sumatriptan, Imitrex
Improvements in health-related quality of life with sumatriptan treatment for migraine.

Jhingran P, Cady RK, Rubino J, Miller D, Grice RB, Gutterman DL.

Glaxo Research Institute, Research Triangle Park, North Carolina, USA.

BACKGROUND. The debilitating effects of migraine might be reduced in patients using an effective migraine medication. The serotonin (5HT1) receptor agonist sumatriptan has been shown in clinical trials to alleviate headache and associated symptoms in the majority of patients treated. METHODS. Three hundred forty-four (344) patients with migraine were allowed to treat an unlimited number of migraine attacks for up to 24 months with subcutaneous sumatriptan (6 mg). Open-label oral sumatriptan (100 mg) could be used between 1 hour and 24 hours after the initial injection for treatment of recurrent or persistent headache. On four occasions during the treatment period, patients completed the Medical Outcomes Study Short Form-36 Health Survey, a general health status instrument; the Migraine-Specific Quality of Life Questionnaire, a disease-specific instrument; and a series of questions designed to measure the impact of migraine on productivity and disability. RESULTS. Treatment with sumatriptan was associated with significant (P < .05) improvements relative to baseline in three of the Short Form-36 Health Survey quality-of-life dimensions (Bodily Pain, General Health Perceptions, and Social Functioning) and three of the Migraine-Specific Quality of Life Questionnaire dimensions (Role Function-Restrictive, Role Function-Preventive, and Emotional Function). Significant (P < .05) improvements in patient-rated productivity and reductions in patient-rated disability also occurred during the trial. CONCLUSIONS. Patients using sumatriptan to treat migraines for up to 24 months experienced improvements in disability and productivity as well as in health-related quality of life as measured either by a general health status instrument or a disease-specific instrument.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8537803&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Sumatriptan (Imitrex) transport by the human placenta.

Schenker S, Yang Y, Perez A, Henderson GI, Lee MP.

Department of Medicine, University of Texas Health Science Center at San Antonio 78284-7878, USA.

Sumatriptan (Imitrex), a selective 5-hydroxytryptamine receptor agonist, has been found to be of therapeutic benefit in the acute management of migraine. There is no information on the transfer of this agent across the human placenta. Accordingly, the current study assessed the transport of this drug across the normal term human placenta, using the isolated perfused single cotyledon technique. We found that only about 15% of a single dose of the agent placed in the maternal reservoir crossed into the fetal compartment over 4 hr. Given the average elimination half-life of 2 hr for sumatriptan, it is evident that only very small amounts of the agent will cross from mother to fetus after single doses of Imitrex. Only the parent drug entered the fetal compartment. Metabolites were not detected in the perfusates, but there was evidence of some metabolism of sumatriptan in the placenta. The nature of the metabolites has not been determined. The mechanism of transfer of the drug across the placenta is passive (i.e., the clearance is similar to L-glucose which is passively transported), the rate of transfer is equal in both directions (maternal to fetal and in the reverse), and the drug does not cross into the fetus against a concentration gradient. This passive transport of sumatriptan across the placenta is consistent with its molecular weight, its water solubility, and its slow penetration across the blood-brain barrier in experimental animals.

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sumatriptan, Imitrex
Effects of U46619 on contractions to 5-HT, sumatriptan and methysergide in canine coronary artery and saphenous vein in vitro.

Kemp BK, Cocks TM.

Department of Pharmacology, University of Melbourne, Victoria, Australia.

1. The aim of this study was to investigate the mechanism of enhanced reactivity to 5'-hydroxytryptamine (5-HT) and sumatriptan previously observed in human isolated coronary arteries when active force was raised with the thromboxane A2-mimetic, U46619. 2. Ring segments of dog isolated coronary artery and saphenous vein were suspended in organ baths and cumulative concentration-contraction curves to 5-HT, sumatriptan and methysergide were constructed in the absence and presence of low concentrations of U46619. 3. In both endothelium-intact and endothelium-denuded rings of coronary artery, precontraction with U46619 to low (< 10% Fmax; the contraction to a maximum depolarizing 125 mM KCl Krebs solution; KPSS) levels of active force had no effect on either the maximum contraction or sensitivity (pEC50) to 5-HT, sumatriptan and methysergide. 4. Ketanserin (1 microM) had no effect on contractions to sumatriptan and methysergide in endothelium-denuded coronary artery rings, but reduced the maximum contraction to 5-HT by approximately 90% to a value (5% Fmax) similar to that for sumatriptan and methylsergide. Under these conditions, U46619 precontraction had no effect on either pEC50 or maximum for 5-HT, sumatriptan or methysergide. 5. In rings of saphenous vein with endothelium and treated with ketanserin (1 microM), 5-HT and sumatriptan caused equal maximum responses of 65% Fmax which were approximately double that of methysergide (32% Fmax). The maximum responses and sensitivity to 5-HT, sumatriptan, methysergide and noradrenaline were unaffected by precontraction with U46619.(ABSTRACT TRUNCATED AT 250 WORDS)

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sumatriptan, Imitrex
Sumatriptan-induced saphenous venoconstriction in the anaesthetized dog through 5-HT1-like receptor activation.

