piperidines and naratriptan

Naratriptan, marketed in a low oral dose of 2.5 mg, is generally regarded as a less-effective triptan with a slower onset of action than most other triptans in the treatment of migraine attacks. In this review, naratriptan will be compared with sumatriptan, the standard triptan.. Papers on pharmacodynamics and pharmacokinetics and results from comparative clinical trials with oral and subcutaneous naratriptan versus other triptans were retrieved from PubMed.. Naratriptan and sumatriptan have similar effects in relevant animal models. In a randomized controlled trial, oral naratriptan 2.5 mg is less effective than oral sumatriptan 100 mg after both 2 h and 4 h. In contrast, oral naratriptan 10 mg has a similar time-effect curve as oral sumatriptan 100 mg, in both its steepness and the efficacy at 2 h and 4 h. Subcutaneous naratriptan 10 mg (88% pain free at 2 h) was in one trial superior to subcutaneous sumatriptan 6 mg (55% pain free at 2 h).. Naratriptan was marketed for the treatment of migraine attacks as the "gentle triptan" in a low oral dose of 2.5 mg, a dose with no more adverse events than placebo. This low dose results in the slow onset of action and low efficacy of oral naratriptan, but in high doses oral naratriptan is similar to oral sumatriptan. Based on one randomized controlled trial, subcutaneous naratriptan has probably the greatest effect of any triptan.

Topics: Animals; Migraine Disorders; Piperidines; Randomized Controlled Trials as Topic; Serotonin Receptor Agonists; Sumatriptan; Tryptamines

Recent triptan development has focused on new administration methods and formulations, triptan combination therapies, treatment in menstrually related migraines, and novel serotonin receptor subtype agonists (5HTf). Areas covered: Clinical triptan research related to migraine was reviewed, analyzing EMBASE and PUBMED data bases from 01/01/2011 to 06/29/2016, with a focus on clinical trials of class 1 or 2 level of evidence. There have been advances in drug combination therapies, as well as administration devices that aid in ease of use, increase efficacy, and decrease adverse reactions. Some new agents and devices have similar or less efficacy compared to previous generic triptan formulations. New agents have action at the 5HTf receptor subtype, and avoid vascular side effects of classic 5Ht1b/d agonists, however adverse reactions may limit their clinic use. Long half-life triptans, frovatriptan and naratriptan, do appear to have good benefit in menstral related migraine. Expert opinion: Recent advances in triptan development can offer some advantages to migraine therapy and patient preferences, but have a much higher cost compared to individual generic triptan agents. In the coming years, triptan advances with high efficacy, limiting ADRs and cost are welcomed, in this regard the 5HT1b/d triptans are already well established.

Topics: Carbazoles; Humans; Migraine Disorders; Piperidines; Serotonin 5-HT1 Receptor Agonists; Serotonin Receptor Agonists; Tryptamines

Migraine is a common, disabling condition and a burden for the individual, health services, and society. Many sufferers choose not to, or are unable to, seek professional help and rely on over-the-counter analgesics. Naproxen is a non-steroidal anti-inflammatory drug (NSAID); its efficacy in acute migraine has not been established by systematic reviews. Co-therapy with an antiemetic should help to reduce the nausea and vomiting commonly associated with migraine headaches.. To determine the efficacy and tolerability of naproxen, alone or in combination with an antiemetic, compared with placebo and other active interventions in the treatment of acute migraine headaches in adults.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library, MEDLINE, EMBASE, and the Oxford Pain Relief Database, together with two online databases (www.gsk-clinicalstudyregister.com and www.clinicaltrials.gov) and reference lists, for studies to 22 May 2013.. We included randomised, double-blind, placebo- or active-controlled studies, with at least 10 participants per treatment arm, using naproxen alone or with an antiemetic to treat a migraine headache episode.. Two review authors independently assessed trial quality and extracted data. We used numbers of participants achieving each outcome to calculate risk ratios and numbers needed to treat (NNT) or harm (NNH) compared with placebo or a different active treatment.. We included six studies using naproxen 275 mg, 500 mg, or 825 mg to treat attacks of moderate or severe pain intensity. Overall, 1241 participants took naproxen (275 mg to 825 mg), 229 took sumatriptan 50 mg, 173 took naratriptan 2.5 mg, and 1092 took placebo. No studies combined naproxen with an antiemetic. Studies using naproxen 275 mg provided no useable data for analysis.Naproxen (500 mg and 825 mg) was better than placebo for pain-free response and headache relief. At two hours, the NNT for pain-free response was 11 (17% response with naproxen, 8% with placebo; risk ratio 2.0 (95% CI 1.6 to 2.6), moderate quality) and for headache relief was 6.0 (45% response with naproxen, 29% with placebo; risk ratio 1.6 (1.4 to 1.8), moderate quality). The NNT for sustained pain-free response during the 24 hours post dose was 19 (12% response with naproxen, 6.7% with placebo), and for sustained headache relief during the 24 hours post dose was 8.3 (30% response with naproxen, 18% with placebo). Analysing only the lower dose of 500 mg of naproxen did not significantly change the results. Adverse events, which were mostly mild or moderate in severity and rarely led to withdrawal, were more common with naproxen than with placebo when the 500 mg and 825 mg doses were considered together, but not when the 500 mg dose was analysed alone.There were insufficient data for analysis of naproxen compared with sumatriptan, and no data suitable for analysis of naproxen compared with naratriptan.. Naproxen is statistically superior to placebo in the treatment of acute migraine, but the NNT of 11 for pain-free response at two hours suggests that it is not a clinically useful treatment. Cochrane reviews examining other commonly used analgesics for acute migraine have reported better (lower) NNT results for the same outcome. Naproxen is not clinically useful as a stand-alone analgesic in acute migraine, as it is effective in fewer than 2 people in 10.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Antiemetics; Drug Therapy, Combination; Humans; Migraine Disorders; Naproxen; Nausea; Piperidines; Randomized Controlled Trials as Topic; Sumatriptan; Tryptamines; Vomiting

Naratriptan 2.5 mg is now an over-the-counter drug in Germany. This should increase the interest in drug. The GSK Trial Register was searched for published and unpublished double-blind, randomised, controlled trials (RCTs) concerning the use of naratriptan in migraine. Only 7 of 17 RCTs are published in full. Naratriptan 2.5 mg is superior to placebo for acute migraine treatment in 6 RCTs, but inferior to sumatriptan 100 mg and rizatriptan 10 mg in one RCT each. This dose of naratriptan has no more adverse events than placebo. Naratriptan 1 mg b.i.d. has some effect in the short-term prophylactic treatment of menstruation-associated migraine in 3 RCTs. In 2 RCTs, naratriptan 2.5 mg was equivalent to naproxen sodium 375 mg for migraine-related quality of life. Naratriptan 2.5 mg (34% preference) was superior to naproxen sodium 500 mg (25% preference). Naratriptan 2.5 mg is better than placebo in the acute treatment of migraine. The adverse effect profile of naratriptan 2.5 mg is similar to that of placebo. The efficacy of naratriptan 2.5 mg versus NSAIDs is not sufficiently investigated. Naratriptan, when available OTC is a reasonable second or third choice on the step care ladder in the acute treatment of migraine.

Topics: Double-Blind Method; Germany; Humans; Migraine Disorders; Piperidines; Randomized Controlled Trials as Topic; Registries; Serotonin 5-HT1 Receptor Agonists; Tryptamines

Topics: Humans; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Tryptamines

In 2006, the triptans sumatriptan 50mg and naratriptan 2.5mg were approved as over-the-counter (OTC) drugs in pharmacies in the UK and Germany, respectively. Both drugs have been used in a large number of patients with migraine and are considered to have good safety profiles. The implications of OTC triptan availability for clinical practice are that more migraine patients will use a triptan and will tend to medicate early when their headache is still mild, which should be beneficial. The problem with OTC access to triptans is medication overuse; therefore, patients should be warned of this and advised to use a triptan on fewer than 10 days per month. Pharmacists should be educated regarding migraine types and symptoms and on contraindications to triptans, so they are then able to discern the patients who should receive triptans and, as importantly, those who should not. The annual cost of migraine is euro27 billion in Europe, $US1.4 billion in the UK and $US16.6 billion in the US. By far the greatest opportunity for cost-savings comes from the potential to reduce costs associated with lost productivity from migraine. OTC availability of triptans will inevitably result in easier access to these medications, which, in turn, may result in improved treatment and lower migraine-related disability. There is currently a lack of empirical evidence that treating migraine effectively does in fact recover lost productivity; well designed studies are required to show this. The availability of triptans OTC is a logical development for the better management of a common, benign, self-limiting but nonetheless burdensome disorder that is currently grossly undertreated. We welcome this development, but recognise that advice at the point of sale is crucial for effective and safe use of these drugs.

Topics: Germany; Humans; Migraine Disorders; Nonprescription Drugs; Piperidines; Serotonin Receptor Agonists; Sumatriptan; Treatment Outcome; Tryptamines; United Kingdom

The clinical efficacy in migraine was compared for oral and subcutaneous sumatriptan and naratriptan. Doses of the two administration forms were chosen as resulting in comparable blood concentrations. Subcutaneous administrations of the drugs were superior for efficacy than the oral forms. This most likely due to a quicker rise in blood concentrations after subcutaneous injections.. In designing new therapies for migraine one should aim at a quick absorption of the drug, which will probably result in an increased efficacy.

Topics: Administration, Oral; Biological Availability; Humans; Infusions, Parenteral; Injections, Subcutaneous; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Sumatriptan; Time Factors; Treatment Outcome; Tryptamines

The basic CNS neuropharmacology of naratriptan is reviewed here. Naratriptan is a second-generation triptan antimigraine drug, developed at a time when CNS activity was thought not to be relevant to its therapeutic effect in migraine. It was, however, developed to be a more lipid-soluble, more readily absorbed and less readily metabolized variant on preexisting triptans and these variations conferred on it a higher CNS profile. Naratriptan is a 5-HT(1B/1D) receptor agonist with a highly selective action on migraine pain and nausea, without significant effect on other pain or even other trigeminal pain. Probable sites of therapeutic action of naratriptan include any or all of: the cranial vasculature; the peripheral terminations of trigeminovascular sensory nerves; the first-order synapses of the trigeminovascular sensory system; the descending pain control system; and the nuclei of the thalamus. Naratriptan may prevent painful dilatation of intracranial vessels or reverse such painful dilatation. Naratriptan can prevent the release of sensory peptides and inhibit painful neurogenic vasodilatation of intracranial blood vessels. At the first order synapse of the trigeminal sensory system, naratriptan can selectively suppress neurotransmission from sensory fibers from dural and vascular tissue, while sparing transmission from other trigeminal fibers, probably through inhibition of neuropeptide transmitter release. In the periaqueductal gray matter and in the nucleus raphe magnus, naratriptan selectively activates inhibitory neurons which project to the trigeminal nucleus and spinal cord and which exert inhibitory influences on trigeminovascular sensory input. Naratriptan has also a therapeutic effect on the nausea of migraine, possibly exerting its action at the level of the nucleus tractus solitarius via the same mechanisms by which it inhibits trigeminovascular nociceptive input. The incidence of naratriptan-induced adverse effects in the CNS is low and it is not an analgesic for pain other than that of vascular headache. In patients receiving selective serotonin uptake inhibitors (SSRIs) naratriptan may cause serotonin syndrome-like behavioral side effects. The mechanism of action involved in the production of behavioral and other CNS side effects of naratriptan is unknown.

Topics: Analgesia; Animals; Cardiovascular Diseases; Humans; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Tryptamines

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

Naratriptan is a selective 5-HT(1B/1D) receptor agonist, with a high affinity at the 5-HT(1B), 5-HT(1D) and 5-HT(1F) receptor subtypes. Naratriptan contracts a number of large isolated cerebral arteries from several species, and has little contractile effect on peripheral blood vessels. It has an inhibitory effect on the cranial neurogenic inflammation model. The clinically recommended dose is 2.5 mg. It was found significantly superior to placebo on headache relief and pain free at 2 and 4 hours, and in relieving nausea, photophobia and phonophobia. It also has a good within-patient consistency, and a low recurrence rate. The side-effect profile is that of the triptan class, wih an incidence no different from placebo at the 25 mg dose. The contraindications are similar to any triptan, including coronary disease. Naratriptan is unlikely to affect metabolism of other drugs. In comparison sumatriptan 100 mg, naratriptan 2.5 mg has a slower onset of action and a lower response rate at 4 h, but it has a lower recurrence rate, and is better tolerated.

Topics: Humans; Indoles; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; 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

Sumatriptan is a 5-HT1B/D receptor agonist of documented efficacy in relieving migraine and associated symptoms such as nausea and vomiting. In the past decade, several studies reported an important delay of gastric emptying induced by sumatriptan in healthy humans. The impact of this gastric motor effect of sumatriptan in migraineurs is difficult to predict: a further delay in gastric emptying could be detrimental (i.e. increased nausea and epigastric symptoms) in patients already having delayed gastric emptying. However, in patients with functional dyspepsia, sumatriptan is also reported to improve gastric accommodation to a meal and reduce perception of gastric distention, hence relieving epigastric symptoms. Thus, reduced visceral perception could be a mechanism involved in reducing nausea during a migraine attack. Paradoxically, sumatriptan is reported both to relieve the nausea of a migraine attack and to have nausea as a side effect. Although careful analysis of the time of onset of nausea may offer a clue as to the origin of this symptom, available data do not support definite conclusions, all the more so because the gastric motor effect of second-generation triptans are still unexplored. Taken together, the available evidence warrants further studies to clarify the following issues: first, the mechanism responsible for the gastric motor effect of sumatriptan [receptor subtype(s) involved; central vs peripheral mechanism]; secondly, the effects on gastric motility/visceral sensitivity of second-generation triptans (which are 5-HT1B/D receptor agonists) and more recent selective 5-HT1D receptor agonists (proposed as investigational antimigraine agents with less potential to induce coronary vasoconstriction through 5-HT1B receptors); finally, the possible use of drugs improving gastric accommodation to a meal in the management of those dyspeptic patients with impaired fundic relaxation/altered visceral sensitivity.

Topics: Forecasting; Gastrointestinal Motility; Humans; Indoles; Nausea; Piperidines; Serotonin Receptor Agonists; Sumatriptan; Tryptamines; Vomiting

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

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

Migraine headaches are a common medical problem that physicians frequently encounter in their practice. They can be disabling, leading to the individual's suffering if not treated appropriately and quickly. There is a variety of medications and treatment approaches that can be used to relieve pain and any associated symptoms. New medications have become available in recent years to aggressively treat migraine headaches. Called "triptans," these medications have been designed to specifically treat an acute migraine attack and can be effective if used early and properly. Many medications are also available to treat symptoms associated with migraines. Patient education, along with nonpharmacologic approaches, is an element of effective treatment. Biofeedback, relaxation, and physical techniques can be effective adjunctive options. Although nonprescription medications can be helpful initially, more specific treatment is often required. Opioids, phenothiazines, ergotamine, and the triptans are generally used in patients with difficult migraines. The newer agents, the triptans, offer new hope in aggressively treating this painful condition that often has an impact on individuals and their families.

Topics: Analgesics; Ergotamine; Humans; Indoles; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Sumatriptan; Tryptamines; Vasoconstrictor Agents

To critically evaluate the literature regarding naratriptan's clinical pharmacology, efficacy, safety, and indications.. A MEDLINE search was conducted for the period from January 1990 to June 1998. Key words used included naratriptan, triptan, serotonin agonists, migraine, and migraine therapy. In addition, pertinent references cited in articles obtained from MEDLINE and product information for triptans were reviewed.. All original and review articles and abstracts pertaining to naratriptan were reviewed, as were product information extracts. Clinical trials of naratriptan were critically reviewed and compared with pertinent clinical trials of other oral triptans.. The treatment of migraine has been dramatically improved with the use of sumatriptan, other triptans, and serotonin-receptor subtype 1B and 1D agonists. Drawbacks to these medications, however, have included poorly tolerated adverse effects and the recurrence of the migraine. Naratriptan has been recently approved for acute oral migraine therapy. In two Phase III trials of naratriptan compared with placebo, relief at four hours was obtained in 60% and 68% of patients using the 2.5-mg dose, with recurrence of headache in 24 hours in 27% and 28% of patients. The data on migraine recurrence were similar to those of other oral triptans; the efficacy of naratriptan at two hours was not specifically analyzed. Adverse effects of naratriptan were similar to placebo, and its tolerability seemed superior compared with studies of other oral triptans.. Naratriptan is a promising new oral therapy for acute migraine; it may successfully treat patients who poorly tolerate other triptan therapies or have longer duration migraine headaches.

Topics: Animals; Clinical Trials as Topic; Humans; Indoles; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Tryptamines; Vasoconstrictor Agents

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

Migraine is a paroxysmal disorder characterized by attacks of headache, nausea, vomiting, photophobia and phonophobia, and malaise. This review summarizes new treatment options for the therapy of acute attacks. Sumatriptan was the first specific serotonin-1B/D agonist for the treatment of acute migraine attacks. Apart from the oral and subcutaneous formulation, it is also available as nasal spray and suppository. The other new migraine drugs zolmitriptan, naratriptan, rizatriptan and eletriptan differ in their pharmacological profiles, which translates into minor differences in efficacy, headache recurrence and side-effects. Importantly, in clinical practice individual patients may show a preference for one treatment over another. New drugs in migraine treatment include substance-P antagonists, nitric oxide synthetase inhibitors and calcitonin gene-related peptide antagonists.

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

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

Although naratriptan is not approved for prophylactic use in migraine, naratriptan has been shown to be significantly more effective than placebo for short-term prevention of menstrually related migraine (MRM). The tolerability of naratriptan administered intermittently for prophylaxis for MRM over the long term has not been assessed.. To assess the tolerability of naratriptan 1 mg given twice daily for 6 days per month, administered for up to 1 year for short-term prevention of MRM in an open-label study.. Patients were eligible for the study if they were between 18 and 65 years of age and had at least a 1-year history of migraine, with or without aura, as defined by 1988 International Headache Society criteria; reported a history of MRM; and had at least 1 MRM attack during their last menstrual cycle. MRM was defined as any migraine beginning during the perimenstrual period (PMP). By definition, the PMP consisted of Days -2, -1, 1, 2, 3, and 4, with Day 1 being the first day of menstrual flow. During each menstrual cycle occurring over a 1-year period, patients began short-term treatment with naratriptan 1 mg twice daily (BID) 3 days before the expected onset of MRM and treated for a total of 6 days. Naratriptan 2.5 mg could be taken for breakthrough MRM attacks. Tolerability and safety measures included adverse events, standard clinical laboratory tests, electrocardiograms (ECGs), and vital signs. The secondary endpoints were the percentage of PMPs without MRM; headache disability as measured by the Headache Impact Test (HIT), and psychological health as measured by the Beck Depression Inventory version 2 (BDI-II).. The number of patients who took at least 1 dose of study medication (safety population) was 457, and the numbers of patients completing 6 months and 12 months of treatment were 318 and 131, respectively. Note that 171 (37%) patients were asked to leave the study once target enrollment numbers were met. The only adverse event occurring at an incidence of more than 2% during the 6-day treatment periods when naratriptan 1 mg BID was taken with or without an additional 2.5-mg dose for breakthrough attacks was ear, nose, throat infection (3%). No specific adverse event considered at least possibly to be related to study medication occurred in more than 2% of patients. No serious drug-related adverse events were reported. Furthermore, no patient experienced clinically relevant drug-related changes in 12-lead ECGs, vital signs, or clinical laboratory tests. Patients in both the 6- and 12-month populations did not experience an MRM in approximately 50% of treated PMPs. Health outcomes results suggested that naratriptan reduced headache impact when used for up to 12 months for the short-term prevention of MRM.. Naratriptan 1 mg BID, with the optional use of an additional 2.5-mg dose for breakthrough attacks, was well tolerated when used for 6 continuous days per month for up to 1 year for short-term prevention of MRM.

