sumatriptan, Imitrex
Effects of dihydroergotamine and sumatriptan on isolated human cerebral and peripheral arteries and veins.

Nilsson F, Nilsson T, Edvinsson L, Bjorkman S, Nordstrom CH.

Department of Anaesthesia and Intensive Care, and Experimental Research, Malmo University Hospital, Sweden.

BACKGROUND: Pharmacological cerebral vasoconstriction has recently been suggested as treatment for patients with increased intracranial pressure (ICP) after severe traumatic brain lesions. Hypothetically, a moderate constriction of precapillary resistance vessels might be advantageous since it decreases intracapillary blood pressure, and a contraction of cerebral veins might effectively reduce intracranial blood volume and ICP. This report examines the in vitro effects of two vasoconstrictors, dihydroergotamine (DHE) and sumatriptan, which may be considered for treatment of increased ICP. METHODS: The reactivity of isolated small human cerebral subcutaneous and omental arteries and veins were studied during exposure to different concentrations of DHE and sumatriptan. RESULTS: Both sumatriptan and DHE induced concentration-dependent contractions in human cerebral arteries and veins and 50% of maximum contractions were obtained at significantly lower concentrations of DHE than of sumatriptan. The maximum contraction of cerebral arteries was significantly higher with sumatriptan than with DHE. Both drugs caused contractions of subcutaneous arteries at concentrations of 10(-7)-10(-6)M, which is within the therapeutic concentration range of sumatriptan, while no effect was obtained in omental vessels. CONCLUSIONS: Both DHE and sumatriptan cause contraction of isolated human cortical arteries and veins at very low concentrations. The differences observed between the two drugs may be explained by the fact that DHE is an alpha-adrenergic as well as a 5-HT agonist while sumatriptan acts specifically on 5-HT receptors. The study supports the hypothesis underlying the use of DHE for the treatment of increased ICP in patients with severe traumatic brain lesions.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9422289&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Using pretreatment quality of life perceptions to predict response to sumatriptan in migraineurs.

Litaker DG, Solomon GD, Genzen JR.

Program for Health Economics and Outcomes Research, Cleveland Clinic Foundation 44195, USA.

Quality of life perceptions vary for individuals with similar medical conditions and reflect disease impact. When correlated with subsequent response to treatment, such data may contribute useful insights in understanding the determinants of therapeutic effectiveness in selected medical conditions. Two hundred thirty-five migraine patients never previously treated with injectable sumatriptan completed a Short Form-36 questionnaire before receiving a supervised test dose and a prescription for the medication. Medical records were examined to determine the number of comorbid conditions, headache characteristics (age at onset, headache frequency, duration of disease, aura, association with menses, unilaterality, and emesis), and documentation of sumatriptan's effect in relieving migraine during 12 months of follow-up. Logistic regression was used to identify patient- and disease-specific features most closely associated with the dependent variable, clinical response. One hundred eighty-four patients (78%) reported both relief of symptoms and continued usage of sumatriptan. Patients who experienced emesis with headaches (OR = 2.05 [1.07, 3.91]) and those with higher pretreatment Physical Functioning scores (OR = 3.27 [1.28, 8.37]) were more likely to respond to sumatriptan. Response to sumatriptan therapy was associated with specific pretreatment quality of life domains and headache features. These results may be useful in improving the efficiency of disease management strategies for patients with migraine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9439083&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Sumatriptan and cerebral blood flow velocity changes during migraine attacks.

Totaro R, De Matteis G, Marini C, Baldassarre M, Carolei A.

Department of Internal Medicine and Public Health, University of L'Aquila, Collemaggio, Italy.

