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PubMed1998

Functional evaluation of 5-hydroxytryptamine receptor activity in rat resistance vessels.

1. To characterize 5-hydroxytryptamine (5-HT) receptors in rat perfused mesenteric vascular bed (MVB), the effect of 5-HT and related compounds was investigated by functional assay. 2. In quiescent preparations, 5-HT elicited a concentration-dependent conctractile response. After addition of ketanserin, a 5-HT2 receptor antagonist, EC50 values were significantly higher than in controls. 3. In noradrenaline (NA)-precontracted preparations, under continuous infusion of ketanserin, 5-HT, 5-carboxamidotryptamine (5-CT) and sumatriptan produced relaxation. Their rank order of relaxant potency and maximum effect were sumatriptan > 5-HT > 5-CT. Methysergide (1 microM) and spiperone (20-100 nM) caused a rightward shift of the relaxation curve to sumatriptan. These data suggest that vasodilatation in rat MVB is mediated by an 'atypical' subtype of 5-HT1-like receptor, which reveals a pharmacological profile similar to that of the 5-HT1D receptor. The involvement of both 5-HT3 and 5-HT4 receptors can be ruled out, since tropisetron (up to 10 microM) was not able to antagonize the relaxant effect by sumatriptan. 4. Under granisetron infusion (3 microM), the contractile response evoked by perivascular nervous stimulation, but not exogenous NA contraction, was significantly reduced (P < 0.001). These data demonstrate the presence of 5-HT3 receptors in peripheral neurones, modulating neurotransmitters release.

Animals↗
PubMed1998

Early clinical experience with subcutaneous naratriptan in the acute treatment of migraine: a dose-ranging study.

Naratriptan is a novel, potent agonist at the 5HT1B/1D receptor. A total of 335 migraine patients were treated in this randomized, double-blind, placebo-controlled, dose-ranging, in-clinic study, to evaluate the efficacy, safety and tolerability of five doses of subcutaneous (sc) naratriptan (0.5, 1, 2.5, 5 or 10 mg) in comparison with sc sumatriptan (6 mg) and placebo in the acute treatment of a moderate/severe migraine attack. Headache relief [reduction of headache severity from moderate or severe (grade 2/3) to mild or none (grade 1/0)] at 1 and 2 h after each dose, was reported by a statistically significantly higher proportion of patients for all doses of sc naratriptan and sc sumatriptan (6 mg) than for placebo. The percentages of patients with headache relief at 2 h post-dose were: naratriptan (0.5 mg) 65%, (1 mg) 75%, (2.5 mg) 83%, (5 mg) 94% and (10 mg) 91%; sumatriptan (6 mg) 89%; placebo 41%, (P < 0.005). The earliest report of a statistically significant difference compared with placebo for the times assessed was with sc naratriptan (10 mg) at 10 min post-dose (P = 0.023). The percentages of patients reporting adverse events were dose-related; sc naratriptan (0.5 mg) 33%, (1 mg) 29%, (2.5 mg) 43%, (5 mg) 59% and (10 mg) 71%; sc sumatriptan 53%; placebo 22%. There were no clinically significant changes in electrocardiogram (ECG), vital signs or laboratory parameters. Systemic exposure increased proportionally to the dose, the absorption of sc naratriptan was rapid (tmax = 10 min) and the half-life was 5 h. In conclusion, sc naratriptan was an effective and well-tolerated acute treatment for migraine. Copyright 1998 Lippincott Williams & Wilkins

Journal Article↗
PubMed2000

Pharmacological properties of the naturally occurring Phe-124-Cys variant of the human 5-HT1B receptor: changes in ligand binding, G-protein coupling and second messenger formation.

