sumatriptan, Imitrex
Preclinical studies characterizing the anti-migraine and cardiovascular effects of the selective 5-HT1D receptor agonist PNU-142633.

McCall RB, Huff R, Chio CL, TenBrink R, Bergh CL, Ennis MD, Ghazal NB, Hoffman RL, Meisheri K, Higdon NR, Hall E.

Department of Neurobiology and Structural, Analytical and Medicinal Chemistry, Pharmacia Corporation, Kalamazoo, MI 49001, USA. robert.b.mcall pharmacia.com

The present study describes the preclinical pharmacology of a highly selective 5-HT1D receptor agonist PNU-142633. PNU-142633 binds with a Ki of 6 nm at the human 5-HT1D receptor and a Ki of> 18 000 nm at the human 5-HT1B receptor. The intrinsic activity of PNU-142633 at the human 5-HT1D receptor was determined to be 70% that of 5-HT in a cytosensor cell-based assay compared with 84% for that of sumatriptan. PNU-142633 was equally effective as sumatriptan and a half-log more potent than sumatriptan in preventing plasma protein extravasation induced by electrical stimulation of the trigeminal ganglion. Like sumatriptan, PNU-142633 reduced the increase in cat nucleus trigeminal caudalis blood flow elicited by electrical stimulation of the trigeminal ganglion compared with the vehicle control. The direct vasoconstrictor potential of PNU-142633 was evaluated in vascular beds. Sumatriptan increased vascular resistance in carotid, meningeal and coronary arteries while PNU-142633 failed to alter resistance in these vascular beds. These data are discussed in relation to the clinical findings of PNU-142633 in a phase II acute migraine study.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12485205&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Pharmacologic characterization of contractile serotonergic receptors in human isolated mesenteric artery.

Gul H, Yildiz O, Simsek A, Balkan M, Ersoz N, Cetiner S, Isimer A, Sen D.

Department of Pharmacology, Gulhane Military Medical Academy, Faculty of Medicine, Etlik, Ankara, Turkey.

The 5-hydroxytryptamine (5-HT) receptors mediating contraction in human isolated mesenteric arteries were characterized. Endothelium-denuded human isolated mesenteric arteries were used. 5-HT induced concentration-dependent contractions in mesenteric arteries (Emax, 127.37 +/- 7.61% of 80 mM KCl maximal contraction; pD2, 6.73 +/- 0.09 [-logEC50]). Sumatriptan, a selective 5-HT1B/1D receptor agonist, induced concentration-dependent contractions in some of the arteries (Emax, 61.82 +/- 10.04%; pD2, 6.56 +/- 0.21, n = 9) but not in the others (Emax < 5%, n = 13), suggesting that functional 5-HT1B/1D receptors exist in some but not in all mesenteric arteries. GR127935 (a selective 5-HT1B/1D receptor antagonist, 3 nM) inhibited sumatriptan-induced contractions in arteries in which sumatriptan responses were strong in an insurmountable manner. GR127935 (10 nM) also inhibited 5-HT responses and shifted the concentration-response curve of 5-HT to the right significantly (p < 0.05; pD2s were 6.54 +/- 0.18 and 5.93 +/- 0.11 in the presence of vehicle and GR127935, respectively). Ketanserin (0.01-1 microM) competitively antagonized 5-HT responses in human mesenteric arteries: pA2 value was 8.40 +/- 0.25 (slope of Schild regression, 1.43 +/- 0.18; r2, 0.98). Tropisetron (5-HT3 receptor antagonist) and prazosin (alpha1-adrenoceptor antagonist) did not affect the contractions induced by 5-HT. These results suggest that 5-HT2A and 5-HT1B/1D receptors, but not 5-HT3 and alpha1-adrenoceptors, are involved in the 5-HT-induced contractions in human isolated mesenteric arteries. Sumatriptan-induced and 5-HT1B/1D receptor-mediated responses vary greatly among patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12548093&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Single use of sumatriptan: a patient interview study.

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

Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, The Netherlands.

OBJECTIVE: To investigate the possible reasons associated with the use of a single prescription of sumatriptan. BACKGROUND: A few population-based studies concerning the usage patterns of sumatriptan have revealed a relatively high incidence (approximately 40%) of sumatriptan users who utilize only a single prescription of the drug. DESIGN AND METHODS: Using automated prescription data from 11 community pharmacies, we identified single and multiple sumatriptan prescription recipients. The data were collected from May 1, 1998, to April 30, 2000. Several patient- and medication-related variables possibly associated with single recipiency of sumatriptan were analyzed. In addition, single recipients of sumatriptan were invited for an interview and asked a number of questions related to their clinical status and their experience with the medication. RESULTS: Four hundred ninety-five, first-time users of sumatriptan were identified during the patient selection period, of whom 38% were single recipients of sumatriptan. Of the latter, 102 patients were considered eligible for interview. Reasons for terminating treatment after only 1 prescription included: inefficacy and/or occurrence of side effects, 78% (n=79); uncertain diagnosis of migraine, 39.2% (n=40); and reduction in headache frequency, 33.3% (n=34). Almost half of the population had terminated treatment without having consulted their physician. More than half relied upon the use of over-the-counter (OTC) analgesics after having tried sumatriptan. Compared to multiple users of sumatriptan, single recipients were far less likely to have used another form of migraine treatment prior to (odds ratio, 0.35; [95% confidence interval, 019 to 0.67]) and after (odds ratio, 0.34 [95% confidence interval, 0.19 to 0.63]) initiating sumatriptan. Furthermore, single recipients had demonstrated an increased tendency towards benzodiazepine use prior to receiving sumatriptan (odds ratio, 1.80 [95% confidence interval, 1.00 to 3.28]). CONCLUSIONS: Single use of a sumatriptan prescription reveals some issues that may impact negatively the provision of effective migraine management. These include: rapidly developing dissatisfaction with the treatment provided and a lower tendency to seek out medical care. Our results also suggest that the drug may be used (inappropriately) as a diagnostic tool.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12558764&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Stimulation of the calcitonin gene-related peptide enhancer by mitogen-activated protein kinases and repression by an antimigraine drug in trigeminal ganglia neurons.

Durham PL, Russo AF.

Department of Physiology and Biophysics, University of Iowa, Iowa City, Iowa 52242, USA. pauldurham smsu.edu

Calcitonin gene-related peptide (CGRP) is involved in the underlying pathophysiology of all vascular headaches, including migraines. Elevated levels of CGRP during migraine are restored to normal coincident with headache relief after treatment with the antimigraine drug sumatriptan. We have used primary cultures of trigeminal neurons under conditions simulating migraine pathology and therapy to study the mechanisms controlling the CGRP promoter. Using reporter genes in transient transfection assays, we demonstrate that an 18 bp enhancer containing a helix-loop-helix element is both necessary and sufficient for full promoter activity. NGF treatment and cotransfection with an upstream activator of the extracellular signal-regulated MAP kinases (MAPKs) activated the enhancer. Treatment with sumatriptan repressed NGF- and MAPK-stimulated CGRP promoter activity. Repression was also observed using a synthetic MAPK-responsive reporter gene. Sumatriptan regulation of CGRP gene expression did not couple to a G(i)/G(o) pathway, but rather caused a prolonged increase in intracellular calcium. The importance of the prolonged calcium signal in repression of MAPK activity was demonstrated by using the ionophore ionomycin to mimic sumatriptan action. We propose that activation of MAPK pathways may increase CGRP gene expression during migraine, and that sumatriptan can diametrically oppose that activation via a prolonged elevation of intracellular calcium.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12574409&dopt=Abstract sumatriptan Imitrex