sumatriptan, Imitrex
Absorption, pharmacokinetics and metabolism of 14C-sumatriptan following intranasal administration to the rat.

Ayres DW, Barrow A, Scully NL, Curtis GC, Hughes HM.

International BioMet Division, Glaxo Wellcome Research and Development, Ware, UK.

1. Studies have been carried out to investigate the absorption of sumatriptan after intranasal administration to rats. The pharmacokinetics, metabolism and excretion of 14C-sumatriptan were compared following intranasal and intravenous dosing to male and female albino rats using an aqueous buffered formulation at pH 5.5. 2. Following intravenous administration sumatriptan was eliminated from plasma with a half-life of about 1.1 h. After intranasal administration there was rapid absorption of part of the dose and two peak plasma concentrations were observed, initially at 0.5 and then at 1.5-2 h. The elimination half-life after the second peak was estimated as being about 4 h. 3. Radioactivity was largely excreted in urine (up to 89% of dose in 168 h) after both intravenous and intranasal administration, with a faster rate of excretion after intravenous dosage (73% males, 64% females within 6 h) than after intranasal dosage (37% males, 40% females within 6 h). 4. 14C-sumatriptan was the major component in urine and in extracts of faeces after both intravenous and intranasal administration. The major metabolite excreted in urine and faeces was GR49336, the indole acetic acid analogue. 5. The results of this in vivo rat study suggest that absorption of the dose via the nasal mucosa is incomplete after intranasal administration and that there is a secondary absorption phase probably reflecting oral absorption of part of the dose. The bioavailability is estimated as about 30%, for the period 0-6 h.

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sumatriptan, Imitrex
Effects of avitriptan, a new 5-HT 1B/1D receptor agonist, in experimental models predictive of antimigraine activity and coronary side-effect potential.

Saxena PR, De Vries P, Wang W, Heiligers JP, Maassen vandenBrink A, Bax WA, Yocca FD.

Department of Pharmacology, Dutch Migraine Research Group, Faculty of Medicine and Health Sciences, Erasmus University Rotterdam, The Netherlands.

Several acutely acting antimigraine drugs, including ergotamine and sumatriptan, have the ability to constrict porcine arteriovenous anastomoses as well as the human isolated coronary artery. These two experimental models seem to serve as indicators, respectively, for the therapeutic and coronary side-effect potential of the compounds. Using these two models, we have now investigated the effects of avitriptan (BMS-180048; 3-[3-[4-(5-methoxy-4-pyrimidinyl)-l-piperazinyl[propyl]-N-methyl-l H-indole-5-methane-sulfonamide monofumarate), a new 5-HT 1B/1D receptor agonist. In anaesthetized pigs, avitriptan (10, 30, 100 and 300 micrograms.kg-1) decreased the total carotid blood flow by exclusively decreasing arteriovenous anastomotic blood flow; capillary blood flow was increased. The mean +/- SEM i.v. dose of avitriptan eliciting a 50% decrease (ED50) in the porcine carotid arteriovenous anastomotic blood flow was calculated to be 76 +/- 23 micrograms.kg-1 (132 +/- 40 nmol.kg-1) and the highest dose (300 micrograms.kg-1) produced a 72 +/- 4% reduction. In recent comparative experiments (DeVries et al. 1996), the mean +/- SEM ED50 (i.v.) of sumatriptan in decreasing carotid arteriovenous anastomotic blood flow was 63 +/- 17 micrograms.kg-1 (158 +/- 43 nmol.kg-1), with a reduction of 76 +/- 4% by 300 micrograms.kg-1, i.v. Both avitriptan (pD2; 7.39 +/- 0.09; Emax: 13.0 +/- 4.5% of the contraction to 100 mM K+) and sumatriptan (pD2: 6.33 +/- 0.09; Emax: 15.5 +/- 2.3% of the contraction to 100 mM K+) contracted the human isolated coronary artery. The above results suggest that avitriptan should be able to abort migraine headaches in patients, but may exhibit sumatriptan-like effects on coronary arteries. Initial clinical studies have demonstrated the therapeutic action of the drug in acute migraine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9050026&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
The haemodynamic effects of subcutaneous sumatriptan, a 5HT1-receptor agonist.