Topics: Adult; Female; Humans; Menstruation; Middle Aged; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Treatment Outcome; Tryptamines

Menstrual migraines are particularly difficult-totreat. Few studies on the use of triptans in short-term prophylaxis of menstrually related migraine have been recently conducted, but evidences of triptans' efficacy in the specific case of pure menstrual migraine (PMM) are lacking. The aim of this study is to explore the efficacy and tolerability of naratriptan as short-term prophylaxis of pure menstrual migraine (PMM) attacks. A multi-centre, open, non comparative, pilot six-month study was conducted in women, aged 18 years or older, with regular menstrual cycles and with a history of migraine without aura exclusively associated to the perimenstrual period. After an observation period of three months, patients took for three consecutive menstrual cycles oral naratriptan 1 mg twice daily, starting two days before the expected onset of menstruation and continuing for six days. Ninety-eight women with a history of PMM were screened for study participation, and 61 entered the study. Fifty-nine comprised the intent-to-treat population. The mean number of PMM attacks decreased from 3.5+/-1.4 in the 3-month observation period to 1.6+/-1.3 in the 3-month treatment with naratriptan. The pecentage of responders (subjects who recorded a decrease-equal or more than 50%-in the mean number of attacks) was 61.4%. A tendency towards a decrease in headache severity and in the presence of associated symptoms was observed during treatment. At least one adverse event during the treatment period was reported by 19 patients (31.1%). No serious adverse events occurred. Naratriptan may be an effective and safe treatment option in the short-prophylaxis of PMM.

Topics: Adolescent; Adult; Drug Evaluation; Dysmenorrhea; Female; Follow-Up Studies; Humans; Indoles; Middle Aged; Migraine Disorders; Pain Measurement; Piperidines; Serotonin Receptor Agonists; Time Factors; Treatment Outcome; Tryptamines

Topics: Adult; Dopamine Antagonists; Drug Therapy, Combination; Female; Humans; Indoles; Middle Aged; Migraine Disorders; Piperidines; Prochlorperazine; Prospective Studies; Serotonin Receptor Agonists; Tryptamines

The aim of this study was to investigate the efficacy of orally administered 2.5 mg naratriptan in the treatment of menstrually related migraine (MRM). A high percentage of women suffering from migraine report increased frequency of attacks in association with menstruation that may be more severe, of longer duration and more difficult to treat than at other times. This was a phase IIIb, randomized, double-blind, placebo-controlled clinical trial. Subjects were given either 2.5 mg naratriptan or placebo to treat a single MRM episode, defined as starting between days -2 and +4 relative to the start of menstruation. The primary efficacy measure was the percentage of subjects who were free of pain 4 h after treatment, the absence of pain at 30 min, 1 and 2 h being secondary efficacy measures. Other secondary measures were the absence of associated symptoms, sustained headache relief 24 h after a single dose of the study medication, recourse to a second dose of study medication or escape medication, pain intensity 4-24 h after first treatment, the ability to carry out work or daily activities, and patient satisfaction. Adverse events were also monitored. A total of 275 women were enrolled in the trial and 229 (115 naratriptan group, 114 placebo group) provided data on the effects of the study medication on MRM. A higher percentage of subjects in the naratriptan group (58%) reported complete pain relief 4 h after medication than in the placebo group (30%) (P<0.001). Significant differences between the naratriptan and placebo groups and in favor of naratriptan were also found for: total pain relief at 2 h (P=0.004), sustained pain-free response within 4-24 h (P<0.001), absence of all associated symptoms at 2 and 4 h (P=0.004), ability to work and carry out daily activities at 2 h (P=0.036), and patient overall satisfaction (P<0.001). Three adverse events were recorded that might potentially be attributable to naratriptan. Naratriptan given orally at a dose of 2.5 mg is effective in the acute treatment of MRM as early as 2 h after treatment.

Topics: Administration, Oral; Double-Blind Method; Female; Humans; Menstruation; Migraine Disorders; Pain Measurement; Patient Satisfaction; Piperidines; Retrospective Studies; Time Factors; Treatment Outcome; Tryptamines; Vasoconstrictor Agents

To evaluate the effect of acute treatment on ictal behavioral functioning of patients with migraine via ambulatory accelerometry.. The inability to carry out daily activities often complicates migraine attacks. Research into the effects of pharmacological drugs on this outcome parameter in the acute treatment of migraine has been based on subjective reports only.. In a double-blind, double-dummy, crossover study, 12 patients with migraine treated 2 migraine attacks with the nonspecific antimigraine drug, naproxen (500-mg capsule) or the more specific antimigraine drug, naratriptan (2.5-mg tablet). The clinical symptoms of headache, nausea, vomiting, photophobia, and phonophobia, and the subjective symptoms reflecting mood, sleepiness, and level of functioning were measured by use of a daily log.. During the first 6 hours after intake of the study medication, the objective behavioral parameters showed no significant effect of time and no significant differences between naproxen and naratriptan, but naratriptan was significantly more efficacious than naproxen in relieving headache, nausea, and vomiting; the interval between treatment and relief was significantly shorter after intake of naratriptan.. Consciously perceived clinical and subjective symptoms do not necessarily run in parallel with their behavioral equivalents. It, thus, may be important to assess the effects of treatment on behavioral functioning in the evaluation of the general efficacy of antimigraine drugs in the acute treatment of a migraine attack.

Topics: Activities of Daily Living; Acute Disease; Adult; Anti-Inflammatory Agents, Non-Steroidal; Cross-Over Studies; Double-Blind Method; Humans; Indoles; Middle Aged; Migraine Disorders; Naproxen; Piperidines; Serotonin Receptor Agonists; Treatment Outcome; Tryptamines

This was a randomized, double-blind study designed to evaluate the comparative efficacy and tolerability of the 40-mg dose of eletriptan and the 2.5-mg dose of naratriptan. Patients (n = 548) meeting International Headache Society (IHS) criteria for migraine were randomized to treat a single migraine attack with either eletriptan 40 mg, naratriptan 2.5 mg, or placebo. Headache response rates at 2 h and 4 h, respectively, were 56% and 80% for eletriptan, 42% and 67% for naratriptan (P < 0.01 for both time-points vs. eletriptan), and 31% and 44% for placebo (P < 0.0001 vs. both active drugs at both time-points). Eletriptan also showed a significantly greater pain-free response at 2 h (35% vs. 18%; P < 0.001) as well as lower use of rescue medication (15% vs. 27%; P < 0.01) and higher sustained headache response at 24 h (38%) compared with naratriptan (27%; P < 0.05) and placebo (19%; P < 0.01). Both eletriptan and naratriptan were well tolerated. The results confirm previous meta-analyses that have suggested the superiority of eletriptan vs. naratriptan in the acute treatment of migraine.

Topics: Adult; Double-Blind Method; Female; Humans; Indoles; Male; Middle Aged; Migraine Disorders; Patient Satisfaction; Piperidines; Pyrrolidines; Serotonin Receptor Agonists; Time Factors; Treatment Outcome; Tryptamines

Chronic migraine (CM) patients frequently overuse symptomatic medications (SM). These medications may create a cycle of rebound, worsening of headache and withdrawal symptoms that perpetuate the headache itself. In addition, the overuse of such substances is believed to counteract the efficacy of preventive treatments. We conducted a prospective randomized open-label trial comparing approaches to out-patient management in 150 CM patients (125 women, 25 men; ages 18-80 years, mean 40.3 +/- 13.8) with overuse of SM. In each group, 50 patients received education and orientation and were then abruptly withdrawn from all SM. Immediately following withdrawal, the first group took prednisone (60 mg/ day 2 days, 40 mg/day 2 days and 20 mg/day 2 days) for 6 days, the second group did not have any regular medications to take and the third group took naratriptan (2.5 mg twice a day) during this initial period. All patients had similar profiles of headache characteristics and consumption (quality and quantity) of SM before initiation of the treatment, but most were not severe headache sufferers, heavy SM overusers or were overusing opioids. After 5 weeks the headache frequency and intensity, the prevalence and frequency of withdrawal symptoms and consumption of rescue medications during the first 6 days were compared between groups. In addition, adherence to treatment (who returned or not and for which reasons, between groups) and headache frequency, week by week, among the groups of patients were also compared. Forty-four (88%) patients from the prednisone group, 41 (82%) from the 'nothing' group and 35 (70%) from the naratriptan group adhered to the treatment and returned. The were no differences between groups with regard to treatment adherence (P = 0.072), headache frequency as well as intensity (P = 0.311) and decreasing of days with headache after 5 weeks and weekly (P = 0.275). However, the incidence of withdrawal symptoms and consumption of rescue drugs was higher among the patients who did not take regular medications during the first 6 days (P = 0.0001 and P = 0.006). We concluded that CM patients with moderate overuse of SM other than opioids may be detoxified on an out-patient basis regardless of the strategy adopted with regard to the use of regular drugs during the initial days of withdrawal, but prednisone and naratriptan may be useful for reducing withdrawal symptoms and rescue medication consumption. Further controlled studies are necessary to confir

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Ambulatory Care; Chi-Square Distribution; Female; Headache Disorders; Humans; Indoles; Male; Middle Aged; Migraine Disorders; Piperidines; Prednisone; Prospective Studies; Statistics, Nonparametric; Substance Withdrawal Syndrome; Tryptamines

Naratriptan is a novel 5-HT1 agonist developed to treat acute migraine. The study objective was to characterize the pharmacokinetics of oral naratriptan in adolescent migraine patients outside a migraine attack. Subjects received a single 2.5 mg naratriptan tablet. Serial serum samples for naratriptan concentrations were collected over 24 hours. Blood pressure, pulse rate, and 12-lead ECG were recorded at baseline and at regular intervals after dosing. Seven patients--3 males and 4 females, 12 to 16 years of age--received drug and completed the study. The geometric mean and 95% confidence interval maximum concentration (Cmax) was 8.0 ng/mL (5.9-10.7), elimination half-life (t1/2) was 4.9 hours (4.5-5.4), area under the concentration-time curve (AUC) was 74.6 ng.h/mL (56.6-98.2), and apparent total clearance (Cl/F) was 558.8 mL/min (424.3-735.9). The median time to maximal concentration (tmax) was 4 hours, with a range of 1.5 to 4. Blood pressure, pulse rate, and ECG parameters did not change significantly from baseline. No serious adverse events or subject withdrawal after drug administration occurred. Oral naratriptan pharmacokinetic parameters in adolescents were similar to values reported in adults. Naratriptan doses for adolescents older than 12 years of age would be expected to be similar to adult doses.

Topics: Adolescent; Area Under Curve; Child; Female; Humans; Indoles; Male; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Tryptamines

To determine the efficacy of naratriptan 1-mg and 2.5-mg tablets twice daily compared with placebo as short-term prophylaxis of menstrually associated migraine.. Approximately 60% of women with migraine report headaches associated with their menstrual cycles. Results from an open-label study suggest that short-term administration of sumatriptan is useful in the prophylaxis of menstrually associated migraine.. A randomized, double-blind, three-arm, parallel-group, placebo-controlled study was conducted in women aged 18 years or older with a history of migraine with or without aura, as defined by the International Headache Society, of at least 6 months. Two dose strengths of naratriptan (1 mg, 2.5 mg) or identical-appearing placebo tablets (1:1:1) were administered twice daily for 5 days starting 2 days prior to the expected onset of menses across four perimenstrual periods. End points included the number of menstrually associated migraines, total migraine days, peak headache severity, lost work/activity time, migraine-related quality of life, and incidence of adverse events.. Overall, the intent-to-treat population comprised 206 women (naratriptan 1 mg, n = 70; naratriptan 2.5 mg, n = 70, and placebo, n = 66); 171 women treated four perimenstrual periods. Significantly more perimenstrual periods per subject treated with naratriptan, 1 mg, were headache-free compared with placebo (50% versus 25%, P =.003). Naratriptan, 1 mg, significantly reduced the number of menstrually associated migraines (2.0 versus 4.0, P <.05) and menstrually associated migraine days (4.2 versus 7.0, P <.01) compared with placebo. More patients treated with naratriptan, 1 mg, were headache-free across all treated perimenstrual periods compared with placebo (23% versus 8%). No difference in headache severity was observed in breakthrough headaches. The incidence and severity of adverse events was similar across treatment groups. Naratriptan, 2.5 mg, was not statistically superior to placebo for any measure.. Naratriptan, 1 mg, with tolerability similar to placebo, is an effective, short-term, prophylactic treatment for menstrually associated migraine.

Topics: Adult; Double-Blind Method; Female; Humans; Indoles; Menstruation; Migraine Disorders; Piperidines; Quality of Life; Serotonin Receptor Agonists; Treatment Outcome; 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

Migraine drugs can produce adverse cardiac effects. The authors have demonstrated previously that ergotamine can lead to a significant reduction of hyperemic myocardial blood flow, but little is known about the effect of the newer serotonin analogues. Coronary artery constriction caused by serotonin or its analogues is mediated mainly by 5HT2 receptors. The selective 5HT1B/1D agonist naratriptan has no significant activity at 5HT2 receptors; however, like all 5HT1B/1D agonists developed for the acute treatment of migraine, naratriptan could potentially constrict coronary arteries by activation of 5HT1B receptors.. The effects on myocardial blood flow of subcutaneous naratriptan 1.5 mg compared with placebo were assessed under resting and hyperemic conditions with PET using oxygen-15 labeled water during two separate visits. This study was a randomized, double-blind, placebo-controlled crossover trial in 34 migraine subjects with no evidence of ischemic heart disease, studied outside a migraine attack.. Naratriptan did not differ significantly from placebo in its effects on resting myocardial blood flow, but did evoke a small, significant fall in hyperemic myocardial blood flow (-13% versus placebo) and an increase in hyperemic coronary resistance (+19% versus placebo) without any signs or symptoms suggestive of myocardial ischemia. Naratriptan did not significantly affect the coronary vasodilator reserve (hyperemic/resting blood flow) compared with placebo.. These results show that at therapeutic doses, naratriptan exerts only a minor effect on myocardial blood flow, coronary vasodilator reserve, or coronary resistance among subjects with no evidence of ischemic heart disease. These results should not be extrapolated to patients with coronary artery disease, in whom all 5HT1 agonists for migraine are contraindicated.

Topics: Adult; Coronary Circulation; Female; Heart; Humans; Indoles; Male; Middle Aged; Migraine Disorders; Myocardium; Piperidines; Serotonin Receptor Agonists; Tomography, Emission-Computed; Tryptamines; Vascular Resistance; Vasodilation

To assess patient satisfaction with and preference for naratriptan hydrochloride therapy over previous "nontriptan" therapy for migraines.. Open-label study conducted at 15 primary care clinics.. One hundred forty-three adults meeting International Headache Society diagnostic criteria for migraine who were not using triptans as first-line therapy for migraines were enrolled; 115 completed the study. INTERVENTION AND OUTCOME ASSESSMENTS: At baseline, satisfaction with current migraine therapy was assessed. Patients were provided with naratriptan hydrochloride, 2.5 mg, to treat 3 migraines and diaries to record headache symptoms and response to treatment. After treating 3 migraines, satisfaction with naratriptan therapy and preference for either previous or naratriptan therapy were assessed.. Eighty-nine (62%) of 143 patients had previous exposure to triptans, with lack of prescribing (55%) as the primary reason for not continuing their use as first-line therapy. Medications used for first-line therapy included simple analgesics (59%), combination products (46%), and narcotics (13%). After treating 3 migraines with naratriptan, satisfaction with migraine therapy increased from 47% to 75%. Sixty-three percent of patients preferred naratriptan therapy over their previous nontriptan therapy, 27% preferred their previous therapy, and 10% had no preference. The main reasons for preference for naratriptan therapy were "relieves pain effectively" (86%) and "restores ability to function/perform task" (81%).. Naratriptan for first-line migraine therapy was preferred by most patients over previous nontriptan therapy.

Topics: Adult; Aged; Female; Humans; Indoles; Male; Middle Aged; Migraine Disorders; Patient Satisfaction; Piperidines; Serotonin Receptor Agonists; Treatment Outcome; Tryptamines; Vasoconstrictor Agents

This study sought to compare the efficacy of several doses of naratriptan tablets with that of sumatriptan tablets and placebo in the acute treatment of a single migraine attack.. This was a randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study. Patients received either naratriptan tablets (1, 2.5, 5, 7.5, or 10 mg), sumatriptan tablets (100 mg), or placebo.. A total of 643 patients took part in the study. Two hours after dosing, headache relief was reported by significantly more patients treated with any dose of naratriptan (52%-69%) or sumatriptan (60%) than with placebo (31%) (P < 0.05). Four hours after dosing, headache relief was reported by significantly more patients treated with any dose of naratriptan (63%-80%) or sumatriptan (80%) than with placebo (39%) and by significantly more patients treated with sumatriptan 100 mg (80%) than with naratriptan 1 mg (64%), 2.5 mg (63%), or 5 mg (65%) (P < 0.05). Twenty-four-hour overall efficacy (headache relief maintained through 24 hours postdose with no worsening, no use of rescue medication, and no recurrence) was reported by more patients treated with any dose of naratriptan (39%-58%) or sumatriptan (44%) than with placebo (22%). Headache recurrence was reported in 17% to 32% of naratriptan-treated patients, 44% of sumatriptan-treated patients, and 36% of placebo recipients. The overall incidence of adverse events was similar in patients treated with naratriptan 1 mg (20%), naratriptan 2.5 mg (21%), and placebo (23%). For naratriptan 5, 7.5, and 10 mg, the incidence of adverse events was 32%, 37%, and 35%, respectively, and for sumatriptan 100 mg it was 26%.. Our results suggest that the 2.5-mg dose of naratriptan tablets offers the optimal efficacy-to-tolerability ratio at the dose range between 1 and 10 mg. Although naratriptan 2.5 mg was less effective than sumatriptan 100 mg at 4 hours after dosing, the 2 medications showed similar efficacy at 24 hours.

Topics: Dose-Response Relationship, Drug; Double-Blind Method; Humans; Indoles; Migraine Disorders; Patient Satisfaction; Piperidines; Placebos; Serotonin Receptor Agonists; Tablets; Tryptamines; Vasoconstrictor Agents

This randomized, double-blind, crossover study was undertaken to compare the incidence of headache recurrence after treatment with naratriptan or sumatriptan in migraine patients with a history of frequent headache recurrence (recurrence in > or =50% of successfully treated attacks).. Although the selective 5-hydroxytryptamine, (5-HT1) agonist sumatriptan is effective and well tolerated for acute treatment of migraine in most patients, headache recurrence within 24 hours of initial successful treatment with sumatriptan and other medications has been reported in approximately 35% of patients. The novel 5-HT1 agonist naratriptan possesses pharmacologic and pharmacokinetic characteristics that may address the issue of headache recurrence.. Men and women aged 18 to 65 years with a > or =1-year history of migraine with or without aura were randomly assigned to treat 1 moderate or severe migraine attack in a nonclinical setting with one 2.5-mg naratriptan tablet and 1 attack with one 100-mg sumatriptan tablet. A pain-free interval of > or =24 hours was required between attacks. At 4 hours, patients not using rescue medication and experiencing headache recurrence could take a second, identical dose of study medication to treat recurrence. No more than 2 tablets of study medication were permitted in any 24-hour period.. A total of 253 patients treated > or =1 migrane attack and were included in the safety analysis; the 225 patients who treated both attacks were included in the efficacy analysis. Of the 164 naratriptan-treated and 181 sumatriptan-treated patients experiencing headache relief after > or =1 attack, headache recurrence 4 to 24 hours after treatment was reported by 74 naratriptan-treated patients (45%) and 101 sumatriptan-treated patients (57%; not statistically significant). (One naratriptan- and 3 sumatriptan-treated patients who experienced headache relief did not record recurrence status and were not included in the denominator for the percentage calculation.) In a subset of patients experiencing headache relief after 2 attacks, headache recurrence 4 to 24 hours after initial dosing was reported by 55 naratriptan- and 77 sumatriptan-treated patients (41% and 57%, respectively; P = 0.005). The overall incidence of adverse events was 22% after treatment with naratriptan and 33% after treatment with sumatriptan. This incidence did not increase after use of a second dose of naratriptan (20%) or sumatriptan (31%).. These data suggest that naratriptan is a long-acting and well-tolerated addition to currently available medications for the treatment of acute migraine.