Drieu la Rochelle C, O'Connor SE.

Synthelabo Recherche, Cardiovascular Department, Bagneux, France.

1. The role of vasoconstrictor 5-HT1-like receptors in the control of vascular reactivity in vivo has been relatively little studied, particularly with regards to venous function. Using an anaesthetized dog model, we have investigated the haemodynamic profile of the selective 5-HT1-like agonist, sumatriptan, focussing on the reactivity of the saphenous venous bed. The key feature of our experimental model was the implantation of ultrasonic crystals on the adventitial surface of the lateral saphenous vein to provide direct and continuous measurement of drug-induced changes in vein diameter. Saphenous vein pressure was measured simultaneously via a proximal branch. 2. Sumatriptan 1-30 micrograms kg-1, i.v., produced pronounced dose-related reductions in saphenous vein diameter which reached congruent to 40% at the highest dose tested. Sumatriptan also produced modest increases in mean blood pressure, total peripheral resistance and left ventricular end diastolic pressure but had little or no effect on cardiac output, heart rate, cardiac contractility or saphenous venous pressure. Sumatriptan-induced reductions in saphenous vein diameter were strongly antagonized by the 5-HT1-receptor antagonist, methiothepin (0.3 mg kg-1, i.v.) but were unaffected by the 5-HT2 antagonist, ketanserin (0.3 mg kg-1, i.v.). 3. Hence, 5-HT1-like receptor stimulation in vivo can result in a powerful local venoconstrictor effect.

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sumatriptan, Imitrex
[Sumatriptan--side effects and problems in routine clinical practice]

[Article in German]

Marterer A, Wober C, Schnider P, Aull S, Wessely P.

Neurologiche Universitatsklinik Wien.

AIM: The study tried to investigate the efficacy, adverse events and possible risk factors of sumatriptan in daily clinical practice. PATIENTS AND METHODS: 72 outdoor patients, who had treated their headaches at least once with sumatriptan, partly prescribed to them by outdoor physicians, were asked about their experiences with the drug. According to the criteria of the International Headache Society (1988) 55 patients were suffering from migraine, 11 from cluster headache and 6 from tension-type headache. RESULTS: Migraine and cluster patients rated the drug as effective as described in literature. Adverse events were reported by 69% of the patients which was more frequent than in most clinic studies described. Adverse events were usually not serious and transient. They were reported significantly more often by migraine patients than by patients with cluster headache and might not all be correlated to the therapy of sumatriptan. CONCLUSION: Sumatriptan has shown to be effective in the treatment of an acute migraine- and cluster-headache. The risk as to severe adverse events, especially cardial adverse events, exists if contraindications for sumatriptan are not considered. Sumatriptan should therefore only be prescribed to carefully diagnosed migraine and cluster headache patients. It should, however, not be given to patients suffering from drug abuse, because they might just change over to sumatriptan.

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sumatriptan, Imitrex
The in vivo pharmacological profile of a 5-HT1 receptor agonist, CP-122,288, a selective inhibitor of neurogenic inflammation.

Gupta P, Brown D, Butler P, Ellis P, Grayson KL, Land GC, Macor JE, Robson SF, Wythes MJ, Shepperson NB.

Pfizer Central Research, Department of Discovery Biology, Sandwich, Kent.

