piperidines and rizatriptan

To evaluate the comparative efficacy and tolerability of naratriptan in the treatment of acute attacks of migraine.. Meta-analysis of randomised controlled trials using a random effects model.. A total of 4499 patients suffering from moderate or severe attacks of acute migraine reported in ten trials.. Response rate ratios for headache relief, pain-free response and sustained relief (4-24 hours). Adverse events were estimated with the rate ratio (RR), risk difference and number needed to harm.. Pooled RRs relative to placebo for pain-free response at 2 and 4 hours for naratriptan 2.5 mg were 2.52 (95% CI: 1.78-3.57) and 2.58 (1.99-3.35). Naratriptan 2.5 mg was more effective than naratriptan 1 mg; the corresponding RRs for pain-free response at 2 and 4 hours were 1.54 (95% CI: 1.28-1.86) and 1.35 (1.20-1.51). In contrast, naratriptan 2.5 mg was less effective in pain-free response than either rizatriptan 10 mg at 4 hours (RR: 0.68; 95% CI: 0.55-0.85) or sumatriptan 100 mg at 4 hours (RR: 0.79; 95% CI: 0.67-0.93). However, significantly fewer patients experienced adverse effects with naratriptan 2.5 mg than with rizatriptan 10 mg (RR: 0.73; 95% CI: 0.56-0.97) or sumatriptan 100 mg (RR: 0.68; 95% CI: 0.55-0.86).. Naratriptan is an effective and well-tolerated treatment for acute attacks of migraine. Head-to-head comparisons suggest that naratriptan 2.5 mg is significantly more effective than the 1 mg dose. Rizatriptan 10 mg and sumatriptan 100 mg were superior to naratriptan in terms of headache relief, while zolmitriptan 2.5 mg seemed to have comparable efficacy. Randomised controlled trials have shown that at licensed doses (1 and 2.5 mg), naratriptan is associated with a lower incidence of adverse effects than rizatriptan, sumatriptan and zolmitriptan. The incidence rates of adverse effects were similar to placebo.

Topics: Dose-Response Relationship, Drug; Humans; Indoles; Migraine Disorders; Oxazolidinones; Piperidines; Randomized Controlled Trials as Topic; Serotonin Receptor Agonists; Sumatriptan; Triazoles; Tryptamines

Topics: Anticonvulsants; Botulinum Toxins; Calcitonin Gene-Related Peptide; Central Nervous System; Clinical Trials as Topic; Drug Design; Fructose; Humans; Indoles; Meta-Analysis as Topic; Migraine Disorders; Pain; Piperidines; Pyrrolidines; Serotonin Receptor Agonists; Signal Transduction; Sumatriptan; Topiramate; Triazoles; Trigeminal Nerve; Tryptamines; Vasodilation

Topics: Carbazoles; Evidence-Based Medicine; Humans; Indoles; Migraine Disorders; Oxazolidinones; Piperidines; Pyrrolidines; Receptor, Serotonin, 5-HT1D; Serotonin Receptor Agonists; Sumatriptan; Triazoles; Tryptamines

Topics: Anti-Inflammatory Agents, Non-Steroidal; Diclofenac; Ergotamine; Humans; Ibuprofen; Indoles; Migraine Disorders; Naproxen; ortho-Aminobenzoates; Oxazolidinones; Piperidines; Pyrrolidines; Salicylates; Sumatriptan; Triazoles; Tryptamines

Topics: Acute Disease; Adult; Analgesics, Non-Narcotic; Anti-Inflammatory Agents, Non-Steroidal; Child; Diclofenac; Drug Therapy, Combination; Ergotamine; Humans; Ibuprofen; Indoles; Migraine Disorders; Naproxen; ortho-Aminobenzoates; Oxazolidinones; Piperidines; Pyrrolidines; Salicylates; Serotonin Receptor Agonists; Sumatriptan; Triazoles; Tryptamines

Recent studies of the pathophysiology of migraine provide evidence that the headache phase is associated with multiple physiologic actions. These actions include the release of vasoactive neuropeptides by the trigeminovascular system, vasodilation of intracranial extracerebral vessels, and increased nociceptive neurotransmission within the central trigeminocervical complex. The 5-HT(1B/1D) receptor agonists, collectively known as triptans, are a major advance in the treatment of migraine. The beneficial effects of the triptans in patients with migraine are related to their multiple mechanisms of action at sites implicated in the pathophysiology of migraine. These mechanisms are mediated by 5-HT(1B/1D) receptors and include vasoconstriction of painfully dilated cerebral blood vessels, inhibition of the release of vasoactive neuropeptides by trigeminal nerves, and inhibition of nociceptive neurotransmission. The high affinity of the triptans for 5-HT(1B/1D) receptors and their favorable pharmacologic properties contribute to the beneficial effects of these drugs, including rapid onset of action, effective relief of headache and associated symptoms, and low incidence of adverse effects.

Topics: Carbazoles; Humans; Indoles; Migraine Disorders; Oxazolidinones; Piperidines; Pyrrolidines; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin; Serotonin Receptor Agonists; Sumatriptan; Triazoles; Tryptamines

Triptans, beginning with sumatriptan, have revolutionized the treatment of migraine. New triptans in several formulations will soon become available in the United States. Although the similarities of these 5-hydroxytryptamine (5-HT) 1B/1D receptor agonists outweigh their differences, important differences in pharmacokinetics and clinical responses do exist. Subcutaneous sumatriptan has the most rapid onset of action and greatest efficacy but the most adverse effects. Intranasal sumatriptan also has rapid onset of action, but at 2 hours its efficacy is comparable to that of oral zolmitriptan. Of the oral triptans, rizatriptan seems to have the greatest early efficacy. Both rizatriptan and zolmitriptan are now available as rapidly dissolving wafers. Almotriptan, the newest of the triptans, has a response rate similar to that of oral sumatriptan and may produce fewer adverse effects. Naratriptan and frovatriptan, with their slow onset, high tolerability, and long half-lives, may have a role in aborting prolonged migraine attacks and in headache prevention. Eletriptan at higher doses (80 mg) has a response rate approaching that of rizatriptan but may be limited by potential side effects. The many triptans available offer the opportunity to individualize migraine treatment, depending on the patient's attack characteristics, tolerance, and preferences.

