sumatriptan, Imitrex
Sensory nerve-mediated relaxation of guinea-pig isolated pulmonary artery: prejunctional modulation by alpha 2-adrenoceptor agonists but not sumatriptan.

Butler A, Worton SP, O'Shaughnessy CT, Connor HE.

Department of Neuropharmacology, Glaxo Group Research Ltd., Ware, Herts.

1. Effects of the alpha 2-adrenoceptor agonists, UK14304 and clonidine, the 5-HT1 receptor agonist, sumatriptan and the kappa-opioid receptor agonist, GR103545, on sensory neurotransmission in histamine-contracted guinea-pig isolated pulmonary artery (GPPA) have been studied. 2. Electrical field stimulation (EFS) induced frequency-dependent relaxations of histamine-contracted GPPA, which were attenuated by tetrodotoxin and capsaicin pretreatment but not by the nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME). 3. Substance P (0.3 microM) induced relaxations which were subject to rapid tachyphylaxis. Neither the NK1 receptor antagonist, (+/-)-CP 96,345, nor desensitization to substance P had any effect of EFS-induced relaxations of histamine-contracted GPPA. 4. Calcitonin gene-related peptide (CGRP; 3 and 30 nM) induced concentration-dependent relaxations of histamine-contracted GPPA. The putative CGRP receptor antagonist, CGRP8-37 (1 microM), markedly attenuated EFS-induced relaxations as well as relaxations induced by a low concentration of CGRP. 5. Sumatriptan (0.1 and 1 microM) and the selective kappa-opioid receptor agonist, GR103545 (10 and 100 nM) had no effect on EFS-induced relaxations of histamine-contracted GPPA. In contrast, the alpha 2-adrenoceptor agonists UK14304 (1-100 nM) and clonidine (300 nM) attenuated responses to EFS, the attenuation of UK14304 (100 nM) being reversed by yohimbine (300 nM). 6. It is concluded that in GPPA, where a presynaptic inhibition of sensory neurotransmission by alpha 2-adrenoceptor activation could be shown, there was no evidence for such modulation by either sumatriptan-sensitive 5-HT1 receptors or kappa-opioid receptors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7684295&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Comparison of the effect of endothelium on the responses to sumatriptan in rabbit isolated iliac, mesenteric and carotid arteries.

Yildiz O, Tuncer M.

Department of Pharmacology, Faculty of Medicine, Gulhane Military Medical Academy, Ankara, Turkey.

The contractions induced by the 5-hydroxytryptamine (5-HT) and 5-HT1-like receptor agonist sumatriptan in open ring segments of rabbit iliac, mesenteric and common carotid arteries were studied isometrically in vitro. The alteration of the responses by removal of the endothelium and by inhibitors of nitric oxide synthase and cyclooxygenase was investigated. 5-HT induced concentration-dependent contractions of all these three arterial segments. Sumatriptan did not induce any contraction of quiescent mesenteric and iliac arteries, but when a moderate tone was given with a threshold concentration of prostaglandin F2 alpha, it elicited contractions of both arteries (Emax values for sumatriptan in mesenteric and iliac arteries were 84.7% and 29.7% of the phenylephrine maximal effect and EC50 values were 0.22 +/- 0.14 and 0.33 +/- 0.06 microM, respectively). Sumatriptan had no contractile effect at all in carotid arteries in which 5-HT-induced contractions seemed to be mediated by 5-HT2 receptors only. Removal of the endothelium did not affect the responses to 5-HT in iliac, mesenteric and carotid arteries. The contractions induced by sumatriptan were not influenced by removal of the endothelium in the mesenteric artery, while sumatriptan responses were potentiated in the endothelium-denuded preparations of the iliac artery (Emax = 50.8% of the phenylphrine maximal effect; EC50 = 0.46 microM). L-NG-monomethyl arginine (100 microM), a nitric oxide synthase inhibitor, also potentiated the sumatriptan responses in the endothelium-intact segments of the iliac artery. Indomethacin (0.1 microM), a cyclooxygenase inhibitor, did not affect the sumatriptan responses. These results suggest that sumatriptan-induced contractions of the rabbit iliac, but not mesenteric artery, were depressed by itself through the release of nitric oxide upon stimulation of 5-HT1-like receptors located on the endothelium, whereas neither on vascular smooth muscle nor on endothelium, 5-HT1-like receptors were present in the rabbit carotid artery.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7710305&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
The 5-HT1-like receptor mediating the increase in canine external carotid blood flow: close resemblance to the 5-HT1D subtype.