1. The aim of the present study was to investigate the in vivo pharmacological profile of CP-122,288, an indole-derivative with a conformationally restricted N-methylpyrrolidinyl basic side chain in the C-3 position. This C-3 substituent structurally differentiates CP-122,288 from the 5-HT1D receptor agonist sumatriptan, which possesses an N,N-dimethylaminoethyl group. [Formula: see text] 2. When administered prior to electrical stimulation of the trigeminal ganglion, CP-122,288 (0.3-300 ng kg-1, i.v.) produced a dose-related inhibition of plasma protein extravasation in rat dura mater (minimum effective dose, MED, 3 ng kg-1 i.v., P < 0.05; maximal inhibition of plasma extravasation at 30 ng kg-1 i.v., P < 0.01). Sumatriptan produced a similar inhibition of plasma leakage in the dura, but at much higher dose levels (MED, 100 micrograms kg-1 i.v., P < 0.05). Thus, CP-122,288 is of the order of 10(4) fold more potent than sumatriptan. 3. At all doses tested, CP-122,288 did not inhibit plasma protein extravasation measured in extracranial tissues such as the lower lip, eyelid, and conjunctiva. 4. In a separate series of studies in the anaesthetized rat, CP-122,288 (0.003-3 micrograms kg-1 i.v.) produced no change in either heart rate or mean arterial blood pressure, thus demonstrating that doses of CP-122,288 which inhibit plasma protein leakage in rat dura, are devoid of hemodynamic effects. 5. Following a 5 min period of electrical stimulation of the trigeminal ganglion, a 20 min period of sustained neurogenically-driven plasma extravasation, occurring in the absence of electrical stimulation, was initiated. By administration of the compound 5 min after completing the phase of electrical stimulation, this protocol permitted the evaluation of the activity of CP-122,288 on an ongoing and established inflammatory event. CP-122,288 (30 and 300 ng kg-1, i.v., P < 0.01 and P < 0.05, respectively) produced a complete inhibition of plasma protein leakage which was consistent with its effects when administered prior to trigeminal ganglion stimulation. 6. In the anaesthetized dog, CP-122,288 and sumatriptan, at 1-300 micrograms kg-1, i.v., produced a dose-dependent reduction in carotid arterial blood flow and coronary arterial diameter. These data demonstrate that sumatriptan inhibits neurogenic inflammation in the rat (MED, 100 micrograms kg-1, i.v.), and produces vasoconstriction in the dog, over a similar dose-range. Interestingly, doses of CP-122,288 that inhibit neurogenic inflammation in rat dura mater (0.3-300 ng kg-1) were demonstrated to be devoid of vasoconstrictor activity in either the carotid or coronary vascular beds of dog. 7. These data demonstrate that in the rat, CP-122,288 is a highly potent and selective inhibitor of neurogenic inflammation in intracranial tissues, at doses which are devoid of vasoconstrictor activity in dog. Potentially, CP-122,288 may be of use for the acute treatment of migraine, without the risk of cardiovascular side-effects.

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sumatriptan, Imitrex
[3H]sumatriptan labels both 5-HT1D and 5-HT1F receptor binding sites in the guinea pig brain: an autoradiographic study.

Waeber C, Moskowitz MA.

Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Charlestown 02129, USA.

We have used in vitro autoradiography to visualize [3H]sumatriptan binding sites in sections of guinea-pig and rat brain. In saturation studies, this ligand recognized a single saturable population of high affinity binding sites in all regions examined (pKD = 8.3-9.3). While 5-HT and the sumatriptan derivative CP-122,288 (5-methyl-aminosulfonylmethyl-3-(N-methylpyrrolidin-2R-yl-me thyl)- 1 H-indole) competed for [3H]sumatriptan binding sites with a high affinity and monophasic profile, displacement experiments with 5-carboxamidotryptamine revealed the existence of 2 classes of binding sites. The high affinity component (pKD = 9.2-9.9) probably corresponded to 5-HT1B (rat) or 5-HT1D (guinea-pig) receptors. The intermediate affinity (pKD = 5.7-7.3) of the other component, taken together with their high affinity for [3H]sumatriptan, was similar to that of the cloned 5-HT1F receptor. The regional distribution of the 5-HT1B/1D [3H]sumatriptan binding sites was in agreement with previously published studies (striatonigral system, hypothalamus, central gray, superficial layer of the superior colliculus) and corresponded to the pattern of serotonin-5-O-carboxymethyl-glycyl [125I]tyrosinamide labeling in consecutive sections. [3H]sumatriptan binding sites with a low affinity for 5-CT predominated in the intermediate neocortical layers, the claustrum (in the guinea-pig only), the mammillary nuclei, most of the thalamic nuclei and the principal oculomotor nucleus (in the guinea-pig only). This distribution is very similar to that of 5-HT1F mRNA, indicating further the identity of these sites with 5-HT1F receptors. Very high densities of 5-HT1F sites were also found in the rat parafascicular nucleus. Some regions, such as the caudate/nucleus, the lateral geniculate nuclei and the spinal trigeminal nucleus appeared to contain both 5-HT1B/1D and 5-HT1F binding sites. Ketanserin had a low affinity for [3H]sumatriptan binding sites in all guinea-pig brain regions, compatible with the presence of the 5-HT1D beta subtype. An exception was the substantia nigra, where a significant proportion of sites displayed an intermediate affinity for this compound, suggesting the presence of 5-HT1D chi receptors. [3H]5-HT labeled 5-HT1F sites in the claustrum and intermediate cortical layers in the guinea-pig. However these data show that [3H]sumatriptan, in the presence of 10 nM 5-carboxamidotryptamine, is a more suitable radioligand to study the distribution of 5-HT1F binding sites.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8584041&dopt=Abstract sumatriptan Imitrex