Topics: Adolescent; Adult; Aged; Cross-Over Studies; Double-Blind Method; Female; Humans; Indoles; Middle Aged; Migraine Disorders; Piperidines; Recurrence; Serotonin Receptor Agonists; Sumatriptan; Tryptamines; Vasoconstrictor Agents

The primary objective of this prospective, open, non controlled, multicenter study was to collect data on migraine patient's health related quality of life before and after treatment of their migraine attacks b naratriptan orl 2.5 mg over a 12 week period.. The impact on health related quality of life was evaluated by the mean change from pre-treatment scores on the French migraine health related quality of life specific questionnaire (QVM).. 244 patients have been included in the study. A statistically significant score improvement in health related quality of life, as measured by the global score and the four scores related to the four dimensions of the QVM questionnaire (functional, psychological, social and therapeutic) was observed compared to the pre-treatment score values. At the end of the treatment period, 67% of patients preferred naratriptan oral 2.5 mg to their usual treatment.. Those data suggest that the use of naratriptan oral 2.5 mg for the treatment of migraine attacks during a 12 week period may be associated with a significant improvement in migraine patient's quality of life.

Topics: Administration, Oral; Adult; Female; Humans; Indoles; Male; Middle Aged; Migraine Disorders; Piperidines; Quality of Life; Treatment Outcome; Tryptamines; Vasoconstrictor Agents

Naratriptan, an effective antimigraine agent, is a selective 5-hydroxytryptamine (5-HT1 )-receptor agonist with a pharmacologic profile similar to that of sumatriptan. The object of this study was to assess the haemodynamic effects of naratriptan in a clinical model previously applied to sumatriptan. Cardiac haemodynamics and coronary artery diameter were measured at baseline and after subcutaneous injections of placebo and naratriptan (1.5 mg, s.c.) in 10 patients undergoing diagnostic cardiac catheterisation. No statistically significant change in mean coronary artery diameter was observed after naratriptan [95% confidence interval (CI), -0.27-0.11 mm: p = 0.37]. Naratriptan injection was associated with statistically significant increases in systolic arterial pressure (95% CI, 7.6-22.0 mm Hg; p = 0.0015), total systemic vascular resistance (95% CI, 74-253 dyn/s/cc; p = 0.003), pulmonary artery systolic pressure (95% CI, 2.0-6.9 mm Hg; p = 0.003), pulmonary vascular resistance (95% CI, 3-34 dyn/s/cc; p = 0.025), and pulmonary artery wedge pressure (95% CI, 1.9-2.4 mm Hg; p = 0.009). Naratriptan, a selective 5-HT1-receptor agonist, caused a vasopressor response in the systemic and pulmonary arterial circulations but was not associated with coronary artery vasoconstriction.

Topics: Adult; Aged; Blood Pressure; Coronary Angiography; Coronary Vessels; Female; Hemodynamics; Humans; Indoles; Injections, Subcutaneous; Male; Middle Aged; Piperidines; Pulmonary Artery; Pulmonary Circulation; Serotonin Receptor Agonists; Time Factors; Tryptamines; Vasoconstriction

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

This randomized, double-blind, placebo-controlled, four-way crossover study was conducted on an in-clinic basis to assess forearm perfusion after subcutaneous (s.c.) naratriptan and placebo by reserve volume (hyperemic/baseline) and basal forearm blood flow (FBF) measured by strain gauge plethysmography. Nineteen male and female volunteer migraine subjects (International Headache Society criteria) received s.c. naratriptan 1 mg, 5 mg, 10 mg, and placebo on four separate study days outside a migraine attack. FBF was recorded at baseline, at 7-min intervals post-dose up to 1 h (basal) and once after sublingual glyceryl trinitrate administered at 1 h (hyperemic). Vital signs and electrocardiograms were recorded at baseline and 15, 30, 45, and 60 min post-dose. There were no statistically significant differences in reserve volume (hyperemic/baseline) between any dose of s.c. naratriptan and placebo. The naratriptan to placebo ratio was 102% (95% CI: 87-120%; p = 0.789) for 1 mg; 97% (95% CI: 83-114%, p = 0.737) for 5 mg; and 92% (95% CI: 79-108%; p = 0.325) for 10 mg. There were no statistically significant differences in basal FBF for any dose compared to placebo. The naratriptan to placebo ratio was 95% (95% CI: 87-104%; p = 0.263) for 1 mg; 94% (95% CI: 86-102%; p = 0.142) for 5 mg; and 94% (95% CI: 86-103%; p = 0.157) for 10 mg. The percentage of patients reporting adverse events was 53% with placebo, 53% with s.c. naratriptan 1 mg, 89% with 5 mg and 89% with 10 mg. In conclusion, these results suggest that s.c. naratriptan doses similar to and above the oral therapeutic dose equivalent (single oral dose 2.5 mg) have no significant effect on peripheral blood flow as measured by FBF. S.c. naratriptan doses 1 mg, 5 mg, and 10 mg were well tolerated.

Topics: Adult; Blood Pressure; Cross-Over Studies; Double-Blind Method; Female; Forearm; Humans; Indoles; Injections, Subcutaneous; Male; Piperidines; Regional Blood Flow; Serotonin Receptor Agonists; Tryptamines

The efficacy and tolerability of naratriptan tablets (2.5 mg, 1 mg, and 0.25 mg) compared with placebo in the acute treatment of migraine were evaluated in a randomized, double-blind, four-period crossover study. Five hundred eighty-six assessable patients received naratriptan 2.5 mg, 595 received 1 mg, 591 received 0.25 mg, 602 received placebo. Headache relief (moderate or severe pain reduced to mild or none) 4 hours postdose was reported in 68% of patients after treatment with naratriptan 2.5 mg compared with 57% after 1 mg, 39% after 0.25 mg, and 33% after placebo (p < 0.001 naratriptan 2.5 mg and 1 mg versus placebo and 1 mg and 2.5 mg versus 0.25 mg). Headache relief was maintained 8, 12, and 24 hours postdose with no use of rescue medication or a second dose of study medication by significantly (p < 0.001) greater percentages of patients after treatment with naratriptan 2.5 mg or 1 mg compared with naratriptan 0.25 mg or placebo. Naratriptan was also more effective than placebo in reducing clinical disability and the incidences of nausea, photophobia, and phonophobia. The overall incidence of adverse events and the incidences of specific adverse events did not differ in the naratriptan groups compared with placebo. No clinically relevant changes in ECG, blood pressure, or laboratory findings were reported. These data demonstrate that naratriptan is effective and well tolerated for the acute treatment of migraine. The 2.5-mg dose was associated with superior efficacy, whereas its adverse event profile was similar to that of placebo.

Topics: Adolescent; Adult; Aged; Cross-Over Studies; Double-Blind Method; Female; Gastrointestinal Diseases; Humans; Hyperesthesia; Indoles; Male; Middle Aged; Migraine Disorders; Piperidines; Recurrence; Serotonin Receptor Agonists; Treatment Outcome; Tryptamines

The hydrosulfamoylation of diverse aryl olefins provides facile access to alkylsulfonamides. Here we report a novel protocol utilizing radical-mediated addition and a thiol-assisted strategy to achieve the hydrosulfamoylation of diverse styrenes in modest to excellent yields under mild and economic reaction conditions. The methodology was found to provide an efficient and convenient approach for the synthesis of the anti-migraine drug naratriptan and it also can be used for the late-stage functionalization of natural products or medicines.

Topics: Catalysis; Molecular Structure; Oxidation-Reduction; Photochemical Processes; Piperidines; Styrenes; Sulfones; Tryptamines

Topics: Arteries; Humans; Infarction; Piperidines; 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

Status migrainosus is a condition with limited epidemiological knowledge, and no evidence-based treatment guideline or rational-driven assessment of successful treatment outcome. To fill this gap, we performed a prospective observational study in which we documented effectiveness of treatment approaches commonly used in a tertiary headache clinic.. Patients with episodic and chronic migraine who experienced continuous and prolonged attacks for more than 72 hours were treated with dexamethasone (4 mg orally twice daily for 3 days), ketorolac (60 mg intramuscularly), bilateral nerve blocks (1-2% lidocaine, 0.1-0.2 ml for both supraorbital and supratrochlear nerves, 1 ml for both auriculotemporal nerves, and 1 ml for both greater occipital nerves), or naratriptan (2.5 mg twice daily for 5 days). Hourly (for the first 24 hours) and daily (for first 30 days) change in headache intensity was documented using appropriate headache diaries.. Fifty-four patients provided eligible data for 60 treatment attempts. The success rate of rendering patients pain free within 24 hours and maintaining the pain-free status for 48 hours was 4/13 (31%) for dexamethasone, 7/29 (24%) for nerve blocks, 1/9 (11%) for ketorolac and 1/9 (11%) for naratriptan. These success rates depended on time to remission, as the longer we allowed the treatments to begin to work and patients to become pain free (i.e. 2, 12, 24, 48, 72, or 96 hours), the more likely patients were to achieve and maintain a pain-free status for at least 48 hours.. These findings suggest that current treatment approaches to terminating status migrainosus are not satisfactory and call attention to the need to develop a more scientific approach to define a treatment response for status migrainosus.

Topics: Adult; Dexamethasone; Female; Humans; Ketorolac; Male; Middle Aged; Migraine Disorders; Nerve Block; Pain Management; Piperidines; Treatment Outcome; Tryptamines

Naratriptan, active pharmaceutical ingredient with antimigraine activity was electrochemically detected in untreated screen-printed carbon electrodes (SPCEs). Cyclic voltammetry and differential pulse voltammetry were used to carry out quantitative analysis of this molecule (in a Britton-Robinson buffer solution at pH 3.0) through its irreversible oxidation (diffusion controlled) at a potential of +0.75V (vs. Ag pseudoreference electrode). Naratriptan oxidation product is an indole based dimer with a yellowish colour (maximum absorption at 320nm) so UV-VIS spectroelectrochemistry technique was used for the very first time as an in situ characterization and quantification technique for this molecule. A reflection configuration approach allowed its measurement over the untreated carbon based electrode. Finally, time resolved Raman Spectroelectrochemistry is used as a powerful technique to carry out qualitative and quantitative analysis of Naratriptan. Electrochemically treated silver screen-printed electrodes are shown as easy to use and cost-effective SERS substrates for the analysis of Naratriptan.

Topics: Electrochemistry; Electrodes; Piperidines; Printing; Spectrophotometry, Ultraviolet; Spectrum Analysis, Raman; Tryptamines

The recent expansion of electronic health and medical record systems may present an opportunity to generate robust post-approval safety data and obviate the limitations of prospective pregnancy exposure registries. We examined and compared, over the same time frame, the outcomes of triptan exposure in pregnancy using (1) a retrospective claims database and (2) a previously completed pregnancy registry.. Using the Marketscan database, the risk of major birth defects was ascertained in live-born infants whose birth mothers were exposed to sumatriptan, naratriptan, or sumatriptan/naproxen during pregnancy. The frequencies of outcomes observed were compared with the findings of the 16-year sumatriptan, naratripan, and sumatriptan/naproxen prospective pregnancy registry.. About 5120 pregnancies were identified in the retrospective claims cohort in contrast to 617 included in the prospective registry during the same time frame. The proportion of major birth defects among first-semester sumatriptan exposures was 4.0%, which is exactly the same as the proportion of major birth defects reported for first-semester sumatriptan exposures in the registry. There were very few non-livebirth outcomes in both the claims analyses and registry.. These results confirm broad agreement between the database analysis and the registry regarding the safety of triptans during pregnancy. Of note, the number of triptan-exposed pregnancies identified in this large US database was about 7-fold that included in the prospective registry over the same time frame. The findings of this study support an approach of using existing health care database (s) in the post-approval assessment of medication exposure in pregnancy.

Topics: Abnormalities, Drug-Induced; Administrative Claims, Healthcare; Adolescent; Adult; Databases, Factual; Drug Combinations; Electronic Health Records; Female; Humans; Infant, Newborn; Migraine Disorders; Naproxen; Piperidines; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Prospective Studies; Registries; Retrospective Studies; Sumatriptan; Tryptamines; United States; Young Adult

Objective Naratriptan has been reported to reduce the frequency of cluster headache. The purpose of this study was to determine whether naratriptan is effective as a prophylactic treatment for cluster headache in Japan. Methods We retrospectively reviewed all 43 patients with cluster headache who received preventive treatment with naratriptan from April 2009 to April 2015. The International Classification of Headache Disorders, 3rd Edition (beta version) (ICHD-3 beta) was used to diagnose cluster headache. This study was conducted at 3 centers (Department of Neurology, Saitama Medical University; Saitama Neuropsychiatric Institute; Saitama Medical University International Medical Center). Patients were recruited from these specialized headache outpatient centers. Naratriptan was taken before the patient went to bed. Results The study population included 30 men (69.8%) and 13 women (30.2%). Twenty-two cases received other preventive treatments (51.2%), while 21 cases only received naratriptan (48.8%). Among the 43 cases, 37 patients (86.0%) achieved an improvement of cluster headache on naratriptan. Conclusion Naratriptan has been suggested as a preventive medicine for cluster headache because of the longer the biological half-life in comparison to other triptans. The internal use of naratriptan 2 hours before attacks appears to achieve a good response in patients with cluster headache.

Topics: Adult; Aged; Cluster Headache; Female; Humans; Japan; Male; Middle Aged; Migraine Disorders; Piperidines; Retrospective Studies; Serotonin Receptor Agonists; Tryptamines; Vasoconstrictor Agents; Young Adult

Topics: Cluster Headache; Humans; Indoles; Migraine Disorders; Piperidines; Tryptamines

Naratriptan is second-generation triptan class of antimigraine drug which selectively bind with 5-HT(1B/1D) receptor. It is widely used to treat the migraine attack due to its better tolerability and lower recurrence rate as compared to other triptans. Despite of the applicability, Naratriptan also have several drawback like slow onset of action and fist pass metabolism which reduce its efficacy. In order to increase the efficacy of naratriptan fast dissolving film is prepared.. Fast dissolving film of Naratriptan hydrochloride was prepared by solvent casting method Based on the patent survey (US 7648712 B2, WO 2012053006 A2, US 20090047330 A1, EP 2821066 A4, WO 2008108940 A1, WO 2010151020 A3) excipients were screened to find out suitable combination of polymer and plasticizer and Hydroxypropylmethyl Cellulose (HPMC E6) and glycerol were selected as film forming polymer and plasticizer respectively. To study the effect of independent variables on dependent variables 32 full factorial design was applied using Concentration of HPMC E6 and Concentration of Glycerol as independent variables and disintegration time, folding endurance, tensile strength and cumulative % drug release at 2 min as dependent or response variables. A statistical model incorporating interactive and polynomial terms was utilized to evaluate the responses. Result & Conclusion: From the results of statistical evaluation batch F3 was selected as the optimized batch which exhibited shorter disintegration time (22sec) with satisfactory mechanical properties (tensile strength 652.17 gm/mm2). Dissolution of drug from F3 formulation was rapid with around 91% drug release in 120sec. Optimized batch was further evaluated for in vitro permeation study using Franz diffusion cell.

Topics: Drug Delivery Systems; Drug Liberation; Glycerol; Hypromellose Derivatives; Models, Statistical; Patents as Topic; Permeability; Piperidines; Tensile Strength; Tryptamines

The present research project involves development and validation of a stability-indicating HPTLC method for the estimation of naratriptan-HCl in their pharmaceutical dosage forms and its content uniformity testing. Naratriptan-HCl was subjected to alkaline, acidic, oxidative, neutral, thermal (dry heat) and photo-degradation conditions. The chromatographic separation was carried out using a precoated silica gel G 60 F254 TLC plate as the stationary phase and dichloromethane-toluene-methanol-triethylamine (4 : 4 : 2 : 1, v/v/v/v) as the mobile phase. The spots of NRT-HCl and its degradation products were detected at 290 nm. The Rf value of NRT-HCl was found to be 0.60 ± 0.02. The linearity was obtained in the range of 100-500 ng/spot. The limit of detection and limit of quantitation were found to be 6.07 ng/spot and 18.41 ng/spot, respectively. The percentage recovery was found in the range of 98.87-99.55%. NRT-HCl was degraded under acidic, alkaline and oxidative conditions while stable under photolytic, neutral and dry heat conditions. The developed method was applied for estimation of naratriptan-HCl in marketed formulations and its content uniformity testing.

Topics: Chromatography, Thin Layer; Drug Stability; Ethylamines; Hydrogen-Ion Concentration; Limit of Detection; Methanol; Methylene Chloride; Oxidation-Reduction; Piperidines; Reproducibility of Results; Solvents; Tablets; Toluene; Tryptamines; Vasoconstrictor Agents

In order to understand the interaction between naratriptan and a fully hydrated bilayer of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidyl-choline (POPC), we carried out molecular dynamics simulations. The simulations were performed considering neutral and protonated ionization states, starting from different initial conditions. At physiological pH, the protonated state of naratriptan is predominant. It is expected that neutral compounds could have larger membrane partition than charged compounds. However, for the specific case of triptans, it is difficult to study neutral species in membranes experimentally, making computer simulations an interesting tool. When the naratriptan molecules were originally placed in water, they partitioned between the bilayer/water interface and water phase, as has been described for similar compounds. From this condition, the drugs displayed low access to the hydrophobic environment, with no significant effects on bilayer organization. The molecules anchored in the interface, due mainly to the barrier function of the polar and oriented lipid heads. On the other hand, when placed inside the bilayer, both neutral and protonated naratriptan showed self-aggregation in the lipid tail environment. In particular, the protonated species exhibited a pore-like structure, dragging water through this environment. Graphical Abstract Different behaviour of Naratriptan and Sumatriptan, when the drugs were originally placed in the lipid core.

