Disposition and pharmacokinetics of the antimigraine drug, rizatriptan, in humans.
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The absorption and disposition of rizatriptan (MK-0462, Maxalt(TM)), a selective 5-HT(1B/1D) receptor agonist used in the treatment of migraine headaches, was investigated in humans. In a two-period, single i.v. (3 mg, 30-min infusion), and single oral (10 mg) dose study with [(14)C]rizatriptan in six healthy human males, total recovery of radioactivity was approximately 94%, with unchanged rizatriptan and its metabolites being excreted mainly in the urine (89% i.v. dose, 82% p.o. dose). Approximately 26 and 14% of i.v. and oral rizatriptan doses, respectively, were excreted in urine as intact parent drug. In a second, high-dose study (60 mg p.o.), five metabolites excreted into urine were identified using liquid chromatography-tandem mass spectrometry and NMR methods. They were triazolomethyl-indole-3-acetic acid, rizatriptan-N(10)-oxide, 6-hydroxy-rizatriptan, 6-hydroxy-rizatriptan sulfate, and N(10)-monodesmethyl-rizatriptan. Urinary excretion of triazolomethyl-indole-3-acetic acid after i.v. and oral administrations of rizatriptan accounted for 35 and 51% of the dose, respectively, whereas the corresponding values for rizatriptan-N(10)-oxide were 4 and 2% of the dose. Plasma clearance (CL) and renal clearance (CL(r)) were 1325 and 349 ml/min, respectively, after i.v. administration. A similar CL(r) value was obtained after oral administration (396 ml/min). The primary route of rizatriptan elimination occurred via nonrenal route(s) (i.e., metabolism) because the CL(r) of rizatriptan accounted for 25% of total CL. Furthermore, the CL(r) was higher than normal glomerular filtration rate ( approximately 130 ml/min), indicating that this compound was actively secreted by renal tubules. The absorption of rizatriptan was approximately 90%, but it experienced a moderate first-pass effect, resulting in a bioavailability estimate of 47%. (+info)
Newer intranasal migraine medications.
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Two new intranasal migraine medications, sumatriptan and dihydroergotamine mesylate, may offer specific advantages for patients who are seeking alternatives to various oral or parenteral migraine abortive therapies. Placebo-controlled clinical studies demonstrate that both intranasal forms are effective in relieving migraine headache pain, but published clinical trial information comparing these two intranasal medications with current abortive therapies is lacking. Both agents are generally well tolerated by patients, with the exception of mild, local adverse reactions of the nose and throat. (+info)
Prevalence of Raynaud's phenomenon in a healthy Greek population.
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OBJECTIVE: Raynaud's phenomenon (RP) is comprised of repeated episodes of colour changes of the skin of digits on cold exposure or emotional stress. The prevalence of RP in the general population is variable fluctuating between 4%-15%, among surveys. The aim of this study was to estimate the prevalence of RP in a healthy working Greek population and to investigate the possible association of RP with various demographic, social and other factors. METHODS: A total of 756 employees of the University Hospital of Ioannina was included in the study. They belong to the administrative (120 subjects), nursing and technical (a representative sample of 418 and 218 subjects, respectively) personnel. Five hundred subjects (111 men and 389 women) responded in a face to face interview based on a specially conformed questionnaire. The study began in November 1997 and was completed in March 1998. RESULTS: Twenty six subjects with RP (1 man and 25 women) were found. Their mean (SD) age was 32.73 (5.77) years. The prevalence of RP was 5.2% (0.9% in men and 6.4% in women). The sex ratio, male/female, was 1/7.1. An association between RP and migraine was found. However, there were no significant correlations of RP with smoking, alcohol and coffee consumption, dietary habits, occupational history and drug exposure. No social or other demographic parameters associated to RP frequency were found. CONCLUSIONS: The prevalence of RP (5.2%) in the population studied is relatively low compared with previous studies. RP focuses on the fourth decade of life and affects mainly women. There was no evidence of any correlation of RP with social, environmental or personal parameters while an association of RP with migraine was found. Geographical or genetic factors, or both, may be responsible for these results. (+info)
Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP antagonist.
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Calcitonin gene-related peptide (CGRP) is one of the most potent endogenous vasodilators known. This peptide is increased during migraine attacks and has been implicated in the pathogenesis of migraine headache. Here we report on the first small molecule selective CGRP antagonist: BIBN4096BS. In vitro, this compound is extremely potent at primate CGRP receptors exhibiting an affinity (Ki) for human CGRP receptors of 14.4 +/- 6.3 (n = 4) pM. In an in vivo model, BIBN4096BS in doses between 1 and 30 micrograms kg-1 (i.v.) inhibited the effects of CGRP, released by stimulation of the trigeminal ganglion, on facial blood flow in marmoset monkeys. It is concluded that BIBN4096BS is a potent and selective CGRP antagonist. (+info)
Three new familial hemiplegic migraine mutants affect P/Q-type Ca(2+) channel kinetics.