Topics: Carbazoles; Cardiovascular Diseases; Humans; Indoles; Migraine Disorders; Oxazolidinones; Patient Satisfaction; Piperidines; Pyrrolidines; Serotonin Receptor Agonists; Sumatriptan; Treatment Outcome; Triazoles; Tryptamines

Topics: Clinical Trials as Topic; Female; Humans; Indoles; Male; Migraine Disorders; Oxazolidinones; Piperidines; Prognosis; Recurrence; Serotonin Receptor Agonists; Severity of Illness Index; Sumatriptan; Treatment Outcome; Triazoles; Tryptamines

Topics: Humans; Indoles; Migraine Disorders; Oxazolidinones; Piperidines; Pyrrolidines; Serotonin Receptor Agonists; Sumatriptan; Triazoles; Tryptamines

The current International Headache Society guidelines for migraine clinical trials recommend assessment of pain relief at 2 hours as a primary end point. Patients, however, express a clear preference for more rapid pain relief, with most patients defining rapid relief as occurring within 30 minutes after drug administration. Thus, consideration should be given to establishing clinical trial end points that more accurately reflect the preferences of patients with migraine. In this case, assessment of pain relief at 1 hour would be an appropriate primary end point. Using speed of relief as a criterion for migraine drug selection also is appropriate. The migraine-specific serotonin(1B/1D) agonists, or triptans, are able to meet this faster relief end point and are preferred by patients.

Topics: Analgesics, Non-Narcotic; Carbazoles; Clinical Trials as Topic; Humans; Indoles; Migraine Disorders; Oxazolidinones; Pain Measurement; Patient Satisfaction; Piperidines; Pyrrolidines; Serotonin Receptor Agonists; Sumatriptan; Time Factors; Treatment Outcome; Triazoles; Tryptamines

To compare the efficacy of oral rizatriptan 10 mg with oral doses of sumatriptan, naratriptan, and zolmitriptan on stringent outcome measures.. Retrospective analysis of data from five randomized, placebo-controlled, double-masked clinical trials in which oral rizatriptan was directly compared with oral sumatriptan 100 mg (n = 772), 50 mg (n = 1116), 25 mg (n = 1183), naratriptan 2.5 mg (n = 413), and zolmitriptan 2.5 mg (n = 580) for the acute treatment of a moderate or severe migraine attack.. Percentage of patients pain-free at 2 hours, symptom-free at 2 hours (no pain, nausea, photophobia, phonophobia, vomiting, or functional disability), 24-hour sustained pain-free (no headache at 2 hours, no recurrence, and no additional antimigraine medications for 24 hours).. More patients taking rizatriptan 10 mg were pain-free at 2 hours than were patients taking sumatriptan 100 mg (40% vs 33%, p = 0.019), sumatriptan 50 mg (40% vs 35%, p = 0.009), sumatriptan 25 mg (38% vs 27%, p < 0.001), naratriptan 2.5 mg (45% vs 21%, p < 0.001), and zolmitriptan 2.5 mg (43% vs 36%, p = 0.041). More patients taking rizatriptan 10 mg were symptom-free at 2 hours than were patients taking sumatriptan 100 mg (31% vs 22%, p = 0.002), sumatriptan 50 mg (33% vs 28%, p = 0.003), sumatriptan 25 mg (33% vs 24%, p < 0.001), naratriptan 2.5 mg (30% vs 11%, p < 0.001), and zolmitriptan 2.5 mg (31% vs 24%, p = 0.042). More patients taking rizatriptan 10 mg had a 24-hour sustained pain-free response than did patients taking sumatriptan 100 mg (27% vs 23%, p = 0.112), sumatriptan 50 mg (30% vs 26%, p = 0.015), sumatriptan 25 mg (27% vs 20%, p = 0.005), naratriptan 2.5 mg (29% vs 17%, p = 0.004), and zolmitriptan 2.5 mg (32% vs 24%, p = 0.013).. Oral rizatriptan 10 mg was more effective than oral sumatriptan, naratriptan, and zolmitriptan on stringent outcome measures of pain-free response at 2 hours, symptom-free response at 2 hours, and 24-hour sustained pain-free response.

Topics: Administration, Oral; Humans; Indoles; Migraine Disorders; Oxazolidinones; Patient Satisfaction; Piperidines; Randomized Controlled Trials as Topic; Retrospective Studies; Serotonin Receptor Agonists; Sumatriptan; Triazoles; Tryptamines

The use of triptans has improved the ability to treat migraine successfully compared with older treatments. Speed of relief, consistency of effect, and good tolerability have been the hallmarks of these agents. All of the currently available triptans have comparable efficacy and tolerability. Variables between the agents may lead to one agent or dose form being preferred over another in various clinical scenarios. The triptans that are forthcoming may improve on these options through enhanced efficacy rates, tolerability, and headache recurrence rates. There exist increasing options for migraine treatment that may further improve the clinical effects of the older and newer triptans through early treatment of migraine at the stages of mild migraine pain, or even during the prodromal phase of the attack. Additionally, recent work suggests that mini-prophylaxis of migraine at the menses is a highly successful treatment option with the triptans. In this age of managed care, providing cost-effective treatment of headache will take on increasing importance. Techniques such as stratification of acute treatments may enhance cost-effective care, whereas ready availability of the triptans may lead to significant improvements in utilization of parameters such as office visits, emergency room treatment, and even hospitalization.

Topics: Acute Disease; Blood Flow Velocity; Carbazoles; Clinical Trials as Topic; Drug Administration Routes; Female; Humans; Indoles; Male; Menstruation; Migraine Disorders; Oxazolidinones; Piperidines; Practice Guidelines as Topic; Pyrrolidines; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin; Serotonin Receptor Agonists; Sumatriptan; Treatment Outcome; Triazoles; Tryptamines; Vasoconstriction; Vasoconstrictor Agents

Two new intranasal migraine medications, sumatriptan and dihydroergotamine mesylate, may offer specific advantages for patients who are seeking alternatives to various oral or parenteral migraine abortive therapies. Placebo-controlled clinical studies demonstrate that both intranasal forms are effective in relieving migraine headache pain, but published clinical trial information comparing these two intranasal medications with current abortive therapies is lacking. Both agents are generally well tolerated by patients, with the exception of mild, local adverse reactions of the nose and throat.

