sumatriptan, Imitrex
Ergotamine, flunarizine and sumatriptan do not change cerebral blood flow velocity in normal subjects and migraneurs.

Diener HC, Peters C, Rudzio M, Noe A, Dichgans J, Haux R, Ehrmann R, Tfelt-Hansen P.

Neurologische Universitatsklinik, Kliniken Schnarrenberg, Tubingen, Federal Republic of Germany.

Changes in the diameter of extracranial and intracranial arteries resulting in changes in cerebral blood flow have previously been assumed to be the most important pathophysiological factor in migraine. To test this hypothesis 20 normal subjects, and three groups of patients (n = 29) with migraine were investigated by means of transcranial Doppler sonography. Blood flow velocities in the middle cerebral (MCA) and in basilar (BA) arteries were measured. Data from patients were obtained in the interval between migraine attacks, during migraine attacks and following treatment with either ergotamine (0.5 mg i.m.; n = 10); flunarizine, a calcium overload blocker (20 mg i.v.; n = 13); or a 5-HT1-like agonist (sumatriptan, 4 mg s.c.; n = 6). Ergotamine and sumatriptan are constrictors of cerebral arteries in animal experiments. The arithmetic mean of flow velocity in the BA was reduced in normal subjects (45 cm/s) as compared with patients with migraine measured in between attacks (53 cm/s). Mean flow velocity in MCA was not different in normals (72.5 cm/s) as compared with migraineurs (75 cm/s). Neither ergotamine nor the 5-HT1 agonist and flunarizine resulted in a significant change in blood flow velocity in MCA and BA. This was true irrespective of whether the drugs were given in the headache-free period, during a migraine attack or during the withdrawal phase of drug-induced headache. Ergotamine was effective in improving headache during migraine attacks and sumatriptan attenuated headache during drug withdrawal from chronic analgesic intake. These results indicate that the action of ergotamine and the 5-HT1-receptor agonist is probably not mediated by their vasoconstrictor action on cerebral arteries.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1655985&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Cortical and striatal variations in drug competition studies with putative 5-hydroxytryptamine1D binding sites.

Peroutka SJ.

Department of Neurology, Stanford University School of Medicine, CA 94305.

The ability of 5-hydroxytryptamine (5-HT), 5-carboxytryptamine (5-CT) and sumatriptan to compete for [3H]5-HT binding sites in various brain tissues was analyzed in bovine, guinea pig, pig and human cortex and caudate. Radioligand binding conditions were designed to allow for the selective labeling of putative 5-HT1D binding sites. 5-HT competed monophasically with putative 5-HT1D binding sites in each of the 8 tissues studied. By contrast, both 5-CT and sumatriptan competed with markedly shallow displacement curves in each of the 8 tissues. In the case of sumatriptan, complete displacement of [3H]5-HT could not be achieved even at concentrations as high as 2000 times its IC50 value. These data indicate that 10(-5) M 5-HT should not be used to define specific binding to 5-HT1D receptors in radioligand binding assays. Instead, 5-HT1D receptor binding sites should be redefined as [3H]5-HT-labeled binding sites displaced by 10(-5) M sumatriptan.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1657281&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Evidence for 5-HT1B/1D receptors mediating the antimigraine effect of sumatriptan and dihydroergotamine.

Buzzi MG, Moskowitz MA.

Dipartimento di Scienze Neurologiche, Universita degli Studi La Sapienza, Roma, Italy.

