sumatriptan, Imitrex
The central cholinergic system has a role in the antinociception induced in rodents and guinea pigs by the antimigraine drug sumatriptan.

Ghelardini C, Galeotti N, Figini M, Imperato A, Nicolodi M, Sicuteri F, Gessa GL, Bartolini A.

Department of Preclinical and Clinical Pharmacology, University of Florence, Italy.

The antinociceptive effect of the antimigraine drug sumatriptan was assessed in mice and rats (hot-plate, abdominal constriction and paw-pressure tests) and in guinea pigs (paw-pressure test). The ACh extracellular concentration also was detected in the hippocampus of freely moving rats by microdialysis experiments. Antinociception was induced by sumatriptan administered both parenterally (5-10 mg.kg-1 i.v.; 10-30 mg.kg-1 i.p.) and i.c.v. (50-100 micrograms per mouse). Sumatriptan antinociception was potentiated by physostigmine (0.05 mg.kg-1 i.p.) and was prevented by the muscarinic antagonist atropine (5 mg.kg-1 i.p.), the ACh depletor HC-3 (1 micrograms per mouse i.c.v.) and the 5-hydroxytryptamine1A antagonist 1-(2-methoxyphenyl)-4-[4-(2 phthalimido)butyl] piperazine (0.5 mg.kg-1 i.p.). Naloxone, 3-aminopropyl-diethoxy-methyl-phosphinc acid, 2-methoxy-4-amino-5-chlorobenzoic acid 2-(diethylamino) ethyl ester and reserpine, administered in doses suitable for blocking analgesi induced by morphine, baclofen, 5-hydroxytryptamine4 agonist and clomipramine, respectively, did not modify sumatriptan antinociception. Sumatriptan, administered in the range of antinociceptive doses, was able to increase the level of ACh present in extracellular hippocampal space. On the basis of these findings we can deduce that sumatriptan was able to induce antinociception by increasing cholinergic activation in the CNS. Such activation, as indicated by the antagonism exerted by 1-(2-methoxyl-phenyl)-4-[4-(2 pethalimido)butyl]piperazine, may depend on stimulation of 5-hydroxytryptamine1A autoreceptors. It remains to be clarified whether the antimigraine activity of sumatriptan in humans is totally dependent on cranial vessel vasoconstriction of whether its central cholinergic antinociception also plays a role.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8930196&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Sumatriptan can inhibit trigeminal afferents by an exclusively neural mechanism.

Hoskin KL, Kaube H, Goadsby PJ.

Institute of Neurology, National Hospital for Neurology and Neurosurgery, London, UK.

Mechanical distortion of the human cranial venous sinuses is painful as is cranial venous sinus distension during migraine. Sumatriptan, the serotonin (5HT)IB/D-like receptor agonist, is highly effective in relieving migraine headache and part of its action may be due to constriction of cranial dural blood vessels. Using immunohistochemical detection of the immediate early gene Fos, we have mapped the spatial pattern of neural activation in the caudal medulla and the upper cervical spinal cord (C1, C2 and C3) in cats following either electrical or mechanical stimulation of the superior sagittal sinus. Fourteen cats were anaesthetized with alpha-chloralose and prepared for physiological monitoring of blood pressure, heart rate, rectal temperature and expired CO2. Electrical stimulation evoked significant increases in the (median) numbers of Fos-positive cells in laminae I and IIo of the superficial dorsal horn of C1, C2 and C3 cervical spinal cord (88, 92 and 18 cells, respectively) and of the trigeminal nucleus caudalis (TNC) (81 cells). Mechanical stimulation revealed a similar pattern of neural activation but with reduced intensity in laminae I and IIo of the TNC (38 cells) and of C1 and C2 (32 and 31 cells, respectively). The temporalis muscle was stimulated mechanically in the control group and the numbers and distribution of Fos-positive cells were no different from those in non-stimulated controls. Treatment with sumatriptan reduced the numbers of Fos-positive cells found in laminae I and IIo of the TNC and C2 (6, 13 cells and 9 cells, respectively) after mechanical stimulation. These data suggest that the neural effect of sumatriptan alone is sufficient for significant attenuation of transmission in the trigeminal system. The fact that sumatriptan can inhibit trigeminal activation without its vascular effects suggests that drugs without a significant activity on blood vessels may be effective in the treatment of migraine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8931567&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Operational characteristics of the 5-HT1-like receptors mediating external carotid vasoconstriction in vagosympathectomized dogs. Close resemblance to the 5-HT1D receptor subtype.