Topics: Administration, Intranasal; Administration, Oral; Analgesics, Non-Narcotic; Clinical Trials as Topic; Dihydroergotamine; Half-Life; Humans; Indoles; Migraine Disorders; Oxazoles; Oxazolidinones; Piperidines; Recurrence; Serotonin Receptor Agonists; Sumatriptan; Triazoles; Tryptamines

Sterile neurogenic inflammation within cephalic tissue, involving vasodilation and plasma protein extravasation, has been proposed as a pathophysiological mechanism in acute migraine. The action of 5-hydroxytryptamine (5-HT1B/1D) agonists--so-called triptans--on receptors located in meningeal arteries (5-HT1B) and trigeminovascular fiber endings (5-HT1D) has an inhibitory effect on this neurogenic inflammation. Recently, a series of second-generation 5-HT1B/1D agonists (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, and zolmitriptan) have been developed and are reviewed in this article. Their in vitro pharmacological properties, pharmacokinetics, clinical efficacy, drug interactions, and adverse effects are evaluated and compared to the golden standard in the treatment of acute migraine, sumatriptan.

Topics: Acute Disease; Carbazoles; Humans; Indoles; Migraine Disorders; Oxazoles; Oxazolidinones; Piperidines; Pyrrolidines; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin; Serotonin Receptor Agonists; Triazoles; Tryptamines

The efficacy of 5-hydroxytryptamine 1B/1D (5-HT 1B/1D) agonists is related to their inhibitory effects on neurogenic inflammation, mediated through serotoninergic control mechanisms. Recently, a series of oral second generation 5-HT 1B/1D agonists (eletriptan, naratriptan, rizatriptan and zolmitriptan) have been developed and are reviewed in this paper. Their in vitro and in vivo pharmacological properties, clinical efficacy, drug interactions, and adverse effects are evaluated and compared to the gold standard in the treatment of acute migraine, sumatriptan.

Topics: Acute Disease; Animals; Clinical Trials as Topic; Coronary Circulation; Coronary Vasospasm; Drug Design; Drug Interactions; Humans; Inactivation, Metabolic; Indoles; Meninges; Migraine Disorders; Molecular Structure; Nociceptors; Oxazoles; Oxazolidinones; Piperidines; Propranolol; Pyrrolidines; Randomized Controlled Trials as Topic; Rats; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin; Recurrence; Serotonin Receptor Agonists; Structure-Activity Relationship; Sumatriptan; Treatment Outcome; Triazoles; Tryptamines; Vasoconstrictor Agents

With the rapid advances in the treatment of acute attacks of migraine in the last few years and a number of new treatments, has come the practical clinical problem of comparing emerging acute attack therapies alone and with regard to current treatments. Acute migraine therapies can usefully be regarded as non-specific and specific, from the perspective of migraine, since some medicines, such as aspirin or paracetamol, are used to treat pain more broadly. In this review I will compare both non-specific and specific compounds. To some extent the introduction into trial then clinical use of sumatriptan, the first of the 5HT1B/1D agonists or triptans, brought new standards in both clinical trial design, and execution and clinical outcome. Thus sumatriptan has become the de facto gold standard and will be thus employed here. To be practical the discussion of the new triptans will be limited to those available widely, naratriptan, rizatriptan and zolmitriptan. There are two broad issues when comparing treatments: what end-point should be considered and then, how can different compounds be compared with respect to that end-point. In terms of end-points those used here relate to pain relief because they have been collected robustly in the clinical studies and, fortunately, rapid pain relief is what patients questioned in population-based studies rate highest in an acute attack medicine. Headache pain has been rated on a scale of nil, mild, moderate and severe and success rated as either a response, nil or mild pain, or headache free, nil pain, at two or four hours. The ideal comparison of the triptans would be a randomized controlled clinical trial directly comparing the medicines in each case. Given that these are not available for all the compounds and the well characterised placebo response in acute migraine studies, summary measures have been developed to express the differences between compounds to try and adjust for the varying placebo effect. The two most widely used are the therapeutic gain, response on active medication minus response on placebo, and the number-needed-to-treat (NNT). The NNT is the reciprocal of the therapeutic gain as a proportion. The strengths and weaknesses of this approach will be discussed, including the importance of the calculation of confidence intervals. It can be concluded that our current instruments are rather blunt and patient preference needs much greater study.

Topics: Acute Disease; Choice Behavior; Dose-Response Relationship, Drug; Humans; Indoles; Migraine Disorders; Models, Biological; Oxazoles; Oxazolidinones; Piperidines; Serotonin Receptor Agonists; Severity of Illness Index; Sumatriptan; Triazoles; Tryptamines

Triptans, serotonin 5-HT1B/1D receptor agonists, exert their action by targeting serotonin 5-HT1B/1D receptors, are used for treatment of migraine attack. Presently, 5 different triptans, namely sumatriptan, zolmitriptan, eletriptan, rizatriptan, and naratriptan, are marketed in Japan. In the present study, we retrospectively analyzed the relationships of clinical efficacy (headache relief) in Japanese and 5-HT1B/1D receptor occupancy (Φ1B and Φ1D). Receptor occupancies were calculated from both the pharmacokinetic and pharmacodynamic data of triptans.. To evaluate the total amount of exposure to drug, we calculated the area under the plasma concentration-time curve (AUCcp) and the areas under the time curves for Ф1B and Ф1D (AUCФ1B and AUCФ1D). Moreover, parameters expressing drug transfer and binding rates (Acp, AФ1B, AФ1D) were calculated.. Our calculations showed that Фmax1B and Фmax1D were relatively high at 32.0-89.4% and 68.4-96.2%, respectively, suggesting that it is likely that a high occupancy is necessary to attain the clinical effect. In addition, the relationships between therapeutic effect and AUCcp, AUCΦ1B, AUCΦ1D, and Acp · AUCcp differed with each drug and administered form, whereas a significant relationship was found between the therapeutic effect and AΦ1B · AUCΦ1B or AΦ1D · AUCΦ1D that was not affected by the drug and the form of administration.. These results suggest that receptor occupancy can be used as a parameter for a common index to evaluate the therapeutic effect. We considered that the present findings provide useful information to support the proper use of triptans.

