Urinary metabolites of amitriptylinoxide and amitriptyline in single-dose experiments and during continuous therapy.

In a cross-over design, six healthy volunteers received 50 mg amitriptylinoxide (AT-NO) IV and orally and 50 mg amitriptyline (AT) IV. Urine was collected completely for 8 h and occasionally up to 48 h. In addition, five patients each under treatment with AT-NO or AT for tension headache collected 24-h urine samples. The following compounds were analysed by HPLC: AT-NO, E- and Z-10-hydroxy-AT-NO (E- and Z-10-OH-AT-NO), free and conjugated AT, E- and Z-10-OH-AT and their mono- and didemethylated analogues, and 2-OH-nortriptyline (2-OH-NT). Unchanged AT-NO in urine accounted for an average of 34% and 22% of the single IV and oral doses, respectively, and for 28% in continuous therapy, with a further 8-9% being excreted as E- and Z-10-OH-AT-NO. The remaining part was converted to the same metabolites as was AT. In the steady state the measured compounds accounted for 74% and 77% of the daily AT-NO and AT doses, respectively. The renal plasma clearance of AT-NO varied between 75 and 265 ml/min in the six volunteers. Tubular secretion must play an important part in the renal excretion of AT-NO.

A 28-week, double-blind, placebo-controlled study with Cerebrolysin in patients with mild to moderate Alzheimer's disease.

Cerebrolysin (Cere) is a compound with neurotrophic activity which has been shown to be effective in the treatment of Alzheimer's disease (AD) in earlier trials. The efficacy and safety of repeated treatments with Cere were investigated in this randomized, double-blind, placebo-controlled, parallel-group study. One hundred and forty-nine patients were enrolled (76 Cere; 73 placebo). Patients received i.v. infusions of 30 ml Cere or placebo 5 days per week for 4 weeks. This treatment was repeated after a 2-month therapy-free interval. Effects on cognition and clinical global impressions were evaluated 4, 12, 16, and 28 weeks after the beginning of the infusions using the Clinical Global Impression (CGI) and the Alzheimer's Disease Assessment Scale-cognitive subpart (ADAS-cog). All assessments, including the 28-week follow-up visit were performed under double-blind conditions. At week 16, the responder rate of the Cere group was 63.5% on the CGI, compared to 41.4% in the placebo group (P < 0.004). In the ADAS-cog, an efficacy difference of 3.2 points in favour of Cere was observed (P < 0.0001). Notably, improvements were largely maintained in the Cere group until week 28, 3 months after the end of treatment. Adverse events were recorded in 43% of Cere and 38% of placebo patients. Cere treatment was well tolerated and led to significant improvement in cognition and global clinical impression. A sustained benefit was still evident 3 months after drug withdrawal.

[Double blind study of intravenous aspirin vs placebo in the treatment of acute migraine attacks.]. / Therapie des akuten Migräneanfalls mit intravenös applizierter Acetylsalicylsäure : Eine plazebokontrollierte Doppelblindstudie.

INTRODUCTION: The empirical use of oral acetylsalicylic acid (ASA) in the treatment of acute migraine attacks has led to the recommendation of ASA as a basic treatment of migraine. However, there are no controlled studies on the intravenous use of acetylsalicylic acid. METHODS: Forty patients with a 1- to 12-year history of migraine were included in this placebo-controlled trial. The sociodemographic data of patients receiving placebo or 500 mg ASA i.v. and migraine symptoms before treatment were identically distributed. Pain relief during attacks was documented by the Visual Analogue Scale (VAS) for 1 h at 5-min intervals. Furthermore, the change of concurrent non-pain symptoms was evaluated by self-rating (worse-unchanged-better-absent). RESULTS: The VAS showed a mean pain reduction of about 60% after 1 h versus placebo. Efficacy varied significantly between patients. We observed a small number of socalled non-responders as well as patients with complete pain relief. The most common concomitant symptoms were nausea, photophobia, vertigo, vomiting and sweating. During the time of observation these symptoms were significantly reduced compared to placebo. The study shows a maximum placebo effect of about 17% (mean value). Significant differences in pain ratings were measured 25-30 min after application (P=0.0008). CONCLUSIONS: In this study i.v. ASA showed a significant reduction in pain intensity during migraine attacks. In addition, most concomitant non-pain symptoms were equally reduced. The onset of pain relief did not correspond with the inhibition of platelet aggregation (after 2-4 min) or with peak plasma concentrations of ASA (immediately after application) or salicylic acid (after 2-3 h). More efficacy studies with higher doses and longer periods of observation are necessary to optimize the treatment of migraine attacks with intravenous ASA. Studies including neurophysiological and vascular parameters are recommended to confirm the results of this study.