Hood S, Birnie D, Hillis S.

University Department of Medicine & Therapeutics, Western Infirmary, Glasgow, UK.

AIMS: Previous in vivo studies with sumatriptan, a 5HT1-receptor agonist, have demonstrated vasopressor responses in the pulmonary and systemic arterial circulation. Pulmonary artery wedge pressure (PAWP) also increases after sumatriptan injection, raising the possibility of an additional venoconstrictive action or a negative inotropic effect. The mechanism for the rise in PAWP was investigated in the study. METHODS: Ten patients undergoing diagnostic coronary arteriography underwent haemodynamic monitoring. RESULTS: There was a significant rise (P < 0.05) in systemic and pulmonary arterial pressure and total systemic and pulmonary vascular resistance. There was a similar rise (P < 0.05) in PAWP and left ventricular end diastolic pressure (LVEDP). There was no change in cardiac output nor in peak rate of left ventricular pressure rise (dP/dt). CONCLUSIONS: The sumatriptan induced rise in PAWP and LVEDP appears consequent upon increased afterload although a negative inotropic effect cannot be excluded.

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sumatriptan, Imitrex
Defective 5-HT 1-receptor-mediated neurotransmission in the control of growth hormone secretion in Parkinson's disease.

Volpi R, Caffarra P, Scaglioni A, Boni S, Saginario A, Chiodera P, Coiro V.

Department of Internal Medicine, University of Parma, Italy.

In order to gain a better insight in the serotonergic disorder affecting the parkinsonian brain, the growth hormone (GH) response to the 5-HT 1 serotonergic receptor agonist sumatriptan was tested. Sumatriptan was injected subcutaneously in 10 de novo parkinsonian patients (aged 58-69 years) and in 9 age-matched normal controls. On different occasions, subjects were also tested with GH-releasing hormone (GH-RH; 1 micrograms/kg body weight in an intravenous bolus) and L-arginine (30 g in 50 ml normal saline over 30 min), which releases GH from somatostatin inhibition, to determine whether GH secretion in response to alternate secretagogues is preserved in Parkinson's disease. In addition, a control test with the administration of normal saline instead of drug treatments was performed. Plasma GH levels were recorded over 2 h in all tests. Placebo administration did not change plasma GH levels in any subject. Similar GH responses were observed in normal controls and parkinsonian patients when GH-RH or arginine were administered. A significant GH increase was observed in normal controls after sumatriptan injection; in contrast, GH secretion was not modified by sumatriptan administration in parkinsonian patients. These data show that Parkinson's disease is associated with an impairment in the 5-HT1-receptor-mediated serotonergic transmission in the control of GH secretion, suggesting that this specific defect might alter other serotonergic-mediated mechanisms in the parkinsonian brain.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9097298&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Sumatriptan treatment of acute migraine attacks in a Saudi population.

al Deeb S, al Kawi Z, Yaqub B, Bohlega S, Cheung P.

Department of Clinical Neurosciences, Riyadh Armed Forces Hospital, Saudi Arabia.

Sumatriptan has been shown to be most effective in migraine attacks, but with transient, slight side effects and high rebound attack rates. We carried out a prospective study on the efficacy and safety of Sumatriptan in a Saudi population. A series of 63 consecutive out-patients with migraine histories ranging from 1/2 to 20 years were given six tablets of 100 mg Sumatriptan plus two diary cards to record the effects and side effects of the drug in two attacks per patient. Effect assessment by patients on a 4-point scale at 4 h after first medication was complemented by a 4-point scale physician's assessment. Time to resolution of attack post-medication, need for second dose (rebound attack), time lapsed to return to daily activities and side-effects were recorded. Exclusion parameters included pregnancy, lactation, hypertension, atherosclerosis, and cardiac and cerebrovascular disease. Inclusion criteria were International Headache Society (IHS)-1988 confirmed migraine characteristics and ages from 15 to 60 years. Physician assessed responses were excellent in 21 patients, good in 21, reasonable in nine and poor to nil in 12 patients. Rebound attacks necessitating second dose occurred in 25 patients. Side effects occurred in 22 (35%) patients. Sumatriptan 100 mg taken orally, is an effective and safe acute treatment mode for migraine attacks in Saudi patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9107463&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Simultaneous measurement of [3H]noradrenaline release and neurogenic contraction under identical conditions, to determine the prejunctional inhibitory effects of SKF 99101H and BRL 56905 in dog saphenous vein.

