sumatriptan, Imitrex
Restoring migraine sufferers' ability to function normally: a comparison of rizatriptan and other triptans in randomized trials.

Bussone G, D'Amico D, McCarroll KA, Gerth W, Lines CR.

National Neurological Institute C. Besta, Milan, Italy.

BACKGROUND: Many migraine patients are unable to function normally during a migraine attack. Assessments of treatment efficacy have tended to focus on migraine symptoms, rather than looking at functional impact. This study compared the efficacy of different oral triptans for restoring normal function in migraine sufferers. METHODS: Retrospective subgroup analysis of data from five randomized, placebo-controlled, double-blind clinical trials in which oral rizatriptan was directly compared with oral sumatriptan 100 mg (772 attacks), 50 mg (2,227 attacks), and 25 mg (1,182 attacks), naratriptan 2.5 mg (413 attacks), and zolmitriptan 2.5 mg (578 attacks) for the acute treatment of a moderate or severe migraine attack. Functional disability was evaluated by patients on a 4-grade scale ('normal', 'mild impairment', 'severe impairment', 'requires bedrest') at baseline and at 0.5, 1, 1.5, 2, 3 and 4 h after dosing. This analysis looked at the percentage of patients who had normal functional ability at 2 h, the last time point before escape medications were allowed, in the subgroup of patients who had some level of disability at baseline. RESULTS: Most patients in each trial and treatment group had some level of disability at baseline (range = 94-100%). At 2 h, more patients on rizatriptan 10 mg were able to function normally compared with sumatriptan 100 mg (39 vs. 32%, odds ratio = 1.4, p = 0.021), sumatriptan 50 mg (47 vs. 42%, odds ratio = 1.2, p = 0.033), sumatriptan 25 mg (48 vs. 36%, odds ratio = 1.7, p < 0.001), naratriptan 2.5 mg (39 vs. 22%, odds ratio = 2.5, p < 0.001), and zolmitriptan 2.5 mg (45 vs. 36%, odds ratio = 1.6, p = 0.008). CONCLUSION: In direct head-to-head comparative clinical trials, oral rizatriptan 10 mg enabled more migraine sufferers to function normally at 2 h after dosing than oral sumatriptan, naratriptan, and zolmitriptan. Copyright 2002 S. Karger AG, Basel

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12373035&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Sumatriptan scavenges superoxide, hydroxyl, and nitric oxide radicals: in vitro electron spin resonance study.

Ikeda Y, Jimbo H, Shimazu M, Satoh K.

Department of Neurosurgery, Showa University School of Medicine, Tokyo, Japan.

BACKGROUND: The molecular mechanisms of migraine have not yet been clarified. Oxygen free radicals have been implicated in the genesis of many pathological processes, including migraine. Sumatriptan succinate is known to be a very effective drug for acute relief of migraine attack. OBJECTIVE: To investigate the direct scavenging activities of sumatriptan for superoxide, hydroxyl, and nitric oxide (NO) radicals using electron spin resonance (ESR) spectroscopy. METHODS: Measurement of superoxide and hydroxyl radical scavenging activities was performed by ESR using 5,5-dimethyl-1-pyrroline-N-oxide as a spin trap. NO was generated from 1-hydroxy-2-oxo-3-(N-3-methyl-3-aminopropyl)-3-methyl-1-triazene and analyzed by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl produced from the reaction between 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide and NO. RESULTS: The ESR study demonstrated that sumatriptan scavenged superoxide, hydroxyl, and NO in a dose-dependent manner. CONCLUSIONS: Sumatriptan has direct scavenging activity on free radicals and NO. Acute migraine drugs with antioxidant properties may provide heretofore unheralded benefits via this mechanism.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12390615&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Decreased sensitivity of 5-HT1D receptors in chronic tension-type headache.

Rainero I, Valfre W, Savi L, Ferrero M, Del Rizzo P, Limone P, Isaia GC, Gianotti L, Pollo A, Verde R, Benedetti F, Pinessi L.

Neurology III-Headache Center, Department of Neuroscience, University of Turin, Italy.

