sumatriptan, Imitrex
Use and overuse of sumatriptan. Pharmacoepidemiological studies based on prescription register and interview data.

Gaist D.

Institute of Public Health, University of Southern Denmark, Denmark. d-gaist win-chs.ou.dk

The serotonin agonist sumatriptan was marketed in Denmark in 1992 for the treatment of acute attacks of migraine and cluster headache. The clinical development program of the drug was impressive. However, knowledge of the long-term use of sumatriptan in unselected patients was lacking. Misuse of sumatriptan was reported in single patients shortly after the introduction of the drug. The aim of the present thesis was, therefore, to provide an epidemiological description of sumatriptan use with particular emphasis on overuse. The author conducted three studies, two of which were exclusively based on population-based data from a regional (Odense Pharmacoepidemiological Database) and a national (Registry of Drug Statistics, Danish Medicines Agency) prescription registry. Both registries record patient-specific information, thus enabling the conduct of longitudinal studies of drug use. The regional registry covers the county of Funen (reimbursable prescription drugs only), while the national registry records information on all prescriptions presented in the entire country. Consumption was described by means of the Defined Daily Dose (DDD) unit. One DDD of sumatriptan amounts to 100 mg orally or 6 mg subcutaneously. Subjects were classified as recipients of single or multiple prescriptions. Individuals in the latter category were characterized by the 30-day period with the most intensive dispensing of sumatriptan (peak use): low (less than 30 DDD/30 days), intermediate (30-59 DDD/30 days) and high-peak users (60 or more DDD/30 days). In 1995, 33,206 users of sumatriptan were identified in Denmark, corresponding to a 1-year period prevalence of use of 7.8 per 1,000 inhabitants (only persons aged > or = 16 years were included). A female-to-male ratio of 3.8:1 was found. Use was most common among women aged 35-54 years and was highest among 45 to 49-year-olds for both sexes. The standardized period prevalence of sumatriptan use varied regionally between the Danish counties from 6.4 to 9.6 per 1,000 inhabitants. The period prevalence of sumatriptan use in the county of Funen was highly comparable with that of the entire nation. Among the 43,389 sumatriptan users presenting prescriptions for sumatriptan in Denmark in 1994 and 1995, 507 (1.1%) and 1726 (4.0%) belonged to the high and intermediate-peak-use group, respectively. Patients belonging to these two groups were responsible for 38% of the total consumption of sumatriptan. For patients in the high-peak-use group the median span between first and last prescription was 693 days while the median quantity of sumatriptan purchased was 648 DDD. Highly comparable patterns of long-term intense sumatriptan use were found in the data from the regional registry, which covered the 27-month period after the introduction of the drug (February 1992). The register data were highly suggestive of overuse, but lacked essential information, e.g., the indication for use. A third study was therefore conducted using a combination of register and interview data. During a 14-day period, current users of sumatriptan were recruited through community pharmacies in the county of Funen. Respondents returned a signed consent form, including their unique personal identification number (CPR), allowing us to retrieve patient-specific data from the regional registry. For each respondent, all available relevant prescription data for the period 1992-96 were retrieved. Subjects were classified into high, intermediate, and low-peak-use groups according to register data from the 4-year period. The register data were used to evaluate representativity after anonymizing nonrespondent data. The response rates were 33% (7/21) in the high-peak-use group, 47% (30/64) in the intermediate-peak-use group, and 56% (196/350) in the low-peak-use group. Respondents and nonrespondents in the three groups were comparable with regard to age and use of other drugs. (ABSTRACT TRUNCATED)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10570730&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Bovine isolated middle cerebral artery contractions to antimigraine drugs.

Roon KI, Maassen Van Den Brink A, Ferrari MD, Saxena PR.

Department of Pharmacology, Erasmus University Medical Centre Rotterdam, The Netherlands.