Medhurst AD, Brown AM, Kaumann AJ, Parsons AA.

Department of Neurology Research, SmithKline Beecham Pharmaceuticals, Harlow, Essex, UK.

Using a tissue bath system which allowed the simultaneous measurement of electrically-induced [3H]noradrenaline release and neurogenic contraction under identical conditions, we investigated the prejunctional inhibitory activity of the selective 5-HT(1D/1B) receptor agonists BRL 56905 ((+/-)-3-amino-6-carboxamido-1,2,3,4-tetrahydrocarbazole) and SKF 99101H (3-(2-dimethylaminoethyl)-4-chloro-5-propoxyindole hemifumarate), compared to sumatriptan and 5-HT. Transmural electrical stimulation (2 Hz) of dog saphenous vein induced consistent increases in [3H]noradrenaline release as well as reproducible contractile responses (<10% decrease over four stimulation periods). BRL 56905, SKF 99101H, sumatriptan and 5-HT (60 nM-6 microM) inhibited electrically-evoked [3H]noradrenaline release and neurogenic contractile responses in dog saphenous vein. However, despite being measured under identical conditions, the inhibition of [3H]noradrenaline release was consistently greater than the inhibition of neurogenic contraction induced by a particular concentration of agonist, suggesting that neurogenic contractile responses in dog saphenous vein result from the combined release of noradrenaline and other non-noradrenergic neurotransmitters. Under the present assay conditions, since the agonists produced only small (BRL 56905, sumatriptan and 5-HT) or marginal (SKF 99101H) contractile responses, it is unlikely that this is the cause of the discrepancy observed between inhibition of release and inhibition of contraction. The inhibitory effects of BRL 56905, sumatriptan and 5-HT were blocked by the 5-HT(1D/1B) receptor antagonist methiothepin, consistent with the involvement of canine ca-5-HT(1D/1B) receptors in inhibiting neurotransmitter release and subsequent smooth muscle contraction in dog saphenous vein. The present results show that the novel 5-HT(1D/1B) receptor agonists BRL 56905 and SKF 99101H are at least as potent as sumatriptan and 5-HT, at activating prejunctional inhibitory ca-5-HT(1D/1B) heteroreceptors on sympathetic axon terminals in dog saphenous vein. In addition, when measured simultaneously in the same tissue preparation, [3H]noradrenaline release was inhibited to a much greater extent than neurogenic contraction by any particular agonist.

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sumatriptan, Imitrex
Comparison of the vasoconstrictor properties of the 5-HT1D-receptor agonists rizatriptan (MK-462) and sumatriptan in human isolated coronary artery: outcome of two independent studies using different experimental protocols.

Longmore J, Hargreaves RJ, Boulanger CM, Brown MJ, Desta B, Ferro A, Schofield WN, Taylor AA, Hill RG.

Merck Sharp and Dohme Research Laboratories, Harlow, Essex, UK.

Rizatriptan (MK-462) is a novel 5-HT1D-receptor agonist and is effective in the treatment of migraine headache. As angiographic studies have shown that the prototypic 5-HT1D/1B-receptor agonist sumatriptan can cause coronary artery constriction in patients with mild coronary artery disease, we have compared the contractile effects of rizatriptan on human isolated coronary artery with those of sumatriptan and 5-HT. Two different experimental protocols were used. In Study 1 (to avoid agonist desensitisation and interaction effects), arterial segments were exposed to a single agonist (either 5-HT, sumatriptan or rizatriptan) and in Study 2 each arterial segment was exposed to all three agonists with randomised first exposure to sumatriptan or rizatriptan. In both these studies the maximum contractions evoked by sumatriptan and rizatriptan were found to be smaller than those evoked by 5-HT, and the maximum contraction evoked by rizatriptan was significantly smaller than that for sumatriptan.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9127118&dopt=Abstract sumatriptan Imitrex