Villalon CM, Sanchez-Lopez A, Centurion D.

Departamento de Farmacologia y Toxicologia, CINVESTAV, I.P.N., Mexico D.F., Mexico.

It has recently been shown that the external carotid vasoconstrictor response to 5-HT in the dog is primarily mediated by sumatriptan-sensitive 5-HT1-like receptors; however, the fact that these receptors are not blocked by metergoline, a 5-HT1D ligand, raises questions about their possible correlation with the 5-HT1D receptor subtype. Since a number of drugs display high affinity for the 5-HT1D (GR127935) and 5-HT1F (e.g. methysergide and oxymetazoline) receptor subtypes, in this study we have used these drugs to determine whether the above vasoconstrictor 5-HT1-like receptors correlate with the 5-HT1D and/or 5-HT1F receptor subtypes. One-minute intracarotid infusions of 5-HT (0.3-30 micrograms/min), sumatriptan (1-30 micrograms/min), oxymetazoline (0.03-3 micrograms/min) and noradrenaline (0.3-3 micrograms/min) resulted in dose-dependent decreases in external carotid blood flow without changes in arterial blood pressure or heart rate. These vasoconstrictor responses remained unaltered after i.v. administration of physiological saline (0.015, 0.05 and 0.15 ml/kg; n = 4) or ritanserin (1 mg/kg; n = 5). In contrast, GR127935 (1, 3 and 10 micrograms/kg, n = 6) potently blocked the responses to 5-HT (unmasking a dose-dependent vasodilator component) and sumatriptan without affecting those to oxymetazoline or noradrenaline. Interestingly, methysergide (10, 30 and 100 micrograms/kg, n = 5) also blocked the vasoconstrictor responses to 5-HT and sumatriptan, but unlike GR127935, did not revert the vasoconstrictor response to 5-HT; the responses to oxymetazoline remained unaffected, but those to noradrenaline were apparently attenuated by the highest dose. Taken together, the above findings suggest that the sumatriptan-sensitive 5-HT1-like receptors mediating canine external carotid vasoconstriction resemble 5-HT1D receptors, probably of the 5-HT1D beta subtype on the basis of the resistance to blockade by ritanserin. The pharmacological profile of these receptors could be similar (bovine and human cerebral arteries, porcine carotid arteriovenous anastomoses and human coronary arteries) to other putative 5-HT1D receptors mediating vascular responses.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8938651&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
The preclinical toxicological evaluation of sumatriptan.

Owen K, Hartley K, Tucker ML, Parkinson MM, Tweats DJ, Jackson MR.

Glaxo Research and Development Ltd, Park Road, Ware, Hertfordshire, UK.