The aim of this study was to analyse whether substitution of phenylalanine in position 124 of the human (h) 5-HT1B receptor by cysteine, a naturally occurring variant of this receptor, modifies not only ligand binding, but also G-protein coupling and second messenger formation. Stably transfected rat C6 glioma cells, which express either the h5-HT1B variant receptor (VR) or the wild-type receptor (WTR) were used. In saturation experiments with [3H]5-carboxamidotryptamine ([3H]5-CT), the maximum binding (Bmax) of the VR amounted to only 60% of that to WTR. In competition experiments with 1 nM [3H]5-CT, the following 5-HT receptor ligands exhibited a higher affinity for the mutant receptor than for the WTR: L-694,247, 5-CT, 5-HT, sumatriptan (agonists listed at decreasing order of potency) and SB-224289 (a selective h5-HT1B receptor inverse agonist with competitive antagonistic properties). In contrast, the mixed 5-HT1B/1D receptor antagonist GR-127935 exhibited equal affinity for both isoforms. The efficacy of L-694,247, 5-CT, 5-HT and sumatriptan in stimulating [35S]GTPgammaS binding (a measure of G protein coupling) to membranes of cells expressing the VR was approximately 50-65% lower compared to membranes of cells expressing the WTR, but their potency was 2.8-3.6-fold higher. SB-224289, which decreased [35S]GTPgammaS binding when given alone, but not GR-127935, was more potent in antagonizing the stimulatory effect of 5-CT on [35S]GTPgammaS binding to membranes expressing the VR compared to membranes expressing the WTR. In whole cells expressing the VR, 5-CT and sumatriptan inhibited the forskolin-stimulated cAMP accumulation 3.2-fold more potently than in cells expressing the WTR. In conclusion, our data suggest that the Phe-124-Cys mutation modifies the pharmacological properties of the h5-HT1B receptor and may account for pharmacogenetic differences in the action of h5-HT1B receptor ligands. Thus, the sumatriptan-induced vasospasm which occurs at low incidence as a side-effect in migraine therapy may be related to the expression of the (124-Cys)h5-HT1B receptor in patients with additional pathogenetic factors such as coronary heart disease.

Animals↗
PubMed2004

LY293558, a novel AMPA/GluR5 antagonist, is efficacious and well-tolerated in acute migraine.

Glutamatergic hyperactivity is implicated migraine pathogenesis. Also, LY293558, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate (KA) receptor antagonist, is effective in preclinical models of migraine. We therefore tested LY293558 in acute migraine. We conducted a randomized, triple-blind, parallel-group, double-dummy, multicentre trial of 1.2 mg/kg intravenous (IV) LY293558, 6 mg subcutaneous (SC) sumatriptan, or placebo in the treatment of acute migraine. The primary efficacy variable was the headache response rate, i.e. headache score improvement from moderate/severe at baseline to mild/none at 2 h. Of 45 enrolled patients, 44 patients (20M:24F; mean age +/- SD = 40 +/- 9 years) completed the study. Response rates were 69% for LY293558 (P = 0.017 vs. placebo), 86% for sumatriptan (P < 0.01 vs. placebo) and 25% for placebo. LY293558 and sumatriptan were superior to placebo (P < 0.01 for all comparisons) on all other measures of improvement in pain and migraine associated symptoms. Fifteen percent of patients who took LY293558 reported adverse events (AEs) (n = 2; one mild, one severe). Fifty-three percent of patients who took sumatriptan (n = 8; seven mild, one moderate) and 31% of those who received placebo reported AEs (n = 5; four mild, one severe). The efficacy and safety results of LY293558 in this small migraine proof of concept trial, together with supportive preclinical data, provide evidence for a potential role of nonvasoactive AMPA/KA antagonists in treating migraine. Larger trials are needed to further test the hypothesis.

Acute Disease↗
PubMed1994

Comparison of the effects of IVth ventricular administration of some tryptamine analogues with those of 8-OH-DPAT on autonomic outflow in the anaesthetized cat.

1 The present study compares the effects on representative autonomic outflows of IVth ventricular application of tryptamine analogues which act at 5-HT1 receptors with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). 2 Cumulative doses of 8-OH-DPAT, N,N-di-n-propyl-5-carboxamidotryptamine (DP-5-CT) and 5-carboxamidotryptamine (5-CT, 2.5-40 nmol kg-1), sumatriptan (10-160 nmol kg-1), indorenate (100-800 nmol kg-1), 5-hydroxytryptamine (5-HT, 20-640 nmol kg-1) both alone and in the presence of cinanserin (0.1 mg kg-1) were given into the IVth ventricle of cats which were anaesthetized with a mixture of alpha-chloralose and pentobarbitone sodium, neuromuscularly blocked and artificially ventilated. Recordings were made of arterial blood pressure, heart rate, renal, cardiac, splanchnic and phrenic nerve activities, femoral arterial flow, tracheal and intragastric pressures. 3 Central application of each of the agonists evoked significant falls in arterial blood pressure. In addition 8-OH-DPAT, DP-5-CT, 5-CT and 5-HT all evoked a differential inhibition of sympathetic nerve activities, with renal nerve activity being the most sensitive and cardiac nerve activity the least sensitive. In the dose-ranges used, administration of sumatriptan evoked reductions only in renal and splanchnic nerve activities whilst indorenate reduced activity in all three sympathetic nerves to a similar extent. 4. The effect of the agonists on heart rate was more inconsistent than the effects on sympathetic outflow.IVth ventricular application of 5-CT and sumatriptan were without effect on heart rate whilst 8-OH-DPAT, DP-5-CT, indorenate and 5-HT alone and in the presence of cinanserin all evoked significant bradycardias. However, whilst atropine partially reversed the bradycardias evoked by 8-OHDPAT and only slightly reversed those caused by indorenate, atropine was without effect on those evoked by DP-5-CT or 5-HT.5. None of the analogues tested had significant effects on gut motility, phrenic nerve discharge or tracheal pressure. 8-OH-DPAT, DP-5-CT, indorenate and 5-HT were without effect on femoral arterial conductance. However, following pretreatment with cinanserin, 5-HT evoked a significant reduction in femoral arterial conductance. At its highest dose, sumatriptan evoked a significant increase in femoral arterial conductance as did 5-CT at the 20 nmol kg-1 dose.6. It is concluded that the present data support the view that 5-HT1A receptors at the level of the brainstem are involved in the central sympathoinhibitory effects caused by intravenous administration of 5-HT1A agonists. Further, brainstem 5-HT1A receptors play an important role in the control of renal sympathetic outflow while brainstem 5-HT2 receptors are involved in the control of skeletal muscle and/or skin blood flow. Selective tryptamine agonists for 5-HT1A receptors differ from non-tryptamine agonists in that they do not cause an increase in central cardiac vagal tone.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1996