Flunarizine i.v. in the acute treatment of the migraine attack. A double-blind placebo-controlled study.

Flunarizine, 20 mg by slow intravenous injection, was studied in the acute treatment of migraine attacks in a multicentre, double-blind, placebo-controlled study. At the end of the 60 min observation period, 23 of the 31 (74.2%) patients treated with flunarizine reported complete relief, or a pain reduction of more than 50%, vs. 8 of 29 (27.6%) placebo patients (p less than 0.017). Accompanying symptoms also improved significantly better in the flunarizine than in the placebo group. The investigators evaluated the therapy as good or excellent in 77.4% of the flunarizine and in 27.6% of the placebo patients, respectively. Tolerance of the therapy was good and comparable in the two groups. Somnolence was the only flunarizine-related adverse reaction. Blood pressure and heart rate were not affected. Flunarizine i.v. deserves further study in the acute treatment of a migraine attack.

Flunarizine i.v. in the acute treatment of common or classical migraine attacks--a placebo-controlled double blind trial.

The efficacy and tolerance of 20 mg flunarizine i.v. were tested in comparison with placebo in a multicentre randomised double-blind trial in the acute treatment of migraine attacks. Sixty case reports were included in the evaluation; 31 patients were treated with flunarizine and 29 with placebo. Flunarizine proved to be significantly superior in its effect on the intensity of pain and the typical concomitant symptoms of the attacks. Patients were classed as responders who displayed a reduction in pain intensity by at least 50% within 60 minutes after the administration of flunarizine. 23 patients (= 74.2%) were responders, including 11 patients being without pain after 60 minutes. In the placebo group the responder rate was 27.6% The fact that both groups were comparable in all respects should be emphasized. The tolerance of intravenously administered flunarizine was excellent and corresponded to that of placebo. Apart from a sedative effect reported by 9 patients there were no side-effects. The circulatory conditions remained largely stable. The result of this study seems to indicate that an intravenous injection of 20 mg flunarizine might represent a genuine alternative, and as regards tolerance even a superior one, to the parenteral administration of ergotamine in migraine attacks.

Efficacy and tolerability of amitriptylinoxide in the treatment of chronic tension-type headache: a multi-centre controlled study.

Amitriptyline is the medication of first choice in the treatment of chronic tension-type headache. In 197 patients with chronic tension-type headache (87M and 110F with a mean age of 38 +/- 13 (18-68)) efficacy and tolerability of 60-90 mg amitriptylinoxide (AO) were compared with 50-75 mg amitriptyline (AM) and placebo (PL) in a double-blind, parallel-group trial consisting of a four weeks' baseline phase and 12 weeks of treatment. The primary study endpoint was a reduction of at least 50% of the product of headache duration and frequency and a reduction of at least 50% in headache intensity. Statistics used were Fisher's exact test and analysis of variance. No significant difference emerged between AO, AM and PL with respect to the primary study endpoint. Treatment response occurred in 30.3% of the AO, 22.4% of the AM and 21.9% of the PL group. A reduction in headache duration and frequency of at least 50% was found in 39.4% on AO, in 25.4% on AM and in 26.6% on PL (PAO-PL = .1384, PAM-PL = 1.000, PAO-AM = .0973). A reduction in headache intensity of at least 50% was found in 31.8% on AO, in 26.9% on AM and in 26.6% on PL (PAO-PL = .5657, PAM-PL = 1.000, PAO-AM = .5715). Trend analysis with respect to a significant reduction of headache intensity (p < 0.05) and the product of headache duration and frequency revealed a superior effect of AO.(ABSTRACT TRUNCATED AT 250 WORDS)

Magnesium in the prophylaxis of migraine--a double-blind placebo-controlled study.

The migraine prophylactic effect of 10 mmol magnesium twice-daily has been evaluated in a multicentre, prospective, randomized, double-blind, placebo-controlled study. Patients with two to six migraine attacks per month without aura, and history of migraine of at least 2 years, were included. A 4-week baseline period without medication was followed by 12 weeks of treatment with magnesium or placebo. The primary efficacy end-point was a reduction of at least 50% in intensity or duration of migraine attacks in hours at the end of the 12 weeks of treatment compared to baseline. With a calculated total sample size of 150 patients, an interim analysis was planned after completing treatment of at least 60 patients, which in fact was performed with 69 patients (64F, 5M), aged 18-64 years. Of these, 35 had received magnesium and 34 placebo. The number of responders was 10 in each group (28.6% under magnesium and 29.4% under placebo). As determined in the study protocol, this was a major reason to discontinue the trial. With regard to the number of migraine days or migraine attacks there was no benefit with magnesium compared to placebo. There were no centre-specific differences, and the final assessments of treatment efficacy by the doctor and patient were largely equivocal. With respect to tolerability and safety, 45.7% of patients in the magnesium group reported primarily mild adverse events like soft stool and diarrhoea in contrast to 23.5% in the placebo group.

