sumatriptan, Imitrex
Human isolated coronary artery contraction to sumatriptan characterised by the selective 5-HT1B/1D receptor antagonist GR55562.

Maassen VanDenBrink A, Reekers M, Bax WA, Saxena PR.

Department of Pharmacology, Erasmus University Medical Center Rotterdam EMCR, The Netherlands.

The antimigraine drug, sumatriptan, contracts the human coronary artery both in vivo and in vitro. Because sumatriptan has been associated with cardiac side effects, it is important to characterise the receptor involved in sumatriptan-induced coronary artery contraction. Using the agonists sumatriptan and 5-carboxamidotryptamine and the selective 5-HT1B/1D receptor antagonist GR55562, we have investigated the involvement of 5-HT1B/1D receptors in the contraction of the human isolated coronary artery. Contractions to sumatriptan (pEC50: 6.1+/-0.2, maximal effect: 21+/-4% of 100 mM K+-induced contraction) were competitively antagonised by GR55562. The pA2 of GR55562 (7.40+/-0.16) was in accord with its reported affinity at the human 5-HT1B receptor. Since the contractions to 5-carboxamidotryptamine did not reach a maximum with the highest concentration used (10 microM), pEC50 values could not be calculated for Schild analysis. However, using the pEC10%/K+ values (negative logarithm of the concentration needed to induce 10% of the contraction to 100 mM K+), GR55562 proved a less potent antagonist against 5-carboxamidotryptamine than against sumatriptan. These results show that sumatriptan contracts the human isolated coronary artery via 5-HT1B/1D receptors, most probably the 5-HT1B subtype. 5-Carboxamidotryptamine may contract the human isolated coronary artery, at least partly, via a novel yet to be characterised, receptor.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10895993&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Calcium-antagonistic activity of sumatriptan in the rat anococcygeus muscle.

Emre-Aydingoz S, Kocaefe C C, Tuncer M.

Department of Pharmacology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.

The relaxant effect of sumatriptan, a 5-HT(1B/1D) receptor agonist, on the rat anococcygeus muscle was investigated. Sumatriptan induced concentration-dependent relaxations of the phenylephrine-precontracted rat anococcygeus muscle. N(G)-nitro-L-arginine, methylene blue, glibenclamide, tetrodotoxin, indomethacin, GR 113808, GR 55562, methysergide, ketanserin, ICS 205930, clozapine, methiothepin, metergoline, mesulergine, and ritanserin did not inhibit the relaxations induced by sumatriptan. Sumatriptan converted calcium-induced contractions into relaxations in the preparations depolarized by a calcium-free, high-potassium solution. In membrane preparations obtained from the rat anococcygeus muscle, the basal rate of cAMP production by adenylate cyclase was 4.77 +/- 0.02 pmol/mg protein/min (n = 15). The enzyme activity was increased to 104 +/- 51.7 pmol/mg protein/min by forskolin (10(-4) mol/l), but did not change in the presence of sumatriptan. The mRNA expression of 5-HT(1B), 5-HT(1D), and 5-HT(7) receptors was not observed in the rat anococcygeus muscle. The results indicate that sumatriptan causes relaxation of the precontracted rat anococcygeus muscle by a calcium-antagonistic activity. Copyright 2002 S. Karger AG, Basel

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11731721&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Effects of subcutaneous sumatriptan on plasma growth hormone concentrations in migraine patients.

Pinessi L, Rainero I, Savi L, Valfre W, Limone P, Calvelli P, Del Rizzo P, Gianotti L, Taliano M, Ghigo E, Arvat E.

Neurology III-Headache Centre, Department of Neuroscience, University of Turin, Italy. Pinessi galeno.medfarm.unito.it

The purpose of this study was to assess the sensitivity of 5-HT1D receptors in migraine using sumatriptan as a pharmacological probe. The drug stimulates the release of growth hormone (GH) and this effect may be used to explore the function of cerebral serotonergic systems in vivo. We administered sumatriptan and placebo to 15 migraineurs and to 10 controls. Blood samples were collected -15, 0, 15, 30, 45, 60 and 90 min after injection. Placebo had no effect on hormone concentrations. Sumatriptan induced a significant (P<0.01) increase in GH concentrations both in migraine patients and healthy controls. The GH increase was not significantly different in the two groups. Our results suggest that cerebral serotonergic functions mediated by 5-HT1D receptors are not altered in migraine. Sumatriptan overuse could lead to adverse effects mediated by its neuroendocrine activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10999671&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Contractile responses to sumatriptan and ergotamine in the rabbit saphenous vein: effect of selective 5-HT(1F) receptor agonists and PGF(2alpha).

