sumatriptan, Imitrex
Cost-benefit analysis of sumatriptan tablets versus usual therapy for treatment of migraine.

Biddle AK, Shih YC, Kwong WJ.

Department of Health Policy and Administration, School of Public Health, University of North Carolina, Chapel Hill 27599-7400, USA.

We performed a systematic assessment of the costs and benefits of sumatriptan and usual therapy for migraine from society's perspective. A decision tree was constructed with probability estimates based on data from an open-label clinical trial assessing the economic and human impacts of sumatriptan and usual therapy on nursing personnel. Direct medical care costs including costs for drug, physician, and emergency room visits were considered. Benefits were estimated using the human capital approach based on the national average of weekly earnings and productivity loss estimated from a migraine clinical trial. The net benefits of sumatriptan and usual therapy for the treatment of a single migraine attack were estimated to be $50 and $20, respectively. The annual incremental net benefit of sumatriptan over usual therapy was estimated to be $114-540/patient. The price difference was offset by benefits of sumatriptan in reducing use of health care resources and productivity loss.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11079284&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Oral therapy for migraine: comparisons between rizatriptan and sumatriptan. A review of four randomized, double-blind clinical trials.

Tfelt-Hansen P, Ryan RE Jr.

Department of Neurology, Glostrup Hospital, University of Copenhagen, Denmark.

The introduction in 1991 of sumatriptan succinate, the first approved 5-HT1B/1D receptor agonist, represented a significant advance in the treatment of acute migraine. The approval of three additional 5-HT receptor agonists, including rizatriptan, has further expanded the options for migraine treatment. Four randomized clinical trials have compared the effects of oral sumatriptan with those of oral rizatriptan. Forty mg rizatriptan was more effective than 100 mg sumatriptan but was associated with a high incidence of adverse events. Five mg rizatriptan was comparable to 50 mg sumatriptan. In two trials, rizatriptan 10 mg, the recommended dose in most countries, had a more rapid onset of action than 50 mg (p<0.05) and 100 mg sumatriptan (p=0.075). In addition, 10 mg rizatriptan resulted in more patients being pain-free after 2 hours than 100 mg sumatriptan (p<0.05), and resulted in fewer drug-related adverse events than sumatriptan.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11089515&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Vascular effects of the new anti-migraine agent almotriptan on human cranial and peripheral arteries.

Bou J, Gras J, Cortijo J, Morcillo EJ, Llenas J, Palacios JM.

Almirall Prodesfarma, Research Centre, Barcelona, Spain.

This paper describes the vascular effects of almotriptan in comparison with sumatriptan in human vessels and tissues in vitro. The contractile properties of almotriptan and sumatriptan were evaluated in vitro in the following arteries: meningeal, temporal, basilar, internal carotid, ophthalmic, pulmonary and coronary. In addition, the effects of almotriptan on the pulmonary vein and on bronchial tissues were studied. Almotriptan showed selectivity of action for migraine-related arteries (i.e. contractile EC(50) of 30 and 700 nm for meningeal and temporal arteries, respectively), whereas the effect on arteries supplying blood to the brain was lower. The contractile effect of almotriptan was lower than that of sumatriptan in pulmonary arteries, whereas in bronchial preparations no clinically relevant contractile responses were observed for either almotriptan or sumatriptan. In ophthalmic arteries the contractile effects of almotriptan and sumatriptan were similar, whereas lower contractile effects were obtained with almotriptan than with sumatriptan in coronary arteries.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11737005&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Craniovascular selectivity of eletriptan and sumatriptan in human isolated blood vessels.

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

Department of Pharmacology, Erasmus University Medical Centre Rotterdam "EMCR," the Netherlands. maassenvandenbrink farma.fgg.eur.nl

