Peer Tfelt-Hansen

THE COMMON MIGRAINE ATTACK MAY NOT BE INITIATED BY CEREBRAL ISCHAEMIA

Abstract Regional cerebral blood-flow was measured in the resting state and during the development of common migraine attacks induced by red wine. The tomographic xenon-133 method was used in four studies, the intra-arterial xenon-133 method in one study, and the xenon-133 inhalation method in the remaining three studies. No significant focal or global reduction of cerebral blood-flow was found at any time. This contrasts with previous findings of reduced cerebral blood-flow in classical migraine. It is suggested that these two forms of migraine have a different pathophysiology.

Spreading Cerebral Oligemia in Classical‐ and Normal Cerebral Blood Flow in Common Migraine

SYNOPSIS

One Hundred Years of Migraine Research: Major Clinical and Scientific Observations From 1910 to 2010

(Headache 2011;51:752‐778)

The phosphodiesterase 3 inhibitor cilostazol dilates large cerebral arteries in humans without affecting regional cerebral blood flow.

Cilostazol, an inhibitor of phosphodiesterase (PDE) type 3, is used clinically in peripheral artery disease. PDE3 inhibitors may be clinically useful in the treatment of delayed cerebral vasospasm after subarachnoid hemorrhage. The authors present the first results on the effect of cilostazol on cerebral hemodynamics in normal participants. In this double-blind, randomized, crossover study, 200 mg cilostazol or placebo was administered orally to 12 healthy participants. Cerebral blood flow was measured using 133Xe inhalation and single photon emission computerized tomography. Mean flow velocity in the middle cerebral arteries (VMCA) was measured with transcranial Doppler, and the superficial temporal and radial arteries diameters were measured with ultrasonography. During the 4-hour observation period, there was no effect on systolic blood pressure (P = 0.28), but diastolic blood pressure decreased slightly compared with placebo (P = 0.04). VMCA decreased 21.5 ± 5.7% after cilostazol and 5.5 ± 12.2% after placebo (P = 0.02, vs. placebo), without any change in global or regional cerebral blood flow. The superficial temporal artery diameter increased 17.6 ± 12.3% (P < 0.001 vs. baseline) and radial artery diameter increased 12.6 ± 8.6% (P < 0.001 vs. baseline). Adverse events, especially headache, were common. The findings suggest that cilostazol is an interesting candidate for future clinical trials of delayed cerebral vasospasm.

Verapamil for Cluster Headache. Clinical Pharmacology and Possible Mode of Action

Verapamil is used mainly in cardiovascular diseases. High‐dose verapamil (360‐720u2003mg) is, however, currently the mainstay in the prophylactic treatment of cluster headache. The oral pharmacokinetics are variable. The pharmacodynamic effect of verapamil, the effect on blood pressure, also varies considerably among subjects. The dose of verapamil used for cluster headache is approximately double the dose used in cardiovascular disease, most likely because verapamil is a substrate for the efflux transporter P‐glycoprotein in the blood–brain barrier. The access of verapamil to the central nervous system is therefore limited. The clinical use of verapamil in cluster headache is reviewed and several relevant drug interactions are mentioned. Finally, its possible mode of action in cluster headache is discussed. The effect of verapamil in cluster headache most likely takes place in the hypothalamus.Verapamil is an L‐type calcium channel blocker but it is also a blocker of other calcium channels (T‐, P‐, and possibly N‐ and Q‐type Ca2+ channels) and the human ether‐a‐go‐go‐related gene potassium channel. With so many different actions of verapamil, it is impossible at the present time to single out a certain mode of action of the drug in cluster headache.

Methodological Aspects of Drug Trials in Migraine. pp 204–215

Treatment of migraine attacks and prophylactic treatment of migraine are each discussed under the four headings: patient selection, trial design, evaluation of results and

Nitroglycerin Headache and Nitroglycerin-Induced Primary Headaches From 1846 and Onwards: A Historical Overview and an Update

Nitroglycerin (NTG) (glyceryl trinitrate) was synthesized by the Italian chemist Ascanio Sobrero in Paris in 1846. A very unstable explosive, Alfred Nobel while working on explosives, combined it with Kiselguhr and patented it as dynamite in 1867. NTG was introduced in 1879 in medicine in the treatment of angina pectoris by the English doctor William Murrell. NTG‐induced headache was quickly recognized as an important adverse event both in the industrial use of NTG, where it was used to produce dynamite, as well as in the use of NTG as drug. This review traces the evolution of our understanding of NTG headache.

Endothelium-Dependent Relaxant Responses to Selective 5-HT(1B/1D) Receptor Agonists in the Isolated Middle Cerebral Artery of the Rat.

The vasomotor effects of triptans in the middle cerebral artery (MCA) of rats were studied using the pressurised arteriography method and in vitro vessel baths. Using the arteriograph, MCAs from Sprague-Dawley rats were mounted on two glass micropipettes, pressurised to 85 mm Hg and luminally perfused. Luminally added 5- hydroxytryptamine (5-HT), sumatriptan and rizatriptan induced maximal dilatations of 22 ± 4, 10 ± 2 and 13 ± 5%, respectively, compared to the resting diameter. The relaxant effect of sumatriptan was blocked by the 5- HT1B/1D receptor selective antagonist GR 55562 (10–6M). The use of Nω-nitro-L-arginine and charybdotoxin revealed that the dilatation involved both nitric oxide and endothelially derived hyperpolarising factor. Thus, the earlier demonstrated expression of 5-HT1B/1D immunoreactivity in the endothelium may well translate into a relaxant response to 5-HT and triptans. Using the vessel bath technique, MCA segments were mounted on two metal wires. The relaxant responses to sumatriptan could not be reproduced using this model; instead, weak contractile responses (6 ± 3% of submaximal contractile capacity) were observed. The difference in observations between the experimental models may be related to the maintenance of shear stress in the arteriograph.

Methodology of clinical trials in migraine

Migraine is a condition characterised by recurrent attacks lasting from a few hours to a few days. If attacks are comparatively rare, patients are advised to take symptomatic medication such as ergotamine, aspirin and antinauseants at each attack. If patients suffer two or more severe attacks a month, prophylactic therapy may be indicated.

Lack of effect of GR43175 on peripheral arteries in man

In a double-blind, placebo-controlled crossover study in eight male volunteers, toe-arm systolic gradients, measured with strain-gauge plethysmography, were measured for 4 h after 2 mg intravenous GR43175 or placebo. No changes were observed, indicating that GR43175 is without significant vasoconstrictor effect on peripheral arteries in man.