sumatriptan, Imitrex
Quantitation of the 5HT1D agonists MK-462 and sumatriptan in plasma by liquid chromatography-atmospheric pressure chemical ionization mass spectrometry.

McLoughlin DA, Olah TV, Ellis JD, Gilbert JD, Halpin RA.

Merck Research Laboratories, West Point, PA 19486, USA.

The 5HT1D agonist sumatriptan is efficacious in the treatment of migraines. MK-462 is a drug of the same class which is under development in our laboratories. Bioanalytical methods of high efficiency, specificity and sensitivity were required to support the preclinical and clinical programs. These assays were based on HPLC with tandem MS-MS detection. MK-462 and sumatriptan were extracted using an automated solid-phase extraction technique on a C2 Varian Bond-Elut cartridge. The n-diethyl analogues of MK-462 and sumatriptan were used as internal standards. The analytes were chromatographed using reversed-phase (nitrile) columns coupled via a heated nebulizer interface to an atmospheric pressure chemical ionization source. The chromatographic run times were less than 7 min. Both methods were precise, accurate and selective down to plasma concentrations of 0.5 ng/ml. The assay for MK-462 was adapted to separately monitor the unlabeled and 14C-labeled species of the drug following intravenous administration of radiolabeled material to man.

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sumatriptan, Imitrex
Selective vasoconstriction by alniditan in the carotid vascular bed of anaesthetized dogs.

Van de Water A, D'Aubioul J, Van Gerven W, Van Ammel K, De Clerck F.

Department of Cardiovascular and Pulmonary Pharmacology, Janssen Research Foundation, Beerse, Belgium.

In anaesthetized dogs, alniditan or (-)-(R)-N-[3,4-dihydro-2H-1- benzopyran-2-yl)methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3- propanediamine dihydrochloride, a new compound with 5-HT1-like receptor ligand effects, dose dependently (0.63-80 micrograms/kg i.v.) reduced common carotid arterial blood flow with comparatively little effect on other cardiovascular variables including coronary, mesenteric and renal arterial blood flow, systemic and pulmonary vascular resistance and airway resistance. The potency of alniditan was higher than that of sumatriptan and comparable to that of ergotamine (dose producing a 50% reduction: alniditan = 5.1 micrograms/kg i.v.; sumatriptan = 13.1 micrograms/kg i.v.; ergotamine = 4.6 micrograms/kg i.v.; median values). The reduction of carotid arterial blood flow by alniditan was accompanied by an increase of carotid arterial vascular resistance and correlated with the increase of the difference in oxygen saturation between arterial and jugular venous blood, suggesting a preferential reduction of extracerebral shunt flow by the compound via constriction of arteriovenous anastomoses in the carotid vascular region. The extent and duration of carotid arterial blood flow reductions after alniditan at 5 micrograms/kg i.v. were similar to those after sumatriptan 15 micrograms/kg i.v. but larger/longer after alniditan at 15 micrograms/kg i.v. than after sumatriptan at 15 micrograms/kg i.v. The dose-dependent increase of carotid arterial vascular resistance by alniditan was similar in dogs premedicated daily for 4 days with solvent or active compound (20 micrograms/kg i.v.), indicating absence of tolerance or resetting of sensitivity to the compound.

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sumatriptan, Imitrex
5-HT1D receptor agonists and human coronary artery reactivity in vitro: crossover comparisons of 5-HT and sumatriptan with rizatriptan and L-741,519.

Longmore J, Boulanger CM, Desta B, Hill RG, Schofield WN, Taylor AA.

Baylor College of Medicine, Center for Experimental Therapeutics, Houston, Texas, USA.