BACKGROUND: Eletriptan is a 5-HT(1B/1D) receptor agonist with proven efficacy in the acute treatment of migraine. OBJECTIVE: To assess the craniovascular selectivity of eletriptan and sumatriptan in blood vessels predictive of therapeutic efficacy (human middle meningeal artery) and adverse coronary side effects (human coronary artery and human saphenous vein). METHOD: The authors obtained coronary artery from organ donors (n = 9), middle meningeal artery from patients (n = 11) undergoing craniotomy, and saphenous vein from patients (n = 9) undergoing coronary bypass surgery. Concentration-response curves to eletriptan and sumatriptan were constructed to obtain measurements of efficacy (maximum contraction, E(max)) and potency (concentration eliciting 50% of E(max), EC(50)). The contraction that is likely to be induced at the maximal free plasma concentration (C(max)) was determined by calculating C(max)/EC(50) ratios and by interpolation of the concentration-response curves. RESULTS: Eletriptan and sumatriptan induced concentration-dependent contractions of meningeal artery, coronary artery, and saphenous vein. Eletriptan was less potent than sumatriptan in coronary artery, whereas both compounds had similar potency in meningeal artery and saphenous vein. However, the potency of eletriptan and sumatriptan was higher in meningeal artery than in coronary artery (86-fold for eletriptan and 30-fold for sumatriptan) or saphenous vein (66- and 25-fold). The efficacy of eletriptan and sumatriptan was similar within tissues. The predicted contraction by eletriptan (40 mg and 80 mg) and sumatriptan (100 mg) at free C(max) observed in clinical trials was similar in meningeal artery, whereas in coronary artery and saphenous vein it was lower for 40 mg eletriptan than for sumatriptan. CONCLUSIONS: At therapeutic concentrations both eletriptan and sumatriptan contract middle meningeal artery more than coronary artery. This suggests that in patients with healthy coronary arteries, they have a limited propensity to cause adverse coronary side effects. However, both drugs remain contraindicated in patients with coronary artery disease.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11094108&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Sumatriptan elicits both constriction and dilation in human and bovine brain intracortical arterioles.

Elhusseiny A, Hamel E.

Laboratory of Cerebrovascular Research, Montreal Neurological Institute, 3801 University Street, McGill University, Montreal, QC, Canada H3A 2B4.

1. Little is known about serotonin (5-HT) receptors present on brain microvessels that are innervated by brainstem serotonergic neurons. Using 5-HT, sumatriptan and subtype selective 5-HT(1) receptor agonists and/or the 5-HT(1) receptor antagonist GR127935, we characterized the 5-HT receptors involved in regulating microvascular tone of pressurized intracortical arterioles (approximately 40--50 microm) isolated from human and bovine cerebral cortex. The role of nitric oxide (NO) on these responses was assessed with the N(omega)-nitro-L-arginine (L-NNA, 10(-5) M), an inhibitor of NO synthesis. Bovine pial arteries were studied for comparative purposes. 2. At spontaneous tone, 5-HT induced a dose-dependent constriction of human and bovine microarteries (respective pD(2) values of 7.3+/-0.2 and 6.9+/-0.1); a response potently inhibited by GR127935 (pIC(50) value of 8.5+/-0.1) in bovine microvessels. 3. In both species, the 5-HT(1) receptor agonist sumatriptan induced a biphasic response consisting of a small but significant dilation at low concentrations (1 and/or 10 nM) followed by a constriction at higher doses (pD(2) for contraction of 6.9+/-0.1 and 6.6+/-0.2 in human and bovine vessels, respectively). Pre-incubation with L-NNA abolished the sumatriptan-induced dilation and significantly shifted the dose-response of the constriction curve to the left. In contrast, the selective 5-HT(1D) (PNU-109291) and 5-HT(1F) (LY344864) receptor agonists were devoid of any vasomotor effect. 4. In bovine pial vessels, 5-HT and sumatriptan elicited potent constrictions (respective pD(2) of 7.2+/-0.1 and 6.6+/-0.1), a weak dilation being occasionally observed at low sumatriptan concentrations. 5. A significant negative correlation was observed between pial and intracortical vessels diameter and the extent of the dilatory response to 10(-9) M sumatriptan. Together, these results indicate that sumatriptan, most likely via activation of distinctly localized microvascular 5-HT(1B) receptors, can induce a constriction and/or a dilation which is sensitive to inhibition of NO synthesis and dependent on the size and, possibly, the existing tone of the vessels.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11156561&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Inhibition of inflammation-induced thermal hypersensitivity by sumatriptan through activation of 5-HT(1B/1D) receptors.

Bingham S, Davey PT, Sammons M, Raval P, Overend P, Parsons AA.