Topics: Lipid Bilayers; Molecular Dynamics Simulation; Piperidines; Tryptamines

Naratriptan (NAR) is currently used as the hydrochloride salt (NAR.HCl) for the treatment of migraine and is available in tablet dosage forms for oral administration. Buccal drug delivery offers a number of advantages compared with conventional oral delivery including rapid absorption, avoidance of first pass metabolism and improved patient compliance. We have previously prepared and characterised the base form of NAR and shown that it has more favourable properties for buccal delivery compared with NAR.HCl. This study describes the design and evaluation of a range of formulations for oral transmucosal delivery of NAR base. Permeation studies were conducted using excised porcine buccal tissue mounted in Franz cells. Of the neat solvents examined, Transcutol

Topics: Administration, Buccal; Animals; Chemistry, Pharmaceutical; Drug Delivery Systems; Mouth Mucosa; Permeability; Piperidines; Swine; Tablets; Tryptamines

To date, the interchangeability of generic drugs has only been investigated for a limited number of medicines. The objective of this study was to investigate generic-generic drug interchangeability in a large subset of generic formulations in order to cover a broad spectrum of drugs.. Orally administered drugs for investigation in this study were selected using strict, predefined criteria, with the purpose to avoid bias. This selection procedure yielded atorvastatin, bicalutamide, naratriptan, olanzapine, perindopril, and venlafaxine. Further, ciclosporin, tacrolimus, and mycophenolate mofetil were investigated as test immunosuppressants. Adjusted indirect comparisons were conducted between generic drugs containing the same active substance, and the 90% confidence interval (CI) for AUC and Cmax was calculated.. In total, 120 bioequivalence studies were identified in the Dutch medicine regulatory agency's database, allowing 292 indirect comparisons between generic drugs. The indirect comparison results indicated that in the vast majority of cases, i.e., 80.5%, the 90% CIs for both AUCt and Cmax fell within the bioequivalence criteria (in 90.1 and 87.0% for AUCt and Cmax, respectively). In 1% of the 292 indirect comparison for AUCt and 3% for Cmax, a wider range of 75-133% (or 80-125%) was exceeded.. Overall, our study suggests that exposure-related risks associated with the exchange of different generic drugs in clinical practice are not increased to a relevant extent compared to the situation in which a generic is exchanged with the innovator.

Topics: Anilides; Area Under Curve; Atorvastatin; Benzodiazepines; Chemistry, Pharmaceutical; Cyclosporine; Drugs, Generic; Humans; Immunosuppressive Agents; Mycophenolic Acid; Nitriles; Olanzapine; Perindopril; Piperidines; Tacrolimus; Therapeutic Equivalency; Tosyl Compounds; Tryptamines; Venlafaxine Hydrochloride

Naratriptan (NAR) is currently used for the management of migraine as the hydrochloride salt (NAR.HCl) and is administered as an oral tablet. This work evaluates the feasibility of buccal delivery of NAR in order to ensure faster onset of action and avoid the side-effects associated with conventional oral formulations. We hypothesized that the unionized form of NAR would permeate buccal tissue to a greater extent than the salt. Therefore the first stage of this work required preparation of the free base from NAR.HCl. Characterisation of the base with thermal and elemental analyses confirmed its purity; logP and logD values were also determined. The pH permeation profile of NAR was also determined in the range 7.4-10. Solubility studies in non-aqueous solvents indicated that Transcutol™ (TC) and dipropylene glycol (DPG) were suitable vehicles for the free base. Maximum amounts of NAR which permeated after 6h were ∼ 130 μg/cm(2). Based on the pH permeation results and studies conducted at two different doses NAR appears to permeate porcine buccal tissue via the transcellular route. Finally, estimates of likely systemic values suggest that optimised formulations should be taken forward for in vivo evaluation.

Topics: Administration, Buccal; Animals; Calorimetry, Differential Scanning; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Chromatography, Liquid; Drug Delivery Systems; Drug Stability; Hydrogen-Ion Concentration; Mass Spectrometry; Mouth Mucosa; Permeability; Piperidines; Solubility; Swine; Thermogravimetry; Tryptamines

Familial hemiplegic migraine type 1 (FHM-1) is a monogenic subtype of migraine with aura caused by missense mutations in the CACNA1A gene, which encodes the pore-forming α1 subunit of voltage-gated neuronal CaV2.1 (P/Q-type) calcium channels. Transgenic knock-in mice expressing the CACNA1A R192Q mutation that causes FHM-1 in patients show a greater susceptibility to cortical spreading depression, the likely underlying mechanism of typical human migraine aura. The aim of this study was to compare neuronal activation within the trigeminal pain pathways in response to nociceptive trigeminovascular stimulation in wild-type and R192Q knock-in mice. After sham surgery or electrical stimulation of the superior sagittal sinus for 2h, or stimulation preceded by treatment with naratriptan, mice underwent intracardiac perfusion, and the brain, including the brainstem, was removed. Fos expression was measured in the trigeminocervical complex (TCC) and the lateral (ventroposteromedial, ventrolateral), medial (parafascicular, centromedian) and posterior thalamic nuclei. In the TCC of wild-type animals, the number of Fos-positive cells increased significantly following dural stimulation compared to the sham control group (P<0.001) and decreased after naratriptan treatment (P<0.05). In R192Q knock-in mice, there was no significant difference between the stimulated and sham (P=0.10) or naratriptan pre-treated groups (P=0.15). The number of Fos-positive cells in the R192Q stimulated group was significantly lower compared to the wild-type stimulated mice (P<0.05). In the thalamus, R192Q mice tended to be more sensitive to stimulation compared to the sham control in the medial and posterior nuclei, and between the two strains of stimulated animals there was a significant difference in the centromedian (P<0.005), and posterior nuclei (P<0.05). The present study suggests that the FHM-1 mutation affects more rostral brain structures in this experimental paradigm, which offers a novel perspective on possible differential effects of mutations causing migraine in terms of phenotype-genotype correlations.

Topics: Animals; Calcium Channels; Cerebellar Ataxia; Electric Stimulation; Gene Knock-In Techniques; Mice; Mice, Inbred C57BL; Mice, Transgenic; Migraine Disorders; Mutation, Missense; Neural Pathways; Neurons; Nociception; Piperidines; Proto-Oncogene Proteins c-fos; Serotonin 5-HT1 Receptor Agonists; Superior Sagittal Sinus; Thalamic Nuclei; Trigeminal Caudal Nucleus; Trigeminal Nuclei; Tryptamines

Previous data showed that neuropathic pain induced by mechanical lesion of peripheral nerves responds differently to alleviating drugs at cephalic versus extracephalic level. Because neuropathic pain evoked by anti-cancer drugs differs from that triggered by mechanical nerve lesion, we investigated whether differences between cephalic and extracephalic levels could also be characterized in rodents rendered neuropathic by treatment with the anti-cancer platinum derivative oxaliplatin. C57BL/6J mice received two injections and Sprague-Dawley rats three injections of oxaliplatin (10 mg/kg, i.p.) or its vehicle, with three days intervals. Supersensitivity to mechanical (von Frey filaments), cold (acetone drop) and chemical/inflammatory (formalin) stimulations was assessed in vibrissae and hindpaw territories. Transcripts of neuroinflammatory markers were quantified by real-time RT-qPCR in rat ganglia and central tissues. Oxaliplatin induced mechanical allodynia, cold hyperalgesia and chemical/inflammatory supersensitivity at both hindpaw and vibrissal levels in mice and rats. Acute treatment with gabapentin (30 mg/kg i.p.), morphine (3 mg/kg s.c.) or the 5-HT1A receptor agonist 8-OH-DPAT (0.16 mg/kg s.c.) significantly reduced oxaliplatin-induced supersensitivity in hindpaw but not vibrissal territory. In contrast, the antimigraine drugs naratriptan (0.1 mg/kg s.c.) and olcegepant (0.6 mg/kg i.v.) decreased oxaliplatin-induced supersensitivity in vibrissal territory only. Among the various markers investigated, only TRPA1 transcript was upregulated in ganglia of oxaliplatin-treated rats. These data showed that oxaliplatin induced supersensitivity to various stimuli in both cephalic and extra-cephalic territories in rodents. Regional differences in the efficacy of drugs to alleviate oxaliplatin-induced allodynia/hyperalgesia further support the idea that mechanisms underlying neuropathic pain have peculiarities at cephalic versus extra-cephalic level.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Amines; Analgesics; Animals; Cold Temperature; Cyclohexanecarboxylic Acids; Dipeptides; Formaldehyde; Gabapentin; gamma-Aminobutyric Acid; Ganglia, Spinal; Hyperalgesia; Male; Mice; Mice, Inbred C57BL; Morphine; Organoplatinum Compounds; Oxaliplatin; Piperazines; Piperidines; Quinazolines; Rats; Rats, Sprague-Dawley; Spinal Cord; Touch; TRPA1 Cation Channel; TRPC Cation Channels; Tryptamines

Topics: Adolescent; Carbazoles; Delayed-Action Preparations; Female; Follow-Up Studies; Humans; Male; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Time Factors; Tryptamines; Weather

CGRP is contained in a substantial proportion of unmyelinated trigeminal neurons innervating intracranial tissues. Previously, we have described a hemisected rodent scull preparation and later the intact trigeminal ganglion to measure stimulated CGRP release from trigeminal afferents.. Here, we establish a preparation for examining CGRP release from central trigeminal terminals using single fresh slices of the mouse medullary brainstem.. Basal and stimulated amount of CGRP substantially exceeded the detection level. Experiments were designed as matched pairs of at least six brainstem slices per animal. Stimulation with high potassium induced calcium-dependent and reversible CGRP release. Capsaicin stimulation of TRPV1 provoked concentration-dependent CGRP release. The anti-migraine drug naratriptan did not inhibit capsaicin-induced CGRP release from peripheral terminals but inhibited the release from brainstem slices. The glutamate antagonist kynurenate showed a similar pattern of site-specific inhibition of CGRP release.. As observed earlier for other drugs used in the treatment of migraine this indicates that the central terminals in the spinal trigeminal nucleus may be the main site of action. The preparation allows evaluating the trigeminal brainstem as a pharmacological site of action.

Topics: Animals; Brain Stem; Calcitonin Gene-Related Peptide; Capsaicin; Dose-Response Relationship, Drug; Female; Kynurenic Acid; Male; Mice; Mice, Inbred C57BL; Neural Inhibition; Organ Culture Techniques; Piperidines; Rats, Sprague-Dawley; Tryptamines

The purpose of this study was to develop and manufacture novel freeze-dried orally disintegrating tablets (ODTs) for migraine therapy containing taste-masked naproxen sodium and naratriptan hydrochloride. The formulation was optimized based on freeze-drying of sucrose solutions with different binders (hydroxyethylstarch, sodium alginate, methylcellulose, and gelatin) and varying amounts of Eudragit® E-coated naproxen sodium granules. Excellent product performance of the ODTs in terms of hardness and disintegration time (<10 s) independent of the mass of particles embedded was found for the solution consisting of sucrose and hydroxyethylstarch. Poloxamer 188, menthol flavor, naratriptan hydrochloride, and taste-masked naproxen sodium granules corresponding to 200 mg of naproxen were then added, and the final batches of ODTs for migraine therapy were produced. The ODTs were fully characterized, and subsequently stored for 1 month at room temperature and at 40°C. The amount of free naproxen sodium after freeze-drying and storage was below the threshold bitterness value, and the coating remained intact. Additionally, the particle size distribution of taste-masked granules was preserved, and more than 90 % naproxen sodium was released after 30 min. Naratriptan hydrochloride was dissolved immediately after disintegration, hence facilitating buccal absorption of the active pharmaceutical ingredient.

Topics: Administration, Oral; Anti-Inflammatory Agents, Non-Steroidal; Drug Compounding; Drug Storage; Excipients; Freeze Drying; Migraine Disorders; Naproxen; Particle Size; Piperidines; Polymethacrylic Acids; Solubility; Tablets; Taste; Tryptamines; Vasoconstrictor Agents

In this work, we report a molecular dynamics simulations study of protonated triptans, sumatriptan and naratriptan, in a fully hydrated bilayer of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidyl-choline (POPC). The simulations were carried out at two concentrations for each drug. Our results show partition between the lipid head-water interphase and water phase for both triptans, with increasing access to the water phase with increasing concentrations. The triptans were stabilized at the interphase through different specific interactions with the POPC bilayer such as hydrogen bonds, salt bridges, and cation-π. Besides, sumatriptan and naratriptan protonated molecules have no access to the hydrophobic region of the bilayer at the studied conditions. Similar results were found for both drugs, however protonated naratriptan shows slightly higher affinity for the water phase. This behavior was attributed to the bulky lateral amino group in its structure under the studied conditions (drugs were originally placed at the water phase). This work represents a first insight to the comprehensive understanding of triptan partition in model membranes.

Topics: Drug Stability; Hydrogen Bonding; Lipid Bilayers; Molecular Dynamics Simulation; Molecular Structure; Phosphatidylcholines; Piperidines; Protons; Solubility; Structure-Activity Relationship; Sumatriptan; Tryptamines; Water

Myocardial infarction as the most severe clinical manifestation of coronary atherosclerosis is the major cause of death in western countries. Although rupture of an atherosclerotic plaque is generally causal for this event, in recent years differential diagnoses have been discussed to further optimize diagnosis and treatment of myocardial ischemia. The "universal definition of myocardial infarction" defines five subtypes of myocardial infarction: in particular, type 2 myocardial infarction includes other diseases related to myocardial ischemia such as hyper- or hypotension, coronary artery spasms, arrhythmia, etc. Some medications for the acute therapy of migraine like triptans can lead to myocardial infarction.

Topics: Combined Modality Therapy; Drug Substitution; Female; Humans; Middle Aged; Migraine Disorders; Myocardial Infarction; Myocardial Ischemia; Piperidines; Self Medication; Substance-Related Disorders; Tryptamines

Topics: Congenital Abnormalities; Female; Humans; Naproxen; Piperidines; Pregnancy; Sumatriptan; Tryptamines

Topics: Acute Coronary Syndrome; Aged; Editorial Policies; Female; Humans; Medical Records, Problem-Oriented; Migraine Disorders; Periodicals as Topic; Piperidines; Publishing; Research Report; Switzerland; Tryptamines; Vasoconstrictor Agents; Writing

While functional imaging and deep brain stimulation studies point to a pivotal role of the hypothalamus in the pathophysiology of migraine and trigeminal autonomic cephalalgias, the circuitry and the mechanisms underlying the modulation of medullary trigeminovascular (Sp5C) neurons have not been fully identified. We investigated the existence of a direct anatomo-functional relationship between hypothalamic excitability disturbances and modifications of the activities of Sp5C neurons in the rat. Anterograde and retrograde neuronal anatomical tracing, intrahypothalamic microinjections, extracellular single-unit recordings of Sp5C neurons, and behavioral trials were used in this study. We found that neurons of the paraventricular nucleus of the hypothalamus (PVN) send descending projections to the superior salivatory nucleus, a region that gives rise to parasympathetic outflow to cephalic and ocular/nasal structures. PVN cells project also to laminae I and outer II of the Sp5C. Microinjections of the GABAA agonist muscimol into PVN inhibit both basal and meningeal-evoked activities of Sp5C neurons. Such inhibitions were reduced in acutely restrained stressed rats. GABAA antagonist gabazine infusions into the PVN facilitate meningeal-evoked responses of Sp5C neurons. PVN injections of the neuropeptide pituitary adenylate cyclase activating peptide (PACAP38) enhance Sp5C basal activities, whereas the antagonist PACAP6-38 depresses all types of Sp5C activities. 5-HT1B/D receptor agonist naratriptan infusion confined to the PVN depresses both basal and meningeal-evoked Sp5C activities. Our findings suggest that paraventricular hypothalamic neurons directly control both spontaneous and evoked activities of Sp5C neurons and could act either as modulators or triggers of migraine and/or trigeminal autonomic cephalalgias by integrating nociceptive, autonomic, and stress processing mechanisms.

Topics: Action Potentials; Animals; Biotin; Corticosterone; Dextrans; Disease Models, Animal; GABA Antagonists; GABA-A Receptor Agonists; Male; Muscimol; Neural Pathways; Neurons; Paraventricular Hypothalamic Nucleus; Physical Stimulation; Piperidines; Pituitary Adenylate Cyclase-Activating Polypeptide; Pyridazines; Rats; Rats, Sprague-Dawley; Serotonin Receptor Agonists; Stilbamidines; Stress, Psychological; Trigeminal Nuclei; Tryptamines

We report on an angioedema patient with a genetic defect in complement 1 inhibitor, manifesting migraine-like episodes of headache, effective prophylaxis with Danazol, and triptan for a treatment of acute clinical episode. The patient was 44-yr-old Korean man with abdominal pain and headache, who was brought into the Emergency Department of Seoul National University Hospital, Seoul. He suffered from frequent attacks of migraine-like headache (3-7 per month), pulsating in nature associated with nausea. Severities were aggravated by activity and his headache had shown recent progression with abdominal pain. No remarkable findings were observed on radiologic examination, brain magnetic resonance images and intracranial and extracranial magnetic resonance angiography. Danazol 200 mg every other day was subsequently used. Following administration of Danazol, symptoms showed improvement and the patient was discharged. While taking Danazol, the migraine-like episodes appeared to be prevented for about 2 yr. At the eighth month, he suffered a moderate degree of migraine-like headache; however, administration of naratriptan 2.5 mg resolved his problem. A case of genetic defect of C1-INH deficiency presented with headache episodes, and was controlled by Danazol and triptan. It suggests that pathogenic mechanism of headache in hereditary angioedema may be mediated by the neurogenic inflammatory-like physiology of migraine.

Topics: Adult; Angioedemas, Hereditary; Brain; Complement C1 Inhibitor Protein; Danazol; Estrogen Antagonists; Humans; Magnetic Resonance Angiography; Male; Migraine Disorders; Piperidines; Radionuclide Imaging; Tryptamines; Vasoconstrictor Agents

We reported the case of a 61-year-old woman, who has been hospitalized in ICU because of an extensive mesenteric ischaemia, involving the small bowel, secondary to a naratriptan overuse. This mesenteric ischaemia was complicated by multiple organ failure and was responsible for extensive small bowel resection and left colectomy. A concomitant abundant absorption of grapefruit juice, a well-known P450 inhibitor, may have enhanced this naratriptan toxicity. This case underscore that an abdominal pain occurring in the context of headache treatment may be related to a mesenteric ischaemia.

Topics: Abdominal Pain; Citrus paradisi; Colectomy; Electrocardiography; Female; Food-Drug Interactions; Humans; Intestines; Ischemia; Middle Aged; Multiple Organ Failure; Piperidines; Serotonin Agents; Shock; Splanchnic Circulation; Tryptamines

Previous studies showed that 5-hydroxytryptamine (5-HT)(1B/1D) receptor stimulation by triptans alleviates neuropathic pain caused by chronic constriction injury to the infraorbital nerve (CCI-ION) but not the sciatic nerve (CCI-SN) in rats. To assess whether such differential effects in the cephalic vs extracephalic territories is a property shared by other antimigraine drugs, we used the same models to investigate the effects of olcegepant, which has an antimigraine action mediated through calcitonin gene-related peptide (CGRP) receptor blockade. Adult male rats underwent unilateral CCI to the ION or the SN, and subsequent allodynia and/or hyperalgesia were assessed in ipsilateral vibrissal territory or hindpaw, respectively, using von Frey filaments and validated nociceptive tests. c-Fos expression was quantified by immunohistochemistry and interleukin 6 and activating transcription factor 3 (ATF3) mRNAs by real-time quantitative reverse transcriptase-polymerase chain reaction. Like naratriptan (0.1 to 0.3mg/kg, subcutaneously), olcegepant (0.3 to 0.9mg/kg, intravenously) markedly reduced mechanical allodynia in CCI-ION rats. In contrast, in CCI-SN rats, mechanical allodynia was completely unaffected and hyperalgesia was only marginally reduced by these drugs. A supra-additive antiallodynic effect was observed in CCI-ION rats treated with olcegepant (0.3mg/kg intravenously) plus naratriptan (0.1mg/kg subcutaneously), whereas this drug combination remained inactive in CCI-SN rats. Olcegepant (0.6mg/kg, intravenously) significantly reduced the number of c-Fos immunolabeled cells in spinal nucleus of the trigeminal nerve and upregulation of ATF3 transcript (a marker of neuron injury) but not that of interleukin-6 in trigeminal ganglion of CCI-ION rats. These findings suggest that CGRP receptor blockade might be of potential interest to alleviate trigeminal neuropathic pain.

