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.     

大剂量硝酸异山梨醇酯抢救急性心源性肺水肿的疗效观察

目的探讨大剂量硝酸异山梨醇酯治疗急性心源性肺水肿的疗效。方法317例急性心源性肺水肿患者，分为实验组和对照组。实验组采用静脉注射大剂量硝酸异山梨醇酯注射液并且静脉滴注维持，对照组按传统疗法治疗。包括利尿．应用糖皮质激素、氨茶碱等。观察2组临床症状、动脉血压、血氧饱和度的变化。结果治疗后实验组有效率89．3％，对照组有效率70．4％（P〈0．01）。实验组在呼吸困难的缓解、肺部水泡音的减少、死亡人数以及血氧饱和度方面明显优于对照组，但2组在心率、呼吸频率上未见明显差异，治疗中均无急性心肌梗死出现，未见其他严重副作用。结论静脉注射大剂量硝酸异山梨醇酯抢救急性心源性肺水肿是一有效、安全的新疗法。     

Flunarizine (10 and 20 mg) i.v. versus placebo in the treatment of acute migraine attacks: a multi-centre double-blind study

In a multi-centre, randomized double-blind study, the effect and tolerance of 10 and 20 mg flunarizine i.v. versus placebo was tested on 102 migraineurs with acute migraine attacks with and/or without aura. Thirty-seven patients received 10 mg flunarizine, 32 received 20 mg and 33 received placebo. The groups were comparable. Response to treatment was defined as pain reduction of at least 50% within 60 min on a visual analogue scale after i.v. drug administration. This effect was noted on 59.4% with 20 mg flunarizine, on 24.3% with 10 mg flunarizine and on 30.3% with placebo. The tolerance of flunarizine i.v. was similar to placebo. Blood pressure and pulse rate were not affected by flunarizine. All in all, 20 mg flunarizine i.v. appeared to be a suitable alternative for treatment of acute migraine attacks.     

Flunarizine Versus Metoprolol in Migraine Prophylaxis: A Double-Blind, Randomized Parallel Group Study of Efficacy and Tolerability

The prophylactic effect of flunarizine and metoprolol was studied in a multi-center randomized, double-blind trial of 149 patients with migraine with or without aura. After a 4-week placebo run-in period, patients were randomly allocated to treatment with flunarizine 10 mg daily or metoprolol 200 mg daily for 16 weeks (parallel group design). Both drugs reduced the number of migraine days per month by 37% (95% confidence interval 21-53%) compared with the placebo run-in period. All efficacy parameters were significantly reduced by both drugs and no significant difference was found between the two drugs at any time of the treatment period. However, calculation of the 95% confidence limits showed that each drug may have a superiority of more than 100% on a single main effect parameter. The most common adverse experiences were day-time sedation (both drugs) and weight gain (flunarizine). Depression was the most serious side-effect occurring in 8% on flunarizine and 3% on metoprolol. We conclude that both drugs are effective in the prevention of migraine attacks but a higher number of dropouts occurred on flunarizine because of depression or weight gain.     

Acute migraine attack therapy: comparison of naproxen sodium and an ergotamine tartrate compound

The efficacy of safety of naproxen sodium and ergotamine tartrate were compared for the treatment of acute migraine attack in a randomized, parallel trial with 114 participating patients. At the start of symptoms, patients took either three tablets of naproxen sodium (275 mg each) or one of an ergotamine combination (containing 2 mg ergotamine tartrate, 91.5 mg caffeine, and 50 mg cyclizine chlorhydrate). Patients were followed for three months or until six attacks were monitored, whichever came first. Both medications substantially shortened the duration of migraine attacks and reduced the severity of symptoms. When the test medications were taken within 2 h of onset of attack, naproxen sodium was statistically significantly more effective than the ergotamine combination in reducing the severity of headache pain, nausea, and lightheadedness. The ergotamine combination was associated with significantly more vomiting, need for rescue medication, and side effects than was naproxen sodium. Four patients required discontinuation of the ergotamine combination and one of naproxen sodium. Both patients and investigators rated tolerance for naproxen sodium as superior to tolerance for the ergotamine combination. Naproxen sodium seems to be an effective and safe treatment for migraine attacks.     

