sumatriptan, Imitrex
Investigation of the effects of naratriptan, rizatriptan, and sumatriptan on jugular venous oxygen saturation in anesthetized pigs: implications for their mechanism of acute antimigraine action.

Letienne R, Verscheure Y, John GW.

Centre de Recherche Pierre Fabre, Castres, France.

The effects of naratriptan, rizatriptan, and sumatriptan on arteriovenous oxygen saturation difference and carotid hemodynamics were compared in the anesthetized pig. Oxygen and carbon dioxide partial pressures in systemic arterial and jugular venous blood as well as hemoglobin oxygen saturation were determined by conventional blood gas analysis. Vehicle (n = 19) or naratriptan, rizatriptan, or sumatriptan (0.63, 2.5, 10, 40, 160, 630, and 2,500 microg/kg i.v.; n = 7/group) were infused cumulatively. In naratriptan-, rizatriptan-, and sumatriptan-treated animals, jugular venous oxygen saturation decreased dose dependently (geometric mean ED50 values of 3.1, 17.9, and 16.0 microg/kg, respectively) concomitantly with increases in carotid vascular resistance. Rizatriptan significantly and dose dependently, from 160 microg/kg, increased PvCO2 (P < 0.05 versus vehicle). Naratriptan and sumatriptan also tended to increase PvCO2 albeit nonstatistically significantly. All three triptans consistently evoked quantitatively similar carotid vasoconstriction, whereas decreases in jugular venous oxygen saturation (VOS) and increases in PvCO2 had different magnitudes and occurred only in around one-half of the animals studied. Maximal variations in PvCO2 were found to correlate highly with those in PvO2 (P = 0.002), but maximal variations in carotid resistance failed to correlate with those in PvCO2 (P = 0.76) or PvO2 (P = 0.28). The results demonstrate that the triptans investigated robustly produced carotid vasoconstriction, but elicited less consistent decreases in VOS and increases in jugular PvCO2, possibly suggestive of distinct mechanisms. Collectively, the data suggest that triptan-induced increases in arteriovenous oxygen saturation difference and carbon dioxide partial pressure in venous blood draining the head are class effects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12954804&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Reduction in the intensity of abortive migraine drug use during coumarin therapy.

Rahimtoola H, Egberts AC, Buurma H, Tijssen CC, Leufkens HG.

Department of Pharmacy Practice Research, SIR Institute, Leiden, The Netherlands.

OBJECTIVE: To investigate the impact of coumarin therapy on migraine attack frequency. BACKGROUND: Sporadic case reports and clinical studies have described beneficial effects of coumarin therapy on migraine severity. Design and METHODS: A retrospective follow-up study based on a prescription database covering a population of 450 000 was conducted. All patients using an abortive migraine drug (ergotamine or sumatriptan) and subsequently treated with either coumarin (index group) or low-dose acetylsalicylic acid (control group) were analyzed. The impact of coumarin and low-dose acetylsalicylic acid on the frequency of migraine attacks was assessed by measuring the intensity of ergotamine and sumatriptan use, in defined daily doses per month per patient, before and during coumarin or acetylsalicylic acid treatment. In addition, a "therapeutic intensity reduction" was determined for each patient. RESULTS: The study population consisted of 92 patients; 35% had been prescribed coumarin and 65% had been prescribed low-dose acetylsalicylic acid after the initiation of ergotamine or sumatriptan. Two thirds of the study population was treated with ergotamine. Overall, ergotamine and sumatriptan use for the coumarin cohort decreased from 6.4 defined daily doses per month prior to coumarin treatment to 3.0 defined daily doses during coumarin treatment, compared with a reduction from 5.2 defined daily doses per month to 4.4 defined daily doses per month for the low-dose acetylsalicylic acid cohort (P>.05). The therapeutic intensity of ergotamine and sumatriptan use was significantly decreased by 40% for the coumarin cohort, compared with 4.7% for the low-dose acetylsalicylic acid cohort (P=.004). CONCLUSIONS: We observed that coumarin treatment was clearly associated with a reduction in the therapeutic intensity of abortive migraine drug use in comparison with low-dose aspirin treatment. This suggests that, overall, the coumarin cohort had experienced a substantial reduction in the frequency of migraine attacks during anticoagulation treatment. Our findings, as well as those of others, justify a controlled clinical trial to further establish the effects of coumarin therapy on migraine severity and its possible role in the prophylactic management of patients suffering from migraine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11576200&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Further characterization of the 5-HT1 receptors mediating cardiac sympatho-inhibition in pithed rats: pharmacological correlation with the 5-HT1B and 5-HT1D subtypes.

Sanchez-Lopez A, Centurion D, Vazquez E, Arulmani U, Saxena PR, Villalon CM.