5-Hydroxytryptamine receptors mediating vasoconstriction in pulmonary arteries from control and pulmonary hypertensive rats.

1. We investigated 5-hydroxytryptamine (5-HT)-receptor mediated vasoconstriction in the main, first branch and resistance pulmonary arteries removed from control and pulmonary hypertensive rats. Contractile responses to 5-HT, 5-carboxamidotryptamine (5-CT, non-selective 5-HT1 agonist), and sumatriptan (5-HT1D-like receptor agonist) were studied. The effects of methiothepin (non-selective 5-HT1 + 2-receptor antagonist) and ketanserin (5-HT2A receptor antagonist) and GR55562 (a novel selective 5-HT1D receptor antagonist) on 5-HT-mediated responses were also studied. Basal levels of adenosine 3':5'-cyclic monophosphate ([cyclic AMP]i) and guanosine 3':5'-cyclic monophosphate ([cyclic GMP]i) were determined and we assessed the degree of inherent tone in the vessels under study. 2. 5-HT was most potent in the resistance arteries. pEC50 values were 5.6 +/- 0.1, 5.3 +/- 0.1, 5.0 +/- 0.2 in the resistance arteries, pulmonary branch and main pulmonary artery, respectively (n = at least 5 from 5 animals). The sensitivity to, and maximum response of, 5-HT was increased in all the arteries removed from the chronic hypoxic (CH) rats. In CH rats the pEC50 values were 5.9 +/- 0.2, 6.3 +/- 0.2, 6.4 +/- 0.2 and the increase in the maximum response was 35%, 51% and 41% in the resistance arteries, pulmonary branch and main pulmonary artery, respectively. Sumatriptan did not contract any vessel from the control rats whilst 5-CT did contract the resistance arteries. In the CH rats, however, they both contracted the resistance arteries (responses to sumatriptan were small) (pEC50: 5-CT; 5.4 +/- 0.2) and the pulmonary artery branches (pEC50: sumatriptan, 5.4 +/- 0.2; 5-CT, 5.4 +/- 0.2). 5-CT also caused a contraction in the main pulmonary artery (pEC50: 6.0 +/- 0.3). 3. Ketanserin (1 nM-1 microM) caused a competitive antagonism of the 5-HT response in all vessels tested. In control rats, the estimated pKb values for ketanserin in resistance arteries, pulmonary branches and main pulmonary artery were 8.3, 7.8 and 9.2, respectively. Methiothepin (1 nM-1 microM) inhibited responses to 5-HT in the first branch (estimated pKb value: 7.8) and main pulmonary artery. In CH rats, the estimated pKb values for ketanserin in resistance arteries, pulmonary branches and main pulmonary artery were 7.7, 8.3 and 9.6, respectively. Methiothepin also inhibited contractions to 5-HT in the pulmonary artery branch and main pulmonary artery with estimated pKb values of 7 and 9.5, respectively. In control animals, GR55562 had no effect on responses to 5-HT in any of the vessels tested. In the CH rats the estimated pKb values for GR55562 were 6.5, 7.8 and 7.0 in the pulmonary resistance arteries, first branch and main pulmonary artery, respectively. 4. Large pulmonary arteries from controls demonstrated inherent tone and this was increased three fold in the CH rats. The resistance arteries from controls demonstrated little inherent tone though this was enhanced in those from the CH rats. 5. [Cyclic AMP]i was 259 +/- 23 pmol mg-1 protein in the pulmonary artery branches removed from control rats and decreased to 192 +/- 11 pml mg-1 protein in the CH rats (P < 0.01, n = 8). [Cyclic GMP]i also decreased in the pulmonary artery branches (from 550 +/- 15, control to 462 +/- 31 pmol mg-1 protein in CH vessels, n = 8, P < 0.01) and in the main pulmonary arteries (from 566 +/- 33, control to 370 +/- 25 pmol mg-1 protein in CH vessels, n = 8, P < 0.001). No changes in either [cyclic AMP]i or [cyclic GMP]i were observed in the resistance arteries. 6. The results suggest that the increased vasoconstrictor response to 5-HT in CH rat pulmonary arteries is due to an increase in 5-HT2A-receptor mediated contraction combined with an increase in r5-HT1B-like receptor-mediated contraction. An increase in vascular tone and decreased levels of [cyclic GMP]i in the large pulmonary arteries may contribute to the observed increase in activity of r5-HT1B-like receptor