Efficacy and tolerability in migraine prophylaxis of flunarizine in reduced doses: a comparison with propranolol 160 mg daily

This was a phase-IV double-blind equivalence trial designed to assess the efficacy and tolerability of two doses of flunarizine (10 mg o.d.=FLU 10 mg and 5 mg o.d.=FLU 5 mg) in the prophylaxis of migraine, in comparison with slow-release propranolol (160 mg o.d.). A total of 808 subjects were treated in a treatment period of 16 weeks. 142 subjects discontinued the trial prematurely, mainly because of adverse events (n=58). The mean attack frequency in the double-blind period was 2.0 for the FLU 5 mg group, 1.9 for the FLU 10 mg group, and 1.9 for the propranolol group. The mean attack frequency in the last 28 days of the double-blind period was 1.8 for FLU 5 mg, 1.6 for FLU 10 mg, and 1.7 for propranolol. Both flunarizine groups were at least as effective as propranolol (P<0.001 in one-sided test). The percentage of responders (defined as subjects for whom attack frequency decreased by at least 50% compared to run-in) in the last 28 days of the double-blind period was 46% (118/259) for FLU 5 mg, 53% (141/264) for FLU 10 mg, and 48% (125/258) for propranolol. Statistical analysis showed that FLU 10 mg is at least as effective as propranolol (P<0.001) and showed a trend for noninferiority of FLU5 and propranolol (P=0.053). No statistically significant differences between the treatment groups were found for any of the secondary parameters. Overall, 190 subjects reported one or more adverse events during the run-in phase: 54 (20.5%) in the FLU 5 mg group, 76 (27.7%) in the FLU 10 mg group and 60 (22.3%) in the propranolol group. The results of this equivalence trial show that 10 mg flunarizine daily with a drug-free weekend is at least as effective as 160 mg propranolol in the prophylaxis of migraine for all evaluated parameters (one-sided equivalence tests) after 16 weeks of treatment. In addition, 5 mg flunarizine proves to be at least as effective as 160 mg propranolol when looking at the mean attack frequency for both the whole double-blind period and the last 28 days of treatment. However, in the analysis of responders, 160 mg propranolol seems to be slightly better than 5 mg flunarizine. In addition, no significant differences between the three treatments were found with regard to safety: all three treatments were generally well-tolerated and safe.     

Screening of single doses of nitrates, calcium antagonists and beta-adrenoblockaders in patients with stenocardia of effort by using pharmacodynamic treadmill studies

Standard single doses of nitrates, Ca-antagonists and beta-adrenoblockers were studied and compared in 37 patients presenting with stable angina pectoris of effort by repeated treadmill tests coupled with ECG monitoring. The use of isosorbide dinitrate (10 mg), nifedipin (20 mg) and propranolol (40 mg) enabled the effective drug to be screened in 86% of patients. Eleven per cent more of patients responded to the raising of the drug dosage. Isosorbide dinitrate was found to be the most effective in 27% of cases, nifedipin in 19%, and propranolol in 11%. The effect of 2 to 3 drugs was similar in 40% of patients. The data obtained during the screening of the most effective drug in 13 patients, performed by two different methods (treadmill pharmacodynamic and pair bicycle ergomentry tests showed a good agreement in the majority of cases).     

Sublingual Administration of Flunarizine for Acute Migraine: Will Flunarizine Take the Place of Ergotamine?

SYNOPSIS
Clinical effectiveness of 10 mg sublingual flunarizine during 89 headache attacks was observed in 68 chronic headache patients. The study population consisted of 36 patients with migraine, 12 with combined headache, 11 with muscle contraction headache (MCH) and nine with cluster headache. Improved cases, defined as cases showing more than moderate improvement, were 75.0% in the migraine group, 50.0% in the combined headache group, 18.2% in the MCH group and 33.3% in the cluster headache group. The migraine group showed a significantly higher percentage of improved cases than did the MCH group (p<0.002). The group in which subjects received flunarizine within 10 min. from the beginning of headache, showed significantly better improvement than did the group in which subjects were treated after 10 min. (p<0.01). No remarkable side effects were observed except for transient numbness of the tongue and a feeling of sleepiness. Four typical case histories utilizing flunarizine administration, and a case showing recovery from angiospasm after sublingual flunarizine administration during an angiographic examination, are reported. A possible favorable role of flunarizine during migraine attacks is discussed. Double blind studies based on the present observations are necessary.     