1 Sumatriptan is a potent and selective 5-HT1 receptor agonist marketed for the treatment of migraine by both oral and subcutaneous routes. An extensive toxicological programme employing high doses of sumatriptan was carried out in a range of animal species. The studies evaluated both the local and systemic tolerance to single and repeated dosing, effects on all stages of reproduction, as well as the genotoxic and oncogenic potential of sumatriptan. 2 The administration of relatively high single and repeated doses of sumatriptan was well tolerated by both rodents and dogs by the oral, subcutaneous and intravenous routes. Behavioural effects, suggestive of involvement of the central nervous system, were the most obvious result of such doses and were generally more pronounced in dogs than rodents. The reason for this may be related to the higher plasma concentrations of the drug achievable in dogs. Additional observations restricted to dogs, were transient, and included tachycardia, facial oedema and breaks in the continuity of secretion films on the corneal surface. A tendency for an increase in weight gain was seen for rats, while a slight decrease was usually seen for dogs. The only pathological changes related to treatment with high concentrations of sumatriptan consisted of local reactions at the site of subcutaneous administration. 3 Sumatriptan is an indole; the structures of this chemical class show varying propensities for nitrosation. However, appropriate testing with sumatriptan failed to identify any mutagenic nitroso compounds. 4 Sumatriptan was neither genotoxic nor oncogenic. 5 Reproductive studies demonstrated that sumatriptan was not teratogenic and had no effect on peri- and postnatal development. Some embryotoxicity was observed, but only at maternally toxic doses. A slight decrease in the success of insemination was also noted at high oral doses in rats. 6 Results of the toxicological programme performed in support of migraine therapy with sumatriptan provide good assurance of safety for subcutaneous and oral use.

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sumatriptan, Imitrex
Alniditan, a new 5-hydroxytryptamine1D agonist and migraine-abortive agent: ligand-binding properties of human 5-hydroxytryptamine1D alpha, human 5-hydroxytryptamine1D beta, and calf 5-hydroxytryptamine1D receptors investigated with [3H]5-hydroxytryptamine and [3H]alniditan.

Leysen JE, Gommeren W, Heylen L, Luyten WH, Van de Weyer I, Vanhoenacker P, Haegeman G, Schotte A, Van Gompel P, Wouters R, Lesage AS.

Department of Biochemical Pharmacology, Janssen Research Foundation, Beerse, Belgium.

Alniditan is a new migraine-abortive agent. It is a benzopyran derivative and therefore structurally unrelated to sumatriptan and other indole-derivatives and to ergoline derivatives. The action of sumatriptan is thought to be mediated by 5-hydroxytryptamine (5-HT)1D-type receptors. We investigated the receptor-binding profile in vitro of alniditan compared with sumatriptan and dihydroergotamine for 28 neurotransmitter receptor subtypes, several receptors for peptides and lipid-derived factors, ion channel-binding sites, and monoamine transporters. Alniditan revealed nanomolar affinity for calf substantia nigra 5-HT1D and for cloned h5-HT1D alpha, h5-HT1D beta and h5-HT1A receptors (Ki = 0.8, 0.4, 1.1, and 3.8 nM, respectively). Alniditan was more potent than sumatriptan at 5-HT1D-type and 5-HT1A receptors. Alniditan showed moderate-to-low or no affinity for other investigated receptors; sumatriptan showed additional binding to 5-HT1F receptors. Dihydroergotamine had a much broader profile with high affinity for several 5-HT, adrenergic and dopaminergic receptors. In signal transduction assays using cells expressing recombinant h5-HT1D alpha, h5-HT1D beta, or h5-HT1A receptors, alniditan (like 5-HT) was a full agonist for inhibition of stimulated adenylyl cyclase (IC50 = 1.1, 1.3, and 74 nM, respectively, for alniditan). Therefore, in functional assays, the potency of alniditan was much higher at 5-HT1D receptors than at 5-HT1A receptors. We further compared the properties of [3H]alniditan, as a new radioligand for 5-HT1D-type receptors, with those of [3H]5-HT in membrane preparations of calf substantia nigra, C6 glioma cells expressing h5-HT1D alpha, and L929 cells expressing h5-HT1D beta receptors. [3H]Alniditan revealed very rapid association and dissociation binding kinetics and showed slightly higher affinity (Kd = 1-2 nM) than [3H]5-HT. We investigated 25 compounds for inhibition of [3H]alniditan and [3H]5-HT binding in the three membrane preparations; Ki values of the radioligands were largely similar, although some subtle differences appeared. Most compounds did not differentiate between 5-HT1D alpha and 5-HT1D beta receptors, except methysergide, ritanserin, ocaperidone, risperidone, and ketanserin, which showed 10-60-fold higher affinity for the 5-HT1D alpha receptor. The Ki values of the compounds obtained with 5-HT1D receptors in calf substantia nigra indicated that these receptors are of the 5-HT1D beta-type. We demonstrated that alniditan is a potent agonist at h5-HT1D alpha and h5-HT1D beta receptors; its properties probably underlie its cranial vasoconstrictive and antimigraine properties.