Transcranial Doppler studies on the effects of sumatriptan on cerebral hemodynamics have shown conflicting results. We evaluated blood flow velocity changes in 21 patients suffering from migraine with (n = 4) or without aura (n = 17) during a spontaneous attack, before and after treatment with sumatriptan. Flow velocity in the internal and external carotid, middle cerebral, and basilar arteries was measured by means of transcranial Doppler. During the attack, measurements were taken before subcutaneous sumatriptan injection, then after 30 minutes, 2 hours, and 24 hours. An additional measurement was taken 1 week later, in a headache-free state. We found a significant reduction of flow velocity during the attack in the middle cerebral artery on both sides (P < 0.05). After sumatriptan administration, flow velocity increased in the internal carotid artery on both sides (P < 0.05) and in the middle cerebral artery on the headache side (P = 0.0001), but not in the external carotid and basilar arteries (P > 0.05). Flow velocity changes may reflect the vasodilation present at the onset of the migraine attack followed by vasoconstriction in the internal carotid and middle cerebral arteries after sumatriptan treatment. Since vasoconstriction occurs in responders and nonresponders to treatment, it is unlikely to be the primary mechanism by which sumatriptan relieves headache.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9439084&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Pharmacological analysis of the haemodynamic effects of 5-HT1B/D receptor agonists in the normotensive rat.

Pagniez F, Valentin JP, Vieu S, Colpaert FC, John GW.

Centre de Recherche Pierre Fabre, Division of Cardiovascular Diseases, Castres, France.

1 The receptors involved in mediating the haemodynamic effects of three 5-HT1B/D receptor agonists were investigated in pentobarbitone anaesthetized rats (n = 6-17 per group). 2 Cumulative intravenous (i.v.) infusions of rizatriptan and sumatriptan (from 0.63 to 2500 microg kg(-1); each dose over 5 min) induced dose-dependent and marked hypotension (-42+/-6 and -34+/-4 mmHg at the highest dose, respectively; both P<0.05 vs vehicle: +5+/-3 mmHg) and bradycardia (-85+/-16 and -44+/-12 beats min(-1) at the highest dose, respectively; both P<0.05 vs vehicle: +16+/-6 beats min(-1)). Zolmitriptan evoked only moderate hypotension at the highest dose (-19+/-9 mmHg; P<0.05 vs vehicle). 3 A high dose of the 5-HT1B/D receptor antagonist, GR 127935 (0.63 mg kg(-1), i.v.), failed to antagonize the hypotension and bradycardia evoked by sumatriptan (-35+/-6 mmHg and -52+/-19 beats min(-1), respectively; both not significant vs sumatriptan in untreated rats), but moderately reduced the hypotension and bradycardia evoked by rizatriptan (-20+/-5 mmHg and -30+/-17 beats min(-1), respectively; both P<0.05 vs vehicle and vs rizatriptan in untreated rats). 4 The selective 5-HT1A receptor antagonist, WAY 100635 (0.16 and 0.63 mg kg(-1), i.v.), dose-dependently attenuated the haemodynamic responses evoked by rizatriptan and sumatriptan, which were almost abolished by the higher dose of WAY 100635 (-4+/-3 mmHg and -15+/-8 beats min(-1); both not significant vs vehicle and P<0.05 vs rizatriptan in untreated rats). A slight but statistically significant reduction in mean arterial pressure (MAP) persisted at the highest dose of sumatriptan (-13+/-4 mmHg following the higher dose of WAY 100635; P<0.05 vs vehicle). 5 In pithed rats with MAP normalized by angiotensin II, rizatriptan failed to induce hypotension or bradycardia (+5+/-4 mmHg and -6+/-16 beats min(-1), respectively; both NS vs vehicle and P<0.05 vs rizatriptan in untreated rats). Similarly, sumatriptan failed to induce bradycardia in pithed rats (+5+/-6 beats min(-1); not significant vs vehicle and P<0.05 vs sumatriptan in untreated rats), whereas a slight but statistically significant reduction in MAP, compared to controls, occurred at the highest dose (-9+/-9 mmHg; P<0.05 vs both vehicle and sumatriptan in untreated rats). 6 In bilaterally vagotomized and atropine-treated (1 mg kg(-1), i.v.) rats, the reductions in MAP and heart rate evoked by rizatriptan (-31+/-4 mmHg and -64+/-9 beats min(-1), respectively; both P<0.05 vs vehicle and not significant vs rizatriptan in controls) and sumatriptan (-47+/-8 mmHg and -56+/-10 beats min(-1), respectively; both P<0.05 vs vehicle and not significant vs sumatriptan in controls) were not statistically significantly different from those observed in controls. 7 In conclusion, the 5-HT1B/D receptor agonists, rizatriptan and sumatriptan, elicit hypotension and bradycardia in the normotensive anaesthetized rat predominantly via activation of central 5-HT1A receptors, and a consequent reduction in sympathetic outflow.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9489607&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Comparison of more and less lipophilic serotonin (5HT1B/1D) agonists in a model of trigeminovascular nociception in cat.