Neurogenic plasma extravasation, endothelial cell activation (increase in vesicle number and vacuole formation), platelet aggregation and adhesion, and mast cell degranulation occur selectively in post-capillary venules of the dura mater following electrical trigeminal ganglion stimulation, and are mediated by release of neuropeptides from perivascular unmyelinated C fibres. Pre-treatment with the antimigraine drugs dihydroergotamine and sumatriptan, two drugs that bind with high affinity to 5-HT1B/1D receptors, markedly attenuated plasma protein extravasation induced by electrical trigeminal ganglion stimulation. Trigeminal stimulation increased plasma calcitonin gene-related peptide levels in rat superior sagittal sinus. Pre-treatment with dihydroergotamine and, to a lesser extent, sumatriptan, attenuated this increase. Both drugs reduced morphological changes in post-capillary venules and mast cells within dura mater following electrical trigeminal ganglion stimulation. Plasma protein extravasation was selectively blocked in dura mater (but not in extracranial tissues) by pre-treatment with those receptor agonists showing a rank order of potency suggesting a 3-HT1B/1D interaction (5-CT greater than 5-BT greater than DHE greater than sumatriptan greater than 8-OH-DPAT). Pre-treatment with 5-HT2 and 5-HT3 antagonists was not effective. Taken together, these data are consistent with the interpretation that putative 5-HT-1B/1D receptors located on sensory fibres are coupled to inhibition of peptide release and blockade of neurogenic inflammation. An important therapeutic action of ergot alkaloids and sumatriptan in migraine headaches is so defined.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1660351&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Vascular 5-HT1-like receptors that mediate contraction of the dog isolated saphenous vein and carotid arterial vasoconstriction in anaesthetized dogs are not of the 5-HT1A or 5-HT1D subtype.

Perren MJ, Feniuk W, Humphrey PP.

Pharmacology Division, Glaxo Group Research Limited, Ware, Hertfordshire.

1. There is controversy about whether 5-HT1A receptors mediate contraction of isolated cerebral blood vessels. We have therefore compared the vascular actions of the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propyl-amino)-tetralin (8-OH-DPAT) with those of the 5-HT1-like receptor agonist, sumatriptan, on the dog isolated saphenous vein, which contains a 5-HT1-like receptor similar to those on cerebral blood vessels, and in the carotid circulation of the anaesthetized dog. 2. 5-Hydroxytryptamine (5-HT), sumatriptan and 8-OH-DPAT each caused contraction of dog isolated saphenous vein with a rank order of agonist potency of 5-HT greater than sumatriptan greater than 8-OH-DPAT and EC50 values (95% confidence limits) of 0.06 (0.04-0.08), 0.3 (0.1-0.8) and 3.9 (2.0-7.5) microM respectively. The maximum contractile effect produced by each agonist was similar. 3. The contractile effects of 5-HT, sumatriptan and 8-OH-DPAT in the dog isolated saphenous vein were resistant to antagonism by the 5-HT1A receptor antagonists spiperone, spiroxatrine and pindolol (all 1 microM). The 5-HT1D receptor ligands, metergoline (0.1 microM) rauwolscine (1 microM) and yohimbine (1 microM) had little or no antagonist activity. In contrast, the non-selective 5-HT1-like receptor blocking drug, methiothepin (0.03-0.3 microM) potently antagonized the contractile effects of 5-HT, sumatriptan and 8-OH-DPAT to a similar degree, suggesting that all three agonists act at the same receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1675143&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Migraine pain associated with middle cerebral artery dilatation: reversal by sumatriptan.

Friberg L, Olesen J, Iversen HK, Sperling B.

Department of Clinical Physiology and Nuclear Medicine, Bispebjerg Hospital, Copenhagen, Denmark.

The combination of measurements of regional cerebral blood flow (rCBF) and blood velocity in the middle cerebral arteries (MCA) by transcranial doppler sonography was used to investigate cerebrovascular involvement in migraine. Ten migraine patients with unilateral headache were studied during an attack and when they had been free of attacks for 5 days (non-attack). On both occasions they were given as intravenous infusion of sumatriptan (2 mg), a 5-HT1-like receptor agonist, which relieved the symptoms within 30 min without affecting rCBF. The MCA velocity was normal on both sides on the non-attack day and on the unaffected side during the attack. However, during the attack the MCA velocity on the headache side was significantly lower than that on the non-headache side (45 vs 61 cm/s:mean difference 16.3 [95% confidence interval 10.3-22.3]; p = 0.02). The MCA velocity on the headache side returned to normal after treatment with sumatriptan and recovery. Since rCBF in the MCA supply territory was unaffected, the lower velocity can be explained only by dilatation of the MCA. The mean MCA diameter increase was estimated to be 20%. Thus, headache was associated with intracranial large arterial dilatation on the headache side. Sumatriptan predominantly had effects on the distended artery, which suggests that the 5-HT receptor system has a role in the pathogenesis of migraine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1676084&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Comparison of contractile responses to donitriptan and sumatriptan in the human middle meningeal and coronary arteries.

van den Broek RW, MaassenVanDenBrink A, Mulder PG, Bogers AJ, Avezaat CJ, John GW, Saxena PR.