Animals↗
PubMed2005

Valdecoxib for treatment of a single, acute, moderate to severe migraine headache.

OBJECTIVE: To evaluate the analgesic efficacy and safety of a single 20- or 40-mg dose of valdecoxib compared with placebo in treatment of a single, acute, moderate or severe migraine headache, with or without aura. BACKGROUND: Valdecoxib, an oral COX-2 specific inhibitor, is indicated for relief of the signs and symptoms of rheumatoid arthritis and osteoarthritis and treatment of primary dysmenorrhea. This study assessed the optimal dose of valdecoxib for treatment of a single, acute, moderate to severe migraine headache. METHODS: This was a double-blind, randomized, placebo- and active-controlled, multicenter, single-dose (primary end point) and multiple-dose (secondary end point), 56-day study of valdecoxib in the treatment of a single, acute, moderate or severe migraine headache, with or without aura. Migraine headaches were diagnosed according to International Headache Society (IHS) criteria. The primary efficacy end point was headache response (defined as reduction of headache pain intensity from moderate or severe to mild or none) at 2 hours postdose. Patients assessed their headache pain intensity and presence or absence of migraine-associated nausea, vomiting, phonophobia, and photophobia at intervals from 0 to 24 hours postdose. Sumatriptan 50 mg (encapsulated, in standard method, to maintain blinding) was included as a positive control for assay sensitivity. No statistical comparisons were performed between active treatment arms (valdecoxib 20 mg, valdecoxib 40 mg, and sumatriptan 50 mg). Adverse events and safety parameters were monitored throughout the study. RESULTS: In the intent-to-treat population of 570 patients (135 valdecoxib 20 mg, 151 valdecoxib 40 mg, 143 sumatriptan, and 141 placebo), no significant differences in baseline demographics among treatment groups were observed. The headache response rate with valdecoxib 40 mg and sumatriptan 50 mg was significantly greater than that with placebo at all time points from 2 to 24 hours postdose. With valdecoxib 20 mg, headache response rate was significantly greater than placebo from 2 to 4 hours. Significantly fewer patients treated with valdecoxib 40 mg, compared with placebo, experienced nausea, vomiting, and phonophobia at 2 hours postdose. CONCLUSIONS: A single 40-mg dose of valdecoxib is effective and well tolerated in treatment of migraine headache pain and associated symptoms.

Adolescent↗
PubMed2001

Almotriptan in the treatment of migraine.

Almotriptan is a new selective serotonin 5-HT(1B/1D) receptor agonist which is chemically related to sumatriptan and is used in the acute treatment of migraine. Almotriptan, like the rest of the triptans, acts by inducing vasoconstriction of the meningeal arteries. The new drug has good oral bioavailability, and in clinical studies has been shown to be as effective or more effective than sumatriptan 100 mg in alleviating migraine headache and associated symptoms (nausea, vomiting, phonophobia and photophobia) when administered as a single oral or subcutaneous dose of 12.5 mg, this being the recommended dose. However, almotriptan has a very good tolerability profile, which has been shown to be superior to that of sumatriptan in a comparative trial. Therefore, almotriptan offers clear advantages over sumatriptan in the acute treatment of migraine attacks. (c) 2001 Prous Science. All rights reserved.

Journal Article↗
PubMed2001

Almotriptan in the treatment of migraine.