1. Rizatriptan (MK-462, (N,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl] ethylamine)) and its structurally related analogue L-741,519 (N-methyl-4-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]piperidine) are novel 5-HT1D-receptor agonists. Rizatriptan has shown efficacy as an anti-migraine agent in clinical trials. Since angiographic studies in patients have shown that sumatriptan (an established 5-HT1D-receptor agonist) can cause coronary artery vasoconstriction, we compared the effects of rizatriptan and L-741,519 with those of 5-HT and sumatriptan on endothelium-denuded segments of human coronary artery in vitro. 2. Coronary arteries were obtained from explanted hearts from patients undergoing cardiac transplantation (n = 16 viable arteries from 13 males, 3 females, aged 38-68 years) and arterial segments (5-6 mm in length) were mounted in organ baths for isometric tension recording. Each segment was first exposed to 45mM KCl and then to 5-HT (1 nM-100 microM). Concentration-effect curves to rizatriptan and sumatriptan (Study 1, n = 6 or 7 arteries) or sumatriptan and L-741,519 (Study 2, n = 8 arteries) were then performed in a consecutive and random manner. The response to repeated application of 5-HT was obtained in separate segments. 3. One artery showed severe atheroma and was not included in the analysis. ANOVA showed that 5-HT responsiveness varied significantly between arteries from different patients; but not between arterial segments from the same patient. Desensitization was seen consistently across all agonists but did not significantly affect inter-agonist comparisons. 4. There was graded effectiveness in the ability of the agonists to cause contraction with the rank order of Emax values being 5-HT >> sumatriptan > L-741,519 > rizatriptan. In terms of EC50 values, L-741,519 was significantly more potent than sumatriptan. 5. The present study (using a 'cross-over' experimental protocol) confirms our previous observation that rizatriptan is less effective than sumatriptan in causing contraction of human isolated coronary artery. Furthermore, it shows that the lower maximum contractile response to rizatriptan, compared with that of sumatriptan, is not merely the consequence of variability in response to 5-HT1D-receptor agonists between patients or between segments from the same artery.

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sumatriptan, Imitrex
Sumatriptan inhibits the release of CGRP and substance P from the rat spinal cord.

Arvieu L, Mauborgne A, Bourgoin S, Oliver C, Feltz P, Hamon M, Cesselin F.

INSERM U 288, Faculte de Medecine Pitie-Salptriere, Paris, France.

The possible presynaptic action of the anti-migraine drug sumatriptan on primary afferent fibres containing substance P and/or calcitonin gene-related peptide was investigated on superfused rat horizontal spinal cord slices with attached dorsal roots. Electrical stimulation of dorsal roots triggered a significant overflow of both peptides; this could be reduced by sumatriptan in a concentration-dependent manner. As expected from the involvement of 5-HT1B/1.D beta receptors, methiothepin, (-)tertatolol and GR 127,935, but not WAY 100,635, prevented the inhibitors effect of sumatriptan. These data support the idea that the anti-migraine action of sumatriptan may involve, at least in part, a presynaptic inhibitory control of nociceptive (trigeminovascular) substance P- and/or calcitonin gene-related peptide-containing sensory fibres.

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sumatriptan, Imitrex
Prescribing practices for the management of headache in Newfoundland and Labrador.

Furlong S, Pryse-Phillips W, Crowley M, Turner CJ.

Memorial University of Newfoundland, St John's, Canada.

To assess the impact of sumatriptan in clinical practice, we undertook a retrospective analysis of the government of Newfoundland and Labrador's prescription drug program data base for 35 consecutive patients prescribed sumatriptan. The number of doses of all drugs prescribed ranged from 121 to 18,874 on from 4 to 357 prescriptions per patient over 1 to 19 months. The mean number of doses of analgesic drugs prescribed before sumatriptan therapy was 56 per month and after initiation of sumatriptan was 46 per month. The prescribing of multiple analgesics was common; 79% received three or more different analgesics. Twenty-two (63%) patients were prescribed medications indicated for the prophylaxis of migraine concomitantly with drugs indicated for symptomatic treatment. Twenty-four (69%) patients were prescribed medication capable of inducing migraine. We conclude that sumatriptan did not have a major impact on the outcomes of these patients judged by their use of analgesics. The simplest explanation is that many of the patients were suffering from analgesic-induced headache rather than migraine. In addition, we conclude that there were deficiencies in prescribing practices including numbers, quantities, and choice of analgesics; the use of analgesics concomitantly with drugs indicated for migraine prophylaxis; and the use of drugs capable of inducing migraine. Further research is required to validate these findings.

