SYNOPSIS The postulated pivotal role of focal brain hypoxia in the genesis of the migraine attack and the anti‐hypoxic properties of flunarizine, have led to the use of the selective calcium‐entry blocker in the treatment of migraine. Clinical experience is reviewed. Open findings, confirmed by double‐blind placebo‐controlled studies and comparisons with pizotifen and cinnarizine, have shown that flunarizine, given at 10 mg daily, is a safe and effective prophylactic drug for both common and classical migraine. Factors determining the efficacy of flunarizine are discussed.

SYNOPSIS The early prodromal phase of a migraine attack, poorly documented yet conceivably relevant to the pathogenesisof the attack, was studied in 149 patients, mainly female, with classic or common migraine who were aware ofthese prodromal phenomena. On a questionnaire a variety of prodromes, nearly all well reproduceable, werereported. Day‐before and day‐of‐attack symptoms were noticed by 79% and 88% of the patients, respectively. Inthe other 12–21% signs were mainly observed by the partner. Some prodromes invoked the “cause orconsequence?” question as to certain trigger factors. Others bore rather striking similarities to the classic aura, sothat evolutive symptoms seemed to merge with the early part of the migraine attack. The incidence, or at least theawareness of prodromes was correlated with the occurrence of some factors aggravating the headache and withpost‐attack symptoms, was higher in women, in patients with long‐standing disease and frequent attacks, inpatients who had other types of headaches as well, and in classic migraine sufferers.

In vitro, ketoconazole has been shown to block testicular and adrenal 17,20-lyase, which converts progestins to androgens. At higher concentrations, it also inhibits 11 beta-hydroxylase, 20,22-desmolase and 17 alpha-hydroxylase. To determine the differential hormonal effects of a 2-week ketoconazole high-dose therapy, the plasma levels of 10 major androgens, gluco- and mineralocorticoids were measured in 14 previously untreated patients with metastatic prostate cancer. Within 24 h, plasma testosterone fell from 14.6 +/- 1.4 nmol/l (mean +/- SEM) to 3.7 +/- 0.7 nmol/l. Thereafter, it decreased to about 2.5 nmol/l and remained at that level. Plasma androstenedione and dehydroepiandrosterone decreased more gradually, respectively from 3.1 +/- 0.4 nmol/l to 0.64 +/- 0.17 nmol/l and from 6.6 +/- 1.0 nmol/l to 2.82 +/- 0.55 nmol/l (on day 14). In contrast, 17 alpha-hydroxyprogesterone and progesterone rose respectively 2- and 5-fold. Plasma cortisol and aldosterone levels remained unchanged whereas 11-deoxycorticosterone and 11-deoxycortisol rose by factors of 14 and 6.7 respectively. Plasma corticosterone also increased, but to a much lesser extent (3-fold). These results demonstrate that ketoconazole high dose therapy blocks mainly the 17,20-lyase of both adrenal and testis. In addition it inhibits mitochondrial 11 beta-hydroxylase to a lesser extent. The inhibition of 20,22-desmolase also seems to be of little clinical relevance. However, since clinical or laboratory symptoms suggestive of hypo-adrenalism have been reported in a small minority of patients, replacement therapy should be considered in such cases.

The hypothesis postulates that a brief episode of focal cerebral hypoxia occurs in every attack of migraine. Clinical biochemical and technical (EEG and CT scans) evidence is summarized suggesting that cerebral hypoxia is seen as the turning-point in the pathogenesis of the attack. It may be provoked by different mechanisms in different patients; the potential role of decreased oxygen supply and of increased oxygen need are reviewed and excess sympathetic drive is considered a potential key mechanism in a majority of patients. Whether or not focal hypoxia leads to a genuine migraine attack, depends largely upon the quality of the whirlpool of biochemical, vascular and hematological changes that follow the hypoxic episode. These changes are discussed and it is concluded that those which have been reported to occur during migraine attacks could be due to a preceding hypoxic event. Finally, the hypoxia viewpoint is confronted with some popular theories about the pathogenesis of migraine. It is found that the other points of view are compatible with the hypoxia hypothesis.

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A design is descirbed of a modified placebo-controlled double-blind clinical trial procedure. The design was evolved in attempt to overcome certain problems inherent in the conventional double-blind procedure, in particular the ethical problem of prolonged exposure of the patient to placebo treatment. The modified designs consist of two phases. In the first (open) phase, patients selected according to the normal protocol requirements are given the medication under study for a predetermined time. Patients responding favorably to such treatment then enter a second (double blind) phase during which is tested the null hypothesis that all the favorable effects observed during the open phase are placebo effects. Experience with this clinical trial design in the evaluation of an antianginal agent is briefly described. In this case, the null hypothesis was disproved, and a potent therapeutic action was evidenced.

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SYNOPSIS Relationships between precipitating factors in the pathogenesis of migraine were studied in a sample of 217 migraineurs. The most frequently cited triggers were the menstrual cycle (51.5% of the women), alcoholic beverages (51.6%) and emotional or psychic stress (48.8%). Analysis of 4 subgroups of patients, i.e. those with only one of these 3 triggers or with none of these (controls), showed that alcohol‐susceptible patients reported significantly (p<0.001) more alimentary triggers than the controls. A similar phenomenon was found in patients with menstrual‐cycle related migraine, but in this group the difference with the controls fell short of reaching statistical significance. A further analysis showed that menstrual migraine attacks are more frequently preceded by depressive symptoms than other migraine attacks. It is suggested that the gut of certain migraineurs may be unduly permeable, either intrinsically or extrinsically (e.g. under the influence of alcohol). In addition, in some patients with menstrual migraine, a depressive episode, associated with the menstrual period, may facilitate the development of a migraine attack.