Almotriptan is a new selective serotonin 5-HT(1B/1D) receptor agonist which is chemically related to sumatriptan and is used in the acute treatment of migraine. Almotriptan, like the rest of the triptans, acts by inducing vasoconstriction of the meningeal arteries. The new drug has good oral bioavailability, and in clinical studies has been shown to be at least as effective than sumatriptan 100 mg in alleviating migraine headache and associated symptoms (nausea, vomiting, phonophobia and photophobia) when administered as a single oral dose of 12.5 mg, this being the recommended dose. However, almotriptan has a very good tolerability profile, which has been shown to be superior to that of sumatriptan in two comparative trials. Therefore, almotriptan offers clear advantages over sumatriptan in the acute treatment of migraine attacks. (c) 2001 Prous Science. All rights reserved.

Journal Article↗
PubMed1999

Rizatriptan: a new 5-HT1B/1D receptor agonist for the treatment of migraine.

Rizatriptan (MAXALT MK-0462) is a new 5-HT(1B/1D) receptor agonist for the acute treatment of migraine. The marketed 10 mg and 5 mg oral doses are rapidly and consistently effective in relieving headache pain with associated migraine symptoms, and in enabling patients to return to their normal activities of daily living. Rizatriptan 10 mg is more effective than rizatriptan 5 mg. Compared to oral sumatriptan, the established agent in this class, rizatriptan has a shorter Tmax and greater bioavailability. In comparative clinical trials, the probability of having pain relief sooner was higher for rizatriptan 10 mg than for sumatriptan 100 mg or 50 mg. Over the 2 h after dosing, rizatriptan 10 mg was also superior to sumatriptan 100 mg and 50 mg on a range of other outcome measures. Both doses of rizatriptan are well-tolerated. The most common side-effects are dizziness, drowsiness, and asthenia/fatigue, which are short-lasting and of mild or moderate severity. In summary, rizatriptan is an effective and well-tolerated acute treatment for migraine, which may offer some advantages over oral sumatriptan.

Journal Article↗
PubMed2001

Pharmacokinetics and pharmacodynamics of the triptan antimigraine agents: a comparative review.

The current approach to antimigraine therapy comprises potent serotonin 5-HT1B/1D receptor agonists collectively termed triptans. Sumatriptan was the first of these compounds to be developed, and offered improved efficacy and tolerability over ergot-derived compounds. The development of sumatriptan was quickly followed by a number of 'second generation' triptan compounds, characterised by improved pharmacokinetic properties and/or tolerability profiles. Triptans are believed to effect migraine relief by binding to serotonin (5-hydroxy-tryptamine) receptors in the brain, where they act to induce vasoconstriction of extracerebral blood vessels and also reduce neurogenic inflammation. Although the pharmacological mechanism of the triptans is similar, their pharmacokinetic properties are distinct. For example, bioavailability of oral formulations ranges between 14% (sumatriptan) and 74% (naratriptan), and their elimination half-life ranges from 2 hours (sumatriptan and rizatriptan) to 25 hours (frovatriptan). Clearly, such diverse pharmacokinetic properties will influence the effectiveness of the compounds and favour the prescription of one over another in different patient populations. This article reviews the pharmacological properties of the triptans (time to peak plasma concentration, half-life, bioavailability and receptor binding) and relates these properties to efficacy and time of onset. It also considers the effects of concomitant medication, food, age and disease on the pharmacokinetics of the compounds. In addition, the relative merits, such as headache recurrence, tolerability and route of administration, are discussed. Finally, the performance of the triptans is considered in the context of direct head-to-head comparative trials that have assessed the efficacy profile of the compounds.

Animals↗
PubMed2003

Newer formulations of the triptans: advances in migraine management.