Topics: Humans; Migraine Disorders; Oxazolidinones; Piperidines; Pyrrolidines; Serotonin 5-HT1 Receptor Agonists; Sumatriptan; Treatment Outcome; Triazoles; Tryptamines

Complete withdrawal from headache medication is the treatment of choice for medication-overuse headache. Discontinuation of the overused headache medication, however, results in the development of withdrawal headache, often associated with nausea, vomiting, and sleep disturbances.. In a prospective study of 95 patients, the authors investigated the duration and severity of withdrawal headache after overuse of various headache drugs, including single and combination analgesics, ergots, and triptans. All patients underwent standard inpatient withdrawal therapy for 14 days.. The duration of withdrawal headache was shorter in patients overusing triptans (4.1 days) than in patients overusing ergots (6.7 days) or analgesics (9.5 days; p < 0.002). The mean headache intensity on the first day of withdrawal did not differ between the groups (p = 0.821). By day 14, however, it was lower in patients overusing triptans (0.08) than in patients overusing ergots (0.4) or analgesics (0.9; p < 0.005). Rescue medication was requested less by patients undergoing triptan withdrawal (0.25 requests) than by patients undergoing ergot withdrawal (1.25) or analgesic withdrawal (1.85; p < 0.05). Similar to findings in the entire patient population, withdrawal headache was shorter and less severe in migraineurs overusing triptans than in those overusing ergots or analgesics. Because only patients with migraine, but no patient with tension-type headache, overused triptans, withdrawal headache was shorter in the group of patients with migraine alone (6.7 days versus 9.6 days for patients with tension-type headache and 8.5 days for patients with combination headache, p < 0.02).. The duration and severity of withdrawal clearly depend on the type of overused headache drug only.

Topics: Adult; Analgesics; Drug Therapy, Combination; Ergotamine; Female; Headache; Humans; Indoles; Male; Middle Aged; Oxazolidinones; Piperidines; Prospective Studies; Substance Withdrawal Syndrome; Sumatriptan; Triazoles; Tryptamines; Vasoconstrictor Agents

Rizatriptan (MAXALT(TM), Merck & Co., Inc.) is a selective 5-HT(1B/1D) receptor agonist with rapid oral absorption and early onset of action for the acute treatment of migraine. This randomized, double-masked, double-dummy, placebo-controlled study compared rizatriptan 10 mg to naratriptan (NARAMIG(TM), AMERGE(TM), both Glaxo Wellcome plc) 2.5 mg in 522 patients treating a single migraine attack. Rizatriptan was more effective than naratriptan. Rizatriptan provided earlier headache relief than naratriptan (hazard ratio 1.62, p < 0.001), acting as early as 30 min. More patients were pain free at 2 h on rizatriptan than on naratriptan (44.8 vs. 20.7%, p < 0.001). Rizatriptan also provided earlier relief of associated migraine symptoms within 2 h than naratriptan and more patients had normal function at 2 h (39.3 vs. 22.6%, p < 0. 001). Both active treatments were effective compared to placebo. Both active treatments were well tolerated. The most common side effects with rizatriptan were dizziness, asthenia/fatigue, nausea and somnolence, while the most common side effects with naratriptan were dizziness and asthenia/fatigue.

Topics: Adult; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Indoles; Male; Middle Aged; Migraine Disorders; Piperidines; Recurrence; Serotonin Receptor Agonists; Treatment Outcome; Triazoles; Tryptamines

Clinical data on the transfer of triptans into human breast milk remain scarce. In a lactation study including 19 breastfeeding women with migraine, we examined the excretion of six different triptans into milk. Following intake of a single dose, each participant collected seven breast milk samples at predefined intervals up to 24 hours after dose. Triptan concentrations in milk were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Infant drug exposure was estimated by calculating the relative infant dose (RID). Twenty-two breast milk sample sets were obtained for sumatriptan (n = 8), rizatriptan (n = 5), zolmitriptan (n = 4), eletriptan (n = 3), almotriptan (n = 1) and naratriptan (n = 1). Based on the average concentration in milk throughout the day, estimated mean RIDs (with range in parenthesis) were as follows: eletriptan 0.6% (0.3%-0.8%), sumatriptan 0.7% (0.2%-1.8%), rizatriptan 0.9% (0.3%-1.4%), almotriptan 1.8% (-), zolmitriptan 2.1% (0.7%-5.3%) and naratriptan 5.0% (-). Infant drug exposure through breastfeeding appears to be low and indicates that use of the triptans in this study is compatible with breastfeeding. Naratriptan may not be first choice in breastfeeding mothers initiating triptans during the neonatal period.

Topics: Adult; Breast Feeding; Female; Humans; Infant; Infant, Newborn; Migraine Disorders; Milk, Human; Oxazolidinones; Piperidines; Pyrrolidines; Triazoles; Tryptamines

Chronic migraine (CM) is a common disorder, affecting 2% to 3% of the general population. Glutamate is implicated in cortical spreading depression, trigeminovascular activation, central sensitization, and may be linked to migraine chronification. Triptans brought a novel option for the acute migraine treatment. As the development of central sensitization impacts upon the effectiveness of triptan therapy, we hypothesized that glutamate might be related to triptan response mechanisms.. We studied 19 patients diagnosed with CM according to the International Headache Society (2004) criteria. Patients were divided in those overusing analgesics (NSAIDs); those without overuse, and those overusing triptans.. Cerebrospinal fluid (CSF) glutamate levels were similar in patients overusing acute medications (0.335 +/- 0.225 micromol) compared to those without overuse (0.354 +/- 0.141 micromol), P= NS). In contrast, patients overusing triptans had CSF glutamate levels significantly lower than that observed in nonoverusers (0.175 +/- 0.057 vs 0.354 +/- 0.141 micromol, P= 0.015), and significantly higher than controls (0.175 +/- 0.057 vs 0.109 +/- 0.066 micromol, P= 0.039). In triptan overusers, CSF glutamate levels, although lower, were not significantly different from patients overusing other types of analgesics.. Our study showed lower glutamate levels in CSF of CM patients overusing triptans. Glutamate may be implicated in triptan response mechanisms, triptans may work in part by reducing extracellular glutamate levels in the brain.

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Female; Glutamic Acid; Headache Disorders; Headache Disorders, Secondary; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Triazoles; Tryptamines

Topics: Acetaminophen; Age Factors; Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Child; Ergot Alkaloids; Humans; Ibuprofen; Life Style; Migraine Disorders; Oxazolidinones; Parents; Patient Education as Topic; Pediatrics; Piperidines; Pyrrolidines; Risk Factors; Serotonin Receptor Agonists; Sumatriptan; Taste Disorders; Triazoles; Tryptamines; Vasoconstrictor Agents

It has been suggested that triptans achieving higher central nervous system (CNS) levels should have an advantage in efficacy, if central actions are important. Objective.-Our aim was to correlate the efficacy and tolerability results of triptans with their lipophilicity.. Data for response and pain free at 2 hours, recurrence, adverse events (AE), CNS AE, and chest symptoms taken from Ferrari et al's meta-analysis publications for the recommended doses of oral triptans were correlated with their lipophilicity coefficients (logD(pH)7.4 = -2.1 almotriptan < -1.5 sumatriptan < -1.0 zolmitriptan < -0.7 rizatriptan < -0.2 naratriptan < 0.5 eletriptan).. We found no significant correlation between lipophilicity coefficients and any of the analyzed parameters. There was, however, some correlation between lipophilicity and CNS AE (P = .09, r = 0.74) and, to a lesser degree, with a reduction in recurrence rate (r = -0.36). The r values for response and pain free with placebo correction ranged from 0.04 to 0.34, suggesting almost no correlation between lipophilicity and efficacy variables.. According to this analysis, a higher lipophilicity does not seem crucial to improve triptan efficacy. This physico-chemical property, however, correlates with higher CNS AE and, possibly, lower recurrence rates.