Departamento de Farmacobiologia, CINVESTAV-IPN, Czda. de los Tenorios 235, Col. Granjas-Coapa, Deleg. Tlalpan, C.P. 14330, Mexico D.F., Mexico.

Serotonin (5-hydroxytryptamine; 5-HT) is capable of inhibiting the tachycardic responses elicited by sympathetic stimulation, but not by exogenous noradrenaline, in pithed rats pre-treated with desipramine. More recently, it has been shown that this cardiac sympatho-inhibitory response to 5-HT, mediated by prejunctional 5-HT1 receptors as well as putative 5-ht5A/5B receptors, is mimicked dose-dependently by the agonists CP 93,129 (r5-HT1B), sumatriptan (5-HT1B/1D) and PNU-142633 (5-HT1D). This study analysed further the pharmacological profile of the above 5-HT1 receptors. Continuous i.v. infusions of CP 93,129, sumatriptan or PNU-142633 (30 micro g kg(-1)min(-1) each) failed to modify the tachycardic responses to exogenous noradrenaline but inhibited those elicited by preganglionic (C7-T1) stimulation of the cardiac sympathetic outflow. These sympatho-inhibitory responses were unaltered after i.v. administration of physiological saline (1 ml kg(-1)) or the 5-HT1A receptor antagonist WAY 100635 (10 micro g kg(-1)). In contrast, the antagonist GR 127935 (5-HT1B/1D; 100 micro g kg(-1), i.v.) abolished the responses to CP 93,129, sumatriptan and PNU-142633, whilst SB224289 (5-HT1B; 300 micro g kg(-1), i.v.) abolished the responses to CP 93,129 without affecting those to sumatriptan and PNU-142633. Interestingly, BRL15572 (5-HT1D; 300 micro g kg(-1), i.v.) abolished the responses to PNU-142633 and attenuated those to sumatriptan, but not those to CP 93,129.WAY 100635, GR 127935, SB224289 and BRL15572, given alone at the above doses, failed to modify the sympathetically induced tachycardic responses. The 5-HT1 receptors producing cardiac sympatho-inhibition in pithed rats thus display the pharmacological profile of the 5-HT1B and 5-HT1D receptor subtypes.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14673512&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Parental satisfaction with sumatriptan nasal spray in childhood migraine.

Pakalnis A, Kring D, Paolicchi J.

Department of Neurology, Ohio State University College of Medicine, Columbus, OH, USA. pakalnisa pediatrics.ohio-state.edu

Migraine headaches are a frequently encountered neurologic problem in children. The utility of the triptans has not been as clearly documented in this population, although it is well delineated in acute migraine attacks in adults. We conducted a retrospective chart review of our experience with using sumatriptan nasal spray in children aged 5 to 12 years from our headache clinic population with migraine headaches. The nasal spray formulation is used frequently in our clinic population with patients who have failed over-the-counter therapy with ibuprofen or acetaminophen. None of the triptans are approved by the US Food and Drug Administration for use in children or adolescents (12 years and older). One hundred of these patients were identified, and their parents or guardians completed a standardized questionnaire regarding their child's response to sumatriptan nasal spray in acute migraine. Fifty-seven of 100 families completed the questionnaire, and 44 of 57 families (77%) reported good to excellent relief of their child's migraine attacks with sumatriptan nasal spray. In our cohort of pediatric patients, sumatriptan nasal spray was effective and well tolerated when used for abortive therapy of acute migraine attacks.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14696905&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Analgesic triptan action in an animal model of intracranial pain: a race against the development of central sensitization.

Burstein R, Jakubowski M.

Departments of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center, Boston, MA, USA. rburstei caregroup.harvard.edu

We have shown that the development of cutaneous allodynia (exaggerated skin sensitivity) during migraine is detrimental to the anti-migraine action of the 5HT(IB/ID) receptor agonists known is triptans. Because cutaneous allodynia is a manifestation of sensitization of central trigeminovascular neurons, we examined whether triptan treatment can intercept such sensitization before its initiation or after its establishment in our rat model for cutaneous allodynia induced by intracranial pain. Single-unit recordings were obtained from spinal trigeminal neurons that proved to received convergent inputs from the dura and facial skin. The effects of sumatriptan (300 microg/kg i.v.) on central sensitization induced by topical application of inflammatory soup (IS) on the dura were determined when the drug was administered either 2 h after IS (late intervention) or at the same time as IS (early intervention). Late sumatriptan intervention counteracted two aspects of central sensitization: dural receptive fields, which initially expanded by IS, shrunk back after treatment; neuronal response threshold to dural indentation, which initially decreased after IS, increased after sumatriptan. On the other hand, late sumatriptan intervention did not reverse other aspects of central sensitization: spontaneous firing rate and neuronal response magnitude to skin brushing which initially increased after IS, remained elevated after sumatriptan; response threshold to heating of the skin, which initially dropped after IS, remained low after sumatriptan. Early sumatriptan intervention effectively blocked the development of all aspects of central sensitization expected to be induced 2 h after IS application: dural receptive fields did not expand; neuronal response threshold to dural indentation and skin stimulation did not decrease; spontaneous firing rate did not increase. The early treatment results suggest that triptan action provides a powerful means of preventing the initiation of central sensitization triggered by chemical stimulation of meningeal nociceptors. The late treatment results suggest that triptan action is insufficient to counteract an already established central sensitization. Thus, triptan action appears to be exerted directly on peripheral rather than central trigeminovascular neurons.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14705109&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
5-Hydroxytryptamine1B receptor-mediated contraction of rabbit saphenous vein and basilar artery: role of vascular endothelium.

