piperidines and almotriptan

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

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

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

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

The aim of this case/non-case study was to assess and compare the risk of drug dependence associated with different migraine-specific drugs, i.e., ergot derivatives and triptans, using the French pharmacovigilance database.. Reports on drug side effects recorded in this database between January 1985 and June 2007 were analyzed, and triptans (almotriptan, eletriptan, naratriptan, sumatriptan, and zolmitriptan) as well as ergot derivatives used in acute migraine were examined. For all reports, cases were defined as those reports corresponding to "drug abuse," "physical or mental drug dependence," and "pharmacodependence," whereas "non-cases" were defined as all the remaining SED reports. The method's reliability was assessed by calculating the risk associated with a negative (amoxicillin) and a positive (benzodiazepines) control. The risk of dependence associated with each drug and control was evaluated by calculating the odds ratio (OR) with a confidence interval of 95%.. Among the 309,178 reports recorded in the database, drug dependence accounted for 0.8% (2,489) of the reports, with 10.9% (449) involving a triptan, and 9.33% (332) an ergot derivative. The risk of dependence was similar for triptans and ergot derivatives and did not differ from that of benzodiazepines. In the triptan group, the risk (odds ratio [95% CI]) ranged from 10.3 [4.8-22.3] for sumatriptan to 21.5 for eletriptan [10.1-45.6], while in the ergot derivative group, it ranged from 12 [8-17.9] for ergotamine to 20.6 [8-53] for dihydroergotamine.. These findings confirm the hypothesis that triptans and ergot derivatives are associated with an increased risk of drug dependence.

Topics: Claviceps; Dihydroergotamine; Ergotamine; Humans; Migraine Disorders; Oxazolidinones; Piperidines; Pyrrolidines; Risk; Substance-Related Disorders; Sumatriptan; Tryptamines

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

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