Ergot alkaloids, sumatriptan and the newer 5-HT1B/1D receptor agonists all contract cranial blood vessels and this effect seems to be primarily responsible for their efficacy in migraine. We have compared the contractile effects of a number of ergot and triptan derivatives on the bovine isolated middle cerebral artery and characterised the 5-hydroxytryptamine (5-HT) receptors involved by using 5-HT2A (ketanserin: 10, 30, 100 nM) and 5-HT1B/1D (GR127935: 30, 100, 300 nM) receptor antagonists. The rank order of agonist potency (pD2) was ergotamine (8.0+/-0.1) approximately dihydroergotamine (8.0+/-0.1) > avitriptan (7.4+/-0.3) >5-HT (7.0+/-0.1) > naratriptan (6.8+/-0.1) > methylergometrine (major metabolite of methysergide; 6.5+/-0.2) > rizatriptan (6.3+/-0.3) approximately zolmitriptan (6.2+/-0.1) approximately sumatriptan (6.0+/-0.2) approximately methysergide (5.9+/-0.3). The rank order of efficacy (Emax expressed as % of contraction to 100 mM K+) was 5-HT (127+/-11) > sumatriptan (56+/-5) > ergotamine (48+/-5) approximately dihydroergotamine (44+/-8) approximately methyl-ergometrine (44+/-7) > avitriptan (37+/-7) approximately rizatriptan (33+/-5) approximately methysergide (29+/-10) approximately zolmitriptan (28+/-3) approximately naratriptan (23+/-2). The concentration-response curve to 5-HT appeared to be biphasic in the presence of 100 nM ketanserin, which hardly affected sumatriptan-induced contractions, but clearly antagonised the second more efficacious phase of the curve to 5-HT. On the other hand, GR127935 caused a rightward shift of the concentration-response curves to 5-HT (in the presence of 10 microM ketanserin) and sumatriptan with pA2 values of 7.0 and 8.1, respectively. In conclusion, all acutely acting antimigraine drugs contract the bovine isolated middle cerebral artery. Whereas sumatriptan contracts the artery via the 5-HT1B/1D receptor, the 5-HT-induced contraction is mediated partly by the 5-HT2A receptor and partly by another, possibly novel receptor differing from the 5-HT1B/1D receptor. This receptor may be a target for the development of future antimigraine drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10598799&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Serotonin 5HT1B/1D receptor agonists abolish NMDA receptor-evoked enhancement of nitric oxide synthase activity and cGMP concentration in brain cortex slices.

Stepien A, Chalimoniuk M, Strosznajder J.

Aviation Institute of Medicine, Polish Academy of Sciences, Warsaw, Poland.

Our previous studies indicating that the function of excitatory amino acids, NMDA type receptor, is modulated by serotonin focused on the interaction between serotonin 5HT1B/1D and glutamate, NMDA receptor in brain cortex. The effect of agonists of 5HT1B/1D receptor, sumatriptan, and zolmitriptan on NMDA receptor-evoked activation of nitric oxide (NO) and cGMP synthesis in adult rat brain cortex slices was investigated. Two kinds of experiment were carried out using adult rats. In one of them, sumatriptan or zolmitriptan was administered in vivo subcutaneously (s.c.) in a dose of 0.1 mg per kg body weight. Brain slices were then prepared and used in the experiments or, in the other exclusively in vitro studies, both agonists at 10 microM concentration were added directly to the incubation medium containing adult rat brain cortex slices. The data obtained from these studies indicated that stimulation of NMDA receptor in brain cortex slices leads to a large increase in calcium, calmodulin-dependent NO synthase (NOS) activity and to significant enhancement of the cGMP level. This NMDA receptor-dependent NO and cGMP release was completely blocked by competitive and noncompetitive NMDA receptor antagonists APV (10 microM) or MK-801 (10 microM.), respectively. The specific inhibitor of Ca(2+)-dependent isoforms of NOS (N-nitro-1-arginine NNLA and 7-nitroindozole (7-N1)) eliminated the NMDA receptor-mediated enhancement of NO and cGMP release. Moreover, the serotonin 5HT1B/1D receptor agonists sumatriptan and zolmitriptan administrated in vivo (s.c.) or in vitro abolished NMDA receptor-evoked NO signalling in brain cortex. The potency of both agonists investigated directly in vitro was similar to their effect after in vivo administration. These results suggest that both serotonin 5HT1B/1D receptor agonists may play an important role in modulating the NO and cGMP-dependent signal transduction pathway in the brain. This effect of sumatriptan and zolmitriptan on NO signaling in the brain system should be taken into consideration when investigating their mechanism of action in the migraine attack.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10668104&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Comparison of the vasoconstrictor effects of the selective 5-HT1D-receptor agonist L-775,606 with the mixed 5-HT1B/1D-receptor agonist sumatriptan and 5-HT in human isolated coronary artery.