Migraine is a common, frequently incapacitating, headache disorder that imposes a substantial burden on both the individual patient and society. The last two decades have witnessed an explosion in our understanding of the pathophysiology of migraine, and in our development of an efficacious and diverse therapeutic armamentarium. There are several routes of drug administration available to patients with migraine. All the serotonin 5-HT(1B/1D) receptor agonists (triptans) are available as oral tablets (sumatriptan, rizatriptan, zolmitriptan, naratriptan, almotriptan, frovatriptan and eletriptan). Only sumatriptan is available as a subcutaneous injection. Some triptans are also available via newer routes of administration, including orally disintegrating tablets (rizatriptan and zolmitriptan), rectal suppositories (sumatriptan) and intranasal sprays (sumatriptan and zolmitriptan). Oral disintegrating tablets and other non-oral triptan routes (subcutaneous, intranasal, rectal) are a useful alternative to conventional oral tablets for patients who have difficulty swallowing pills or prefer not to do so, and for patients whose nausea and/or vomiting precludes swallowing tablets and/or makes the likelihood of complete absorption unpredictable. This is important because epidemiological studies in migraine reveal that the vast majority of patients (>90%) have experienced nausea during a migraine attack and more than 50% have nausea with the majority of attacks. Similarly, most (almost 70%) have vomited at some time during an attack and of these patients, almost one-third vomit in the majority of attacks. The newer formulations, rapidly dissolving tablets and intranasal sprays, afford patients the opportunity to use abortive therapy without the need for liquids, at anytime and anywhere, at the onset of a migraine attack. Furthermore, the intranasal sprays are absorbed rapidly and have a prompt onset of action allowing for significant pain free rates versus placebo as early as 15 minutes post administration. The ability to administer treatment early in a migraine attack and have a rapid onset of action is particularly important in acute migraine treatment in order to prevent the development of central sensitisation. While many patients and physicians choose conventional oral tablets because of familiarity and ease of administration, the newer formulations, oral disintegrating tablets and intranasal sprays, should be given consideration as first-line agents in selected patients.

Analgesics↗
PubMed2005

Rizatriptan: a pharmacoeconomic review of its use in the acute treatment of migraine.

Rizatriptan (Maxalt; Maxalt-MLT; Maxalt-Melt) is an oral serotonin 5-HT(1B/1D) receptor agonist (triptan) used in the acute treatment of migraine with or without aura in adults. Rizatriptan 5 mg and 10 mg are effective in relieving the symptoms of migraine and the 10 mg dose provided faster pain relief than sumatriptan 50 mg, naratriptan 2.5 mg, ergotamine/caffeine 2 mg/200 mg and possibly zolmitriptan 2.5 mg, while displaying similar tolerability. Two cost-utility analyses performed from a societal perspective indicated that rizatriptan 10 mg was dominant over ergotamine/caffeine 2 mg/200 mg, sumatriptan 50 mg or 100 mg, naratriptan 2.5 mg, zolmitriptan 2.5 mg and analgesic-based usual care in the acute treatment of migraine. In one analysis also performed from the perspective of a healthcare payer, rizatriptan was still dominant over naratriptan, sumatriptan and zolmitriptan. Rizatriptan was cost effective compared with usual care with an incremental cost per quality-adjusted life-year (QALY) gained of 31,845 Can dollars (2002 values) and an incremental cost per additional attack aborted of 49.82 Can dollars. A modelled cost-effectiveness analysis conducted from a healthcare payer's perspective indicated that almotriptan 12.5 mg was more cost effective than rizatriptan 10 mg as a result of better tolerability. The incremental cost per additional successfully treated patient (defined as being sustained pain free without adverse events) with almotriptan was 6.94 US dollars (1999 values). In other nonmodelled cost-effectiveness analyses, rizatriptan 10 mg, eletriptan 40 mg and almotriptan 12.5 mg most consistently displayed the greatest cost effectiveness in different analyses using different clinical endpoints. A modelled analysis of the costs of migraine-related productivity losses in US corporations indicated that the use of rizatriptan rather than usual care to treat migraines could result in annual cost offsets of approximately 84-118 US dollars (2000 values) per employee in lost productivity avoided. An intervention study in Spanish postal service workers demonstrated that replacement of usual care with rizatriptan reduced the mean per-patient cost of lost productivity per migraine attack from 34.47 euros (2001/2002 values) before the intervention to 13.94 euros and 4.59 euros for the first and second post-intervention migraine attacks. In conclusion, rizatriptan is one of the more clinically effective and therefore cost-effective oral triptans available for the acute treatment of migraine. The available data from cost-utility analyses suggest that rizatriptan is more cost effective than ergotamine/caffeine, simple analgesics, naratriptan, zolmitriptan and sumatriptan. The economic value of rizatriptan depends on the payer's perspective, as the greatest savings can be expected to be achieved in terms of reduced migraine-related loss of work productivity compared with less effective treatments. For healthcare payers, the high acquisition cost appears to be at least partly offset by reduced migraine-related healthcare resource use when compared with usual care. The comparative cost effectiveness of the newer triptans requires further elucidation from comprehensive direct comparisons.

Economics, Pharmaceutical↗
PubMed1999

[Spanish study of quality of life in migraine (II). Profile of medication consumption and subjective efficacy].