OBJECTIVE: To assess the sensitivity of 5-HT1D receptors in chronic tension-type headache using sumatriptan as a pharmacological probe. BACKGROUND: Previous studies have suggested involvement of serotonergic systems in chronic tension-type headache (CTTH), but relevant experimental data are limited. Sumatriptan, a 5-HT1B/1D receptor agonist, stimulates the release of growth hormone (GH) and inhibits the release of ACTH, cortisol, and prolactin. These effects may be used to explore the function of serotonergic systems in vivo. METHODS: We measured GH, ACTH, cortisol and prolactin (PRL) plasma concentrations in 15 patients with chronic tension-type headache and in 18 healthy controls after subcutaneous administration of sumatriptan (6 mg) or placebo. RESULTS: Placebo administration had no effect on hormone concentrations. GH and PRL secretion after sumatriptan administration was significantly (P<0.01 and <0.05) altered in CTTH patients in comparison with controls. CONCLUSION: Our results suggest that cerebral serotonergic functions mediated by 5-HT1D receptors are altered in CTTH.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12390633&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Amplification of sumatriptan-induced contraction in rabbit saphenous vein but not in basilar artery.

Bhattacharya A, Schenck KW, Cohen ML.

Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.

The modulation of serotonin (5-HT(1B/1D)) receptor-induced vascular contractility by histamine and U-46619 was compared in the rabbit basilar artery and saphenous vein. In the saphenous vein, histamine (5 x 10(-7) M) significantly increased the potency (from pEC(50) of 6.0 to 6.8) and efficacy (from 52.3% to 88.2%) of sumatriptan. Likewise, U-46619 (5 x 10(-9) M) also increased the potency (from pEC(50) of 5.9 to 6.6) and efficacy (from 51.8% to 92.1%) of sumatriptan in the saphenous vein. In contrast, equieffective concentrations of histamine (10(-7) M) and U-46619 (3 x 10(-9) M) failed to amplify contraction to sumatriptan in the basilar artery. Contraction to sumatriptan was inhibited by nitrendipine (10(-7) M) in the basilar artery but not in the saphenous vein, suggesting that different contractile signaling mechanisms are operating in these tissues. Furthermore, U-46619- and thrombin-induced contractility in the basilar artery were also not amplified by histamine, suggesting that lack of amplification of contraction in the basilar artery was not restricted to sumatriptan but was rather a characteristic of this cerebral vessel. These data suggest that in the in vivo plasma milieu sumatriptan will more markedly contract the peripheral saphenous vein than the basilar artery, a cerebral blood vessel.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12424094&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Lack of sumatriptan-induced aortic contraction or relaxation: 5-HT1B receptor protein detected in endothelium and smooth muscle of vasa vasorum but not aorta.

Cohen ML, Galbreath EJ, Schenck KW, Li D, Hoffman BJ, Bhattacharya A.

Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. cohenml lilly.com

Since 5-HT1B receptor mRNA was reported in rat aorta, and 5-HT1B receptor activation has been linked to vascular contraction, we explored sumatriptan-induced contractility and immunohistochemical density of 5-HT1B receptor protein in rat aorta. Sumatriptan (up to 10(-4) M), a 5-HT1B/1D receptor agonist, did not contract the endothelial intact or denuded rat aorta, even in the presence of L-NAME or after induction of modest tone with PGF2 alpha (10(-6) M). Sumatriptan also did not relax aortic preparations precontract with PGF2 alpha (3 x 10(-6) M) or phenylephrine (3 x 10(-7) M). Using a polyclonal antibody directed against the 5-HT1B receptor, minimal 5-HT1B receptor protein was detected in either the endothelium or smooth muscle of the rat aorta. However, dense 5-HT1B receptor protein was found in the vascular smooth muscle of the vasa vasorum supplying the aorta. Thus, the 5-HT1B receptor mRNA detected in tissue extracts of the rat aorta most likely reflects 5-HT1B receptor expression in the arterioles of the vasa vasorum. These studies support the link between the 5-HT1B receptor and vascular contraction in that the aorta with low density of 5-HT1B receptors lacked responses to sumatriptan, an agonist thought to contract blood vessels via 5-HT1B/1D receptors. Furthermore, caution must be observed when using 5-HT1B receptor mRNA to suggest receptor protein in tissues since this RT-PCR product may be derived predominantly from small blood vessels.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12448788&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Costs and outcomes of early versus delayed migraine treatment with sumatriptan.

Halpern MT, Lipton RB, Cady RK, Kwong WJ, Marlo KO, Batenhorst AS.