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sumatriptan, Imitrex
Augmented contraction of the human isolated coronary artery by sumatriptan: a possible role for endogenous thromboxane.

Maassen VanDenBrink A, Bax WA, Ferrari MD, Zijlstra FJ, Bos E, Saxena PR.

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

1. The antimigraine drug, sumatriptan, contracts the human coronary artery and, in some patients, elicits chest symptoms (e.g. pressure and pain), particularly after subcutaneous administration. We studied the effects of the thromboxane A2 (TxA2) analogue, U46619 and endothelin-1 on contractile responses to sumatriptan in the human isolated coronary artery as well as the role of endogenously produced TxA2 and endothelin-1 in contractions evoked by sumatriptan. 2. In the presence of U46619 (1 and 3 nM), mean concentration-response curves to sumatriptan in the human coronary artery were shifted vertically due to the initial contraction by U46619, but when this initial contraction was subtracted from the response to sumatriptan, no significant augmentation was observed. However, analysis of the degree of augmentation in individual arterial segments revealed that the augmentation was variable and related inversely to the Emax of sumatriptan in the absence of U46619 (r = 0.78 and 0.81 for 1 and 3 nM, respectively; P < 0.05). 3. Treatment with the TxA2 receptor antagonist, SQ30741 (100 nM), or incubation of vessel segments with aspirin (10 microM), significantly reduced responses to sumatriptan; in aspirin-treated vessel segments, SQ30741 failed to decrease further the contractions to sumatriptan. The decrease in Emax of sumatriptan by both SQ30741 and aspirin correlated significantly with the Emax of sumatriptan without SQ30741 (r = 0.74; P < 0.01) or aspirin (r = 0.94; P < 0.01). In aspirin-treated vessel segments, responses to sumatriptan were significantly augmented in the presence of U46619 (3 nM; P < 0.05). 4. The specificity of SQ30741 was demonstrated by its ability to antagonize coronary artery contractions to U46619 (pA2: 7.54 +/- 0.30), but not endothelin-1. Similarly, incubation with aspirin (10 microM) did not affect contractile responses to endothelin-1, but significantly reduced TxA2 production in coronary artery segments as judged by a decrease in thromboxane B2 (TxB2) from 4.77 +/- 0.98 to 1.38 +/- 0.36 ng g-1 2 h-1. 5. Endothelin-1 (1 nM) did not significantly augment contractions to sumatriptan; there was also no relationship between the degree of augmentation and the control Emax of sumatriptan in the absence of endothelin-1. Furthermore, unlike SQ30741 or aspirin, a high concentration (100 nM) of the non-selective ETA/ETB receptor antagonist, SB 209670, failed to affect contractile responses to sumatriptan. However, SB 209670 potently antagonized coronary artery contractions induced by endothelin-1 with a pA2 of 8.84 +/- 0.32. 6. Compared to control vascular segments, endothelial denudation did not reduce TxA2 production (with endothelium = 2.56 +/- 1.38 vs. without endothelium = 12.32 +/- 4.94 ng TxB2 g-1 2 h-1), suggesting that the production of TxA2 is not confined to the endothelium. The sumatriptan-induced contractions were also unaffected by endothelial denudation. 7. The results of the present study suggest that endogenously produced TxA2 enhances contractions to sumatriptan in the human isolated coronary artery. Such a mechanism may play a role in causing chest symptoms after sumatriptan by potentiating coronary vascular contraction by sumatriptan in vivo.

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sumatriptan, Imitrex
5-Hydroxytryptamine receptors mediating vasoconstriction in pulmonary arteries from control and pulmonary hypertensive rats.

MacLean MR, Sweeney G, Baird M, McCulloch KM, Houslay M, Morecroft I.

Division of Neuroscience and Biomedical Systems, University of Glasgow.