OBJECTIVES: The response to the different antimigraine medications is variable. In this study we have analysed the profile of prescription of these antimigraine medications, both preventive and symptomatic, by a group of spanish neurologists and examined the subjective efficacy of these compounds. PATIENTS AND METHODS: Neurologists from 7 hospitals in different spanish regions interviewed 305 patients (at least 40 per hospital) who met migraine diagnostic criteria. They used an ad hoc questionnaire in which the antimigraine medications, both symptomatic and preventive, taken by the patients, as well as their subjective response were registered. Patients with transformed migraine or tension-type headache more than 2 days per week were excluded. RESULTS: Analgesics, non-steroidal anti-inflammatory drugs, ergotics and sumatriptan had been taken by 99, 69, 54 and 40% of the 305 interviewed patients, respectively. A subjective good response was refered to by 9% of patients who had taken analgesics, 23% of patients who had taken non-steroidal anti-inflammatory drugs, 39% of those who had taken ergotics and 63% of patients with sumatriptan. The current symptomatic treatment was: analgesics 34% of cases, non-steroidal anti-inflamatory drugs 26%, ergotics 13% and sumatriptan 63%. Regarding preventive treatments, 108 patients (35%) had been treated with calcium-antagonists, 87 (29%) with beta-blockers, 55 (18%) with amitriptyline and only 7 (2.2%) with valproic acid. The percentages of good responses to these drugs were: 55% for beta-blockers, 42% for calcium-antagonists and 31% for amitriptyline. CONCLUSIONS: Our data confirm that analgesics are not efficacious in the majority of migraine patients and that the advent of sumatriptan has clearly improved the quality of migrane symptomatic treatment, even though about one-third of migraine patients do not respond to this drug. This study confirm that calcium-antagonists are the antimigraine preventive treatment most frequently prescribed in our country, even though their subjective efficacy is lower than that of beta-blockers.

Analgesics, Non-Narcotic↗
PubMed1999

5-Hydroxytryptamine(1F) receptors do not participate in vasoconstriction: lack of vasoconstriction to LY344864, a selective serotonin(1F) receptor agonist in rabbit saphenous vein.

Recently, several novel approaches to the treatment of migraine have been advanced, including selective 5-hydroxytryptamine (or serotonin) 1B/1D (5-HT(1B/1D)) receptor agonists such as sumatriptan and 5-HT(1F) receptor agonists such as LY344864. Many 5-HT(1B/1D) receptor agonists have been identified based on their ability to produce cerebral vascular contraction, whereas LY344864 was identified as an inhibitor of trigeminal nerve-mediated dural extravasation. In our study, several triptan derivatives were compared with LY344864 for their ability to contract the rabbit saphenous vein, a tissue used in the preclinical identification of sumatriptan-related agonists. Sumatriptan, zolmitriptan, rizatriptan, and naratriptan all contracted the rabbit saphenous vein from baseline tone, whereas LY344864 in concentrations up to 10(-4) M did not contract the rabbit saphenous vein. Furthermore, vascular contractions to sumatriptan were markedly augmented in the presence of prostaglandin F(2alpha) (PGF(2alpha)). However, even in the presence of PGF(2alpha) (3 x 10(-7) M), LY344864 did not contract the rabbit saphenous vein in concentrations well in excess of its 5-HT(1F) receptor affinity (pK(i) = 8.2). Only when concentrations exceeded those likely to activate 5-HT(1B) and 5-HT(1D) receptors (>10(-5) M) did modest contractile responses occur in the presence of PGF(2alpha). Use of these serotonergic agonists revealed a significant correlation between the contractile potency in the rabbit saphenous vein and the affinities of these agonists at 5-HT(1B) and 5-HT(1D) receptors, although contractile agonist potencies were not quantitatively similar to 5-HT(1B) or 5-HT(1D) receptor affinities. In contrast, no significant correlation existed between the contractile potencies of these serotonergic agonists in the rabbit saphenous vein and their affinity at 5-HT(1F) receptors. These data support the contention that activation of 5-HT(1F) receptors will not result in vascular contractile effects.

Animals↗
PubMed2005

[Economic evaluation of acute migraine attack treatment with triptans in Spain].