Hoskin KL, Goadsby PJ.

Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, United Kingdom.

The trigeminovascular system consists of bipolar neurons innervating pain-producing intracranial structures, such as the superior sagittal sinus (SSS), and projecting to the medullary and upper cervical dorsal horn second order neurons. Zolmitriptan is a newly developed 5HT1B/1D receptor agonist with both peripheral and central sites of action in the trigeminovascular system due to greater lipophilicity relative to the more hydrophilic antimigraine compound sumatriptan. Given that we have seen electrophysiological and autoradiographic binding data to suggest that the compound may inhibit activity at second-order neurons this study was designed to examine whether such an effect could be demonstrated in a population of trigeminal neurons using Fos immunohistochemistry. Cats were anesthetised with alpha-chloralose (60 mg/kg intraperitoneal then 20 mg/kg intravenous maintenance) with all surgery being conducted using halothane (1-3%). The animals were prepared for physiological monitoring, including blood pressure, heart rate, rectal temperature, and end-expiratory CO2. They were intubated, ventilated, and paralyzed with gallamine triethiodide (6 mg/kg i.v.). A midline craniotomy was performed to expose the sinus for electrical stimulation using hook electrodes. Twenty-four hours after completion of the surgical procedures the animal was ready for treatment. Vehicle, sumatriptan (85 micrograms/kg), or zolmitriptan (30 micrograms/kg) was administered and the SSS was stimulated (250 microseconds, 100 V at 0.3 Hz) for 1 h. Following an additional 1 h the animal was perfused and immunohistochemistry was used to detect the protein product of the immediate early gene c-Fos. We compared the dorsal horns of the medulla (trigeminal nucleus caudalis) and the C1 and C2 cervical spinal cords in control animals with those receiving zolmitriptan or sumatriptan. We noted a significant reduction in Fos expression after treatment with zolmitriptan but no effect with sumatriptan. Given that zolmitriptan accesses central neurons and that the method of stimulation we have employed would bypass peripheral trigeminal mechanisms it is likely that the reduction in second-order trigeminal neuronal activity was due to a direct inhibitory effect of the compound on those cells. These neurons form a possible site for the treatment of acute attacks of migraine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9514827&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Chronic paroxysmal hemicrania and hemicrania continua: lack of efficacy of sumatriptan.

Antonaci F, Pareja JA, Caminero AB, Sjaastad O.

University Centre for Adaptive Disorders and Headache (UCADH), Section of Pavia I, C. Mondino Foundation, Italy.