Ergotamine and dihydroergotamine: a review

The ergot alkaloids were the first specific antimigraine therapy available. However, with the advent of the triptans, their use in the treatment of migraine has declined and their role has become less clear. This review discusses the pharmacology, efficacy, and safety of the ergots. In randomized clinical trials, oral ergotamine was found to be superior to placebo, but inferior to 100 mg of oral sumatriptan. In contrast, rectal ergotamine was found to have higher efficacy (73% headache relief) than rectal sumatriptan (63% headache relief). Intranasal dihydroergotamine was found to be superior to placebo, but less effective than subcutaneous and intranasal sumatriptan. Ergotamine is still widely used in some countries for the treatment of severe migraine attacks. It is generally regarded as a safe and useful drug if prescribed for infrequent use, in the correct dose, and in the absence of contraindications; however, safer and more effective options do exist in the triptans. In patients with status migrainous and patients with frequent headache recurrence, ergotamine is still probably useful.     

Flunarizine in the prevention of classical migraine: a placebo-controlled evaluation

Pharmacological data and early clinical experience have suggested that the calcium entry blocker flunarizine may be a valuable gain in the prophylaxis of migraine. This was supported by a study in 20 patients with classical migraine who were, after a drug free run-in phase, orally treated with either placebo or flunarizine (10 mg at night) for 3 to 4 months. Flunarizine significantly reduced the frequency, duration and severity of the migraine attacks. A corrected migraine index, based on these 3 variables was reduced by 82% in the drug group but increased by 66% in the control patients. Only 1 patient did not clearly benefit from flunarizine. In some cases flunarizine should be administered for at least 4 months before judging its efficacy. No side-effects occurred.     

Efficacy and tolerability of prochlorperazine buccal tablets in treatment of acute migraine

OBJECTIVES: To study the efficacy and tolerability of prochlorperazine (PCZ) management of acute migraine. DESIGN AND METHODS: A double blind comparative study was conducted to assess the efficacy of buccal PCZ 3 mg compared with oral ergotamine tartarate 1 mg plus caffeine 100 mg (ERG) or placebo (buccal or oral) for treatment of acute migraine. In all, 114 episodes of acute migraine were evaluated. Patients graded symptoms on a four-point scale before and up to 4 hours after treatment. The primary efficacy parameters included headache resolution within 2 hours (grade 3 or 2 to grade 0) and alleviation of other accompanying symptoms of migraine. The supplementary endpoints included improvement in quality of life (QOL). RESULTS: The percentage of patients reporting resolution of headache (to grade 0) was 51.4% for buccal PCZ and 21.7% for buccal placebo, 23.1% for oral ERG and 28.6% for oral placebo, headache tended to recur in both the placebo and ERG groups after initial improvement. Buccal PCZ was well tolerated; no signs of local irritation were evident, and patients found the formulation easy to use. Mild but transient sedation and drowsiness were observed in 41%. CONCLUSIONS: In the present study, PCZ 3 mg via the buccal route produced faster improvement and greater efficacy than placebo (oral as well as buccal) or oral ERG. The global QOL score 2 hours after treatment scores was higher in the PCZ group. Buccal PCZ may represent a particularly effective alternative for acute migraine treatment.     

High Dose Oral Isosorbide Dinitrate and Ischemic Heart Pain: A Preliminary Report

During the past two years, the author has treated 50 patients with angina pectoris, acute coronary insufficiency and acute myocardial infarction with high-dose oral isosorbide dinitrate. The daily dosage used varied between 120 and 360 mg daily, in contrast to the very small doses (10 mg tid and hs), usually recommended by the manufacturer and by many physicians. Previous articles in the literature suggest that oral isosorbide dinitrate is not effective in the prophylaxis of anginal pain. However, there are strong differences of opinion on this point, and our experience suggests that the lack of effect has been the result of the small dosage recommended.     

硫氮(艹卓)酮加硝酸异山梨酯与硝酸异山梨酯对冠心病患者心功能的影响

应用硫氨(艹桌)酮加硝酸异山梨酯与硝酸异山梨酯,对65例冠心病心绞痛患者进行9项心功能指标及临床疗效观察。结果表明:硫氮革酮与硝酸异山梨酯合用组(治疗组)用药前后,左心收缩功能指标SV、EF、Fs、PEP/LVET,舒张功能指标LA、E、A、A/E、DC均有显著差异(P<0.01),改善心绞痛症状有效率为94％。而单用硝酸异山梨酯组(对照组)用药后除每搏输出量及射血分数有明显差异外(P<0.01),其它各项指标无明显差异,改善心绞痛症状有效率为59％。提示:两药联合应用对改善冠心病患者左心功能疗效好,副作用少,值得在临床进一步观察。     