Topics: Central Nervous System Diseases; Chemical Phenomena; Chemistry, Physical; Humans; Indoles; Migraine Disorders; Oxazolidinones; Piperidines; Serotonin Receptor Agonists; Statistics as Topic; Sumatriptan; Treatment Outcome; Triazoles; Tryptamines

A common side effect of migraine treatment with triptans is chest symptoms. The origin of these symptoms is not known. The aim of the present study was to examine the vasocontractile effect of triptans in human arteries and veins from the thoracic wall and in coronary artery bypass grafts. In vitro pharmacology experiments showed that the 5-hydroxytryptamine (5-HT) type 1B and 1D receptor agonists, eletriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan, induced vasoconstriction in the thoracic blood vessels from 38% to 57% of the patients. 5-carboxamidotryptamine (5-CT) and sumatriptan elicited a vasoconstriction that was antagonized by the 5-HT1B receptor antagonist SB224289, whereas the 5-HT1D receptor antagonist BRL115572 had no effect. 5-HT induced a contraction that was inhibited by the 5-HT2A receptor antagonist ketanserin. 5-HT2A, 5-HT1B, and 5-HT1D receptor mRNA levels were detected by real-time PCR in all blood vessels studied. In conclusion, triptans induce vasoconstriction in arteries and veins from the thoracic wall, most likely by activation of 5-HT1B receptors. This response could be observed in only 38% to 57% of the patients, which may provide an explanation for why a similar number of patients experience chest symptoms as a side effect of migraine treatment with triptans.

Topics: Aged; Aged, 80 and over; Arteries; Dose-Response Relationship, Drug; Female; Humans; Indoles; Male; Middle Aged; Oxazolidinones; Piperidines; Polymerase Chain Reaction; Serotonin Receptor Agonists; Sumatriptan; Thorax; Triazoles; Tryptamines; Vasoconstriction; Veins

Managed care and other decision makers need sound comparative information to support the formulary selection process and reimbursement decisions for the treatment of migraine. The objective of this study was to compare currently marketed triptan therapies using number-needed-to-treat (NNT) and doses-needed-to-treat (DNT) measures. DNT was further used to derive triptan treatment cost to achieve 100 successfully treated patients such that the cost-effectiveness of each treatment regime could be compared from the payer perspective.. Using published meta-analysis data to categorize patients as treatment success or failure, an NNT and a DNT were derived for each triptan. Treatment success was defined as achieving a 2-hour pain response, sustained through 24 hours postdose. Costs were derived by multiplying DNT by the average wholesale price (AWP) minus 15% for each triptan.. Eletriptan 40 mg had the lowest NNT, with 361 patients needing to be treated in order to have 100 patients achieve clinical benefit; rizatriptan 5 mg had the highest NNT (597 patients). Eletriptan 40 mg required 388 doses to successfully treat 100 patients.the lowest number of doses of the triptans considered; rizatriptan 5 mg required the highest number (662 doses). Eletriptan 40 mg had the lowest total triptan cost of USD 5,630 to successfully treat 100 patients. The highest total triptan cost of treatment was USD 11,136 for naratriptan 2.5 mg.. Eletriptan 40 mg provides the best value in terms of the lowest DNT, assuming an approximately equal AWP discount for each triptan. Eletriptan 40 mg also was found to have the lowest total triptan cost to successfully treat 100 patients. Future research should further explore the utility of DNT in managed care decision making.

Topics: Algorithms; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Costs; Humans; Managed Care Programs; Migraine Disorders; Piperidines; Pyrrolidines; Recurrence; Serotonin Receptor Agonists; Time Factors; Treatment Outcome; Triazoles; Tryptamines

Using a series of triptans we characterized in vitro the 5-hydroxytryptamine (5-HT) receptor that mediates the contraction in guinea-pig iliac arteries moderately precontracted by prostaglandin F2alpha (PGF2alpha). Additionally, we investigated by reverse-transcriptase polymerase chain reaction (RT-PCR) which triptan-sensitive receptor is present in this tissue. Frovatriptan, zolmitriptan, rizatriptan, naratriptan, sumatriptan, and almotriptan contracted guinea-pig iliac arteries with pD2 values of 7.52+/-0.04, 6.72+/-0.03, 6.38+/-0.06, 6.22+/-0.05, 5.86+/-0.05 and 5.26+/-0.04 respectively. For comparison, the pD2 values for 5-HT and 5-carboxamidotryptamine (5-CT) were 7.52+/-0.02 and 7.55+/-0.03 respectively. In contrast to all other triptans tested, the concentration-response curve for eletriptan was biphasic (first phase: 0.01-3 microM, pD2 approximately 6.6; second phase: > or = 10 microM). Contractions to 5-HT, 5-CT, frovatriptan, zolmitriptan, rizatriptan, naratriptan, sumatriptan, almotriptan, and eletriptan (first phase) were antagonized by the 5-HT1B/1D receptor antagonist GR127935 (10 nM) and the 5-HT1B receptor antagonist SB216641 (10 nM). RT-PCR studies in guinea-pig iliac arteries showed a strong signal for the 5-HT1B receptor while expression of 5-HT1D and 5-HT1F receptors was not detected in any sample. The present results demonstrate that triptan-induced contraction in guinea-pig iliac arteries is mediated by the 5-HT1B receptor. The guinea-pig iliac artery may be used as a convenient in vitro model to study the (cardio)vascular side-effect potential of anti-migraine drugs of the triptan family.