Villalon CM, Terron JA.

Departameto de Farmacologia y Toxicologia, Instituto Politecnico Nacional, Mexico, D.F., Mexico.

1. It has recently been shown that the increase in external carotid blood flow induced by 5-hydroxy-tryptamine (5-HT) in the anaesthetized dog, being mimicked by 5-carboxamidotryptamine (5-CT), inhibited by methiothepin, vagosympathectomy and sympatho-inhibitory drugs, and resistant to blockade by ritanserin and MDL 72222, is mediated by stimulation of prejunctional 5-HT1-like receptors leading to an inhibitory action on carotid sympathetic nerves; these 5-HT1-like receptors are unrelated to either the 5-HT1A, 5-HT1B or 5-HT1C (now 5-HT2C) receptor subtypes. Inasmuch as 5-CT, 5-methoxytryptamine, sumatriptan and metergoline display high affinity, amongst other 5-HT binding sites, for the 5-HT1D subtype, in the present study we have used these drugs in an attempt to determine whether the above inhibitory prejunctional 5-HT1-like receptors correlate with the 5-HT1D subtype. 2. One-minute intracarotid (i.c.) infusions of 5-HT (0.3, 1, 3 and 10 micrograms), 5-CT (0.01, 0.03, 0.1 and 0.3 micrograms), 5-methoxytryptamine (1, 3, 10 and 30 micrograms) and sumatriptan (1, 3, 10, 30 and 100 micrograms) resulted in dose-dependent increases in external carotid blood flow (without changes in mean arterial blood pressure or heart rate) with the following rank order of agonist potency: 5-CT >> 5-HT > 5-methoxytryptamine > or = sumatriptan. Interestingly, sumatriptan-induced vasodilatation was followed by a more pronounced vasoconstriction. 3. The external carotid vasodilator effects of 5-HT, 5-CT, 5-methoxytryptamine and sumatriptan were dose-dependently and specifically antagonized by metergoline (10, 30 and/or 100 micrograms kg-1, i.v.).(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7812603&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Adverse reactions attributed to sumatriptan. A postmarketing study in general practice.

Ottervanger JP, van Witsen TB, Valkenburg HA, Grobbee DE, Stricker BH.

Netherlands Centre for Monitoring of Adverse Reactions to Drugs, Rijswijk.

There are several reports on cardiac adverse reactions attributed to the antimigraine drug sumatriptan in the recent literature. In order to assess the frequency and the character of adverse reactions to sumatriptan, a postmarketing cohort study was performed one year after registration of the drug in The Netherlands. With assistance of 86% of the drug dispensing general practitioners in The Netherlands, 1727 patients who had received sumatriptan were traced in July, 1992. Via their general practitioners, a questionnaire about use of sumatriptan, adverse reactions and other medication was sent to the patients in December 1992. During the study period, seven patients were lost to follow-up. Of the 1720 remaining patients, 1202 (70%) responded to the questionnaire, of whom 1187 had actually used sumatriptan. The most frequently reported suspected adverse reactions were paraesthesiae (139 patients, 95% CI 9.9%-13.5%) and dizziness (96 patients, 95% CI 6.5%-9.7%). Chest pain after use of sumatriptan was reported by 94 patients (7.9%, 95% CI 6.4%-9.4%), and according to the close temporal relationship with the intake of sumatriptan and a positive rechallenge, a causal relationship was probable in most of those patients. The frequency of chest pain attributed to sumatriptan was higher in females (9.0% vs 4.6%; relative risk 1.9, 95% CI 1.1-3.4). Age and hypertension were not associated with chest pain attributed to sumatriptan. Dyspnoea attributed to sumatriptan was reported by 26 patients (2.2%), and was associated with obstructive lung disease (relative risk 5.4 95% CI 1.7-16.9).(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7875179&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Disposition of sumatriptan in laboratory animals and humans.

Dixon CM, Saynor DA, Andrew PD, Oxford J, Bradbury A, Tarbit MH.

Department of Drug Metabolism III, Glaxo Group Research Ltd., Ware, Herts, UK.