Cohen ML, Schenck K.

Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. cohenml lilly.com

Contractile responses to ergotamine, sumatriptan and the novel 5-HT(1F) receptor agonists, LY334370 and LY344864 were examined using the rabbit saphenous vein. Ergotamine (pEC(50)=8.7+/-0.06) was 30 fold more potent than 5-hydroxytryptamine (5-HT) (pEC(50)=7.2+/-0.13) and 300 fold more potent than sumatriptan (pEC(50)=6.0+/-0.08) in contracting the rabbit saphenous vein in vitro. The selective 5-HT(1F) receptor agonists, LY334370 or LY344864 (up to 10(-4) M), did not contract the rabbit saphenous vein. The contractile response to ergotamine in this tissue resulted from activation of both alpha(1) and 5-HT(1B/1D) receptors based on the observation that prazosin (10(-6) M), an alpha-adrenoceptor antagonist, and GR127935 (10(-8) M) a 5-HT(1B/1D) receptor antagonist, dextrally shifted the contractile response to ergotamine. In contrast, prazosin (10(-6) M) did not alter contraction to sumatriptan whereas GR127935 (10(-8) M) was a potent antagonist (-log K(B)=10.0) suggesting that sumatriptan-induced contraction of the rabbit saphenous vein was mediated only by activation of receptors similar or identical to 5-HT(1B/1D) receptors. PGF(2alpha) (3x10(-7) M) produced a modest increase (approximately 5.0 - 10.0% maximum PGF(2alpha) contraction) in saphenous vein force. Precontraction with PGF(2alpha) (3x10(-7) M) dramatically augmented the potency and maximal contractile response to sumatriptan (pEC(50)=7.1) and modestly enhanced the contractile potency of ergotamine (pEC(50)=9.0) in the rabbit saphenous vein. However, PGF(2alpha) (3x10(-7) M) only unmasked a contraction to the 5-HT(1F) receptor agonists when concentrations exceeded 10(-5) M, concentrations considerably higher than their 5-HT(1F) receptor affinities. LY334370 (10(-6) M) pretreatment did not alter contraction to either sumatriptan or ergotamine and a higher concentration (10(-5) M) of LY334370 or LY344864 inhibited contraction to sumatriptan. Thus, activation of 5-HT(1F) receptors will not induce vascular contraction (either alone or following modest tone with PGF(2alpha)) or augment contraction to other contractile agonists in the rabbit saphenous vein.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11015308&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Pharmacological properties of the naturally occurring Phe-124-Cys variant of the human 5-HT1B receptor: changes in ligand binding, G-protein coupling and second messenger formation.

Kiel S, Bruss M, Bonisch H, Gothert M.

Institute of Pharmacology and Toxicology, University of Bonn, Germany.

The aim of this study was to analyse whether substitution of phenylalanine in position 124 of the human (h) 5-HT1B receptor by cysteine, a naturally occurring variant of this receptor, modifies not only ligand binding, but also G-protein coupling and second messenger formation. Stably transfected rat C6 glioma cells, which express either the h5-HT1B variant receptor (VR) or the wild-type receptor (WTR) were used. In saturation experiments with [3H]5-carboxamidotryptamine ([3H]5-CT), the maximum binding (Bmax) of the VR amounted to only 60% of that to WTR. In competition experiments with 1 nM [3H]5-CT, the following 5-HT receptor ligands exhibited a higher affinity for the mutant receptor than for the WTR: L-694,247, 5-CT, 5-HT, sumatriptan (agonists listed at decreasing order of potency) and SB-224289 (a selective h5-HT1B receptor inverse agonist with competitive antagonistic properties). In contrast, the mixed 5-HT1B/1D receptor antagonist GR-127935 exhibited equal affinity for both isoforms. The efficacy of L-694,247, 5-CT, 5-HT and sumatriptan in stimulating [35S]GTPgammaS binding (a measure of G protein coupling) to membranes of cells expressing the VR was approximately 50-65% lower compared to membranes of cells expressing the WTR, but their potency was 2.8-3.6-fold higher. SB-224289, which decreased [35S]GTPgammaS binding when given alone, but not GR-127935, was more potent in antagonizing the stimulatory effect of 5-CT on [35S]GTPgammaS binding to membranes expressing the VR compared to membranes expressing the WTR. In whole cells expressing the VR, 5-CT and sumatriptan inhibited the forskolin-stimulated cAMP accumulation 3.2-fold more potently than in cells expressing the WTR. In conclusion, our data suggest that the Phe-124-Cys mutation modifies the pharmacological properties of the h5-HT1B receptor and may account for pharmacogenetic differences in the action of h5-HT1B receptor ligands. Thus, the sumatriptan-induced vasospasm which occurs at low incidence as a side-effect in migraine therapy may be related to the expression of the (124-Cys)h5-HT1B receptor in patients with additional pathogenetic factors such as coronary heart disease.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11037806&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Pharmacological analysis of contractile effects of eletriptan and sumatriptan on human isolated blood vessels.