Cyclandelate in the prophylaxis of migraine: a randomized, parallel, double-blind study in comparison with placebo and propranolol. The Study group.

Cyclandelate inhibits calcium-induced contraction of vascular smooth muscle cells, platelet aggregation induced by thrombin, platelet-activating-factor and adenosine, and also suppresses a provoked 5HT release from platelets. This pharmacological profile suggests that cyclandelate may have a potential prophylactic effect in migraine. To test this hypothesis, a double-blind multicentre study was performed in 214 patients to investigate the efficacy and tolerability of cyclandelate compared to placebo and propranolol. After a 4-week baseline period, eligible patients (randomization 3:2:3) were treated for 12 weeks with daily doses of 1.200 mg cyclandelate (n = 81), placebo (n = 55) or 120 mg propranolol (n = 78). The number of migraine attacks (> or = 50% responders) and the migraine duration/month were compared based on the difference between baseline and the last 4 weeks of prophylactic treatment. The percentage of patients with a reduction in migraine attacks of > or = 50% treated with cyclandelate (37.0%) or propranolol (42.3%) was not significantly superior to placebo (30.9%; p > 0.025). The mean duration of migraine in hours (h) per month decreased in both active treatment groups (cyclandelate: 36.8 h, p = 0.046; propranolol: 34.4 h, p = 0.039) compared to placebo (13.7 h) without reaching statistical significance (alpha/2 = 0.025). The clinical efficacy of cyclandelate and propranolol was comparable. Adverse experiences were reported by 13 patients (16.0%) treated with cyclandelate, by 5 patients (9.1%) treated with placebo and by 19 patients (24.4%) treated with propranolol. These were drug-related in 7.1% (n = 6) of patients treated with cyclandelate and in 9% (n = 7) of patients treated with propranolol. In summary, cyclandelate has a comparable efficacy to that of propranolol, an established drug of first choice in the prophylaxis of migraine. Both drugs were better than placebo, but not significantly so. Both active treatments were well tolerated.

[Effectiveness and tolerance of amitriptyline oxide in chronic tension headache--a multicenter double-blind study versus amitriptyline versus placebo]. / Wirksamkeit und Verträglichkeit von Amitriptylinoxid beim chronischen Spannungskopfschmerz--Eine Multizentrische Doppelblindstudie versus Amitriptylin versus Plazebo.

Tricyclic antidepressants, especially amitriptyline, are the medication of first choice in the treatment of chronic tension headache. Few previous studies meet modern standards of study design and statistical analysis. Tolerability and efficacy of 60-90 mg amitriptyline oxide (AO) as a single dose in the evening were compared with 50-75 mg amitriptyline (AM) and placebo (PL) in a double-blind, parallel-group trial consisting of a 4-week baseline phase and 12 weeks of treatment. The 3-armed study was conducted in 7 centers. The inclusion criterion was tension-type headache on at least 15 days monthly with a duration of at least 6 months. Exclusion criteria were a migraine history, previous participation in another clinical trial within the last 3 months, drug abuse, medication with other antidepressants or tranquilizers, current use of other acknowledged prophylactic headache medication, lack of compliance, major psychiatric disorder according to DSM-III and medical contra-indications against tricyclic antidepressants. The primary study endpoint was a reduction at least 50% of the product of headache duration and frequency and a reduction at least 50% in headache intensity. Statistics used were Fisher's Exact Test and an analysis of variance. A total of 211 patients were included in this trial. One hundred ninety-seven cases, 87 males and 110 females, with a mean age of 38 +/- 13 (18-68) years, could be analysed completely (66 AO, 67 AM, 64 PL). With regard to the strictly defined primary study endpoint, no significant difference emerged between AO, AM and PL: treatment responders were 30.3% with AO, 22.4% with AM and 21.9% with PL (PAO-PL = 0.3210, PAM-PL = 1.000, PAO-AM = 0.3299 respectively).(ABSTRACT TRUNCATED AT 250 WORDS)