Department of Pharmacology, Erasmus University Medical Centre Rotterdam, Post Box 1738, 3000 DR, Rotterdam, The Netherlands.

Donitriptan is a potent, high efficacy agonist at 5-HT(1B/1D) receptors. We investigated the contractile effects of donitriptan and sumatriptan on human isolated blood vessels of relevance to therapeutic efficacy in migraine (middle meningeal artery) and coronary adverse events (coronary artery). Furthermore, using the concentration-response curves in the middle meningeal artery, we predicted the plasma concentration needed for the therapeutic effect of donitriptan. Both donitriptan and sumatriptan contracted the middle meningeal artery with similar apparent efficacy (E(max): 103+/-8% and 110+/-12%, respectively), but the potency of donitriptan (pEC(50): 9.07+/-0.14) was significantly higher than that of sumatriptan (pEC(50): 7.41+/-0.08). In the coronary artery, the contraction to donitriptan was biphasic with a significantly higher maximal response (E(max): 29+/-6%) than sumatriptan (E(max): 14+/-2%; pEC(50): 5.71+/-0.16), yielding two distinct pEC(50) values (8.25+/-0.16 and 5.60+/-0.24). Incubation with the 5-HT(2) receptor antagonist ketanserin (10 microM) eliminated the low affinity component of the concentration-response curve of donitriptan and the resultant E(max) and pEC(50) were 9+/-2% and 7.33+/-0.21, respectively. Ketanserin was without effect on the sumatriptan-induced contraction. Based on the middle meningeal artery contraction, concentrations (C(max)) of donitriptan that may be expected to have a therapeutic efficacy equivalent to that of 50 and 100 mg sumatriptan are predicted to be around 2.5 and 4.3 nM, respectively. Such concentrations are likely to induce only a small coronary artery contraction of 2.9+/-1.5% and 3.8+/-2.0%, respectively; these are not different from those by C(max) concentrations of sumatriptan (1.7+/-0.4% or 2.2+/-0.4%). The present results suggest that, like sumatriptan, donitriptan exhibits cranioselectivity and would be effective in aborting migraine attacks with a similar coronary side-effect profile as sumatriptan.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12044802&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Role of 5-HT1-like receptors in the reduction of porcine cranial arteriovenous anastomotic shunting by sumatriptan.

den Boer MO, Villalon CM, Heiligers JP, Humphrey PP, Saxena PR.

Department of Pharmacology, Faculty of Medicine and Health Sciences, Erasmus University Rotterdam, The Netherlands.

1. The new tryptamine derivative sumatriptan (GR43175) is effective in the treatment of migraine. Since several antimigraine agents reduce cranial arteriovenous anastomotic blood flow in the anaesthetized pig, we have investigated the carotid haemodynamic effects of sumatriptan. 2. Sumatriptan (10, 30, 100 and 300 micrograms kg-1, i.v.) reduced total common carotid blood flow, exclusively by affecting its arteriovenous anastomotic fraction; the capillary fraction even increased with the highest doses. 3. These reductions in the carotid arteriovenous anastomotic ('shunt') blood flow were mediated by a 5-HT1-like receptor, as methiothepin, but not ketanserin, antagonized the responses to sumatriptan. 4. Sumatriptan increased the difference in oxygen saturation between arterial and jugular venous blood, which is likely to be a consequence of the reduction of the carotid shunt blood flow. 5. The selective reduction in arteriovenous anastomotic blood flow produced by sumatriptan may reflect its antimigraine action, thought to involve vasoconstriction of those cranial vessels, be they 'shunt' vessels or not, which are distended and inflamed during a migraine attack.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1849764&dopt=Abstract sumatriptan Imitrex