Comparison of flunarizine (Sibelium®) and pizotifen (Sandomigran®) in migraine treatment: A double-blind study

In this double-blind, randomized multicenter study involving 75 patients, the calcium-entry blocker flunarizine (10 mg nocte) was compared with pizotifen (2–3 mg per day in three administrations). Duration of treatment was four months. The results suggest that, in the dosage used, flunarizine is at least as effective as pizotifen in both classical and common migraine as regards effect on attack frequency. Flunarizine might tend to more markedly suppress severity of the attack, though. The weight gain seen with both drugs might be slightly less with flunarizine. A practical advantage of flunarizine is its simple dosage schedule (one intake per day).     

Early administration of isosorbide dinitrate improves survival of cyanide-poisoned rabbits

Abstract

Context. More effective, rapidly delivered, safer antidotes are needed for cyanide poisoning. Previous study has demonstrated a beneficial effect of isosorbide dinitrate on the survival of cyanide-poisoned mice. Objective. To evaluate the effectiveness of isosorbide dinitrate compared with that of sodium nitrite in cyanide poisoning. Materials and methods. A comparative animal study was performed using 18 rabbits, randomized into 3 study groups. Animals were poisoned intravenously with potassium cyanide (1 mg/kg). The first group was not given any further treatment. The second and third groups were treated intravenously 1 min after poisoning with sodium nitrite (6 mg/kg) and isosorbide dinitrate (50 μg/kg), respectively. The primary outcome was short-term survival of up to 30 min. Secondary outcomes included time to death, a clinical score, mean blood pressure, pulse, blood pH, and lactate and methemoglobin levels. Results. Rabbits treated with isosorbide dinitrate or sodium nitrite survived while only one untreated rabbit survived. Median time to death of the 5 poisoned and untreated animals was 10 min. All the animals collapsed soon after poisoning, exhibiting rapidly disturbed vital signs and developed lactic metabolic acidosis; average peak blood lactate levels were 15.5–19.1 mmol/L at 10 min after poisoning. The treated animals improved gradually with practically full recovery of the clinical scores, vital signs, and blood gas levels. Sodium nitrite administration raised methemoglobin to an average peak of 7.9%, while isosorbide dinitrate did not change methemoglobin levels. Conclusion. Early administration of isosorbide dinitrate improved the short-term survival of cyanide-poisoned rabbits. Isosorbide dinitrate shows potential as an antidote for cyanide poisoning and may exert its effect using a nitric-oxide-dependent mechanism.     

Tolfenamic acid, metoclopramide, caffeine and their combinations in the treatment of migraine attacks

Tolfenamic acid is a fenamate which inhibits prostaglandin (PG) biosynthesis and may act as a PG antagonist as well. Caffeine and metoclopramide are used in combination with analgesics and ergotamine in the treatment of migraine attacks, but controlled clinical studies on fixed combinations with analgesics are rare. The effects of orally given tolfenamic acid (200 mg), caffeine (100 mg), metoclopramide (10 mg), tolfenamic acid + caffeine (200 mg + 100 mg), tolfenamic acid + metoclopramide (200 mg + 10 mg) and placebo were studied in 49 migraine patients (3 men, 46 women) in a double-blind randomized cross-over study comprising 482 migraine attacks. The patients were allowed to take either one or two capsules of each preparation for an attack. Additional drugs were allowed after 3 h. Parameters characterizing the effects and side-effects of the drugs were registered. Tolfenamic acid and its combinations were found to be effective in the treatment of acute migraine, but caffeine and metoclopramide alone did not differ from placebo. Combination with metoclopramide was better than tolfenamic acid alone as judged by the smaller dose needed and the intensity of attack. Between tolfenamic acid alone and its caffeine combination there were no statistically significant differences.     

Bioavailability and antimigraine efficacy of effervescent ergotamine

SYNOPSIS
In about 20% of migraine patients treatment with enterally administrated ergotamine tartrate proves unsuccessful. One of the causes for this might be a poor systemic availability of the drug from the ordinary solid tablets. The present study aimed to investigate the bioavailability and the therapeutic value of ergotamine tartrate in effervescent form.
In twenty volunteers the plasma ergotamine levels were measured by using a radioimmunoassay after oral administration of 2.0 mg ergotamine tartrate combined with 50.0 mg caffeine in effervescent form. Measurable plasma drug levels were found in 14 (70%) of the subjects and the mean maximum plasma ergotamine level of 0.45 ng/ml was achieved at 30 minutes.
In the clinical part of the study 25 migraine patients treated their migraine attacks with effervescent ergotamine. The therapeutic value of it was considered as good by 9, moderate by 11 and poor by 5 of the patients. Among 18 of them the therapeutic effect seemed to be equal to their earlier ergotamine medications. The results indicate that the plasma pharmacokinetics of ergotamine tartrate in effervescent form is similar to and possibly faster on the absorptive phase than that reported earlier after enteral administration. In patients who do not gain benefit from the usual ergotamine tablets or suppositories, effervescent ergotamine would appear to be an alternative worth consideration.     