Longmore J, Maguire JJ, MacLeod A, Street L, Schofield WN, Hill RG.

Merck Sharp & Dohme Research Laboratories, Eastwick Road, Harlow, Essex, CM20 2QR, UK.

AIMS: Vasoconstriction in human coronary artery can be mediated via activation of both 5-HT2 and 5-HT1B-receptors. Coronary vasoconstriction is a rare, but potential adverse effect of the antimigraine drug sumatriptan. In order to investigate the receptor population involved we compared the vasoconstrictor effects of sumatriptan (a mixed 5-HT1B/1D-receptor agonist) with those of L-775, 606 (a selective 5-HT1D-receptor agonist) and 5-HT (the endogenous ligand) in human isolated coronary arteries. METHODS: Coronary arteries were obtained from human hearts removed prior to transplant surgery. Several endothelium denuded ring segments (4 mm in length) were obtained from each artery and mounted for isometric tension recording. Each segment was first exposed to 45 mm KCl and then to 5-HT (1 nm-100 microm ). Concentration-effect curves to L-775,606 (1-(3-(5-(1,2, 4-triazol-4-yl)-1H-indol-3-yl)propyl)-4-(2-(3-fluorophenyl)ethyl)p ipe razine) and sumatriptan were then performed in a consecutive and random manner. The response to repeated application of 5-HT was obtained in separate segments. RESULTS: Twenty-five segments from seven different coronary arteries were studied. Concentration-effect curves were fitted to the data using nonlinear regression analysis. The maximum contraction for L-775,606 was significantly less than that for sumatriptan with Emax values (% relative to 45 mm KCl=100%) of 30.1+/-4.22 and 41.5+/-2.7, respectively. L-775,606 was significantly (30-fold) less potent than sumatriptan in causing contraction compared with sumatriptan (EC50 values were 6.0 microm and 0.2 microm, respectively). For comparison the Emax value for 5-HT was 77.2% and the EC50 value was 0.2 microm. CONCLUSIONS: The selective 5-HT1D-receptor agonist L-775,606 has less propensity towards vasoconstriction in human isolated coronary artery (endothelium-denuded) than was mixed 5-HT1B/1D-receptor agonist sumatriptan. The contractions produced were at concentrations where L-775,606 would be expected to occupy 5-HT1B-receptors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10671906&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
No contractile effect for 5-HT1D and 5-HT1F receptor agonists in human and bovine cerebral arteries: similarity with human coronary artery.

Bouchelet I, Case B, Olivier A, Hamel E.

Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Quebec, Canada.

1. Using subtype-selective 5-HT1 receptor agonists and/or the 5-HT1 receptor antagonist GR127935, we characterized in vitro the 5-HT receptor that mediates the contraction of human and bovine cerebral arteries. Further, we investigated which sumatriptan-sensitive receptors are present in human coronary artery by reverse-transcriptase polymerase chain reaction (RT-PCR). 2. Agonists with affinity at the 5-HT1B receptor, such as sumatriptan, alniditan and/or IS-159, elicited dose-dependent contraction in both human and bovine cerebral arteries. They behaved as full agonists at the sumatriptan-sensitive 5-HT1 receptors in both species. In contrast, PNU-109291 and LY344864, selective agonists at 5-HT1D and 5-HT1F receptors, respectively, were devoid of any significant vasocontractile activity in cerebral arteries, or did not affect the sumatriptan-induced vasocontraction. The rank order of agonist potency was similar in both species and could be summarized as 5-HT = alniditan > sumatriptan = IS-159 >>> PNU-109291 = LY344864. 3. In bovine cerebral arteries, the 5-HT1 receptor antagonist GR127935 dose-dependently inhibited the vasoconstrictions elicited by both 5-HT and sumatriptan, with respective pA2 values of 8.0 and 8.6. 4. RT-PCR studies in human coronary arteries showed a strong signal for the 5-HT1B receptor while message for the 5-HT1F receptor was weak and less frequently detected. Expression of 5-HT1D receptor mRNA was not detected in any sample. 5. The present results demonstrate that the triptan-induced contraction in brain vessels is mediated exclusively by the 5-HT1B receptor, which is also present in a majority of human coronary arteries. These results suggest that selective 5-HT1D and 5-HT1F receptor agonists might represent new antimigraine drugs devoid of cerebro- and cardiovascular effects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10711348&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Pregnancy and perinatal outcomes in migraineurs using sumatriptan: a prospective study.

