sumatriptan, Imitrex
Sumatriptan blocks neurogenic inflammation in the peripheral nerve trunk.

Zochodne DW, Ho LT.

University of Calgary, Department of Clinical Neurosciences, AB, Canada.

We tested the action of intraperitoneal sumatriptan, a 5-HT1D receptor agonist that aborts migraine headaches, using a model of neurogenic inflammation induced by capsaicin applied to the rat sciatic epineurium. Sumatriptan prevented the development of capsaicin-induced hyperemia without inducing pretreatment vasoconstriction or altering AV shunt flow. The findings indicate that sumatriptan prevents "neurogenic" vasodilation by a mechanism other than vasoconstriction or changes in AV shunt flow.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8290056&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
L-694,247: a potent 5-HT1D receptor agonist.

Beer MS, Stanton JA, Bevan Y, Heald A, Reeve AJ, Street LJ, Matassa VG, Hargreaves RJ, Middlemiss DN.

Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex.

1. The 5-hydroxytryptamine (5-HT) receptor binding selectivity profile of a novel, potent 5-HT1D receptor agonist, L-694,247 (2-[5-[3-(4-methylsulphonylamino)benzyl-1,2,4-oxadiazol-5-yl ]- 1H-indole-3-yl]ethylamine) was assessed and compared with that of the 5-HT1-like receptor agonist, sumatriptan. 2. L-694,247 had an affinity (pIC50) of 10.03 at the 5-HT1D binding site and 9.08 at the 5-HT1B binding site (sumatriptan: pIC50 values 8.22 and 5.94 respectively). L-694,247 retained good selectivity with respect to the 5-HT1A binding site (pIC50 = 8.64), the 5-HT1C binding site (6.42), the 5-HT2 binding site (6.50) and the 5-HT1E binding site (5.66). The pIC50 values for sumatriptan at these radioligand binding sites were 6.14, 5.0, < 5.0 and 5.64 respectively. Both L-694,247 and sumatriptan were essentially inactive at the 5-HT3 recognition site. 3. L-694,247, like sumatriptan, displayed a similar efficacy to 5-HT in inhibiting forskolin-stimulated adenylyl cyclase in guinea-pig substantia nigra although L-694,247 (pEC50 = 9.1) was more potent than sumatriptan (6.2) in this 5-HT1D receptor mediated functional response. L-694,247 (pEC50 = 9.4) was also more potent than sumatriptan (6.5) in a second 5-HT1D receptor mediated functional response, the inhibition of K(+)-evoked [3H]-5-HT release from guinea-pig frontal cortex slices.(ABSTRACT TRUNCATED AT 250 WORDS)

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sumatriptan, Imitrex
Effects of sumatriptan on the cerebral intraparenchymal microcirculation in the cat.

Kobari M, Fukuuchi Y, Tomita M, Tanahashi N, Konno S, Takeda H.

Department of Neurology, School of Medicine, Keio University, Tokyo, Japan.

1. Sumatriptan, a 5-hydroxytryptamine (5-HT)1-like receptor agonist, is effective against the headache of migraine. The effects of sumatriptan injected via the carotid artery on the cerebral microcirculation were studied in 10 anaesthetized cats. 2. The local cerebral blood volume (CBV), mean transit time of blood (MTT) and cerebral blood flow (CBF) in the parieto-temporal cortex were measured by a photoelectric method. CBV represents the cumulative dimensions of the cerebral microvessels. 3. Sumatriptan at 5 and 50 micrograms kg-1 had no significant effects on the CBV, MTT, CBF, and mean arterial blood pressure (MABP); 500 micrograms kg-1 of sumatriptan reduced the CBV, prolonged the MTT, and decreased the CBF (approximately -20%) without affecting the MABP. Sumatriptan, 5 mg kg-1, elicited transient reductions in CBV and CBF, which were attributable to the rapid and marked falls of MABP seen with this dose. 4. Thus, while a high dose of sumatriptan (500 micrograms kg-1) exhibits direct vasoconstrictor actions on the cerebral vessels, low doses of sumatriptan, within the therapeutic range, elicit no vasoconstriction. The data do not support a vasoconstrictor action of sumatriptan playing a primary role in reversing the headache of migraine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8306085&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Sumatriptan relaxes isolated porcine ophthalmic artery, but inhibits VIP-induced relaxation.