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sumatriptan, Imitrex
Chest symptoms after sumatriptan: a two-year clinical practice review in 735 consecutive migraine patients.

Visser WH, Jaspers NM, de Vriend RH, Ferrari MD.

Department of Neurology, University Hospital, Leiden, The Netherlands.

OBJECTIVES: To assess, in clinical practice, the (i) incidence, (ii) within-patient consistency, and (iii) clinical spectrum of chest symptoms (chest symptoms) after subcutaneous (sc) and oral sumatriptan, and (iv) to identify risk factors for chest symptoms. Design: Two-year retrospective survey with mailed self-administered questionnaire. Setting: Neurology outpatient clinic of university hospital. SUBJECTS: Migraine patients with or without aura (n = 869). MAIN OUTCOME MEASURES: Incidence, within-patient consistency and characteristics of chest symptoms; demographic and clinical characteristics of patients. RESULTS: There were 735 (85%) respondents. Sumatriptan was used by 453 patients, during 25 months (median), for 28000 attacks (median: 33 attacks/patient). Of sumatriptan users, 41% (sc) and 24% (oral) had chest symptoms in all attacks, 39% (sc) and 58% (oral) in none, and the remaining in some attacks. Because of chest symptoms, 10% discontinued sumatriptan. Chest symptoms mostly consisted of heavy arms and chest pressure, started within 5 (sc) to 30 (oral) min, and lasted 30 (sc) to 60 (oral) min. Compared with patients without chest symptoms, patients with chest symptoms more often were females and younger, and went to rest immediately after sumatriptan administration (all p < 0.001); they also tended to have lower body mass indices, more severe attacks and less efficacy of sumatriptan (all 0.001 < p < 0.05). Patients with chest symptoms had no higher incidence of cardiovascular symptoms or risk factors. CONCLUSIONS: Chest symptoms are frequent, within-patients consistent, but rarely important, adverse events of (notably sc) sumatriptan. The risk of chest symptoms is patient-dependent and not related, even opposite, to cardiovascular disease. This contradicts the hypothesis that chest symptoms after sumatriptan are caused by cardiac ischemia. Patient acceptance of chest symptoms is improved by pre-advising on the risk and nature of chest symptoms.

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sumatriptan, Imitrex
Sumatriptan and lost productivity time: a time series analysis of diary data.

Miller DW, Martin BC, Loo CM.

Glaxo Wellcome Research and Development, Greenford, Middlesex, UK.

Two previously conducted clinical studies assessed lost nonworkplace activity time and lost workplace productivity time due to migraine symptoms in subjects using sumatriptan for 6 months to treat their migraines after a 12- to 18-week period of using their usual therapy without sumatriptan. Although statistically significant differences in lost nonworkplace activity time and lost workplace productivity time between the usual therapy and sumatriptan treatment periods were detected using the Wilcoxon signed-rank test, this test could not determine whether differences were attributable to inherent trends in the data. This current study employed time series analysis, which detects and controls for preexisting trends in data, to further explore the possibility that the observed reductions in lost time in the two clinical studies were related to management of the subjects with sumatriptan. The intercepts and slopes of the computed linear models suggest that the initiation of sumatriptan therapy produced savings of 0.8 hours of nonworkplace activity time and 0.5 hours of workplace productivity time per patient per week. These savings were sustained throughout the sumatriptan treatment period. Preexisting trends in the data were not detected in the models. Thus the productivity gains are not associated with either time effects or the statistical phenomenon of regression to the mean, but variables that are extreme in initial measurements will tend to be closer to the center of the distribution in subsequent measurements. This strengthens the hypothesis that management of migraine with sumatriptan is associated with reductions in lost productivity time.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9001842&dopt=Abstract sumatriptan Imitrex