sumatriptan, Imitrex
Functional characterization of 5-HT1D autoreceptors on the modulation of 5-HT release in guinea-pig mesencephalic raphe, hippocampus and frontal cortex.

el Mansari M, Blier P.

Neurobiological Psychiatry Unit, McGill University, Montreal, Quebec, Canada.

1. The aims of the present study were (i) to characterize further the pharmacology of 5-HT1D autoreceptors modulating 5-HT release in guinea-pig mesencephalic raphe, hippocampus and frontal cortex; (ii) to determine whether 5-HT1D receptors in the mesencephalic raphe are located on 5-HT neurones; (iii) to determine whether 5-HT1D autoreceptors are coupled to G proteins; and (iv) to assess their sensitivity following long-term 5-HT reuptake blockade and inhibition of type-A monoamine oxidase. 2. In mesencephalic raphe, hippocampus and frontal cortex slices, the 5-HT1D/1B receptor agonist, sumatriptan and the 5-HT1 receptor agonist, 5-methoxytryptamine (5-MeOT) but not the 5-HT1B receptor agonist, CP93129, inhibited electrically the evoked release of [3H]-5-HT in a concentration-dependent manner. This effect was antagonized by the 5-HT1D/1B receptor antagonist GR127935 in the three structures, but not by the 5-HT1A receptor antagonist, (+)-WAY100635 in mesencephalic raphe slices. These results confirm the presence of functional 5-HT1D autoreceptors controlling 5-HT release within the mesencephalic raphe as well as in terminal regions. 3. The inhibitory effect of sumatriptan on K(+)-evoked release of [3H]-5-HT was not reduced by the addition of the Na+ channel blocker, tetrodotoxin to the superfusion medium, suggesting that these 5-HT1D receptors in the mesencephalic raphe are located on 5-HT neurones and may be considered autoreceptors. 4. The in vitro treatment with the alkylating agent N-ethylmaleimide (NEM) was used to determine whether these 5-HT1D autoreceptors are coupled to G proteins. The inhibitory effect of sumatriptan on electrically evoked release of [3H]-5-HT was attenuated in NEM-pretreated slices from mesencephalic raphe, hippocampus and frontal cortex, indicating that the 5-HT1D autoreceptors activated by sumatriptan are coupled to G proteins in these three structures. Taken together with our previous results, this suggests that, in addition to the 5-HT1D autoreceptor activated by sumatriptan, another subtype of 5-HT autoreceptor is activated by 5-MeOT in the hippocampus. 5. Following a 3-week treatment with the selective 5-HT reuptake inhibitor, paroxetine (10 mg kg-1 day-1) and a 48 h washout period, the electrically evoked release of [3H]-5-HT was enhanced in mesencephalic raphe, hippocampus and frontal cortex slices. There was an attenuation of the capacity of sumatriptan to inhibit the evoked release of [3H]-5-HT from mesencephalic raphe slices but not from frontal cortex and hippocampus slices. Only in the latter structure was the suppressant effect of 5-MeOT attenuated. After a 3-week treatment with the reversible type-A monoamine oxidase inhibitor, befloxatone (0.75 mg kg-1 day-1) and 48 h washout period, the effectiveness of sumatriptan and 5-MeOT on the evoked release of [3H]-5-HT was unaltered in the same brain structures. 6. The enhancement of [3H]-5-HT release by long-term paroxetine treatment is possibly due to a desensitization of 5-HT1D autoreceptors activated by sumatriptan in mesencephalic raphe and by terminal 5-HT autoreceptors activated by 5-MeOT in hippocampus. In the case of the frontal cortex, it appears that 5-MeOT and sumatriptan may act on the same 5-HT1D autoreceptor which is not desensitized either after paroxetine or befloxatone treatment, as previously reported.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8762094&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
[18 months long-term analysis of effectiveness, safety and tolerance of sumatriptan s.c. in acute therapy of migraine attacks]

[Article in German]

Gobel H, Stolze H, Heinze A, Dworschak M, Heuss D, Christiani K, Lindner V.