Vincent MB, White LR, Bakken IJ, Sjaastad O.

Department of Neurology, University of Trondheim-NTH, Norway.

Sumatriptan, a 5-hydroxytryptamine (5HT)1-like receptor agonist, is a new antimigraine drug which is also effective in cluster headache (CH), a disorder with marked ocular circulatory abnormalities. Sumatriptan could putatively exert a therapeutic effect in this vascular bed. The present study is an attempt to assess sumatriptan's vasoactivity in isolated porcine ophthalmic artery (POA) and to verify whether it has similar activity to 5HT, and whether it interferes with the vasodilation induced by calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP). In contrast to 5HT, sumatriptan induced only slight contraction in POA at high concentrations. However, in some artery segments pre-contracted with PGF2 alpha, sumatriptan induced a slight and short-lasting but marked relaxation. In addition, relaxations induced by VIP were inhibited significantly by sumatriptan, whereas CGRP effects were not influenced by the drug. Such reactions suggest that sumatriptan's effect in CH is probably unrelated to direct ocular arterial vasoconstriction.

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sumatriptan, Imitrex
Amplifying effect of sumatriptan on noradrenaline venoconstriction in migraine patients.

Panconesi A, Franchi G, Anselmi B, Curradi C, Tarquini B.

Institute of Internal Medicine IV, University of Florence, Italy.

The venoconstrictive activity of sumatriptan and its interaction with noradrenaline (NA)- and 5-hydroxytryptamine (5HT) venoconstriction was studied in vivo in the hand vein of migraineurs. Sumatriptan, injected at increasing doses into the vein, caused local venoconstriction after a 500 microgram dose, comparable to that induced by 0.5-1 micrograms of 5HT. This venoconstriction was completely inhibited by low doses of ketanserin (5 micrograms). Subcutaneous sumatriptan (6 mg) provoked a minor increase in vein tone, lasting less than 30 min. Non-venoconstrictive doses of sumatriptan (10-100 micrograms), injected in the hand vein, produced an amplification of NA-venoconstriction but not of 5HT-induced venoconstriction. A similar increased effect was displayed by subcutaneous sumatriptan (6 mg) for at least 1 h. Sumatriptan appears to cause peripheral venoconstriction only at high doses locally applied (in the hand vein), by acting on 5HT2 receptors. Clinical subcutaneous doses (6 mg) do not show significant venoconstrictive effects. The amplifying effect on NA venoconstriction, also caused by 5HT, ergotamine and dihydroergotamine in human cranial arteries, may be important in explaining the therapeutic action of sumatriptan in migraine attacks.

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sumatriptan, Imitrex
Autoradiographic characterisation and localisation of 5-HT1D compared to 5-HT1B binding sites in rat brain.

Bruinvels AT, Palacios JM, Hoyer D.

Preclinical Research 360/604, Sandoz Pharma Ltd., Basel, Switzerland.