Topics: Animals; Benzamides; Brain; Carbazoles; Dinoprost; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Endothelium, Vascular; Female; Forecasting; Guinea Pigs; Iliac Artery; Indoles; Ketanserin; Male; Muscle Contraction; Muscle, Smooth; Oxadiazoles; Oxazolidinones; Piperazines; Piperidines; Pyrrolidines; Receptor, Serotonin, 5-HT1B; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Serotonin; Serotonin 5-HT1 Receptor Antagonists; Sumatriptan; Triazoles; Tryptamines

"Reaction phenotyping" studies were performed with eletriptan (ETT) to determine its propensity to interact with coadministered medications. Its ability to serve as a substrate for human P-glycoprotein (P-gp) was also investigated since a central mechanism of action has been proposed for this "triptan" class of drug. In studies with a characterized bank of human liver microsome preparations, a good correlation (r2 = 0.932) was obtained between formation of N-desmethyl eletriptan (DETT) and CYP3A4-catalyzed testosterone 6 beta-hydroxylation. DETT was selected to be monitored in our studies since it represents a significant ETT metabolite in humans, circulating at concentrations 10 to 20% of those observed for parent drug. ETT was metabolized to DETT by recombinant CYP2D6 (rCYP2D6) and rCYP3A4, and to a lesser extent by rCYP2C9 and rCYP2C19. The metabolism of ETT to DETT in human liver microsomes was markedly inhibited by troleandomycin, erythromycin, miconazole, and an inhibitory antibody to CYP3A4, but not by inhibitors of other major P450 enzymes. ETT had little inhibitory effect on any of the P450 enzymes investigated. ETT was determined to be a good substrate for human P-gp in vitro. In bidirectional transport studies across LLC-MDR1 and LLC-Mdr1a cell monolayers, ETT had a BA/AB transport ratio in the range 9 to 11. This finding had significance in vivo since brain exposure to ETT was reduced 40-fold in Mdr1a+/+ relative to Mdr1a-/- mice. ETT metabolism to DETT is therefore catalyzed primarily by CYP3A4, and plasma concentrations are expected to be increased when coadministered with inhibitors of CYP3A4 and P-gp activity.

Topics: Animals; Aryl Hydrocarbon Hydroxylases; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Brain; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Erythromycin; Genes, MDR; Humans; Indoles; Injections, Intravenous; Male; Mice; Mice, Mutant Strains; Miconazole; Microsomes, Liver; Oxazolidinones; Oxidoreductases, N-Demethylating; Phenotype; Piperidines; Pyrrolidines; Recombinant Proteins; Statistics as Topic; Sumatriptan; Triazoles; Troleandomycin; Tryptamines

The effects of naratriptan, rizatriptan, and sumatriptan on arteriovenous oxygen saturation difference and carotid hemodynamics were compared in the anesthetized pig. Oxygen and carbon dioxide partial pressures in systemic arterial and jugular venous blood as well as hemoglobin oxygen saturation were determined by conventional blood gas analysis. Vehicle (n = 19) or naratriptan, rizatriptan, or sumatriptan (0.63, 2.5, 10, 40, 160, 630, and 2,500 microg/kg i.v.; n = 7/group) were infused cumulatively. In naratriptan-, rizatriptan-, and sumatriptan-treated animals, jugular venous oxygen saturation decreased dose dependently (geometric mean ED50 values of 3.1, 17.9, and 16.0 microg/kg, respectively) concomitantly with increases in carotid vascular resistance. Rizatriptan significantly and dose dependently, from 160 microg/kg, increased PvCO2 (P < 0.05 versus vehicle). Naratriptan and sumatriptan also tended to increase PvCO2 albeit nonstatistically significantly. All three triptans consistently evoked quantitatively similar carotid vasoconstriction, whereas decreases in jugular venous oxygen saturation (VOS) and increases in PvCO2 had different magnitudes and occurred only in around one-half of the animals studied. Maximal variations in PvCO2 were found to correlate highly with those in PvO2 (P = 0.002), but maximal variations in carotid resistance failed to correlate with those in PvCO2 (P = 0.76) or PvO2 (P = 0.28). The results demonstrate that the triptans investigated robustly produced carotid vasoconstriction, but elicited less consistent decreases in VOS and increases in jugular PvCO2, possibly suggestive of distinct mechanisms. Collectively, the data suggest that triptan-induced increases in arteriovenous oxygen saturation difference and carbon dioxide partial pressure in venous blood draining the head are class effects.

Topics: Anesthesia; Animals; Blood Gas Analysis; Hemodynamics; Indoles; Jugular Veins; Male; Migraine Disorders; Oxygen; Piperidines; Sumatriptan; Swine; Triazoles; Tryptamines; Vasoconstriction; Vasoconstrictor Agents

Topics: Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Indoles; Migraine Disorders; Oxazolidinones; Piperidines; Pyrrolidines; Receptors, Serotonin, 5-HT1; Serotonin Receptor Agonists; Sumatriptan; Triazoles; Tryptamines

Many migraine patients are unable to function normally during a migraine attack. Assessments of treatment efficacy have tended to focus on migraine symptoms, rather than looking at functional impact. This study compared the efficacy of different oral triptans for restoring normal function in migraine sufferers.. Retrospective subgroup analysis of data from five randomized, placebo-controlled, double-blind clinical trials in which oral rizatriptan was directly compared with oral sumatriptan 100 mg (772 attacks), 50 mg (2,227 attacks), and 25 mg (1,182 attacks), naratriptan 2.5 mg (413 attacks), and zolmitriptan 2.5 mg (578 attacks) for the acute treatment of a moderate or severe migraine attack. Functional disability was evaluated by patients on a 4-grade scale ('normal', 'mild impairment', 'severe impairment', 'requires bedrest') at baseline and at 0.5, 1, 1.5, 2, 3 and 4 h after dosing. This analysis looked at the percentage of patients who had normal functional ability at 2 h, the last time point before escape medications were allowed, in the subgroup of patients who had some level of disability at baseline.. Most patients in each trial and treatment group had some level of disability at baseline (range = 94-100%). At 2 h, more patients on rizatriptan 10 mg were able to function normally compared with sumatriptan 100 mg (39 vs. 32%, odds ratio = 1.4, p = 0.021), sumatriptan 50 mg (47 vs. 42%, odds ratio = 1.2, p = 0.033), sumatriptan 25 mg (48 vs. 36%, odds ratio = 1.7, p < 0.001), naratriptan 2.5 mg (39 vs. 22%, odds ratio = 2.5, p < 0.001), and zolmitriptan 2.5 mg (45 vs. 36%, odds ratio = 1.6, p = 0.008).. In direct head-to-head comparative clinical trials, oral rizatriptan 10 mg enabled more migraine sufferers to function normally at 2 h after dosing than oral sumatriptan, naratriptan, and zolmitriptan.