Klinik fur Neurologie der Christian-Albrechts-Universitat, Kiel.

The aim of the open prospective study was to investigate the efficacy, safety and tolerability of subcutaneous sumatriptan in acute migraine treatment. Patient self-treatment was monitored over a time period of 6-18 months with 6 mg of sumatriptan administered subcutaneously by an autoinjector. In total, 2,263 patients participated in the study. Headache intensity was documented by the patient in a headache diary before and 1 and 2 h after application. During the study period from October 1991 to June 1993, 43,691 migraine attacks were investigated. Treatment with sumatriptan was efficient in 89.5% of the attacks. Headache relief was achieved in 71%. Headache reoccurred in 22.7% of the attacks, and therefore a second injection was administered. An intraindividual treatment efficacy of 80-100% was achieved in 82.9% of the patients. During long-term treatment the ratio of effective treatment and headache frequency was constant; 4.9% of the patients withdrew from the study because of adverse events and because they felt the treatment was not effective. A total of 44.5% of the patients reported adverse events that were serious in 1.7%. Subcutaneous self-treatment with sumatriptan in the acute treatment of migraine is effective and well tolerated by the patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8767202&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Different effects of the serotonergic agonists buspirone and sumatriptan on the posterior pituitary hormonal responses to hypoglycemia in humans.

Chiodera P, Volpi R, Capretti L, Caffarri G, Magotti MG, Coiro V.

Cattedra di Endocrinologia, Universita di Parma, Italy.

The responses of serum oxytocin (OT) and vasopressin (AVP) to the serotonergic HT1A agonist buspirone (15 mg p.o.) or the HTD1 agonist sumatriptan (6 mg injected subcutaneously) were evaluated in 7 normal men either in basal conditions or during an insulin (0.15 iu/kg as an i.v. bolus) tolerance test (ITT). Neither buspirone nor sumatriptan administration modified the basal secretion of AVP and OT. Stimulation of 5HT-1D receptors with sumatriptan was unable to change neither AVP nor OT response to insulin-induced hypoglycemia. On the other hand, the pretreatment with the 5HT1A agonist buspirone significantly enhanced the OT response during hypoglycemia, without modifying the AVP rise. The results of this study suggest that serotonergic 5HT1A receptors may interact with hypoglycemia in the stimulation of OT, but not AVP secretion.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8771561&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Subcutaneous sumatriptan in the clinical setting: the first 50 consecutive patients with acute migraine in a pediatric neurology office practice.

Linder SL.

Dallas Pediatric Neurology Associates, TX, USA.

An open prospective study was undertaken to assess the efficacy and safety of subcutaneous sumatriptan in 50 consecutive children ages 6 to 18 years with severe migraine. There were 28 females and 22 males. The dose of sumatriptan was 0.06 mg/kg. Parameters included overall efficacy, time to relief, recurrence rate, adverse events, and objective global rating. Overall efficacy, defined by headache reduction from severe or moderate to mild or none, was 78%. Twenty-six percent responded within 30 minutes, 46% responded in 60 minutes, and 6% responded between 1 to 2 hours. Twenty-two percent had no response or a suboptimal response. Recurrence rate was only 6%. There was a difference in efficacy between male and female, as 91% of the males responded, while only 68% of the females responded. The males had more migraine alone while the females had migraine often with a coexistent tension-type headache. Eighty percent of all the patients had some adverse event which was usually mild and transient; however, one patient developed a transitory confusional state which resolved in 2 hours. Eighty-four percent reported a global rating of good to excellent, while 16% rated the treatment only fair to poor. These findings suggest that subcutaneous sumatriptan can be both effective and safe in childhood migraine, especially in dealing with migraine alone.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8783473&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Alcoholism abolishes the growth hormone response to sumatriptan administration in man.

Coiro V, Vescovi PP.

Center for Alcohology, University of Parma, Italy.