A placebo-controlled, double-blind, cross-over trial of flunarizine in common migraine

After four weeks of medication-free baseline observation, 29 patients with common migraine randomly received flunarizine (10 mg daily) or placebo for a 16-week period. After four weeks wash-out they crossed treatments for another 16 weeks; 27 patients completed the trial. Compared with placebo, flunarizine significantly reduced the frequency of migraine attacks and the derived headache indices, but the duration and severity of single attacks remained unchanged (Mann-Whitney U-test). The effect of flunarizine increased during the 16-week treatment period and during the last four weeks the number of migraine attacks reduced to 50% compared to the wash-out period. The only side-effect of flunarizine was mild daytime sedation in three patients. It is concluded that flunarizine is a valuable new prophylactic agent for common migraine.     

Efficacy of acupuncture for migraine prophylaxis: a single-blinded, double-dummy, randomized controlled trial

Insufficient clinical trial data were available to prove the efficacy of acupuncture for migraine prophylaxis. A multicenter, double-dummy, single-blinded, randomized controlled clinical trial was conducted at the outpatient departments of acupuncture at 5 hospitals in China to evaluate the effectiveness of acupuncture. A total of 140 patients with migraine without aura were recruited and assigned randomly to 2 different groups: the acupuncture group treated with verum acupuncture plus placebo and the control group treated with sham acupuncture plus flunarizine. Treated by acupuncture 3 times per week and drugs every night, patients from both groups were evaluated at week 0 (baseline), week 4, and week 16. The primary outcome was measured by the proportion of responders (defined as the proportion of patients with a reduction of migraine days by at least 50%). The secondary outcome measures included the number of migraine days, visual analogue scale (VAS, 0 to 10 cm) for pain, as well as the physical and mental component summary scores of the 36-item short-form health survey (SF-36). The patients in the acupuncture group had better responder rates and fewer migraine days compared with the control group (P < .05), whereas there were no significant differences between the 2 groups in VAS scores and SF-36 physical and mental component summary scores (P > .05). The results suggested that acupuncture was more effective than flunarizine in decreasing days of migraine attacks, whereas no significantly differences were found between acupuncture and flunarizine in reduction of pain intensity and improvement of the quality of life.     

Pharmacology and efficacy of eletriptan for the treatment of migraine attacks

Sumatriptan, a 5-HT 1B/1D agonist, was introduced 10 years ago and was the most effective therapy for migraine attacks at that time. Eletriptan is a new 5-HT 1B/1D agonist with high potency and selectivity at 5-HT 1B/1D receptors. It is effective in animal models in which the vascular and neurogenic mechanisms implicated in migraine were measured. Eletriptan is selective for the intracranial blood vessels over other extracranial vasculature, in particular coronary arteries. Eletriptan has a rapid and complete oral absorption and a good oral bioavailability in migraineurs. In comparative trials 20 mg, 40 mg and 80 mg eletriptan, 100 mg sumatritpan and placebo were compared for the treatment of migraine attacks. All three doses of eletriptan were statistically superior to placebo for headache response and headache-free patients. The 80 mg dose of eletriptan was also superior to sumatriptan 100 mg. Headache recurrence, defined as return of moderate or severe headache within 24 hours of dosing and following a headache response at two hours after initial dosing, occurred in 33% of the patients following 100 mg sumatriptan and in 28%, 34% and 32% after 20 mg, 40 mg and 80 mg eletriptan. In another large trial, headache response rates were significantly higher for both doses of eletriptan (64% for 40 mg and 67% for 80 mg) than for two doses of sumatriptan (50% for 50 mg and 53% for 100 mg). Eletriptan 40 mg or 80 mg was also superior to ergotamine plus caffeine (Cafergot). In summary, eletriptan is a highly effective and fast-acting drug for the treatment of acute migraine attacks.