Sumatriptan is a new 5HT1-like agonist that has proved a novel and effective treatment for migraine. The disposition of the 14C-radiolabeled drug in laboratory animals and humans after oral and parenteral administration is described. Oral absorption of sumatriptan is essentially complete in dogs and rabbits, but only approximately 50% in rat. In humans, at least 57% of an oral dose is absorbed. Bioavailabilities are species dependent (14, 23, 37, and 58% in humans, rabbits, rats, and dogs) reflecting differing degrees of first-pass metabolism. These data correlate well with hepatic extraction ratios, which are highest in rabbits and humans and lowest in dogs. Renal clearance is significant in all species and exceeds the glomerular filtration rate in rats, rabbits, and humans, but not in dogs. The compound is a weak base that shows widespread tissue distribution, including passage across the placental barrier and into milk, but low CNS penetration. Protein binding of sumatriptan is low in all species. Elimination half-lives of sumatriptan are approximately 1 hr in rats and rabbits, and approximately 2 hr in dogs and humans. In all species the majority of the absorbed dose is renally excreted, predominantly as the indole acetic acid metabolite and unchanged drug. Interesting species differences are evident in the metabolism of sumatriptan. Thus, in humans, the indole acetic acid metabolite is excreted partly as a glucuronide, whereas in animals conjugation of this metabolite is not apparent. In addition, demethylation of the sulfonamide side chain of the drug is evident in rodent and lagomorph species only.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7902233&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Effect of sumatriptan on cerebral blood flow in the baboon model.

Oliver DW, Dormehl IC, Hugo N.

Department of Pharmacology, Potchefstroom University for Christian Higher Education (C.H.E.), Pretoria, Republic of South Africa.

Changes in cerebral blood flow are implicated to be important in the pathophysiology of migraine. Furthermore, serotonin (5-HT) is known to be the most important substance in the etiology of migraine. Sumatriptan (CAS 103628-46-2), a 5-HTID receptor agonist was recently introduced in the treatment of migraine. In the present study a baboon model was used to investigate the changes in cerebral blood flow due to anaesthesia and pharmacological interventions using 99mTc-labelled hexamethylpropylene amine oxime (99mTc-HMPAO) and single photon emission computed tomography (SPECT). The effect of sumatriptan on cerebral blood flow was investigated after 10 min and again after 23 min, with the animal under anaesthesia, i.e. induction with ketamine and maintenance on thiopental. Sumatriptan did not alter the cerebral blood flow during the 10 min procedure. However, sumatriptan reversed the increased cerebral blood flow due to the prolonged anaesthesia (23 min), lowering the cerebral blood flow by more than 20%. No significant changes in the biochemical parameters (blood pressure, heart rate, pO2 and pCO2) were observed. These results also suggest that sumatriptan reverses the increased cerebral blood flow most likely via 5-HTID receptor stimulation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7945534&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
[Clinical experience with sumatriptan ++ in the treatment of migraine symptoms]

[Article in Spanish]

Pascual J.

Servicio de Neurologia, Hospital Universitario Marques de Valdecilla, Santander.

Although sumatriptan has proven effective in treating migraine symptoms, there have been no studies comparing this drug with non-steroid anti-inflammatory drugs (NSAIDs) and ergotamine compounds under ideal dosage and delivery conditions. Our study aimed to establish the objective and subjective effects of treatment of severe migraine attacks with subcutaneous sumatriptan in a series of patients who were resistant to or intolerant of NSAIDs or ergotamine derivatives. Twenty-three patients were treated for a total of 140 attacks of migraine (mean +/- SD = 6 +/- 4 attacks). In 26% of the patients and in 23% of the attacks the response to sumatriptan was inadequate, while the response was clearly positive in 74% of the patients and in 77% of the attacks. More than half the patients responded within the first 30 min after injection of the drug. In 52% side effects were reported, although none were severe. Side effects continued with the same intensity or decreased in 91% of the patients in the course of the study. No patient considered treatment with sumatriptan worse than treatment with ergotamines or NSAIDs, while 86% and 91% labelled sumatriptan as "better" or "much better" than NSAIDs and ergotamines, respectively. Eighteen (78%) stated that they would continue using sumatriptan for future migraine attacks. Finally, most considered price to be a factor to be taken into consideration in deciding whether to inject the drug indiscriminately.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7946423&dopt=Abstract sumatriptan Imitrex