Attacks of chronic paroxysmal hemicrania are prevented by the continuous administration of indomethacin. Sumatriptan, an agonist of 5-HT1-like receptors, has proven effective in the treatment of cluster headache attacks. There are clear clinical similarities between chronic paroxysmal hemicrania and cluster headache. A natural consequence of these considerations would be to establish whether chronic paroxysmal hemicrania also responds similarly to sumatriptan. Since hemicrania continua is another unilateral headache responsive to indomethacin, it would be meaningful to also include hemicrania continua in such a study. Sumatriptan, 6 mg subcutaneous, was tried in an open fashion in 7 patients (6 women and 1 man) with chronic paroxysmal hemicrania and 7 patients (5 women and 2 men) with hemicrania continua. In chronic paroxysmal hemicrania, the mean interval between the last three attacks prior to sumatriptan treatment (40 +/- 23 minutes) was not statistically different from the mean interval between the three attacks subsequent to sumatriptan treatment of an attack (32 +/- 20 minutes). In none of the patients did the mean duration of the "test attack" decrease as compared to the attacks antedating the test attack (25 +/- 11 minutes and 19 +/- 9 minutes, respectively) (P = 0.027, Wilcoxon). In 2 patients with chronic paroxysmal hemicrania, placebo (saline) administration did not lead to any change in the interval between attacks. There was a mild, but statistically significant reduction in visual analog scale values for headache intensity in hemicrania continua (P = 0.04, Wilcoxon). There was no clear, i.e., clinically meaningful, reduction in visual analog scale values in any particular patient with hemicrania continua. Taken together, these results seem to show that sumatriptan is of no benefit in chronic paroxysmal hemicrania, but may have a partial efficacy in hemicrania continua. However, the latter effect is clinically unimportant. This minor difference in regard to the clinical effect may, nevertheless, be of some interest pathogenetically, indicating minor differences between the two headaches. The lack of sumatriptan effect in chronic paroxysmal hemicrania clearly and markedly strengthens the nonalignment concept in regard to chronic paroxysmal hemicrania and cluster headache.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9563210&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Contractile responses evoked by dihydroergotamine, naratriptan and sumatriptan in the canine isolated coronary artery.

Valentin JP, Bonnafous R, John GW.

Centre de Recherche Pierre Fabre, Division of Cardiovascular Diseases, Castres, France.

Contractile responses evoked by the 5-HT IB/D receptor agonists, dihydroergotamine, naratriptan and sumatriptan, were compared in canine isolated coronary artery rings before and after endothelial dysfunction as obtained by inhibition of nitric oxide synthase with Nw-nitro-L-arginine methyl ester (L-NAME; 10 microM). The three agonists contracted rings in the potency order of dihydroergotamine (geometric mean pD2 value with 95% confidence limits in parentheses: 6.9 [5.3-7.9] and 7.0 [5.4-7.3] in the absence and presence of nitric oxide synthase (NOS) inhibition [I], respectively) > or = naratriptan (6.8 [5.7-7.3] and 6.4 [5.7-6.6]) > sumatriptan (4.8 [3.6-5.6] and 5.0 [3.6-5.6]) independently of the presence or absence of L-NAME. In absence of L-NAME, efficacy, as assessed by the mean maximal contractile response (Emax), tended to be greater, although not significantly, for sumatriptan and naratriptan compared to dihydroergotamine. L-NAME per se markedly increased developed tension (43.0 +/- 4.6 mN; n = 50) and potentiated maximal responses (0.6 +/- 0.2 and 10.7 +/- 2.4 mN for dihydroergotamine in the absence and presence of L-NAME respectively; 1.7 +/- 0.6 and 18.7 +/- 3.7 mN for naratriptan; 2.5 +/- 0.6 and 21.3 +/- 3.8 mN for sumatriptan; P < 0.01 in each case). Emax values of sumatriptan and naratriptan were greater than those produced by dihydroergotamine in the presence of L-NAME but remained lower than the sub-maximal contractile responses evoked by the thromboxane A2 analogue, U-46619 (ie, 32.4 +/- 5.2 mN in the absence of L-NAME; n = 50), or L-NAME per se. In conclusion, 5-HT IB/D receptor agonist efficacies in contracting coronary arteries are relatively low under basal conditions and are potentiated in the presence of a dysfunctional endothelium, whereas agonist potencies remain unaffected.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9565768&dopt=Abstract sumatriptan Imitrex