Topics: Activating Transcription Factor 3; Animals; Biomarkers; Calcitonin Gene-Related Peptide Receptor Antagonists; Dipeptides; Hyperalgesia; Interleukin-6; Locomotion; Male; Maxillary Nerve; Neuralgia; Pain Measurement; Piperazines; Piperidines; Proto-Oncogene Proteins c-fos; Quinazolines; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptors, Calcitonin Gene-Related Peptide; RNA, Messenger; Rotarod Performance Test; Sciatic Nerve; Serotonin 5-HT1 Receptor Agonists; Tryptamines

Spinal and bulbar muscular atrophy (SBMA) is a motor neuron disease caused by the expansion of the CAG triplet repeat within the androgen receptor (AR) gene. Here, we demonstrated that pathogenic AR upregulates the gene encoding calcitonin gene-related peptide α (CGRP1). In neuronal cells, overexpression of CGRP1 induced cellular damage via the activation of the c-Jun N-terminal kinase (JNK) pathway, whereas pharmacological suppression of CGRP1 or JNK attenuated the neurotoxic effects of pathogenic AR. The depletion of CGRP1 inactivated JNK and suppressed neurodegeneration in a mouse model of SBMA. Naratriptan, a serotonin 1B/1D (5-hydroxytryptamine 1B/1D, or 5-HT1B/1D) receptor agonist, decreased CGRP1 expression via the induction of dual-specificity protein phosphatase 1 (DUSP1), attenuated JNK activity and mitigated pathogenic AR-mediated neuronal damage in cellular and mouse SBMA models. These observations suggest that pharmacological activation of the 5-HT1B/1D receptor may be used therapeutically to treat SBMA and other polyglutamine-related neurodegenerative diseases.

Topics: Animals; Calcitonin; Calcitonin Gene-Related Peptide; Cell Survival; Cells, Cultured; Dual Specificity Phosphatase 1; JNK Mitogen-Activated Protein Kinases; Male; Mice; Mice, Transgenic; Motor Neuron Disease; Muscular Disorders, Atrophic; Peptides; Piperidines; Protein Precursors; Receptors, Androgen; RNA Interference; RNA, Small Interfering; Serotonin 5-HT1 Receptor Agonists; Spinal Cord; Trinucleotide Repeat Expansion; Tryptamines

Topics: Animals; Calcitonin; Male; Muscular Disorders, Atrophic; Peptides; Piperidines; Protein Precursors; Receptors, Androgen; Serotonin 5-HT1 Receptor Agonists; Trinucleotide Repeat Expansion; Tryptamines

Trigeminal autonomic cephalalgias are highly disabling primary headache disorders, characterized by severe unilateral head pain and associated ipsilateral cranial autonomic features. There is limited understanding of their pathophysiology and how and where treatments act to reduce symptoms; this is significantly hindered by a lack of animal models. We have developed the first animal model to explore trigeminal autonomic cephalalgias, using stimulation within the brainstem, at the level of the superior salivatory nucleus, to activate the trigeminal autonomic reflex arc. Using electrophysiological recording of neurons of the trigeminocervical complex and laser Doppler blood flow changes around the ipsilateral lacrimal duct, superior salivatory nucleus stimulation exhibited both neuronal trigeminovascular and cranial autonomic manifestations. These responses were specifically inhibited by the autonomic ganglion blocker hexamethonium bromide. These data demonstrate that brainstem activation may be the driver of both sensory and autonomic symptoms in these disorders, and part of this activation may be via the parasympathetic outflow to the cranial vasculature. Additionally, both sensory and autonomic manifestations were significantly inhibited by highly effective treatments for trigeminal autonomic cephalalgias, such as oxygen, indomethacin and triptans, and some part of their therapeutic action appears to be specifically on the parasympathetic outflow to the cranial vasculature. Treatments more used to migraine, such as naproxen and a calcitonin gene-related peptide receptor inhibitor, olcegepant, were less effective in this model. This is the first model to represent the phenotype of trigeminal autonomic cephalalgias and their response to therapies, and indicates the parasympathetic pathway may be uniquely involved in their pathophysiology and targeted to relieve symptoms.

Topics: Action Potentials; Analysis of Variance; Animals; Disease Models, Animal; Electric Stimulation; Electric Stimulation Therapy; Functional Laterality; Ganglionic Blockers; Hexamethonium; Laminectomy; Laser-Doppler Flowmetry; Male; Neurons; Oxygen; Piperidines; Rats; Rats, Sprague-Dawley; Reaction Time; Serotonin 5-HT1 Receptor Agonists; Trigeminal Autonomic Cephalalgias; Trigeminal Nuclei; Tryptamines

A simple, sensitive, selective, and rapid high-performance liquid chromatography-tandem mass spectrometry method is developed and validated for the quantitation of naratriptan, using sumatriptan as internal standard (IS). The method included liquid-liquid extraction of naratriptan and IS with methyl-tert-butyl ether and dichloromethane mixture from 100 μL human plasma. The chromatographic separation is achieved on ACE C18 (50 mm × 2.1 mm, 5 μm) analytical column under isocratic conditions, using 0.1% acetic acid and acetonitrile (15:85, v/v) at a flow-rate of 0.4 mL/min. The precursor → product ion transitions for naratriptan (m/z 336.10 → 98.06) and IS (m/z 296.09 → 251.06) were monitored on a triple quadrupole mass spectrometer, operating in the multiple reaction monitoring (MRM) and positive ion mode. The linearity of the method for naratriptan is determined in the range of 103-20690 pg/mL with the analysis time of 1.5 min. The method is fully validated according to USFDA guidelines. A systematic post-column infusion study is conducted for ion-suppression due to endogenous matrix components. The process efficiency of analyte (96%) and IS (93%) from spiked plasma samples was consistent and reproducible. The application of the method is demonstrated by a bioequivalence study of 2.5 mg naratriptan tablet formulation in 31 healthy volunteers under fasting conditions.

Topics: Adult; Area Under Curve; Chromatography, Liquid; Drug Stability; Humans; Piperidines; Reproducibility of Results; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization; Sumatriptan; Tandem Mass Spectrometry; Therapeutic Equivalency; Tryptamines

The c-AMP-responsive element binding protein (CREB) and its phosphorylated product (P-CREB) are nuclear proteins expressed after stimulation of pain-producing areas of the spinal cord. There is evidence indicating that central sensitization within dorsal horn neurons is dependent on P-CREB transcriptional regulation. The objectives of the study were to investigate the expression of P-CREB in cells in rat trigeminal nucleus caudalis after noxious stimulation and to determine whether pre-treatment with specific anti-migraine agents modulate this expression. CREB and P-CREB labelling was investigated within the trigeminal caudalis by immunohistochemistry after capsaicin stimulation. Subsequently, the effect of i.v. pre-treatment with either sumatriptan (n = 5), or naratriptan (n = 7) on P-CREB expression was studied. Five animals pre-treated with i.v. normal saline were served as controls. CREB and P-CREB labelling was robust in all animal groups within Sp5C. Both naratriptan and sumatriptan decreased P-CREB expression (p = 0.0003 and 0.0013) within the Sp5C. Triptans attenuate activation of CREB within the central parts of the trigeminal system, thereby leading to potential inhibition of central sensitization. P-CREB may serve as a new marker for post-synaptic neuronal activation within Sp5C in animal models relevant to migraine.

Topics: Animals; Capsaicin; Cyclic AMP Response Element-Binding Protein; Hyperalgesia; Immunohistochemistry; Male; Pain; Phosphorylation; Piperidines; Rats; Rats, Sprague-Dawley; Sensory System Agents; Sumatriptan; Trigeminal Caudal Nucleus; Tryptamines

Authors developed a simple, sensitive, selective, rapid, rugged, and reproducible liquid chromatography-tandem mass spectrometry method for the quantification of eletriptan (EP) in human plasma using naratriptan (NP) as an internal standard (IS). Chromatographic separation was performed on Ascentis Express C18, 50 × 4.6 mm, 2.7 μm column. Mobile phase was composed of 0.1% formic acid: methanol (40:60 v/v), with 0.5 mL/min flow rate. Drug and IS were extracted by liquid-liquid extraction. EP and NP were detected with proton adducts at m/z 383.2→84.3 and 336.2→97.8 in multiple reaction monitoring (MRM) positive mode, respectively. The method was validated with the correlation coefficients of (r(2)) ≥ 0.9963 over a linear concentration range of 0.5-250.0 ng/mL. This method demonstrated intra- and inter-day precision within 1.4-9.2% and 4.4-5.5% and accuracy within 96.8-103% and 98.5-99.8% for EP. This method is successfully applied in the bioequivalence study of 24 human volunteers.

Topics: Chromatography, High Pressure Liquid; Humans; Liquid-Liquid Extraction; Piperidines; Pyrrolidines; Reference Standards; Reproducibility of Results; Sensitivity and Specificity; Serotonin Receptor Agonists; Tandem Mass Spectrometry; 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

This paper is the first report describing the characterization of local diatomite of Caldiran-Van region (Eastern Anatolia, Turkey). Special attention was paid to the ability of its electroanalytical performance at modified electrodes and to the potential application of diatomite-modified electrode. For this purpose, the determination of Naratriptan which is a novel oral triptan (5-hydroxytryptamine receptor agonist) in migraine treatment, by means of a carbon paste electrode modified with 10% (w/w) of diatomite was studied using cyclic and square-wave voltammetry. The experimental conditions that affect the electrode reaction process were studied in terms of pH of the supporting electrolyte, scan rate, accumulation variables, modifier composition and square-wave parameters. Using square-wave stripping mode, the drug yielded a well-defined voltammetric response in Britton-Robinson buffer, pH 4.0 at 0.84 V (vs. Ag/AgCl) (a pre-concentration step being carried out with an open circuit at 120 s). The process could be used to determine Naratriptan concentrations in the range 5x10(-7)-9x10(-7) M, with a detection limit of 1.25x10(-7) M (46.5 mug L(-1)). The applicability of the method to spiked human urine samples was illustrated.

Topics: Carbon; Diatomaceous Earth; Electrochemistry; Electrodes; Hydrogen-Ion Concentration; Molecular Structure; Piperidines; Spectroscopy, Fourier Transform Infrared; Surface Properties; Tryptamines; Turkey

A 60-year-old female with sudden onset of abdominal pain and hematochezia was diagnosed with histology-proven ischemic colitis. She used naratriptan on a regular basis for migraine. By exclusion of other causes for colonic ischemia and the absence of cardiovascular risk factors, naratriptan was considered the causal agent. Discontinuation resulted in a complete clinical recovery. With the increasing use of triptans, health care providers should be aware of the possible serious ischemic events associated with these drugs.

Topics: Colitis, Ischemic; Female; Humans; Middle Aged; Migraine Disorders; Piperidines; Tryptamines; Vasoconstrictor Agents

A patient who just found out that she is pregnant and suffers from migraine headaches informs me that she has been taking naratriptan. She indicates that she is planning on breastfeeding her baby and might need to continue treatment. How safe are the medications from this class of drugs during pregnancy and breastfeeding?. Accumulated data suggest that exposure to sumatriptan during pregnancy does not increase the risk of birth defects above the baseline rate. There are currently insufficient data to confirm the safety of other triptans; however, evidence to date is reassuring. Information regarding safety of triptans while breastfeeding is limited but also reassuring, as the minimal amounts excreted into the milk are insufficient to cause any adverse effects on the breastfeeding infant.

Topics: Breast Feeding; Female; Humans; Migraine Disorders; Piperidines; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Risk Factors; Serotonin 5-HT1 Receptor Agonists; Sumatriptan; Tryptamines

The electrochemical behavior and the analytical application of the selective serotonin agonist naratriptan (N-methyl-3-(1-methyl-4-piperidyl)indole-5-ethanesulfonamide) are presented herein. Naratriptan exhibits an anodic response in aqueous media over a broad pH range (pH 2-12), as determined by differential pulse voltammetry and cyclic voltammetry using glassy carbon electrodes. This response is irreversible in nature, diffusion-controlled and probably caused by the oxidation of the naratriptan indole moiety. The differential pulse voltammetry technique was performed in 0.1 mol L(-1) Britton-Robinson buffer (pH=3), which elicited the most reproducible results. The percentage of naratriptan recovery was 102.1+/-1.8%, and the limits of detection and quantitation were 9.5x10(-6) and 2.0x10(-5) mol L(-1), respectively. Selectivity trials revealed that the oxidation signal of the drug was not disturbed by the presence of excipients or degradation products. Thus, we conclude that the method presented herein is useful for the quantification of naratriptan in pharmaceutical drugs and that this method requires no separations or extractions. Finally, this voltammetric method was successfully applied to determine the quantity and the content uniformity of naratriptan in drug tablets. A comparison of this technique to the standard high-performance liquid chromatography technique was conducted at the end of our study.

Topics: Carbon; Chromatography, High Pressure Liquid; Electrochemistry; Electrodes; Glass; Molecular Structure; Piperidines; Serotonin Receptor Agonists; Tablets; Tryptamines

This case report describes for the first time acute coronary syndrome in a 67-year old patient after oral intake of naratriptan for migraine. So far in the literature, only sumatriptan, zolmitriptan and frovatriptan have been described to cause acute coronary syndromes. A 67-year old Swiss woman with thoracic pain after intake of 2.5 mg naratriptan presented with T-wave inversions in the ECG and a positive troponin-T at our hospital. Coronary angiography showed normal coronary arteries. Naratriptan-induced coronary vasospasms were thought to have caused the acute coronary syndrome.Triptans should not be prescribed in patients with pre-existing coronary heart disease. However, triptans can also cause acute coronary syndromes in patients without coronary heart disease--as described in our case report. Severe or persistent thoracic pain after intake of triptans should therefore be investigated accordingly.

Topics: Acute Coronary Syndrome; Aged; Electrocardiography; Female; Humans; Migraine Disorders; Piperidines; Serotonin Agents; Treatment Outcome; Troponin T; Tryptamines

The efficacy of triptans in the treatment of migraine was recently contested. How high is then the maximum effect of a triptan? After subcutaneous naratriptan 10 mg a 88% pain-free response was observed. This result was obtained despite the fact that more half of the patients had a migraine duration of > 4 h. These results indicate that subcutaneous naratriptan in a high dose can overcome central sensitization that occurs in migraine attacks.

Topics: Dose-Response Relationship, Drug; Humans; Injections, Subcutaneous; Migraine Disorders; Pain Measurement; Piperidines; Randomized Controlled Trials as Topic; Sumatriptan; Treatment Outcome; Tryptamines

Molecules of eletriptan hydrobromide monohydrate (systematic name: (1S,2R)-1-methyl-2-{5-[2-(phenylsulfonyl)ethyl]-1H-indol-3-ylmethyl}pyrrolidinium bromide monohydrate), C(22)H(27)N(2)O(2)S(+) x Br(-) x H(2)O, (I), and naratriptan hydrochloride (systematic name: 1-methyl-4-{5-[2-(methylsulfamoyl)ethyl]-1H-indol-3-yl}piperidinium chloride), C(17)H(26)N(3)O(2)S(+) x Cl(-), (II), adopt conformations similar to other triptans. The C-2 and C-5 substituents of the indole ring, both of which are in a region of conformational flexibility, are found to be oriented on either side of the indole ring plane in (I), whilst they are on the same side in (II). The N atom in the C-2 side chain is protonated in both structures and is involved in the hydrogen-bonding networks. In (I), the water molecules create helical hydrogen-bonded chains along the c axis. In (II), the hydrogen bonding of the chloride ions results in macrocyclic R(4)(2)(20) and R(4)(2)(24) ring motifs that form sheets in the bc plane. This structural analysis provides an insight into the molecular structure-activity relationships within this class of compound, which is of use for drug development.

Topics: Analgesics; Crystallography, X-Ray; Halogens; Humans; Hydrogen Bonding; Migraine Disorders; Molecular Structure; Piperidines; Pyrrolidines; Salts; Structure-Activity Relationship; Tryptamines

To study the contractile responses of the human basilar artery to 5-hydroxytryptamine (5-HT), sumatriptan, zolmitriptan and naratriptan, and to characterize the 5-HT receptor subtypes involved on those responses, human basilar artery rings were prepared for isometric contraction, protein isolation and Western blotting analysis. Concentration-response (CR) curves were made for all agonists in the absence or in the presence of selective antagonists at 5-HT1B (cyanopindolol), 5-HT1D (BRL 15,572) and 5-HT2 (ketanserin) receptors. We also used anti-5-HT1B and 5-HT1D receptor antibodies to search for the expression of protein of these receptor subtypes. From the CR curves, the relative intrinsic activity and potency of these agonists were determined. The ranking order for the intrinsic activity was 5-HT > or = sumatriptan > zolmitriptan > or = naratriptan, whereas that for the potency was zolmitriptan > or = 5-HT > or = sumatriptan > naratriptan. Our results also show that the human basilar artery seems to have a mixed population of 5-HT1B/1D receptors mediating the contractile response to triptans, which is also suggested by the expression of both receptor subtypes. There is also a population of 5-HT2 receptors for which the antimigraine drugs used have no apparent affinity. From this study, one can conclude that the second generation triptans have lower contractile capacity than sumatriptan, suggesting that they have a better cerebrovascular safety profile.

Topics: Basilar Artery; Female; Humans; In Vitro Techniques; Male; Middle Aged; Oxazolidinones; Piperidines; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT1D; Serotonin; Serotonin Receptor Agonists; Sumatriptan; Tryptamines; Vasoconstriction; Vasoconstrictor Agents

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

Migraine is a prevalent neurological disorder that can be alleviated by specific treatment for acute headaches, in particular, the triptans, including naratriptan. France has developed official guidelines for the use of triptans as part of migraine management. This pharmacoepidemiological study sought to evaluate how naratriptan is prescribed and used in community medicine in France.. The protocol called for general practitioners to be randomly selected from a list of all physicians in France and for each to include two patients with migraine. Data came from questionnaires completed by the physician and by the patient (including HIT-6 and QVM to assess headache impact and quality of life) as well as a patient diary.. In all, 2530 physicians included 3863 patients: 54.3% were treated with naratriptan, 22.4% with another triptan and 23.3% with a non-triptan medication. Of the patients receiving naratriptran, 82.3% were women. Migraine impact was greater and quality of life worse in the patients receiving triptans than those treated with other medications (p<0.0001). Naratriptan was prescribed as second-line treatment following failure of an NSAID in 44.2% of patients taking it; 55.3% of them were prescribed a single dose per headache. Overall, initial treatment was taken right at the beginning of the migraine attack in 70.5% of headaches.. Data from this cross-sectional study indicate that triptans in general and naratriptan in particular are most often prescribed for patients with the most severe migraines. Consistent with official French guidelines, physicians often recommend taking naratriptan after and only if a NSAID fails to provide relief. Nonetheless, one patient in three starts treatment late, which may significantly reduce the efficacy rate, increase the risk of recurrence and side effects, and prolong the headache.. Naratriptan is generally prescribed in accordance with official guidelines. Delay in taking medication by around one third of patients probably reduces its efficacy.

Topics: Adult; Drug Prescriptions; Drug Utilization; Family Practice; Female; France; Humans; Male; Migraine Disorders; Piperidines; Surveys and Questionnaires; Tryptamines

Topics: Adult; Headache; Humans; Lymphocytic Choriomeningitis; Male; Piperidines; Serotonin 5-HT1 Receptor Agonists; Serotonin Receptor Agonists; Tryptamines

In this report, a case with vitamin B12 deficiency showing a temporary confusion depending on the usage of naratriptan during the migraine attack was presented.