The regional distribution and the pharmacology of the binding sites labelled with the novel 5-hydroxytryptamine (serotonin) 5-HT1B/1D selective radioligand serotonin-O-carboxy-methyl-glycyl-[125I]tyrosinamide (abbreviated [125I]GTI for the sake of simplicity) was determined using quantitative autoradiography in rat brain. The distribution of [125I]GTI binding sites was largely comparable to that of [125I]iodocyanopindolol ([125I] ICYP) which labels 5-HT1B binding sites (in the presence of 8-OH-DPAT (8-hydroxy-[2N-dipropylamino]tetralin) and isoprenaline, to prevent binding to 5-HT1A and beta-adrenoceptor binding sites), although a detailed analysis revealed differences. The pharmacology of the [125I]GTI binding sites was analysed using compounds known to display high affinity for and/or distinguish between 5-HT1B and 5-HT1D sites: 5-carboxamidotryptamine (5-CT), sumatriptan, CP 93129 (5-hydroxy-3(4-1,2,5,6-tetrahydropyridyl)-4-azaindole), (-)pindolol, PAPP (4[2-[4-[3-(trifluoromethyl)phenyl]-1- piperazinyl]ethyl]benzeneamine), rauwolscine, and 8-OH-DPAT. The displacement of [125I]GTI by 5-CT was monophasic. By contrast, the selective 5-HT1B compound CP 93129 and (-)pindolol produced biphasic curves showing a majority of high affinity sites in the globus pallidus and the substantia nigra, whereas PAPP and sumatriptan (which are somewhat 5-HT1D selective) produced biphasic curves indicating a minority of high affinity sites in these areas. In addition, by blocking the 5-HT1B sites with 100 nM CP 93129, the remaining population of [125I]GTI binding sites could be studied and was found to have high affinity for PAPP, rauwolscine and 8-OH-DPAT. The pharmacological profile of the major binding component was typical of the 5-HT1B type: 5-CT > CP 93129 > or = (-)pindolol > sumatriptan > or = PAPP > rauwolscine. The profile of the minor component of [125I]GTI binding is best characterised as that of a 5-HT1D site: 5-CT > PAPP > or = sumatriptan > rauwolscine > (-)pindolol > or = CP 93129. The localisation of the non 5-HT1B [125I]GTI binding sites was characterised by blocking the 5-HT1B receptors with 100 nM CP 93129. Low densities of the 5-HT1D recognition sites were found to be present in globus pallidus, ventral pallidum, caudate-putamen, subthalamic nucleus, entopeduncular nucleus, substantia nigra (reticular part), nuclei of the (normal and accessory) optic tract, different nuclei of the geniculate body and frontoparietal cortex, although higher densities of 5-HT1B sites were always observed in the same structures.(ABSTRACT TRUNCATED AT 400 WORDS)

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sumatriptan, Imitrex
Effect of subcutaneous sumatriptan, a selective 5HT1 agonist, on the systemic, pulmonary, and coronary circulation.

MacIntyre PD, Bhargava B, Hogg KJ, Gemmill JD, Hillis WS.

Department of Medicine and Therapeutics, University of Glasgow, Scotland.

BACKGROUND. Sumatriptan (GR43175) is a selective 5-hydroxytryptamine (5HT1) receptor agonist effective in the acute treatment of migraine. Recent in vitro experiments suggest that it has vasoactive properties in vascular beds distinct from the cerebral circulation. The object of this study was to assess the vasoactive effects of the standard 6-mg subcutaneous dose of sumatriptan used in migraine on the systemic and pulmonary circulations and the coronary artery vasculature. METHODS AND RESULTS. Ten patients undergoing diagnostic coronary arteriography were studied with digital subtraction angiography and invasive hemodynamic monitoring. After subcutaneous injection of sumatriptan, there was no significant change in heart rate or ECG morphology. There was a significant rise in the systemic (20%, p < 0.05 by ANOVA) and pulmonary artery (40%, p < 0.05 by ANOVA) pressures. There was no change in cardiac output, but there was a significant increase in total systemic (27%, p < 0.05) and total pulmonary vascular resistance (40%, p < 0.05). Sumatriptan caused a significant reduction (p < 0.001 by ANOVA) in mean absolute coronary artery diameter, from 4.36 +/- 1.60 mm at baseline to 3.67 +/- 1.49 mm (16%) at 10 minutes and to 3.63 +/- 1.49 mm (17%) at 30 minutes after injection. There were no clinical sequelae. CONCLUSIONS. Sumatriptan, a 5HT1 receptor agonist administered by the subcutaneous route, causes a vasopressor response in the systemic and pulmonary arterial circulations and coronary artery vasoconstriction.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8381056&dopt=Abstract sumatriptan Imitrex