Exponent Inc, Alexandria, VA 22314, USA. mhalpern exponent.com

OBJECTIVE: To evaluate the impact on costs and outcomes of early migraine treatment with sumatriptan while pain is mild versus sumatriptan treatment of moderate to severe pain. BACKGROUND: Migraines result in substantial pain, impairment, and costs. Recent clinical studies have shown that early treatment with sumatriptan when migraine pain is mild is more effective than sumatriptan treatment when pain is moderate to severe. DESIGN/METHODS: We developed a decision analytical model to assess the costs and outcomes per treated migraine attack, comparing early treatment while pain is mild versus delayed treatment when pain may become moderate/severe using 50 and 100 mg of sumatriptan. Parameters for the model were derived from published literature and analysis of migraine patient diary data. For each patient group the model determined the duration of mild and moderate/severe migraine pain, the proportion of patients pain free at 4 hours after initial therapy with no recurrence, medical care costs, and work loss costs (from migraine-related absenteeism and decreased productivity) during a 24-hour period. Total costs were calculated as the sum of medical care costs plus work loss costs. RESULTS: Early treatment with sumatriptan when migraine pain is mild resulted in substantially decreased total costs per treated attack as compared with treatment when pain is moderate/severe. Early treatment also resulted in decreased time with headache pain, an increased proportion of patients pain free at 4 hours without recurrence, and decreased physician and emergency department visits. Treatment with 100 mg sumatriptan resulted in better outcomes than did treatment with 50 mg sumatriptan, but outcomes with either dose for early treatment of mild pain were superior to those for either dose in delayed treatment when pain may be moderate/severe. CONCLUSIONS: Model-based results indicate that on a treated attack basis, early treatment of migraine with sumatriptan while pain is mild leads to decreased costs and improved outcomes compared to delayed sumatriptan treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12453030&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
The antimigraine 5-HT 1B/1D receptor agonists, sumatriptan, zolmitriptan and dihydroergotamine, attenuate pain-related behaviour in a rat model of trigeminal neuropathic pain.

Kayser V, Aubel B, Hamon M, Bourgoin S.

NeuroPsychoPharmacologie Moleculaire, Cellulaire et Fonctionnelle, INSERM U288, Faculte de Medecine Pitie-Salpetriere, 91 Boulevard de l'Hopital, 75634 Paris Cedex 13, France. kayser ext.jussieu.fr

1. Peripheral lesion to the trigeminal nerve may induce severe pain states. Several lines of evidence have suggested that the antimigraine effect of the triptans with 5-HT(1B/1D) receptor agonist properties may result from inhibition of nociceptive transmission in the spinal nucleus of the trigeminal nerve by these drugs. On this basis, we have assessed the potential antinociceptive effects of sumatriptan and zolmitriptan, compared to dihydroergotamine (DHE), in a rat model of trigeminal neuropathic pain. 2. Chronic constriction injury was produced by two loose ligatures of the infraorbital nerve on the right side. Responsiveness to von Frey filament stimulation of the vibrissal pad was used to evaluate allodynia. 3. Two weeks after ligatures, rats with a chronic constriction of the right infraorbital nerve displayed bilateral mechanical hyper-responsiveness to von Frey filament stimulation of the vibrissal pad with a mean threshold of 0.38+/-0.04 g on the injured side and of 0.43+/-0.04 g on the contralateral (left) side (versus > or =12.5 g on both sides in the same rats prior to nerve constriction injury). 4. Sumatriptan at a clinically relevant dose (100 microg kg(-1), s.c.) led to a significant reduction of the mechanical allodynia-like behaviour on both the injured and the contralateral sides (peak-effects 6.3+/-1.1 g and 4.4+/-0.7 g, respectively). A more pronounced effect was obtained with zolmitriptan (100 microg kg(-1), s.c.) (peak-effects: 7.4+/-0.9 g and 3.2+/-1.3 g) whereas DHE (50-100 microg kg(-1), i.v.) was less active (peak-effect approximately 1.5 g). 5. Subcutaneous pretreatment with the 5-HT(1B/1D) receptor antagonist, GR 127935 (3 mg kg(-1)), prevented the anti-allodynia-like effects of triptans and DHE. Pretreatment with the 5-HT(1A) receptor antagonist, WAY 100635 (2 mg kg(-1), s.c.), did not alter the effect of triptans but significantly enhanced that of DHE (peak effect 4.3+/-0.5 g). 6. In a rat model of peripheral neuropathic pain, which consisted of a unilateral loose constriction of the sciatic nerve, neither sumatriptan (50-300 microg kg(-1)) nor zolmitriptan (50-300 microg kg(-1)) modified the thresholds for paw withdrawal and vocalization in response to noxious mechanical stimulation. 7. These results support the rationale for exploring the clinical efficacy of brain penetrant 5-HT(1B/1D) receptor agonists as analgesics to reduce certain types of trigeminal neuropathic pain in humans.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12466238&dopt=Abstract sumatriptan Imitrex