers with a film-coated tablet. Pharmacokinetic parameters appeared to be unaffected by this change in galenical formulation. In study 4 daily doses of 400, 1,200, and 1,800 mg losigamone were given 28 days to 24 subjects. The kinetics of caffeine and antipyrine were compared on days 1 and 29. With the exception of t1/2 for antipyrine in the 400 mg group there was no statistically significant change in pharmacokinetic parameters. Generally, losigamone was well tolerated and no serious adverse side-effects occurred. In some subjects a reversible increase in transaminases was observed.

The influence of social isolation, hypoxia and immobilization on potassium-stimulated dopamine release from telencephalon slices of mice.

Dopamine release from mice telencephalon slices was investigated following immobilization or hypobaric hypoxia exposure during periods of social isolation of different length which itself affects dopamine release in a characteristic manner. Isolation initially results in a decreasing release, which is compensated at the end by adaptive processes. The decrease of dopamine release induced by immobilization is highly dependent on the foregoing isolation. On the other hand, a hypoxia-induced decrease of release always dominates the results. Adaptive processes in consequence of social isolation are supposed to be important in relation to immobilization effects but not to hypoxia-induced changes.

The influence of social isolation on ethanol preference behavior and dopamine release in telencephalon slices in mice.

We examined the relation between the duration of social isolation and alterations in ethanol preference behavior and the dopamine release in telencephalon slices in mice. Ethanol preference developed only after an isolation period of 2 weeks and a further ethanol treatment of 2 weeks. It did not appear after an isolation period of 6 weeks, in mice without ethanol treatment, and in group-housed mice. The dopamine release was lowered in mice isolated for 2 weeks and is normalized in combination with ethanol treatment. The dopamine release inhibition evoked by social isolation of 2 weeks probably reflects a functional state with high sensitivity for induction of an ethanol preference behaviour.

Influence of nootropic drugs on drinking behaviour in ethanol-preferring mice and ethanol-induced increase of seizure susceptibility.

The influence of several nootropic drugs (piracetam, pyritinol, meclofenoxat, methylglucamine orotate (MGO) and dihydroergotoxine (DHET) on both the ethanol preference and the enhanced seizure susceptibility after a single dose of ethanol was studied. Piracetam, MGO and DHET reduce the ethanol drinking in ethanol-preferring mice. The enhanced seizure susceptibility after a single dose of ethanol was abolished by piracetam and MGO.

Ethanol preference behaviour and dopamine release in the rat.

The development of ethanol preference behaviour in rats is connected with a decrease of dopamine release from striatum slices seen after alcohol cessation. The inhibition of dopamine release vanishes spontaneously within a few days. Restitution is highly accelerated by piracetam, exhibiting similarities to posthypoxic membrane damages.

[Effect of nootropic agents on the lowering of the spasm threshold after a single ethanol application]. / Einfluss von Nootropika auf die Ernierdrigung der Krampfschwelle nach einmaliger Athanolapplikation.

We used the effect of ethanol on the convulsion threshold as model of injuriousness to analyse the CNS protective efficacy of nootropics. The CD50 of picrotoxine in mice was significantly diminished in comparision with the controls between 5 and 6 hours after 66 mmol/kg ethanol administered intraperitoneally and between 7 and 8 h after 92.4 mmol/kg. In this moment the administered ethanol was already eliminated; the effect is explained as a reversible consequence of the previous ethanol exposition. The influence of nootropics was examined. Piracetam (0.7 mmol/kg i.p.) as well as methylglucaminorotate (MGO) (0.68 mmol/kg-1 i.p.) suppressed the ethanol effect on the convulsibility, pyritinol (0.82 mmol/kg) was ineffective, and meclophenoxate (1.02 mmol/kg) by itself decreased the convulsions threshold.