O'Quinn S, Ephross SA, Williams V, Davis RL, Gutterman DL, Fox AW.

US Medical Affairs, Glaxo Wellcome Research Institute, Research Triangle Park, NC 27709, USA.

BACKGROUND: Sumatriptan is an acute treatment for migraine which is often used by women in their child-bearing years, and who become unexpectedly pregnant. Within the context of the post-marketing use of sumatriptan injection for the acute treatment of migraine, and in compliance with approved labeling, we wished to compare perinatal pregnancy outcomes in women who did and did not use the drug after conception. METHODS: Open-label, prospective study conducted in 12,339 migraineurs (including 9,861 women) whose demography and consumption pattern of sumatriptan injections were typical, and were predicted to include 150 pregnancies. Outcome of pregnancy was the end-point. RESULTS: There were 168 of 173 pregnancies that were well-documented. Sumatriptan was only used prior to conception in 92 cases. There were 76 first trimester exposures to sumatriptan. There were no differences in pregnancy outcome between the two groups. CONCLUSIONS: Perinatal and pregnancy outcome did not differ between patients who had and had not used sumatriptan after conception, at the resolution of these sample sizes. This study design complements the ongoing pregnancy registry, which is now widened to patients exposed to all formulations of sumatriptan.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10728620&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Pregnancy outcome following prescription for sumatriptan.

Olesen C, Steffensen FH, Sorensen HT, Nielsen GL, Olsen J.

Danish Epidemiology Science Centre at the Department of Epidemiology and Social Medicine, University of Aarhus, Aarhus C.

BACKGROUND: Some 2.5% of fertile Danish women use sumatriptan, and the drug is also taken during pregnancy. Although sumatriptan reacts selectively in brain vessels, the possibility of reactions with placental blood flow and uterotonic activity cannot be ruled out. The aim of our study was to examine the association between sumatriptan exposure during pregnancy and the risk of preterm delivery and low birth weight. METHODS: Data from the Pharmaco-Epidemiological Prescription Database of North Jutland county regarding all women who had given birth in the county of North Jutland from 1991 to 1996 were linked to the Danish Medical Birth Registry. Women who were exposed to sumatriptan during pregnancy were identified (n = 34), and using logistic regression models their pregnancy outcome was compared with two groups of pregnant women: (1) healthy women (n = 15 955) and (2) migraine controls (n = 89), defined as migraine patients who did not redeem prescriptions for migraine treatment during pregnancy. RESULTS: The risk of preterm delivery was elevated among women exposed to sumatriptan compared with migraine controls (odds ratio [OR] 6.3, 95% confidence interval [CI] 1.2-32.0) and healthy women (OR 3.3, 95% CI 1.3-8.5). The odds ratio for having a newborn with a low birth weight was increased (OR 3.0, 95% CI 1.3-7.0) for all migraine patients who delivered at term (n=115) compared with the outcome of healthy pregnancies. CONCLUSIONS: We found that sumatriptan exposure during pregnancy was associated with an increased risk of preterm delivery and low birth weight. These findings may be due to drug exposure, but they may also reflect the impact of disease severity rather than the treatment itself, or confounding, or chance.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10759898&dopt=Abstract sumatriptan Imitrex