Topics: Confusion; Female; Humans; Magnetic Resonance Imaging; Middle Aged; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Tryptamines; Vitamin B 12 Deficiency

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

Triptans, serotonin 5-HT(1B/1D), receptor agonists, which are so effective in acute migraine, are considered to act directly on the trigeminovascular system. Using an in vivo model of trigeminovascular nociception, we report a potentially novel action for the triptans within the somatosensory thalamus. Both microiontophoretically applied and intravenous naratriptans potently and reversibly modulate nociceptive neurotransmission by trigeminovascular thalamic neurons in the ventroposteromedial nucleus (VPM) driven by stimulation of the superior sagittal sinus. Naratriptan also suppresses l-glutamate activated trigeminovascular VPM neurons. Co-ejection of naratriptan with the 5-HT(1B/1D) receptor antagonist GR127935 antagonized this effect. (S)-WAY 100135 the 5-HT(1A) receptor antagonist also partially inhibited the effect of naratriptan in the VPM when co-ejected with it. Taken together, the new data suggest a potential effect of triptans in the VPM nucleus of the thalamus acting through 5-HT(1A/1B/1D) mechanisms, and offer an entirely new direction for the development of and understanding of the effects of anti-migraine medicines.

Topics: Afferent Pathways; Animals; Cerebral Arteries; Drug Interactions; Glutamic Acid; Male; Migraine Disorders; Nociceptors; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Synaptic Transmission; Trigeminal Nerve; Tryptamines; Ventral Thalamic Nuclei

The treatment of migraine consists of the acute treatment of the migraine attack and prophylactic measures for either pharmacological or non-pharmacological management. Since the retreat of the ergotamines one can only choose between one of the well-established analgesics and one of seven triptans for the treatment of the migraine attack. Although neither a new triptan nor an innovative new application form has been introduced, the year 2006 will be remembered as the year when the first triptan (naratriptan) was released as a prescription-free over-the-counter drug and when the first sumatriptan generics were marketed in Germany. In addition to the beta-blockers metoprolol and propranolol and the calcium antagonist flunarizine two antiepileptic drugs, topiramate and valproic acid, have been rated as first-line prophylactic drugs in Germany. Due to an extensive and successful study program topiramate has been officially approved in Germany.

Topics: Anticonvulsants; Humans; Migraine Disorders; Piperidines; Serotonin Agents; Tryptamines

Currently, direct comparisons between 5-HT(1B/d) receptor agonists are used to assess differences and similarities in antimigraine response. Such comparisons depend on the selected sampling time and do not allow evaluation of entire response profiles. A thorough evaluation of drug properties requires that the time course of the response be taken into account. In this investigation we show the advantages of a model-based approach to compare the efficacy of two triptans (sumatriptan vs. naratriptan).. A Markov model was used to describe the course of a migraine attack over three clinically identified stages. Drug effects were modelled as concentration-dependent increases in transition rates and were parameterised as potency (EC(50)) and maximum effect (E(max)). Parameters were estimated using headache measurements from efficacy studies. Model estimates were then used to compare the pharmacodynamics of the two drugs in a time-independent manner.. Efficacy parameters could be derived, allowing for comparison between compounds. The potency ratio (EC50(suma)/EC50(nara)) for headache relief was 3.3 (0.9, 12). The ratio of maximum effects (Emax(suma)/Emax(nara)) for this endpoint was 0.74 (0.55, 0.97). To interpret these efficacy measures and explore their value for the development of antimigraine drugs, results were evaluated against the reported in vitro potency at 5-HT(1B) and 5-HT(1D) receptors.. Comparison of the effects of two or more drugs based on preset sampling times does not allow proper assessment of the antimigraine properties in vivo. Disease dynamics must be considered to evaluate treatment response adequately and optimise the dosing regimen in migraine.

Topics: Dose-Response Relationship, Drug; Humans; Markov Chains; Migraine Disorders; Models, Biological; Piperidines; Serotonin Receptor Agonists; Sumatriptan; Treatment Outcome; 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

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

Ischemic colitis has not been reported in association with naratriptan therapy. We describe the occurrence of ischemic colitis in a patient who was treated with abortive doses of naratriptan for migraine and was also taking long-term oral contraceptives. Concurrent use of naratriptan and oral contraceptives should probably be avoided.

Topics: Adult; Colitis, Ischemic; Contraceptives, Oral; Drug Interactions; Female; Humans; Indoles; Migraine Disorders; Piperidines; Tryptamines

This study introduces a laboratory model of compulsive behavior based on persistence in the context of rewarded spatial alternation.. Rats were screened for spontaneous persistence during T-maze reinforced alternation. Experiment 1: One high and one low spontaneous persistence group (n = 8) received 20 injections of fluoxetine, a matched pair saline, both followed by 4 days of meta-chlorophenylpiperazine (mCPP) challenge. Experiment 2: Five matched groups of rats (n = 9) received pretreatment (20 injections) with fluoxetine, mCPP, desipramine, diazepam or saline, followed by 4 days of mCPP challenge (fluoxetine in mCPP group). After washout, animals received 2 days of naratriptan, followed by another 2-day mCPP challenge.. In both experiments mCPP significantly increased persistence in saline controls. Fluoxetine also acutely increased persistence scores: after a gradual return to baseline, these scores showed tolerance to mCPP. Experiment 1: This pattern was significant in high but not low initial persistence groups. Experiment 2: Fluoxetine and mCPP showed cross-tolerance. Neither desipramine nor diazepam protected against mCPP challenge. Persistence scores returned to baseline during washout and naratriptan and were thereafter increased by another mCPP challenge in all but the fluoxetine and mCPP groups, suggesting 5-HT2C receptor mediation.. This model is based on spontaneous persistence behavior showing pharmacological responses concordant with those of compulsive symptomatology.

Topics: Animals; Anti-Anxiety Agents; Antidepressive Agents, Tricyclic; Desipramine; Diazepam; Disease Models, Animal; Fluoxetine; Indoles; Male; Maze Learning; Obsessive-Compulsive Disorder; Piperazines; Piperidines; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1D; Receptor, Serotonin, 5-HT2C; Reinforcement, Psychology; Selective Serotonin Reuptake Inhibitors; Serotonin Receptor Agonists; Tryptamines

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

The aim of the study was to predict pain relief of migraine in patients following naratriptan oral (tablet) administration by using uncertainty analysis. The analysis was based on phase I pharmacokinetic naratriptan data, sumatriptan pharmacodynamic data, and naratriptan preclinical (animal) potency information, together with general knowledge as to how migraine affects oral absorption.. A previously developed pharmacokinetic (PK)/pharmacodynamic (PD) model for naratriptan disposition and effect was used. The uncertain parameters in the model, which were associated with absorption and scaling between first-in-class compound sumatriptan and naratriptan, were modeled using fuzzy sets theory. Global sensitivity analysis was then used to investigate the impact of each PK/PD parameter on the responses.. Acknowledging parametric uncertainty did not improve prediction of the probability of pain relief. Global sensitivity analysis demonstrated that predictions were heavily influenced by interindividual variability in pharmacodynamics, as the dose response relationship was relatively insensitive to the pharmacokinetics.. To predict the probability of pain relief following oral (tablet) administration of naratriptan, a simple dose response, instead of the PK/PD model, would have yielded very similar predictions. The naratriptan PK/PD model may be improved by either refining the PD model or better still by specifying the interindividual error by additional data collecting with an improved design.

Topics: Algorithms; Analgesics; Female; Humans; Male; Migraine Disorders; Models, Biological; Piperidines; Serotonin Receptor Agonists; Software; Sumatriptan; Tryptamines; Vasoconstrictor Agents

Migraine pain arises in the trigeminovascular system and is often associated with nausea and sometimes with vomiting. In this study, an in vivo cat model of trigeminovascular stimulation was used to determine first whether there is a functional connection between the trigeminovascular system and the nucleus tractus solitarius (NTS), which is involved in regulating vomiting, and second whether anti-migraine drugs have any effect on such a connection. Chloralose-anaesthetised cats (n=16) were prepared for single neuron recording. The superior sagittal sinus (SSS) was isolated and stimulated electrically. The brainstem near the obex was exposed and a metal microelectrode equipped with six glass barrels for microiontophoresis was placed in the NTS. Recordings were made from 44 NTS neurons which responded to SSS stimulation with A-delta latencies. Iontophoretic ejection (50 nA) of eletriptan or naratriptan suppressed the response in 75% (15/20) and 78% (11/14) of cells and caused an average suppression of cell firing of 42+/-5% (n=20) and 54+/-8% (n=14), respectively. This suppression could be antagonized by the concurrent ejection (20-50 nA) of the 5-HT(1B/1D) receptor antagonist GR127935. We conclude that activation of the trigeminovascular system excites cells in the NTS that can be inhibited by eletriptan and naratriptan through activation of 5-HT(1B/1D) receptors. It is possible that in patients having a migraine attack trigeminovascular activation triggers nausea and vomiting, and that the alleviation of these symptoms by anti-migraine compounds may be via an action at 5-HT(1B/1D) receptors in the NTS.

Topics: Action Potentials; Animals; Cats; Drug Interactions; Electric Stimulation; Indoles; Maximum Tolerated Dose; Neural Inhibition; Oxadiazoles; Piperazines; Piperidines; Pyrrolidines; Reaction Time; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Serotonin 5-HT1 Receptor Agonists; Serotonin Antagonists; Serotonin Receptor Agonists; Solitary Nucleus; Trigeminal Nuclei; Tryptamines

The triptans are agonists at serotonin (5-HT)1B/1D receptors; however, they are also active at 5-HT1A and 5-HT1F receptors. We conducted this series of experiments to further elucidate the site of action of naratriptan using a well-established animal model of trigeminovascular stimulation. Following electrical stimulation of the superior sagittal sinus of the cat, single cell responses (n=83) were recorded in the trigeminal nucleus caudalis. Most cells (91%) also responded to electrical and mechanical stimulation of cutaneous or mucosal facial receptive fields. The microiontophoretic application of naratriptan resulted in a significant suppression of the response to sagittal sinus stimulation (response suppressed by 47 +/- 4%, P<0.001). The effect of naratriptan was significantly attenuated by application of either the 5-HT(1B/1D) receptor antagonist GR-127935 (P<0.001) or the 5-HT1A antagonist WAY-100635 (P<0.05). The response of single cells to receptive field stimulation was also suppressed by microiontophoretic application of naratriptan, but by only 20 +/- 3%. Intravenous administration of naratriptan resulted in a similar selective suppression of sagittal sinus vs. receptive field responses in trigeminal neurones. These results indicate that naratriptan has a central effect in the trigeminovascular system, selectively inhibiting afferent activity in craniovascular neurones, via both 5-HT(1B/1D) and 5-HT1A receptors.

Topics: Action Potentials; Animals; Cats; Cerebrovascular Circulation; Electric Stimulation; Indoles; Microelectrodes; Migraine Disorders; Neurons; Physical Stimulation; Piperidines; Receptors, Serotonin, 5-HT1; Serotonin Antagonists; Serotonin Receptor Agonists; Trigeminal Caudal Nucleus; 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

Pooled data from multiple clinical trials can provide information for medical decision-making that typically cannot be derived from a single clinical trial. By increasing the sample size beyond that achievable in a single clinical trial, pooling individual-patient data from multiple trials provides additional statistical power to detect possible effects of study medication, confers the ability to detect rare outcomes, and facilitates evaluation of effects among subsets of patients. Data from pharmaceutical company-sponsored clinical trials lend themselves to data-pooling, meta-analysis, and data mining initiatives. Pharmaceutical company-sponsored clinical trials are arguably among the most rigorously designed and conducted of studies involving human subjects as a result of multidisciplinary collaboration involving clinical, academic and/or governmental investigators as well as the input and review of medical institutional bodies and regulatory authorities. This paper describes the aggregation, validation and initial analysis of data from the sumatriptan/naratriptan aggregate patient (SNAP) database, which to date comprises pooled individual-patient data from 128 clinical trials conducted from 1987 to 1998 with the migraine medications sumatriptan and naratriptan. With an extremely large sample size (>28000 migraineurs, >140000 treated migraine attacks), the SNAP database allows exploration of questions about migraine and the efficacy and safety of migraine medications that cannot be answered in single clinical trials enrolling smaller numbers of patients. Besides providing the adequate sample size to address specific questions, the SNAP database allows for subgroup analyses that are not possible in individual trial analyses due to small sample size. The SNAP database exemplifies how the wealth of data from pharmaceutical company-sponsored clinical trials can be re-used to continue to provide benefit.

Topics: Clinical Trials as Topic; Data Collection; Databases, Factual; Humans; Indoles; Logistic Models; Migraine Disorders; Piperidines; Sumatriptan; Tryptamines

A 54-year-old woman with acute onset of hematochezia and lower abdominal pain proved to have ischemic colitis associated with the use of naratriptan. The diagnosis was established by colonoscopy with biopsy. There were no other obvious risk factors for intestinal ischemia. The condition resolved within 4 days. Because the use of triptans for the treatment of migraine is increasing, health care providers should be aware of their potential for inducing ischemic colitis.

Topics: Abdominal Pain; Colon; Colonic Diseases; Female; Headache; Humans; Indoles; Ischemia; Middle Aged; Piperidines; Serotonin Receptor Agonists; Tryptamines

Topics: Drug Administration Schedule; Humans; Indoles; Migraine Disorders; Pain Measurement; Piperidines; Secondary Prevention; Serotonin Receptor Agonists; Treatment Outcome; Tryptamines; Vasoconstrictor Agents

To review the efficacy of naratriptan as preventive treatment in 27 patients with chronic migraine refractory to other commonly used preventive therapies.. The treatment of chronic migraine often poses a major challenge to the clinician. Even when given expert care, patients with chronic migraine may continue to have daily or near-daily headaches.. Clinical records and headache calendars were reviewed of 27 patients fulfilling the following inclusion criteria: (1) aged 18 to 65 years; (2) diagnosis of chronic migraine (formerly transformed migraine), according to the criteria proposed by Silberstein et al; (3) previous failure of at least 4 preventive medications prescribed as part of a management program that included nonpharmacological measures, preventive medication, acute care medication, and detoxification from overused medication; and (4) have used daily naratriptan for no less than 2 consecutive months. The dose of naratriptan prescribed was 2.5 mg twice daily. We considered the following outcomes: (1) frequency of headache, (2) intensity of pain, (3) number of days per month with severe headache, (4) headache index (frequency times intensity), and (5) proportion of patients who reverted to an episodic pattern of pain after 6 months of treatment.. There was a statistically significant reduction in the frequency of headache days 2 months (15.3 days versus 24.1 days at baseline, P<.001), 6 months (9.1 days, P<.001), and 1 year (7.3 days, P<.001) after daily treatment with naratriptan was initiated. There was also a statistically significant reduction in the number of days per month of severe pain at 1 month (5.6 days versus 12.5 days at baseline, P<.01), 2 months (5.7 days, P<.01), 6 months (2.8 days, P<.01), and 1 year (2.6 days, P<.01). Similarly, there was a statistically significant reduction in the headache index at 2 months (33 versus 56.4 at baseline, P<.001), 6 months (19.5, P<.001), and 1 year (17.2, P<.001). Of the 20 patients who continued to use naratriptan daily for at least 6 months, 13 (65%) reverted to an episodic pattern of pain (migraine). At 1 year, 11 (55%) still continued to experience episodic headache, 1 (5%) relapsed to chronic migraine, and 2 (10%) were lost to follow-up. No patients had intolerability to naratriptan during the treatment period, and no one stopped treatment due to adverse events.. Naratriptan may have a role in the preventive treatment of intractable chronic migraine. Prospective, controlled studies should be considered.

Topics: Adolescent; Adult; Female; Humans; Indoles; Male; Middle Aged; Migraine Disorders; Pain, Intractable; Piperidines; Retrospective Studies; Serotonin Receptor Agonists; Tryptamines

The objective of this study was to provide an epidemiological description of naratriptan use in ambulatory medicine. 1695 patients were recruited by 384 primary care physicians and 111 neurologists, and followed for 12 weeks. Physicians had to document the migraine history, and to report symptoms and health care in a structured case report form. Patients were to document each episode of migraine (EM) in a diary. At baseline, 45 p.cent of the patients reported their migraine treatment as unsatisfactory. Ninety-eight percent of included patients were migraineurs according to criteria of the International Headache Society (IHS), including migrainous disorders. Ninety-two percent of naratriptan prescriptions were established in the second intention in patients with migraine, according to the IHS classification, including migrainous disorders. A total of 79 p.cent of patients had complied with the good practices for all EMs. More appropriate health education strategies should target the small group of patients who over-use naratriptan, and patients with aura. However, this study shows that naratriptan tends to be correctly prescribed by physicians, and used by patients with acute migraine.

Topics: Acute Disease; Adult; Ambulatory Care; Female; Follow-Up Studies; Humans; Indoles; Male; Migraine Disorders; Piperidines; Prospective Studies; Tryptamines; Vasoconstrictor Agents

Neurogenic inflammation of the meninges, expressed in plasma extravasation and vasodilatation, putatively contributes to certain types of headache. Both, non-steroidal antiinflammatory drugs (NSAIDs) and serotonin-1 (5-HT1) receptor agonists are similarly effective antimigraine drugs but their mechanism of action is unclear. The clinical observation that sumatriptan lowered plasma levels of calcitonin gene-related peptide (CGRP), found increased during migraine attacks, drew attention to a possible inhibition of pro-inflammatory neuropeptide release from trigeminal afferents. An isolated preparation of fluid-filled rat skull cavities was used to study effects of NSAIDs and 5-HT(1B/D) agonists on the dura stimulated by inflammatory mediators (bradykinin, histamine and serotonin, 10(-5)M each). The release of immunoreactive CGRP (iCGRP) and immunoreactive PGE(2) (iPGE(2)) was measured in 5-min samples of superfusates using enzyme immunoassays. S(+)-flurbiprofen (10(-6)M) strongly reduced the basal and stimulated iCGRP release and abolished iPGE(2) release; R(-)-flurbiprofen showed much less effect on iPGE(2) liberation and did not influence iCGRP release. The 5-HT(1B/D) agonists naratriptan and CP93,129 were ineffective on both iCGRP and iPGE(2) release. Inspite of its weak COX blocking effect, R(-)-flurbiprofen is reported to exert antinociceptive effects, although it has not been tested in migraine. Only the potent COX blocker S(+)-flurbiprofen also suppressed iCGRP release while the 5-HT(1B/D) agonists were ineffective. Thus, inhibition of meningeal neuropeptide secretion is not a common action principle of the drugs that could be essential for their antimigraine effects.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Calcitonin Gene-Related Peptide; Culture Media, Conditioned; Dinoprostone; Drug Interactions; Dura Mater; Flurbiprofen; Immunoassay; In Vitro Techniques; Indoles; Inflammation Mediators; Male; Piperidines; Pyridines; Pyrroles; Rats; Rats, Wistar; Serotonin Receptor Agonists; Time Factors; 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

Intractable migraine presents a significant treatment challenge to both patient and physician. Most attacks are treatable or self-limiting, but occasionally they may continue for extended periods regardless of treatment.. To determine the efficacy of naratriptan 2.5 mg twice daily for the treatment of intractable migraine.. We reviewed 24 patients treated with naratriptan twice daily for an intractable migraine attack. Patients were permitted to take prophylactic medication if such treatment had been effective in the past.. Nineteen patients (79%) improved. Twelve patients showed excellent response with cessation of pain and associated symptoms, 7 patients partially responded with lessening of pain and cessation of associated symptoms, and 5 patients were nonresponsive.. Short-term daily administration of naratriptan may be effective in terminating status migrainosus.