To assess the possible influence of alcoholism on serotonergic control of growth hormone (GH) secretion, 6 mg of the 5-HT1D serotonergic receptor agonist, sumatriptan, was injected subcutaneously in a group of nine normal controls (aged 32 to 49 years) and in nine age-matched nondepressed male alcoholic subjects after 10 to 25 days of abstinence from alcohol. During the same period, subjects were also tested with GH-releasing hormone ([GHRH] 1 microgram/kg body weight in an intravenous [i.v.] bolus) and L-arginine, which releases GH from somatostatin inhibition (50 g in 50 mL normal saline over 30 minutes) to determine whether GH secretion in response to alternate secretagogues is preserved in alcoholics. A control test with administration of normal saline instead of drug treatments was also performed. Plasma GH levels were recorded over 2 hours in all tests. Administration of placebo did not change plasma GH levels in any subject. Similar GH responses were observed in normal controls and alcoholic subjects when GHRH or arginine were administered. A significant GH increase was observed in normal controls after sumatriptan injection; in contrast, GH secretion was not modified by sumatriptan administration in alcoholic patients. These data show that alcoholism is associated with an impairment in the serotonergic-stimulatory regulation of GH secretion, whereas GH responses to direct pituitary stimulation with GHRH or to release from somatostatinergic inhibition with arginine appear to be preserved in alcoholics.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8786727&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Sumatriptan: vasoactive effect on human dural vessels, demonstrated by subselective angiography.

Henkes H, May A, Kuhne D, Berg-Dammer E, Diener HC.

Klinik fur Radiologische Diagnostik und Neuroradiologie, Alfried Krupp Krankenhaus, Essen, Germany.

Sumatriptan, a selective 5-hydroxytryptamine (5HT1D)-receptor agonist, has recently been introduced in the pharmacotherapy of acute migrane attacks. The potential vasoactive effect of sumatriptan on human dural vessels in vivo, however, is still a matter of controversy. We investigated the effects of sumatriptan on dural vessels after subcutaneous or intra-arterial injection. During interventional angiography, the middle meningeal artery (MMA) of nine patients was catheterized with a microcatheter using the transfemoral route. Three MMA were entirely normal, two supplied a dural arteriovenous fistula (AVF) and four were transdural feeders to a brain arteriovenous malformation (AVM). Sumatriptan was injected either into the subcutaneous tissue of the right shoulder (6 mg, two patients) or into the catheterized MMA (2 mg, six patients). The substance caused a marked vasoconstriction of the three normal MMA, visible angiographically and confirmed by intravascular Doppler ultrasonography. Vasoconstriction was still present in the last angiogram obtained 15 min post-injection. Slightly hypertrophied feeders to dural AVF and to brain AVM showed some vasoconstriction in one and four patients, respectively. In two patients with markedly hypertrophied dural feeders to a dural AVF and to a brain AVM, respectively, rapid shunting probably prevented obvious vasoactive effects of sumatriptan. The data obtained by angiography and intravascular Doppler ultrasonography provide strong evidence that sumatriptan has a vasoconstrictive effect on normal as well as hypertrophied dural vessels.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8792033&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Risk factors for headache recurrence after sumatriptan: a study in 366 migraine patients.

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

Department of Neurology, Leiden University Hospital, The Netherlands.

Headache recurrence (HR) is the major limitation of sumatriptan in the acute treatment of migraine attacks. The risk of HR is mainly patient-dependent. We analyzed, in 366 migraine patients, clinical differences between patients who always have HR and patients who never have HR. We found remarkably few differences. HR more frequently occurred in patients with more severe attacks and longer untreated attack duration; in patients who experienced a sensation of a subclinically ongoing attack, despite headache relief after sumatriptan; and in females, mainly with menstruation-related migraine, most probably due to the more severe and longer lasting attacks these patients suffer, rather than due to hormonal factors. The incidence of HR was, among other factors, not related to the (other) clinical effects of sumatriptan, the timing of administration within the attack, the duration of use of sumatriptan, pharmacokinetic factors, or whether patients were experiencing HR after use of ergot alkaloids.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8792039&dopt=Abstract sumatriptan Imitrex