1. We investigated 5-hydroxytryptamine (5-HT)-receptor mediated vasoconstriction in the main, first branch and resistance pulmonary arteries removed from control and pulmonary hypertensive rats. Contractile responses to 5-HT, 5-carboxamidotryptamine (5-CT, non-selective 5-HT1 agonist), and sumatriptan (5-HT1D-like receptor agonist) were studied. The effects of methiothepin (non-selective 5-HT1 + 2-receptor antagonist) and ketanserin (5-HT2A receptor antagonist) and GR55562 (a novel selective 5-HT1D receptor antagonist) on 5-HT-mediated responses were also studied. Basal levels of adenosine 3':5'-cyclic monophosphate ([cyclic AMP]i) and guanosine 3':5'-cyclic monophosphate ([cyclic GMP]i) were determined and we assessed the degree of inherent tone in the vessels under study. 2. 5-HT was most potent in the resistance arteries. pEC50 values were 5.6 +/- 0.1, 5.3 +/- 0.1, 5.0 +/- 0.2 in the resistance arteries, pulmonary branch and main pulmonary artery, respectively (n = at least 5 from 5 animals). The sensitivity to, and maximum response of, 5-HT was increased in all the arteries removed from the chronic hypoxic (CH) rats. In CH rats the pEC50 values were 5.9 +/- 0.2, 6.3 +/- 0.2, 6.4 +/- 0.2 and the increase in the maximum response was 35%, 51% and 41% in the resistance arteries, pulmonary branch and main pulmonary artery, respectively. Sumatriptan did not contract any vessel from the control rats whilst 5-CT did contract the resistance arteries. In the CH rats, however, they both contracted the resistance arteries (responses to sumatriptan were small) (pEC50: 5-CT; 5.4 +/- 0.2) and the pulmonary artery branches (pEC50: sumatriptan, 5.4 +/- 0.2; 5-CT, 5.4 +/- 0.2). 5-CT also caused a contraction in the main pulmonary artery (pEC50: 6.0 +/- 0.3). 3. Ketanserin (1 nM-1 microM) caused a competitive antagonism of the 5-HT response in all vessels tested. In control rats, the estimated pKb values for ketanserin in resistance arteries, pulmonary branches and main pulmonary artery were 8.3, 7.8 and 9.2, respectively. Methiothepin (1 nM-1 microM) inhibited responses to 5-HT in the first branch (estimated pKb value: 7.8) and main pulmonary artery. In CH rats, the estimated pKb values for ketanserin in resistance arteries, pulmonary branches and main pulmonary artery were 7.7, 8.3 and 9.6, respectively. Methiothepin also inhibited contractions to 5-HT in the pulmonary artery branch and main pulmonary artery with estimated pKb values of 7 and 9.5, respectively. In control animals, GR55562 had no effect on responses to 5-HT in any of the vessels tested. In the CH rats the estimated pKb values for GR55562 were 6.5, 7.8 and 7.0 in the pulmonary resistance arteries, first branch and main pulmonary artery, respectively. 4. Large pulmonary arteries from controls demonstrated inherent tone and this was increased three fold in the CH rats. The resistance arteries from controls demonstrated little inherent tone though this was enhanced in those from the CH rats. 5. [Cyclic AMP]i was 259 +/- 23 pmol mg-1 protein in the pulmonary artery branches removed from control rats and decreased to 192 +/- 11 pml mg-1 protein in the CH rats (P < 0.01, n = 8). [Cyclic GMP]i also decreased in the pulmonary artery branches (from 550 +/- 15, control to 462 +/- 31 pmol mg-1 protein in CH vessels, n = 8, P < 0.01) and in the main pulmonary arteries (from 566 +/- 33, control to 370 +/- 25 pmol mg-1 protein in CH vessels, n = 8, P < 0.001). No changes in either [cyclic AMP]i or [cyclic GMP]i were observed in the resistance arteries. 6. The results suggest that the increased vasoconstrictor response to 5-HT in CH rat pulmonary arteries is due to an increase in 5-HT2A-receptor mediated contraction combined with an increase in r5-HT1B-like receptor-mediated contraction. An increase in vascular tone and decreased levels of [cyclic GMP]i in the large pulmonary arteries may contribute to the observed increase in activity of r5-HT1B-like receptor

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8922741&dopt=Abstract sumatriptan Imitrex