Topics: Adult; Female; Humans; Indoles; Middle Aged; Migraine without Aura; Piperidines; Serotonin Receptor Agonists; Treatment Outcome; Tryptamines

Topics: Administration, Oral; Controlled Clinical Trials as Topic; Delayed-Action Preparations; Female; Headache; Humans; Indoles; Male; Migraine Disorders; Oxazolidinones; Piperidines; Placebos; Pyrrolidines; Serotonin Receptor Agonists; Sumatriptan; Time Factors; Tryptamines

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

Severe headache and meningism provide clear evidence for the activation of trigeminal neurotransmission in meningitis. The authors assessed the antiinflammatory potential of 5HT1B/D/F receptor agonists (triptans), which inhibit the release of proinflammatory neuropeptides from perivascular nerve fibers. In a 6-hour rat model of pneumococcal meningitis, zolmitriptan and naratriptan reduced the influx of leukocytes into the cerebrospinal fluid, and attenuated the increase of regional cerebral blood flow. Elevated intracranial pressure as well as the brain water content at 6 hours was reduced by triptans. These effects were partially reversed by a specific 5HT1D as well as by a specific 5HT1B receptor antagonist. Meningitis caused a depletion of calcitonin gene-related peptide (CGRP) and substance P from meningeal nerve fibers, which was prevented by zolmitriptan and naratriptan. In line with these findings, patients with bacterial meningitis had significantly elevated CGRP levels in the cerebrospinal fluid. In a mouse model of pneumococcal meningitis, survival and clinical score at 24 hours were significantly improved by triptan treatment. The findings suggest that, besides mediating meningeal nociception, meningeal nerve fibers contribute to the inflammatory cascade in the early phase of bacterial meningitis. Adjunctive treatment with triptans may open a new therapeutic approach in the acute phase of bacterial meningitis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzamides; Calcitonin Gene-Related Peptide; Cerebrovascular Circulation; Dura Mater; Humans; Indoles; Laser-Doppler Flowmetry; Leukocytes; Male; Meningitis, Pneumococcal; Mice; Mice, Inbred Strains; Oxadiazoles; Oxazolidinones; Piperidines; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1B; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Substance P; Survival Rate; 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

Topics: Colitis, Ischemic; Female; Humans; Indoles; Middle Aged; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Tryptamines; Vasoconstrictor Agents

We describe the preventive use of naratriptan, mostly as add-on to high-dose verapamil treatment, in nine patients with cluster headache. The addition of the naratriptan further improved the headaches in seven of the nine patients.

Topics: Adult; Aged; Cluster Headache; Female; Humans; Indoles; Male; Middle Aged; Piperidines; Tryptamines

The importance of 5-HT(1B) and 5-HT(1D) receptors in the actions of the anti-migraine drug naratriptan was investigated using the relatively selective 5-HT(1) receptor ligands SB224289 and BRL15572. Electrical stimulation of the superior sagittal sinus (SSS) in cats activated neurones in the trigeminal nucleus caudalis. Facial receptive fields (RF) were also electrically stimulated to activate the same neurones. Responses of these neurones to SSS stimulation were suppressed by iontophoretic application of naratriptan (5-50 nA). There were two distinct populations of neurones in the nucleus--those in deeper laminae in which the responses to SSS and RF stimulation were equally suppressed by naratriptan ('non-selective') and more superficial neurones in which only the SSS responses were suppressed by naratriptan ('selective'). Concurrent micro-iontophoretic application (50 nA) of the 5-HT(1D) antagonist BRL15572 antagonised the suppression by naratriptan of the response of 'selective' cells to SSS stimulation. Iontophoretic application of SB224289 (50 nA), a 5-HT(1B) antagonist, antagonised the suppression by naratriptan of responses of 'non-selective' cells to RF stimulation and, to a lesser extent, also antagonised the suppression of responses to SSS stimulation. Intravenous administration of SB224289 antagonised the suppression only of RF responses of "non-selective" neurons by naratriptan and intravenous administration of BRL15572 antagonised the suppression only of SSS responses of "selective" neurons by naratriptan. These results suggest that the response of nucleus caudalis neurons to stimulation of the sagittal sinus can be modulated by both 5-HT(1B) and 5-HT(1D) receptor activation, with the 5-HT(1D) receptors perhaps playing a greater role. The response to RF stimulation is more influenced by 5-HT(1B) receptor modulation with 5-HT(1D) receptors being less important. Therefore, this suggests that selective 5-HT(1D) agonists may be able to target the neuronal population, which is selectively involved in the transmission of dural inputs. We conclude that the central terminals of trigeminal primary afferent fibres contain 5-HT(1B) and 5-HT(1D) receptors. Primary afferents from the dura mater may predominantly express 5-HT(1D) receptors, while facial afferents may predominantly express 5-HT(1B) receptors. Activation of 5-HT(1D) receptors in particular may be important in the anti-migraine effect of naratriptan.

Topics: Animals; Cats; Indoles; Neural Inhibition; Piperidines; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Trigeminal Nuclei; Tryptamines

A 36-year-old man with cluster headache refractory to trials of standard prophylactic treatment and only partially responsive to parenteral sumatriptan and inhaled oxygen was admitted to an inpatient pain unit. The diagnosis of cluster headache was confirmed by direct observation of a typical attack. Despite efforts at prophylaxis, the patient continued to experience three to four severe headaches per day. Attempts to control his headaches with scheduled parenteral dihydroergotamine were successful, but headaches recurred when the medication was tapered, and continuous or intermittent use of parenteral dihydroergotamine was not felt to be a practical option for the patient. Naratriptan 2.5 mg twice daily completely abolished his headaches, which recurred when the medication was discontinued. No electrocardiographic or laboratory abnormalities were observed during treatment, and the patient reported no side effects.

Topics: Adult; Cluster Headache; Humans; Indoles; Male; Piperidines; Preventive Medicine; Serotonin Receptor Agonists; Treatment Outcome; 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

1. Sumatriptan or eletriptan produced vasocontraction in common carotid artery (CCA) by stimulating 5HT(1B) receptors (see also Akin & Gurdal, this issue). 2. Naratriptan as a 5HT(1B/D) agonist, was unable to produce vasocontraction in this artery, but inhibited the vasocontractile response induced by sumatriptan or eletriptan. 3. All these agonists inhibited forskolin-stimulated cyclic AMP production with comparable potencies and maximal responses. This inhibition was mediated by 5HT(1B) receptors: 5HT(1B) antagonist SB216641 (1 microM) completeley antagonized sumatriptan-, eletriptan- or naratriptan-induced cyclic AMP inhibition, but 5HT(1D) antagonist BRL15572 (1 microM) did not affect this response. 4. Naratriptan-induced stimulation of 5-HT(1B) receptors resulted only in adenylate cyclase inhibition, whereas stimulation of these receptors by sumatriptan or eletriptan produced vasocontraction as well. Hence, we concluded that the 5HT(1B)-mediated inhibition of adenylate cyclase was not a sufficient condition to couple the receptor stimulation to vasocontraction. 5. We discussed agonist-induced trafficking as a plausible mechanism for the observed phenomenon.

Topics: Animals; Carotid Artery, Common; Cyclic AMP; Dose-Response Relationship, Drug; In Vitro Techniques; Indoles; Piperidines; Protein Transport; Rabbits; Serotonin Receptor Agonists; Sumatriptan; Tryptamines; Vasoconstriction

Modulatory effects of the new antimigraine drug naratriptan, a 5-HT(1)-receptor-agonist, on neurons of the nucleus raphé magnus were examined in rat by extracellular recordings. In the nucleus raphé magnus neuronal activity decreased in on-cells and increased in off-cells after intravenous administration of naratriptan. The modulatory effects of naratriptan were similar to the well-known effects of morphine on neurons in the nucleus raphé magnus. The results of this study suggest central actions of naratriptan and may point to an involvement of the endogenous pain control system in the antinociceptive effects of the 5-HT(1)-receptor-agonist.

Topics: Animals; Indoles; Male; Migraine Disorders; Neurons; Piperidines; Raphe Nuclei; Rats; Rats, Wistar; Serotonin Receptor Agonists; Tryptamines

Topics: Cluster Headache; Humans; Indoles; Male; Middle Aged; Piperidines; Serotonin Receptor Agonists; Tryptamines

To evaluate the cost-effectiveness of naratriptan for the treatment of migraine in Canada.. The substantial disability brought on by migraine, coupled with the high prevalence of this disorder, leads to substantial costs. Naratriptan is a newly developed triptan shown to be effective in the treatment of migraine.. Monte Carlo modeling techniques were used to simulate the experience of Canadian migraineurs over the course of 1 year. Data from a multinational study comparing oral naratriptan 2.5 mg to customary therapies were used in the cost-effectiveness analysis.. Naratriptan leads to an annual reduction in symptom duration of 225 hours compared to customary therapy not including other triptans. Reductions in lost productivity yield savings of Can $390 (1998 Canadian dollars) relative to customary therapy, which exceed the increase in drug costs resulting in overall savings of Can $109 per year.. The use of naratriptan in the treatment of migraine is an economically attractive option, leading to savings in overall costs. Increases in drug costs seem acceptable in light of reductions in symptom duration.

Topics: Canada; Cost-Benefit Analysis; Humans; Indoles; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Tryptamines; Vasoconstrictor Agents

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

The overall aim of the present study was to investigate retrospectively the feasibility and utility of model-based clinical trial simulation as applied to the clinical development of naratriptan with effect measured on a categorical scale.. A PK-PD model for naratriptan was developed by using information gathered from previous naratriptan and sumatriptan preclinical and clinical trials. The phase IIa naratriptan data were used to check the PK-PD model in its ability to describe future data. A further PK-PD model was developed by using the phase IIa naratriptan data, and a phase IIb trial was designed by simulation with the use of Matlab. The design resulting from clinical trial simulation was compared with that derived by using D-optimal design.. The PK-PD model showed reasonable agreement with the data observed in the phase IIa naratriptan clinical trial. Clinical trial simulation resulted in a design with four or five arms at 0 mg, 2.5 and/or 5 mg, 10 mg, and 20 mg, PD measurements to be taken at 0, 2, and 4 or 6 h and at least 150 patients per arm. A sub-D-optimal design resulted in two dosing arms at 0 and 10 mg and PD measurements to be taken at 1 and 2 h.. Clinical trial simulation is a useful tool for the quantitative assessment of the influence of the controllable factors and is the only tool for the quantitative assessment of the uncontrollable factors on the power of a clinical trial.

Topics: Administration, Oral; Algorithms; Clinical Trials, Phase II as Topic; Computer Simulation; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Humans; Indoles; Injections, Subcutaneous; Models, Biological; Piperidines; Research Design; Serotonin Receptor Agonists; Software; Tryptamines

Topics: Contraindications; Coronary Circulation; Dose-Response Relationship, Drug; Humans; Indoles; Injections, Subcutaneous; Migraine Disorders; Piperidines; Product Surveillance, Postmarketing; Risk Factors; Serotonin Receptor Agonists; Sumatriptan; Tryptamines; Vasoconstrictor Agents

Topics: Headache Disorders; Humans; Indoles; Migraine Disorders; Piperidines; Primary Health Care; Serotonin Receptor Agonists; Sumatriptan; Treatment Outcome; Tryptamines; Vasoconstrictor Agents

Topics: Administration, Oral; Biological Availability; Clinical Trials as Topic; Dose-Response Relationship, Drug; Humans; Indoles; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Structure-Activity Relationship; Sumatriptan; Treatment Outcome; Tryptamines; Vasoconstrictor Agents

Nasal administration to rats of small molecules (tritiated water, tyrosine, and propanol) results in a higher concentration in the brain arterial blood than in other arteries. The preferential distribution is based on a counter current transfer, which takes place between nasal vein blood and brain arterial blood in the cavernous sinus-carotid artery complex. This model was used to investigate whether the antimigraine 5HT(1B/1D) receptor agonists sumatriptan and naratriptan may also be transferred by the system. The ratio of 'head':'heart' plasma concentrations obtained from two carotid catheters after intranasal administration was not different from 1.00 for either compound, and thus, there was no experimental evidence of a preferential local transfer of drug from the nose to the carotid artery circulation. However, plasma concentrations increased from the first minute after intranasal dosing suggesting that sumatriptan and naratriptan are absorbed into the general systemic circulation from the nasal cavity in rats in a first-order fashion with no lag time. This is consistent with the clinical onset of efficacy of sumatriptan after an intranasal dose which occurs as early as 15 min post dose.

Topics: Absorption; Animals; Cerebral Arteries; Indoles; Male; Nasal Cavity; Piperidines; Rats; Rats, Sprague-Dawley; Serotonin Receptor Agonists; Sumatriptan; Tryptamines

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

To evaluate clinical parameters that may affect the incidence of headache recurrence or the time to headache recurrence, or both, in migraineurs treated with naratriptan, 2.5-mg tablets.. The incidence of headache recurrence within 24 hours of treatment with naratriptan, 2.5-mg tablets (17%-28%), is lower than that reported for other currently available selective serotonin agonists. Identifying clinical parameters that influence headache recurrence may further reduce the incidence of headache recurrence or prolong the time to recurrence, or both, for naratriptan-treated patients.. We examined the effects of three clinical parameters (predose pain severity, headache duration prior to treatment, and relief status 4 hours post dose) on the incidence of and time to headache recurrence across four placebo-controlled naratriptan clinical trials. The impact of these parameters on headache recurrence was examined individually and in combination.. Predose pain severity had no effect on the incidence of headache recurrence (overall 23%; moderate 22%, severe 23%). The median time to recurrence was longer for patients with moderate pain before treatment compared with patients with severe pain before treatment (14.5 hours versus 9.3 hours, respectively). Overall time to headache recurrence was 11.8 hours. Patients with headache recurrence reported a longer time until they treated the headache compared with patients without headache recurrence (median, 145 minutes versus 97.5 minutes). Patients who treated headache pain within 3 hours of onset had a lower incidence of headache recurrence (20%) than patients who treated their headache more than 3 hours after onset (28%). Patients with no pain 4 hours post dose had a lower incidence of and a longer time to headache recurrence compared with patients with mild pain 4 hours post dose (17% versus 32%; median, 17.8 hours versus 8.1 hours, respectively). The interaction of all three clinical parameters was significant in predicting headache recurrence.. The overall incidence of headache recurrence is low after naratriptan, 2.5 mg, compared with other currently available selective serotonin agonists. Predose pain severity, time to treatment, and 4-hour relief status appear related to the incidence of or time to headache recurrence, or both. Treating less severe migraine attacks, treating earlier within an attack, and obtaining complete relief post dose may enhance the low incidence of headache recurrence and achieve longer times to recurrence with naratriptan, 2.5 mg.

Topics: Acute Disease; Adult; Aged; Female; Humans; Indoles; Male; Middle Aged; Migraine Disorders; Piperidines; Recurrence; Retrospective Studies; Serotonin Receptor Agonists; Tryptamines

Topics: Humans; Indoles; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; 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

To determine the role of naratriptan in preventing migraine headache when administered during prodrome.. Baseline phase: patients recorded prodrome symptoms and time of onset, time when patient knew that headache was inevitable, time of onset and severity of headache. Treatment phase: patients given naratriptan 2.5 mg to take at the time they knew headache was inevitable. Patients recorded prodrome symptoms and time of onset, time they knew headache was inevitable, time naratriptan administered, time of onset and severity of any headache. Patients treated three prodromes separated by at least 48 h.. Twenty patients completed both phases. During baseline phase, 59 prodromes were reported and all were followed by headache. Severity of headache: 5% mild, 51% moderate, 44% severe. During treatment phase, 63 prodromes were reported. Of these, 38/63 (60%) were not followed by headache. Among headaches that occurred, the majority occurred within 2 h of naratriptan administration, suggesting that naratriptan is more effective in preventing headache if taken early in prodrome. Severity of 25 headaches: 44% mild, 24% moderate, 32% severe.. Naratriptan 2.5 mg appears to prevent migraine headache when given early in prodrome. If headache occurs, severity appears to be reduced.

Topics: Adult; Female; Humans; Indoles; Male; Middle Aged; Migraine with Aura; Pilot Projects; Piperidines; Serotonin Receptor Agonists; Tryptamines

Topics: Humans; Indoles; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Tryptamines; Vasoconstrictor Agents

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

This open-label study was conducted to evaluate the tolerability and efficacy of the 5HT1 agonist naratriptan with repeated use in the acute treatment of migraine attacks for 1 year. Four hundred and seventeen (417) migraine patients treated 15,301 migraine attacks over the course of the study.. The results show that 84% of attacks treated with a single 2.5 mg dose of naratriptan were not associated with the occurrence of an adverse event. The percentage of attacks associated with an adverse event did not increase with number of doses used to treat a given attack (1 vs. 2) or duration of use (0-6 months vs. > 6-12 months). The only adverse events experienced in > 2% of attacks throughout the 1-year study were nausea (3% of attacks), hyposalivation (2% of attacks), and drowsiness/sleepiness (2% of attacks). Headache relief 4 h post-dose was reported in a median 70% of moderate or severe attacks and a median 86% of mild attacks treated with naratriptan tablets 2.5 mg. The percentages of patients reporting headache relief did not diminish as a function of increased duration of treatment (0-6 months vs. > 6-12 months) or frequency of use (for > 36 vs. < 36 attacks). The mean number of tablets taken per attack was 1.2. A second naratriptan 2.5 mg tablet was taken for headache recurrence in a mean 16% (median 8%) of attacks.. The results of this study demonstrate that naratriptan tablets 2.5 mg taken for acute migraine attacks over a 1-year period are well-tolerated and effective.

Topics: Adult; Dose-Response Relationship, Drug; Female; Humans; Indoles; Male; Middle Aged; Migraine Disorders; Patient Satisfaction; Piperidines; Retreatment; Salvage Therapy; Serotonin Receptor Agonists; Tablets; Time Factors; Tryptamines

1997, sumatriptan-treated migraineurs had significantly higher depression PCRs (22.3%) compared with non-triptan users (19.3%), a difference of 6.4% (95% confidence interval (CI) 4.6-8.4%, P < 0.001). In the year (April 1997 to March 1998) following the launch of the TELs, depression PCRs were significantly higher among patients using these compounds compared with sumatriptan-treated patients (5.1%, CI 1.8-12.0%, P < 0.05). However, after taking account of prior depression (odds ratio (OR) 6.45, 95% CI 3.63-11.43), TELs were not significantly associated with depression (OR 0.27, 95% CI 0.03-2.13). Furthermore, rates of newly diagnosed depression after treatment were similar in the two triptan groups (sumatriptan 4.2%; TELs 3.9%). Although, the TELs are being prescribed to patients with higher pre-existing rates of depression, they are not associated with subsequently increased consulting for depressive illness compared with patients taking sumatriptan. This study highlights the potential to use GPRD to test targeted hypotheses exploring pharmacovigilance issues for patients using new medicines.