van den Broek RW, MaassenVanDenBrink A, de Vries R, Bogers AJ, Stegmann AP, Avezaat CJ, Saxena PR.

Department of Pharmacology, Erasmus University Medical Centre Rotterdam, P.O. Box 1738, 3000 DR, Rotterdam, Netherlands.

Eletriptan, a second-generation triptan with high affinity for 5-HT(1B/1D) receptors, is highly effective in migraine, with or without aura. We compared the effects of eletriptan and sumatriptan on the human isolated middle meningeal and coronary arteries and saphenous vein, used as models for therapeutic efficacy and potential side effects, and have investigated the role of 5-HT(1B/1D) receptors in contractions induced by these triptans. Concentration-response curves to eletriptan and sumatriptan were constructed in the absence or presence of a selective 5-HT(1B/1D) receptor antagonist, N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-methyl-4-(4-py rid yl) benzamide (GR125743). All three blood vessels constricted in response to eletriptan and sumatriptan, but the middle meningeal artery relaxed following the highest concentration (100 microM) of eletriptan. In the middle meningeal artery, GR125743 antagonised the contractions induced by both eletriptan (pEC(50): 7.34+/-0.13) and sumatriptan (pEC(50): 6.91+/-0.17) to a similar degree (pA(2): 8. 81+/-0.17 and 8.64+/-0.21, respectively). In the human coronary artery and saphenous vein, sumatriptan-induced contractions (pEC(50): 6.24+/-0.14 and 6.19+/-0.12, respectively) were also potently antagonised by GR125743 (pA(2): 8.18+/-0.27 and 8.34+/-0.12, respectively). The eletriptan-induced contractions of the human saphenous vein (pEC(50): 6.09+/-0.13) were antagonised less effectively by GR125743 (pK(B): 7.73+/-0.18), and those of the human coronary artery (pEC(50): 5.54+/-0.22) remained unaffected by GR125743 up to a concentration of 100 nM. These results suggest that (i) based on the differences in pEC(50) values, the cranioselectivity of eletriptan (63-fold) is higher than that of sumatriptan (5-fold) in coronary artery, (ii) the contractile effects of sumatriptan and eletriptan (lower concentrations) in the three blood vessels are mediated via the 5-HT(1B) receptor, and (iii) additional mechanisms seem to be involved in coronary artery and saphenous vein contractions and middle meningeal artery relaxation following high concentrations of eletriptan.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11050304&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Sumatriptan overuse in episodic cluster headache: lack of adverse events, rebound syndromes, drug dependence and tachyphylaxis.

Centonze V, Bassi A, Causarano V, Dalfino L, Cassiano MA, Centonze A, Fabbri L, Albano O.

Dept of Internal Medicine and Public Medicine, University of Bari, Italy.

This observational study was designed to examine the pattern of sumatriptan use in patients with cluster headache using more than the recommended daily dose of subcutaneously injected (s.c.) sumatriptan. Thirteen patients suffering from episodic cluster headache were asked to record the characteristics of their attacks and drug intake for 1 year. All reported a high daily frequency of attacks (more than 3 per day) and the related overuse of s.c. sumatriptan. The results show that the overall incidence of adverse events among patients receiving sumatriptan injections for the treatment of cluster headache is low. The extended administration of this drug in episodic cluster headache did not result in tolerance problems or tachyphylaxis. Only 4 patients experienced minor adverse events and recovered more slowly than the others. They suffered from migraine without aura and cluster headache, and showed a family history of migraine. Even though they must be viewed with caution, due to the observational nature of the study and the low number of patients included, these results suggest that the profile of sumatriptan may differ in cluster headache compared with migraine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11062845&dopt=Abstract sumatriptan Imitrex