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Missense mutations in the pore-forming human alpha(1A) subunit of neuronal P/Q-type Ca(2+) channels are associated with familial hemiplegic migraine. We studied the functional consequences on P/Q-type Ca(2+) channel function of three recently identified mutations, R583Q, D715E, and V1457L after introduction into rabbit alpha(1A) and expression in Xenopus laevis oocytes. The potential for half-maximal channel activation of Ba(2+) inward currents was shifted by > 9 mV to more negative potentials in all three mutants. The potential for half-maximal channel inactivation was shifted by > 7 mV in the same direction in R583Q and D715E. Biexponential current inactivation during 3-s test pulses was significantly faster in D715E and slower in V1457L than in wild type. Mutations R583Q and V1457L delayed the time course of recovery from channel inactivation. The decrease of peak current through R583Q (30.2%) and D715E (30. 1%) but not V1457L (18.7%) was more pronounced during 1-Hz trains of 15 100-ms pulses than in wild type (18.2%). Our data demonstrate that the mutations R583Q, D715E, and V1457L, like the previously reported mutations T666M, V714A, and I1819L, affect P/Q-type Ca(2+) channel gating. We therefore propose that altered channel gating represents a common pathophysiological mechanism in familial hemiplegic migraine. (+info)
Visual field losses in subjects with migraine headaches.
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PURPOSE: To characterize the visual fields of subjects with migraine headaches using static and temporal modulation perimetry. METHODS: Sixteen subjects with migraines (15 with aura, 1 without) and 15 nonheadache controls were tested. Perimetry was conducted 7 days after the offset of a headache with both static and temporally modulated targets using the Medmont M-600 automated perimeter (Medmont Pty Ltd., Camberwell, Victoria, Australia). Flicker thresholds were measured using the autoflicker test, which varies flicker rate with eccentricity. A subset of four subjects with migraines (3 with aura, 1 without) had the temporal tuning characteristics of their loss evaluated using fixed temporal frequencies (4, 6, 9, 12, and 16 Hz). RESULTS: Field losses were identified with temporal modulation perimetry in 11 of 16 migraine subjects. The majority of these losses occurred in the presence of normal static thresholds (8/11). The deficits displayed temporal tuning, being greatest for higher temporal frequencies (> or =9 Hz). None of the subjects revealed deficits typical of cortical lesions. The migraine-without-aura subject displayed a selective loss to temporally modulated stimuli, which was consistent with the aura group. This defect altered over time, decreasing for 30 to 40 days but remaining, to a smaller extent, for up to 75 days after the headache event. CONCLUSIONS: Visual dysfunction that is selective for temporally modulated targets occurs in migraine subjects. The migrainous pattern of dysfunction shares some features with that identified in early stages of glaucoma and raises the possibility for a common precortical vascular involvement in these two conditions. (+info)
A new family with paroxysmal exercise induced dystonia and migraine: a clinical and genetic study.
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OBJECTIVE: To characterise the phenotype of a family with paroxysmal exercise induced dystonia (PED) and migraine and establish whether it is linked to the paroxysmal non-kinesigenic dyskinesia (PNKD) locus on chromosome 2q33-35, the familial hemiplegic migraine (FHM) locus on chromosome 19p, or the familial infantile convulsions and paroxysmal choreoathetosis (ICCA syndrome) locus on chromosome 16. METHODS: A family, comprising 30 members, was investigated. Fourteen family members in two generations including three spouses were examined. Haplotypes were reconstructed for all the available family members by typing several microsatellite markers spanning the PNKD, FHM, and ICCA loci. Additionally, the four exons containing the known FHM mutations were sequenced. RESULTS: Of 14 members examined four were definitely affected and one member was affected by history. The transmission pattern in this family was autosomal dominant with reduced penetrance. Mean age of onset in affected members was 12 (range 9-15 years). Male to female ratio was 3:1. Attacks of PED in affected members were predominantly dystonic and lasted between 15 and 30 minutes. They were consistently precipitated by walking but could also occur after other exercise. Generalisation did not occur. Three of the affected members in the family also had migraine without aura. Linkage of the disease to the PNKD, FHM, or ICCA loci was excluded as no common haplotype was shared by all the affected members for each locus. In addition, direct DNA sequential analysis of the FHM gene (CACNL1A4) ruled out all known FHM point mutations. CONCLUSIONS: This family presented with the classic phenotype of PED and is not linked to the PNKD, FHM, or ICCA loci. A new gene, possibly coding for an ion channel, is likely to be the underlying cause of the disease. (+info)
Prevalence of migraine and Raynaud's phenomenon in Japanese patients with vasospastic angina.
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The prevalence of migraine and Raynaud's phenomenon in Japanese patients with vasospastic angina (group I) were compared with those in 2 control groups: one with effort angina (group II) and the other group without known ischemic heart disease (group III). There were no significant differences among the 3 groups with respect to age and sex. The prevalence of migraine in group I was 23 of 100, as compared with 4 of 100 in group II (p<0.01) and 11 of 100 in group III (p<0.05). The prevalence of Raynaud's phenomenon in group I was 9 of 100, as compared with 3 of 100 in group II and 4 of 100 in group III. Thus, in Japan, the prevalence of migraine in patients with vasospastic angina was higher than those in the 2 control groups, whereas the prevalence of Raynaud's phenomenon did not differ significantly among the 3 groups. The prevalence of Raynaud's phenomenon in Japanese patients with vasospastic angina was different from that reported from North America, although the prevalence of migraine was the same. This may be partially explained by racial differences. (+info)