Topics: Cohort Studies; Depression; Female; Humans; Indoles; Male; Migraine Disorders; Oxazolidinones; Piperidines; Referral and Consultation; Regression Analysis; Serotonin Receptor Agonists; Sumatriptan; Tryptamines

Topics: Adult; Female; Headache; Humans; Indoles; Middle Aged; Migraine Disorders; Oxazoles; Oxazolidinones; Piperidines; Serotonin Receptor Agonists; 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

Topics: Clinical Trials as Topic; Humans; Indoles; Migraine Disorders; Piperidines; Tryptamines; Vasoconstrictor Agents

G-protein activation mediated by serotonin 5-HT1A receptors in human and monkey brain was investigated by using quantitative autoradiography of agonist-stimulated [35S]GTPgammaS binding to whole-hemisphere brain sections. [35S]GTPgammaS binding was stimulated by the mixed 5-HT1A/1B/1D agonist L 694247 (10 microm) in human brain regions enriched in 5-HT1A binding sites [e.g. hippocampus (132-137%), superficial layers of the neocortex (37-61%), and cingulate and entorhinal cortex (34 and 32%, respectively)]. L 694247 caused virtually no stimulation in regions with 5-HT1B/1D receptors, such as substantia nigra, caudate nucleus and putamen. Similar results were obtained with monkey brain sections. The L 694247-mediated [35S]GTPgammaS-binding responses in human and monkey brain sections were antagonized by the selective, silent 5-HT1A antagonist WAY 100635 (10 microm). The 5-HT1B inverse agonist SB 224289 (10 microm) did not affect the [35S]GTPgammaS-binding response of L 694247. The distribution pattern of the [35S]GTPgammaS-binding response and the antagonist profile suggest the L 694247-induced response in human and monkey brain is mediated by 5-HT1A receptors. A weak stimulation of [35S]GTPgammaS binding was also observed in human hippocampus with either 10 microm 8-OH-DPAT (25 +/- 4%) or naratriptan (42 +/- 2%) compared with that obtained with L 694247. In conclusion, G-protein activation by 5-HT1A receptors can be measured in human and monkey brain sections. L 694247 appears to possess higher efficacy at 5-HT1A receptors compared with 8-OH-DPAT and naratriptan.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Autoradiography; Binding, Competitive; Brain Chemistry; Female; Guanosine 5'-O-(3-Thiotriphosphate); Humans; Indoles; Macaca fascicularis; Male; Oxadiazoles; Piperazines; Piperidines; Pyridines; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Serotonin Antagonists; Serotonin Receptor Agonists; Sulfur Radioisotopes; Tritium; Tryptamines

Naratriptan, launched by Glaxo Wellcome under the trade name Naramig, is a potent and selective agonist of 5-HT1B and 5-HT1D vascular receptors. Available as tablets of 2.5 mg, it is indicated in the acute treatment of migraine, with or without aura. A single oral dose of 2.5 mg naratriptan is characterized by a satisfactory clinical efficacy (already significant after one hour, maximum after 4 hours and persisting during 24 hours), a reduction by half of the recurrence of the migraine crisis within the 24 hours and an excellent tolerance profile.

Topics: Drug Administration Schedule; Humans; Indoles; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Tryptamines

Topics: Humans; Indoles; Migraine Disorders; Piperidines; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin; Risk Factors; Serotonin Receptor Agonists; Sumatriptan; Tryptamines; Vasoconstrictor Agents

Topics: Analgesics, Non-Narcotic; Ergotamine; Headache; Humans; Indoles; Oxazoles; Oxazolidinones; Piperidines; Serotonin Receptor Agonists; Sumatriptan; Tryptamines

Because the "intensity dependence" of cortical auditory evoked potentials (IDAP) is under serotonergic control, it can be used to assess central antimigraine effects of 5HT1B/1D agonists. We measured IDAP before and 2 h after naratriptan (5 mg, n = 19) and zolmitriptan (5 mg, n = 19) in healthy volunteers. IDAP was expressed as the amplitude-stimulus intensity function ("ASF slope"). Naratriptan tended to increase ASF slope (mean difference 0.23 +/- 0.62 microV/10 dB, p = 0.06) while zolmitriptan (0.08 +/- 0.95 microV/10 dB, p = 0.35) did not. We assessed the suitability of IDAP for measuring central antimigraine drug effects using repeatability data (see companion paper). We calculated the trade-off between the size of the expected drug effects (ASF slope difference) and the necessary sample size. Because of poor repeatability 36 to 80 subjects are required to detect ASF slope changes in the 0.25-0.5 microV/10 dB range. These data can be used to design trials using IDAP.

Topics: Adolescent; Adult; Cerebral Cortex; Evoked Potentials, Auditory; Female; Humans; Indoles; Male; Oxazoles; Oxazolidinones; Piperidines; Reproducibility of Results; Sample Size; Serotonin Receptor Agonists; Tryptamines

Topics: Acute Disease; Clinical Trials as Topic; Humans; Indoles; Migraine Disorders; Oxazoles; Oxazolidinones; Piperidines; Serotonin Receptor Agonists; Sumatriptan; Tryptamines

Topics: Drug Approval; Humans; Indoles; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Tryptamines; United States; United States Food and Drug Administration

Contractile responses evoked by the 5-HT IB/D receptor agonists, dihydroergotamine, naratriptan and sumatriptan, were compared in canine isolated coronary artery rings before and after endothelial dysfunction as obtained by inhibition of nitric oxide synthase with Nw-nitro-L-arginine methyl ester (L-NAME; 10 microM). The three agonists contracted rings in the potency order of dihydroergotamine (geometric mean pD2 value with 95% confidence limits in parentheses: 6.9 [5.3-7.9] and 7.0 [5.4-7.3] in the absence and presence of nitric oxide synthase (NOS) inhibition [I], respectively) > or = naratriptan (6.8 [5.7-7.3] and 6.4 [5.7-6.6]) > sumatriptan (4.8 [3.6-5.6] and 5.0 [3.6-5.6]) independently of the presence or absence of L-NAME. In absence of L-NAME, efficacy, as assessed by the mean maximal contractile response (Emax), tended to be greater, although not significantly, for sumatriptan and naratriptan compared to dihydroergotamine. L-NAME per se markedly increased developed tension (43.0 +/- 4.6 mN; n = 50) and potentiated maximal responses (0.6 +/- 0.2 and 10.7 +/- 2.4 mN for dihydroergotamine in the absence and presence of L-NAME respectively; 1.7 +/- 0.6 and 18.7 +/- 3.7 mN for naratriptan; 2.5 +/- 0.6 and 21.3 +/- 3.8 mN for sumatriptan; P < 0.01 in each case). Emax values of sumatriptan and naratriptan were greater than those produced by dihydroergotamine in the presence of L-NAME but remained lower than the sub-maximal contractile responses evoked by the thromboxane A2 analogue, U-46619 (ie, 32.4 +/- 5.2 mN in the absence of L-NAME; n = 50), or L-NAME per se. In conclusion, 5-HT IB/D receptor agonist efficacies in contracting coronary arteries are relatively low under basal conditions and are potentiated in the presence of a dysfunctional endothelium, whereas agonist potencies remain unaffected.

Topics: Animals; Coronary Vessels; Dihydroergotamine; Dogs; Endothelium, Vascular; Enzyme Inhibitors; In Vitro Techniques; Indoles; Male; Muscle Contraction; Muscle, Smooth, Vascular; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Piperidines; Serotonin Receptor Agonists; Sumatriptan; Tryptamines; Vasoconstrictor Agents

This open-label study was conducted to examine the long-term tolerability and efficacy of the novel 5HT1 agonist naratriptan tablets 2.5 mg used to treat all migraine attacks for 6 months. Patients could reduce the dose to 1 mg in the event of intolerable adverse events. The results demonstrate that the majority (median 83%) of attacks treated with naratriptan tablets 2.5 mg were not associated with an adverse event. Among attacks treated with naratriptan tablets 2.5 mg (+ optional 2.5 mg for headache recurrence), the most frequently reported adverse event was nausea (4% of attacks after a single naratriptan dose). Both the overall incidence of adverse events and the incidences of specific adverse events were no higher during months 4-6 of treatment compared with months 1-3. Only 5 of 414 patients elected to reduce their naratriptan dose to 1 mg. Headache relief 4 h postdose was reported in a mean of 68% of 6770 moderate or severe migraine attacks treated with naratriptan tablets 2.5 mg. The median number of naratriptan tablets used per attack was 1.0 (mean 1.25); patients treated only a median 7% of attacks (mean 13%) with a 2nd naratriptan tablet for headache recurrence. Patients rated naratriptan tablets as good or excellent in 61% of 7566 treated attacks. In summary, the data from this study demonstrate that naratriptan tablets 2.5 mg were very well tolerated and effective for the acute treatment of migraine for 6 months in a situation closely resembling actual clinical use.

Topics: Adolescent; Adult; Aged; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Indoles; Long-Term Care; Male; Middle Aged; Migraine Disorders; Piperidines; Serotonin Receptor Agonists; Treatment Outcome; Tryptamines; Vasoconstrictor Agents

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: Administration, Oral; Adult; Contraindications; Female; Humans; Indoles; Migraine Disorders; Patient Selection; Piperidines; Serotonin Receptor Agonists; Sumatriptan; Time Factors; Tryptamines

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

Topics: Clinical Trials as Topic; Humans; Indoles; Injections, Subcutaneous; Piperidines; Serotonin Receptor Agonists; Tryptamines

One of the outstanding therapeutic revolutions of this last decade has been the introduction of selective serotonin agonists in the acute treatment of migraine. After sumatriptan, introduced in Belgium in 1992, other "triptans" are emerging. The efficacy and the pharmacoeconomic profile of zolmitriptan, the second "triptan" now available in Belgium, are reviewed and the arrival of a third triptan, naratriptan is announced.

Topics: Chemistry, Pharmaceutical; Humans; Indoles; Migraine Disorders; Oxazoles; Oxazolidinones; Piperidines; Serotonin Receptor Agonists; Sumatriptan; Tryptamines

In vivo electrophysiological assays in anesthetized rats have been used to compare the effects of the 5HT1B/1D receptor agonist, naratriptan, on central trigeminal nociceptive processing from dural and cutaneous inputs with its effects on nociceptive processing in the spinal cord. Naratriptan inhibited responses of single trigeminal neurons, to noxious electrical and mechanical stimulation of the dura and face, dose dependently by a maximum of 67+/-3% and 70+/-18%, respectively, at 3 mg kg(-1) i.v. In contrast, naratriptan did not affect spinal dorsal horn neuronal responses to noxious mechanical stimulation of the hind-paw. These findings suggest that 5HT1B/1D receptors have differential effects on nociceptive processing in the trigeminal versus spinal dorsal horns and provide a potential explanation for the lack of general analgesic effects of brain penetrant 5HT(1B/1D) agonist antimigraine drugs.

Topics: Animals; Drug Evaluation, Preclinical; Dura Mater; Electric Stimulation; Indoles; Male; Piperidines; Rats; Rats, Sprague-Dawley; Serotonin Receptor Agonists; Spinal Cord; Stress, Mechanical; Trigeminal Nerve; Tryptamines

MDL 74,721 (I), sumatriptan(II) and naratriptan(III) are new 5-HT1-like agonists that have potential as a novel treatment for migraine. Liquid chromatographic-electrospray-mass spectrometric (LC-ESI-MS) assay have been developed to compare the pharmacokinetics of these three antimigraine compounds. The concentration of each parent drug was determined using a solid-phase extraction method and LC-ESI-MS analysis demonstrating the high sensitivity and specificity of the methods down to subnanogram levels in rabbit plasma samples. Pharmacokinetic parameters evaluated after administration of single intravenous and oral doses were very similar and the ANOVA analysis did not show any statistically significant differences for t1/2, Cmax, V or AUC (normalised). The pharmacokinetic parameters showed short t1/2 (range 1.14-1.9 h) either after intravenous (i.v.) or oral (p.o.) administration and high total body clearance (CL) after the p.o. dose both probably due to extensive and rapid metabolism of the parent drugs as suggested by the low values for bioavailability (range 13.4-22.8%).

Topics: Administration, Oral; Animals; Chromatography, Liquid; Indoles; Injections, Intravenous; Male; Mass Spectrometry; Piperidines; Rabbits; Reproducibility of Results; Sensitivity and Specificity; Serotonin Receptor Agonists; Sulfonamides; Sumatriptan; Tetrahydronaphthalenes; Tryptamines; Vasoconstrictor Agents

The biological profile of naratriptan (N-methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethane-sulphonamide), a novel 5HT1B/1D receptor agonist, was investigated in a variety of experimental models of relevance to migraine. Naratriptan has high affinity for human recombinant 5HT1B and 5HT1D receptors (pKi = 8.7 +/- 0.03 and 8.3 +/- 0.1, respectively) and causes contractions of dog isolated basilar and middle cerebral artery (EC50 values of 0.11 and 0.07 microM, respectively). Naratriptan causes small contractions of human isolated coronary arteries (EC50 value of 0.17 microM; maximum contraction equivalent to 33% of 5HT maximum). In anaesthetized dogs, naratriptan causes selective vasoconstriction of the carotid arterial bed (CD50 dose = 19 +/- 3 micrograms kg-1) and, in anaesthetized rats, naratriptan selectively inhibits neurogenic plasma protein extravasation in the dura (ID50 = 4.1 micrograms kg-1). In a variety of antinociceptive tests, naratriptan has no effect even at high doses. In conscious rats and dogs, naratriptan has high oral bioavailability (71% and 95%, respectively). The data show that naratriptan is a selective agonist at 5HT1B/1D receptors, with a pharmacological profile very similar to that of sumatriptan, albeit 2-3 fold more potent. These observations, coupled with high oral bioavailability in animals, suggest that naratriptan has the profile of an orally effective anti-migraine drug.

Topics: Animals; Basilar Artery; Cerebrovascular Circulation; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Female; Humans; Indoles; Male; Mice; Muscle Contraction; Piperidines; Rats; Sumatriptan; Tryptamines

The actions of several serotonergic ligands in use or under development for the treatment of migraine headaches were examined at recombinant human 5-HT1A receptors stably expressed in Chinese Hamster Ovary cells. Affinities (K(i)s) at this site were determined in competition binding experiments with [3H]-8-OH-DPAT ([3H](+/-)8-hydroxy-N,N-dipropylaminotetralin), whilst agonist efficacy was measured by stimulation of [35S]-GTP gamma S (guanylyl-5'-[gamma[35S]thio]-triphosphate) binding. Of the prophylactic antimigraine drugs tested, methysergide and lisuride behaved as efficacious agonists (Emax > or = 90% relative to 5-HT) whereas pitozifen and (-)propranolol acted as a partial agonist (60%) and an antagonist, respectively. This suggests that there is no correlation between agonism at 5-HT1A receptors and prophylactic antimigraine action. In contrast, serotonin, dihydroergotamine, sumatriptan, naratriptan and alniditan, which are effective in acute interruption of migraine attacks, each displayed high efficacy (Emax = 100, 100, 92.6, 79.3, 79.1% respectively) and marked affinity (Ki = 18.7, 0.6, 127, 26.4 and 3.0 nM respectively) at 5-HT1A receptors. EC50 values for agonist stimulation of [35S]-GTP gamma S binding correlated with respective Ki values at 5-HT1A receptors (r = 0.93) and the stimulation of [35S]-GTP gamma S binding by these compounds was antagonised by the selective 5-HT1A antagonist WAY 100,635 (N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl) cyclo-hexanecarboxamide; 100 nM). These data suggest that agonism at 5-HT1A receptors may be involved in some actions of drugs used in acute antimigraine therapy. In comparison with the above compounds, novel ligands targeted at 5-HT1B/1D receptors, such as GR125,743 (N-[4-methoxy-3-(4-methyl-piperazin-1-yl)phenyl] -3-methyl-4-(4-pyridyl)benzamide) and GR 127,935 (N-[4-methoxy-3-(4-methylpiperazin-1-yl)-phenyl]-2'-methyl-4'-(5-m ethyl-1, 2,4-oxadiazol-3-yl)-biphenyl-4-carboxamide), only weakly activated [35S]-GTP gamma S binding (32.4 and 32.1% efficacy) and displayed moderate affinity at 5-HT1A receptors (Kis 53.1 and 49.8 nM) suggesting that they constitute useful tools to differentiate 5-HT1A and 5-HT1B/1D receptor-mediated actions. In conclusion, the present data indicates that several antimigraine agents exhibit marked 5-HT1A receptor activity and that although this is unlikely to be important for prophylactic action it may be relevant to the ancilliary properties of drugs used for a

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Benzopyrans; Binding, Competitive; Cell Membrane; Cricetinae; Dihydroergotamine; Guanosine 5'-O-(3-Thiotriphosphate); Guinea Pigs; Humans; In Vitro Techniques; Indoles; Lisuride; Methysergide; Migraine Disorders; Piperazines; Piperidines; Pizotyline; Propranolol; Propylamines; Protein Binding; Pyridines; Pyrimidines; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Recombinant Proteins; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Sumatriptan; Tryptamines

The serotonin (5-HT) receptor subtype mediating inhibition of neurogenic dural inflammation in guinea pigs was investigated using a series of serotonin agonists with differing affinities for the 5-HT1B, 5-HT1D and 5-HT1F receptors. When agonist potencies for inhibiting neurogenic inflammation were compared with affinities for these receptor subtypes, a significant positive correlation was seen only with the 5-HT1F receptor. The potency of agonists in inhibiting adenylate cyclase in cells transfected with human 5-HT1F receptor was also highly correlated with their potency in the animal model of migraine. In situ hybridization demonstrated 5-HT1F receptor mRNA in guinea pig trigeminal ganglion neurons. These data suggest that the 5-HT1F receptor is a rational target for migraine therapeutics.

Topics: Animals; Benzamides; Carbazoles; Disease Models, Animal; Guinea Pigs; In Situ Hybridization; Indoles; Inflammation; Male; Piperidines; Pyrazoles; Rabbits; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; RNA, Messenger; Serotonin Receptor Agonists; Trigeminal Ganglion; Tryptamines

1. The observation that 5-hydroxytryptamine (5-HT) is effective in treating acute attacks of migraine when administered intravenously resulted in a research effort that led to the discovery of the 5-HT(1B/1D) receptor agonist sumatriptan. 2. Clinical experience has shown sumatriptan to be an effective treatment with some limitations, such as relatively poor bioavailability, which naratriptan was developed to address. Increasing bioavailability has been achieved with greater lipophilicity and thus the potential for greater activity in the central nervous system. 3. In this study the increased access to central sites has been exploited in an attempt to characterize the pharmacology of those central receptors with the newer tools available. Trigeminovascular activation was examined in the model of superior sagittal sinus stimulation. 4. Cats were anaesthetized with alpha-chloralose (60 mg kg(-1), intraperitoneal), paralyzed (gallamine 6 mg kg(-1), intravenously) and ventilated. The superior sagittal sinus was accessed and isolated for electrical stimulation (250 micros pulses, 0.3 Hz, 100 V) by a mid-line circular craniotomy. The region of the dorsal surface of C2 spinal cord was exposed by a laminectomy and an electrode placed for recording evoked activity from sinus stimulation. 5. Stimulation of the superior sagittal sinus resulted in activation of cells in the dorsal horn of C2. Cells fired with a probability of 0.69+/-0.1 at a latency of 9.2+/-0.2 ms. Intravenous (i.v.) administration of naratriptan at clinically relevant doses (30 and 100 microg kg(-1)), inhibited neuronal activity in trigeminal neurones of the C2 dorsal horn, reducing probability of firing without affecting latency. 6. The effect of naratriptan could be reversed by administration of the selective 5-HT(1B/1D) receptor antagonist GR127935 (100 microg kg(-1), i.v.). 7. These data establish that naratriptan acts on central trigeminal neurones since sagittal sinus stimulation activates axons within the tentorial nerve and there are no inhibitory effects mediated within the trigeminal ganglion. Furthermore, given that this inhibition could be reversed by the relatively selective 5-HT(1B/1D) receptor antagonist GR127935, it is highly likely that the anti-migraine effects of drugs of this class with central nervous system access are mediated, at least in part, by 5-HT(1B/1D) receptors within the trigeminal nucleus.

Topics: Animals; Cats; Craniotomy; Electric Stimulation; Evoked Potentials, Somatosensory; Indoles; Injections, Intravenous; Neurons; Oxadiazoles; Piperazines; Piperidines; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Trigeminal Nucleus, Spinal; Tryptamines