OBJECTIVE: To perform an economic evaluation of migraine attack treatment comparing standard doses of existing triptans in 2003, and using different outcome measurements of anti-migraine effectiveness. METHODS: A cost-effectiveness analysis was performed from the National Health System perspective, using 2003 prices, comparing almotriptan 12.5 mg, eletriptan 40 mg, naratriptan 2.5 mg, rizatriptan 10 mg, sumatriptan 50 mg, sumatriptan 100 mg, zolmitriptan 2.5 mg and zolmitriptan 5 mg. Effectiveness measurements were obtained from an efficacy meta-analysis of published clinical trials, and they consisted of therapeutic gain (crude effect of triptan after placebo effect subtraction) for 2 h--anti-migraine response, pain free at 2 h, and 24 h--sustained pain free. Rescue medication use and 24 h-attack relapse rates were assessed. RESULTS: Thirty-eight clinical trials (19,872 patients) were used to assess triptans effectiveness. Eletriptan 40 mg and rizatriptan 10 mg showed the highest 24 h-sustained pain free response (20.2 % in both cases), pain-free at 2 h (27.7 % and 32.2 %) and antimigraine response at 2 h (38.6 % and 31.3 %), respectively. Less rescue medication was used with eletriptan 40 mg and sumatriptan 50 mg (21 % and 20 %), and the lowest 24 h-relapse rates were observed with eletriptan 40 mg and naratriptan 2.5 mg (27 % and 21 %). Eletriptan 40 mg and sumatriptan 50 mg showed the lowest costs per successfully treated attacks with 2 h--anti-migraine response (16.50 and 17.44e) and with 24 h--sustained pain free (31.47 and 33.61e), while the lowest costs per attack that was pain free at 2 h were observed with rizatriptan 10 mg (21.36e) and eletriptan 40 mg (22.99e). CONCLUSIONS: Considering the cost-effectiveness measurements assessed, eletriptan 40 mg was the most costeffective triptan in the majority of economic analyses carried out.

Acute Disease↗
PubMed2006

[Experience with intranasal zolmitriptan in cluster headache].

INTRODUCTION: The objective is to analyse our experience with the new intranasal formulation of zolmitriptan 5 mg in the symptomatic treatment of cluster headache in daily clinical practice. PATIENTS AND METHODS: We collected a total of 18 patients with cluster headache and experience with intranasal zolmitriptan; 17 had used subcutaneous sumatriptan and 8 oral triptans. The main reasons for trying intranasal zolmitriptan were: poor tolerability in 12 patients and insufficient efficacy in 6. RESULTS: Among the 17 patients experienced in subcutaneous sumatriptan, 12 (71 %) preferred nasal zolmitriptan, 2 (18 %) subcutaneous sumatriptan and 2 (12 %) did not express any preference. The reasons for preferring intranasal zolmitriptan were: higher convenience (n = 6), better tolerability (n = 5), lower price (n = 2) and higher efficacy (n = 1). Seven out of the 8 patients who had taken oral triptans preferred nasal zolmitriptan, in all cases due to higher subjective efficacy. A total of 11 patients showed efficacy within 30 minutes. Only 3 patients referred to adverse events, always mild. CONCLUSIONS: The 5 mg nasal formulation of zolmitriptan is a potential new option for the symptomatic treatment of cluster headache. This formulation should be considered in patients with poor tolerability to subcutaneous sumatriptan and in those attacks where quick access to inhaled oxygen is not possible. These results suggest that a controlled trial with nasal zolmitriptan in this indication would be worthwhile.

Administration, Intranasal↗
PubMed1994

5-Hydroxytryptamine1D-like receptors mediate contraction of partially depolarized rabbit renal arteries.

This study characterizes the 5-hydroxytryptamine (5-HT) receptors involved in the contraction of rabbit renal arteries which had been previously precontracted submaximally by partial depolarization. In the presence of ketanserin (10(-6) M) to block 5-HT2 receptors, 5-HT, 5-carboxamido-tryptamine (5-CT) and other 5-HT receptor agonists caused contraction of partially depolarized (22 mM KCl) rabbit renal arteries whereas they were without effect in quiescent tissues (4.7 mM KCl). 5-CT was the most potent agent tested, producing concentration-related increases in tension over the range of 10(-9) to 10(-6) M, attaining 44 +/- 2% of the tissue maximum with a EC50 of 4.8 +/- 0.9 x 10(-8) M. The relative order of agonist potency in partially depolarized tissues was 5-CT > 5-HT > 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H indole > or = sumatriptan > 8-hydroxy-2-(di-n-propyl-amino)tetralin > cisapride. Responses to 5-CT and sumatriptan were antagonized in a concentration-dependent fashion by methiothepin (3 x 10(-8)-3 x 10(-7) M). In the case of 5-CT, Schild analysis showed that this antagonism was competitive, giving a pA2 value of 7.72. Rauwolsine (3 x 10(-7)-10(-6) M) and metergoline (10(-6) M) also produced modest antagonism of 5-CT and sumatriptan-induced responses. With sumatriptan as agonist, rauwolscine gave a pKB of 6.43, however its antagonism of 5-CT appeared noncompetitive because it was associated with a reduction in maximum response (pKB' = 6.54).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