Topics: Administration, Oral; Adolescent; Adult; Aged; Female; Humans; Indoles; Male; Middle Aged; Migraine Disorders; Oxazolidinones; Piperidines; Randomized Controlled Trials as Topic; Retrospective Studies; Serotonin Receptor Agonists; Sumatriptan; Treatment Outcome; Triazoles; Tryptamines

To compare patient self-reported tablet consumption of rizatriptan 10 mg per attack (24 hours) with that of sumatriptan 50 mg, zolmitriptan 2.5 mg, and naratriptan 2.5 mg on an unselected, prescription-based, Spanish migraine population.. One hundred twenty community pharmacies recruited patients with migraine, who used their pharmacies, to fill a triptan prescription. In diaries, patients recorded baseline pain intensity and the number of triptan tablets and additional medication taken per attack. Patients treated a maximum of three attacks. Analysis of variance or the Student t test and chi-square or Fisher exact tests were used for univariate comparisons. Hochberg corrections were used for multiple-group comparisons. A generalized estimating equation method was used to correct for within-subject correlation. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated.. Two hundred thirty-one patients (84% women) treated 589 evaluable migraine attacks (sumatriptan, n = 135; naratriptan, n = 90; zolmitriptan, n = 149; rizatriptan, n = 149). Triptan tablet consumption per attack (mean +/- SD) for rizatriptan (1.24 +/- 0.56) was significantly lower than that of sumatriptan (1.75 +/- 1.2; P< .05), zolmitriptan (1.61 +/- 0.86; P < .05), or naratriptan (1.46 +/- 0.62; P= .05). The average number of triptan tablets taken and additional medication use increased according to baseline pain severity. More attacks were treated with one tablet of rizatriptan (81.2%) than with one tablet of sumatriptan (51.9%), zolmitriptan (55.7%), or naratriptan (60%). The probability of using more than one triptan tablet per attack (24 hours) was more than three times greater for sumatriptan (adjusted OR = 3.71; CI, 2.05 to 6.7; P = .001) and zolmitriptan (adjusted OR = 3.32; CI, 1.82 to 6.17; P = .001), and more than two times greater for naratriptan (adjusted OR = 2.66; CI, 1.36 to 5.21; P =.004) than for rizatriptan.. Rizatriptan was associated with significantly lower triptan tablet use and additional medication use per attack than the other triptans. Additional randomized studies are needed to confirm the conclusions of this study.

Topics: Female; Humans; Indoles; Male; Migraine Disorders; Oxazolidinones; Piperidines; Prospective Studies; Serotonin Receptor Agonists; Sumatriptan; Tablets; Triazoles; Tryptamines

To compare the effects of oral rizatriptan, sumatriptan, naratriptan, and zolmitriptan on the relief and emergence of nausea during a migraine attack.. Data from five randomized, placebo-controlled, double-blind clinical trials in which oral rizatriptan 10 mg was directly compared with oral sumatriptan 100 mg (N = 772), 50 mg (N = 1168), 25 mg (N = 1180), naratriptan 2.5 mg (N = 406), or zolmitriptan 2.5 mg (N = 571) for the acute treatment of a migraine attack were retrospectively analyzed. Migraine was diagnosed according to International Headache Society criteria. Presence or absence of nausea was recorded at baseline and at 0.5, 1, 1.5, and 2 hours after dosing. The end points analyzed were relief of nausea in those who had it at baseline and emergence of nausea in those who were free of it at baseline. Treatments were compared using odds ratios estimated from logistic regression models at 2 hours, and averaged odds ratios for the first 2 hours posttreatment.. Approximately 60% of patients in each treatment group had nausea at baseline. In those patients with nausea at baseline, significantly more patients treated with rizatriptan 10 mg were free of nausea at 2 hours compared with sumatriptan 100 mg (66% versus 58%, P =.043), sumatriptan 50 mg (68% versus 57%, P =.010), sumatriptan 25 mg (68% versus 59%, P =.017), and naratriptan 2.5 mg (59% versus 45%, P =.014). Averaging over the four posttreatment time points in the first 2 hours, significantly more patients treated with rizatriptan 10 mg were free of nausea compared with sumatriptan 100 mg (P =.004), sumatriptan 50 mg (P =.001), and naratriptan 2.5 mg (P =.015). No significant differences in nausea relief were seen between rizatriptan 10 mg and zolmitriptan 2.5 mg, either at 2 hours (65% versus 61%, P =.210) or over the first 2 hours (P =.781). Rates of treatment-emergent nausea at 2 hours ranged from 11% to 18% with placebo, from 5% to 13% with rizatriptan 10 mg, and from 10% to 20% with other comparator triptans.. Oral rizatriptan 10 mg was more effective than oral sumatriptan and naratriptan at eliminating nausea within 2 hours in patients who had it at baseline. Rates of emergent nausea in patients who were free of it at baseline were low, and no consistent differences were observed between active treatments.

Topics: Administration, Oral; Adult; Double-Blind Method; Humans; Indoles; Migraine Disorders; Nausea; Oxazolidinones; Piperidines; Randomized Controlled Trials as Topic; Serotonin Receptor Agonists; Sumatriptan; Triazoles; Tryptamines; Vasoconstrictor Agents

Four drugs in the triptan class are now available for the treatment of acute migraine--sumatriptan, rizatriptan, naratriptan, and zolmitriptan. For clinicians prescribing these drugs, data on the comparative advantages and disadvantages of each medication can aid in drug selection. For example, in 2 recently conducted clinical trials, rizatriptan was found to have several advantages over naratriptan and zolmitriptan. Compared with both drugs, rizatriptan provided more rapid relief of headache pain and associated nausea, and allowed patients to return to normal activities more quickly. These are important advantages for patients, particularly when migraine affects their ability to function on the job or at home.