Bhattacharya A, Schenck KW, Xu YC, Nisenbaum L, Galbreath E, Cohen ML.

Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, Indiana, USA. anindya.bhattacharya roche.com

This study characterizes the sumatriptan-sensitive [5-hydroxytryptamine (5-HT)(1B/1D)] receptor in rabbit saphenous vein and basilar artery. (S)-(-)-1-[2-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-ethyl]isochroman-6-carboxylic acid methylamide (PNU-109291), a 5-HT(1D) subtype-selective agonist (human K(i) = 2.5 +/- 0.07 nM), did not contract either tissue, whereas o-methoxyphenylpiperazide derivative 4F (MPPA-4F), a 5-HT(1B) subtype-selective antagonist (human K(i) = 4.6 +/- 0.6 nM) potently inhibited sumatriptan-induced contraction in the saphenous vein and basilar artery. These results suggested that sumatriptan-induced contraction was mediated via the 5-HT(1B) receptor in these blood vessels. 5-HT(1B) receptor-mediated contraction was then compared in endothelium-intact and denuded vessels to evaluate the role of the endothelium in regulating sumatriptan-induced contractility in these tissues. The presence of an intact endothelium inhibited 5-HT(1B)-induced contraction in both tissues. Endothelial denudation or nitric-oxide synthase inhibition with N(omega) nitro-L-arginine methyl ester (L-NAME) (100 microM) increased the efficacy and potency of sumatriptan in the saphenous vein and basilar artery. Surprisingly, in endothelial-denuded vascular tissues, L-NAME (100 microM) also significantly increased the maximal 5-HT(1B) receptor-induced contraction in both tissues, with no effect on potency of sumatriptan. The effect of L-NAME after endothelial denudation may reflect the presence of a low density of residual endothelial cells as estimated by CD31 antibody staining combined with the modulating effect of nitric oxide released from nonendothelial cells in vascular tissue. Endothelial modulation was specific to 5-HT(1B) receptors because removal of the endothelium did not significantly alter contraction to norepinephrine, histamine, prostaglandin, or potassium chloride in the saphenous vein or basilar artery.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14724223&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
The 40-mg dose of eletriptan: comparative efficacy and tolerability versus sumatriptan 100 mg.

Diener HC, Ryan R, Sun W, Hettiarachchi J.

Department of Neurology, University of Essen, Essen, Germany. h.diener uni-essen.de

Meta-analysis provides valuable information regarding relative efficacies of triptans, but head-to-head comparator studies remain the gold standard. Three similar head-to-head trials comparing eletriptan 40 mg (E40) with sumatriptan 100 mg (S100) provide a rare opportunity and sufficient power, for robust comparisons of efficacy. Data were combined from three double-blind, placebo-controlled, first-dose, first-attack acute migraine treatment studies comparing E40 (n=1132), S100 (n=1129), and placebo (n=645). The primary outcome was headache response at 2 h. Secondary outcomes included headache response at 1 h, pain-free and functional responses, and sustained headache and pain-free responses. Odds ratios were calculated for summary estimates of probability of response. There were higher headache response rates with eletriptan versus sumatriptan at 2 h (67% vs. 57%; P<0.0001) and 1 h (34% vs. 26%; P<0.0001). Eletriptan also had higher 2 h pain-free (35% vs. 25%; P<0.0001) and functional responses (67% vs. 58%; P<0.0001). Sustained headache (42%) and pain-free (22%) response rates were higher for eletriptan versus sumatriptan (34%, P<0.0001; 15%, P<0.0001). The probability of response for eletriptan versus sumatriptan ranged from 36% higher (relief of nausea) to 64% higher (sustained pain-free rate). Combined analysis demonstrates that E40 has superior efficacy versus S100 across all clinically relevant outcomes.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14748774&dopt=Abstract sumatriptan Imitrex