Neuroscience Research, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park-North, Third Avenue, Harlow, Essex, England, CM19 5AW, United Kingdom.

Migraine is effectively treated by drugs acting via 5-HT(1B/1D) receptors; however, the antinociceptive effects of such agents have not been fully investigated, particularly in models in which sensitization may be present. The aim of these studies was to evaluate the effects of the 5-HT(1B/1D) receptor agonist sumatriptan in specific models of pain states: a mouse model of inflammation-induced thermal hyperalgesia and a rat model of nerve injury-induced thermal hyperalgesia. In female mice, following intraplantar injection of carrageenan 225 min earlier, sumatriptan (300 microg/kg intraperitoneally; i.p.) increased paw withdrawal latency (PWL) from 3.1 +/- 0.4 s in the saline group to 5.6 +/- 0.9 s, measured 240 min postcarrageenan (P < 0.05 ANOVA followed by post hoc Dunnett's test). A similar effect was seen in male mice. Sumatriptan was also effective in male mice when given i.p. and subcutaneously 15 min precarrageenan, with a maximum effect at 30 microg/kg (i.p. latency 7.4 +/- 1.3 s compared to saline group, 2.6 +/- 0.7 s; i.v. latency 5.9 +/- 0.8 s compared to saline group, 2.9 +/- 0.3 s; P < 0.05 ANOVA followed by post hoc Dunnett's test). The number of mice required to give a response that could be reliably attributed to sumatriptan (number needed to treat) was calculated using discriminant analysis and found to be 2.6. The ability of sumatriptan to attenuate the carrageenan-induced reduction in PWL was blocked by the mixed 5-HT(1B/1D) receptor antagonist GR-127935 (3 mg/kg i.p.) but not by the 5-HT(1B) receptor antagonist SB-224289 (10 mg/kg i.p.). Sumatriptan had no effect on thermal hyperalgesia induced by sciatic nerve ligation in the rat at any time point. These data demonstrate that sumatriptan attenuates the hypersensitivity to noxious thermal stimuli induced by intraplantar carrageenan.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11161594&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Cortical spreading depression produces increased cGMP levels in cortex and brain stem that is inhibited by tonabersat (SB-220453) but not sumatriptan.

Read SJ, Hirst WD, Upton N, Parsons AA.

Neuroscience Research, SmithKline Beecham Pharmaceuticals, Third Avenue, Harlow, CM19 5AW, Essex, UK. simon_read sbphrd.com

Migraine headache is proposed to be mediated by nitric oxide (NO). Suitable mechanisms for eliciting increases in brain NO concentration in migraineurs have not yet been identified, although, animal models highlight cortical spreading depression (CSD) as a potential candidate. These studies have focused on CSD-associated NO release at highly acute time points (min-hours) and have not employed markers of NO metabolism with direct clinical application e.g. cGMP. The current study evaluated changes in plasma cGMP concentrations 3 h, 24 h and 3 days post-CSD and compared these to cortical and brainstem cGMP concentrations at 3 days. Moreover, this study also examined the effect of sumatriptan, a clinically effective antimigraine agent, and tonabersat (SB-220453) a potential novel antimigraine agent, on any observed changes in cGMP. Following pre-treatment with vehicle (n=3), sumatriptan (300 microg kg(-1) i.v, n=3) or tonabersat (SB-220453 10 mg kg(-1) i.p., n=3), CSD was evoked in anaesthetised rats by a 6-min KCl application to the parietal cortex. In the vehicle-treated group a median of eight depolarisations, were observed. Sumatriptan had no effect on the number of depolarisations, whereas tonabersat significantly reduced the number of events (median=2). No depolarisation events were observed throughout the recording period in the sham group. Following KCl application plasma cGMP concentrations were reduced up to 24 h post-CSD, but not significantly different from sham animals at 3 days. CSD in vehicle-treated animals produced a highly significant elevation in cGMP concentration in the brain stem 3 days after application of KCl. cGMP concentration increased 2.3-fold from 68+/-8 fmol/mg in sham animals (n=3) to 158+/-28 fmol/mg in the vehicle group. This increase in brain stem cGMP was abolished by tonabersat pre-treatment but not by sumatriptan.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11164810&dopt=Abstract sumatriptan Imitrex