Topics: Adolescent; Adult; Aged; Female; Humans; Male; Middle Aged; Migraine Disorders; Oxazolidinones; Piperidines; Serotonin Receptor Agonists; Time Factors; Treatment Outcome; Triazoles; Tryptamines; Vasoconstrictor Agents; Young Adult

Development of a rapid, sensitive and selective method for the determination of antimigraine drugs from human serum is essential for understanding the pharmacokinetics of these drugs when administered concurrently. Solid phase extraction (SPE) using Oasis HLB was used to extract the drugs (sumatriptan, naratriptan, zolmitriptan and rizatriptan) and the internal standard bufotenine from serum. A method based on liquid chromatography/tandem mass spectrometry (LC/MS/MS) was developed and validated to simultaneously quantitate these antimigraine drugs from human serum. The precursor and major product ions of the analytes were monitored on a triple quadrupole mass spectrometer with positive ion electrospray ionization (ESI) in the multiple reaction monitoring (MRM) mode. The base peak in all the analytes is formed by alpha cleavage associated with protonation of the secondary amine. Mechanisms for the formation of the collision-induced dissociation products of these antimigraine compounds are proposed. Linear calibration curves were generated from 1-100 ng/mL with all coefficients of determination greater than 0.99. The inter- and intraday precision (%RSD) were less than 9.3% and accuracy (%error) was less than 9.8% for all components. The limits of detection (LOD) for the method were 250 pg/mL for sumatriptan and 100 pg/mL for the remaining analytes based on a signal-to-noise ratio of 3.

Topics: Bufotenin; Chromatography, High Pressure Liquid; Humans; Indoles; Mass Spectrometry; Migraine Disorders; Molecular Structure; Oxazoles; Oxazolidinones; Piperidines; Sensitivity and Specificity; Serotonin Receptor Agonists; Sumatriptan; Triazoles; Tryptamines; Vasoconstrictor Agents

Topics: Absenteeism; Adult; Cost-Benefit Analysis; Efficiency; Female; Humans; Indoles; Injections, Subcutaneous; Male; Migraine Disorders; Oxazoles; Oxazolidinones; Piperidines; Randomized Controlled Trials as Topic; Self Administration; Serotonin Receptor Agonists; Sumatriptan; Treatment Outcome; Triazoles; Tryptamines; Workplace

Topics: Analgesics; Headache; Humans; Indoles; Oxazolidinones; Piperidines; Randomized Controlled Trials as Topic; Serotonin Receptor Agonists; Sumatriptan; Time Factors; Triazoles; Tryptamines

The affinity of eletriptan ((R)-3-(1-methyl-2-pyrrolidinylmethyl)-5-[2-(phenylsulphonyl )ethyl]-1H-indole) for a range of 5-HT receptors was compared to values obtained for other 5-HT1B/1D receptor agonists known to be effective in the treatment of migraine. Eletriptan, like sumatriptan, zolmitriptan, naratriptan and rizatriptan had highest affinity for the human 5-HT1B, 5-HT1D and putative 5-ht1f receptor. Kinetic studies comparing the binding of [3H]eletriptan and [3H]sumatriptan to the human recombinant 5-HT1B and 5-HT1D receptors expressed in HeLa cells revealed that both radioligands bound with high specificity (>90%) and reached equilibrium within 10-15 min. However, [3H]eletriptan had over 6-fold higher affinity than [3H]sumatriptan at the 5-HT1D receptor (K(D)): 0.92 and 6.58 nM, respectively) and over 3-fold higher affinity than [3H]sumatriptan at the 5-HT1B receptor (K(D): 3.14 and 11.07 nM, respectively). Association and dissociation rates for both radioligands could only be accurately determined at the 5-HT1D receptor and then only at 4 degrees C. At this temperature, [3H]eletriptan had a significantly (P<0.05) faster association rate (K(on) 0.249 min(-1) nM(-1)) than [3H]sumatriptan (K(on) 0.024 min(-1) nM(-1)) and a significantly (P<0.05) slower off-rate (K(off) 0.027 min(-1) compared to 0.037 min(-1) for [3H]sumatriptan). These data indicate that eletriptan is a potent ligand at the human 5-HT1B, 5-HT1D, and 5-ht1f receptors and are consistent with its potent vasoconstrictor activity and use as a drug for the acute treatment of migraine headache.

Topics: Animals; Binding, Competitive; Cell Line; Cold Temperature; COS Cells; HeLa Cells; Humans; Indoles; Kinetics; Oxazoles; Oxazolidinones; Piperidines; Pyrrolidines; Radioligand Assay; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin; Sumatriptan; Triazoles; Tritium; Tryptamines

The antimigraine drugs ergotamine and sumatriptan may cause angina-like symptoms, possibly resulting from coronary artery constriction. We compared the coronary vasoconstrictor potential of a number of current and prospective antimigraine drugs (ergotamine, dihydroergotamine, methysergide and its metabolite methylergometrine, sumatriptan, naratriptan, zolmitriptan, rizatriptan, avitriptan).. Concentration-response curves to the antimigraine drugs were constructed in human isolated coronary artery segments to obtain the maximum contractile response (Emax) and the concentration eliciting 50% of Emax (EC50). The EC50 values were related to maximum plasma concentrations (Cmax) reported in patients, obtaining Cmax/EC50 ratios as an index of coronary vasoconstriction occurring in the clinical setting. Furthermore, we studied the duration of contractile responses after washout of the acutely acting antimigraine drugs to assess their disappearance from the receptor biophase. Compared with sumatriptan, all drugs were more potent (lower EC50 values) in contracting the coronary artery but had similar efficacies (Emax <25% of K+-induced contraction). The Cmax of avitriptan was 7- to 11-fold higher than its EC50 value, whereas those of the other drugs were <40% of their respective EC50 values. The contractile responses to ergotamine and dihydroergotamine persisted even after repeated washings, but those to the other drugs declined rapidly after washing.. All current and prospective antimigraine drugs contract the human coronary artery in vitro, but in view of low efficacy, these drugs are unlikely to cause myocardial ischemia at therapeutic plasma concentrations in healthy subjects. In patients with coronary artery disease, however, these drugs must remain contraindicated. The sustained contraction by ergotamine and dihydroergotamine seems to be an important disadvantage compared with sumatriptan-like drugs.

Topics: Adolescent; Adult; Aged; Angina Pectoris; Child; Coronary Vessels; Dihydroergotamine; Ergotamine; Female; Humans; In Vitro Techniques; Indoles; Male; Methysergide; Middle Aged; Migraine Disorders; Piperidines; Sulfonamides; Sumatriptan; Triazoles; Tryptamines; Vasoconstrictor Agents

Topics: Adrenergic beta-Antagonists; Amitriptyline; Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents, Tricyclic; Calcium Channel Blockers; Dihydroergotamine; Drug Interactions; Ergotamine; Humans; Indoles; Methysergide; Migraine Disorders; Naproxen; Oxazoles; Oxazolidinones; Piperidines; Propranolol; Selective Serotonin Reuptake Inhibitors; Serotonin Receptor Agonists; Sumatriptan; Time Factors; Timolol; Triazoles; Tryptamines; Valproic Acid; Vasoconstrictor Agents