Triptan Class Research Articles

Inhibition of Human Plasma Leucine5-Enkephalin Aminopeptidase Hydrolysis by Various Endogenous Peptides and a Select Number of Clinically Used Drugs

We identified a number of clinically used drugs and biologically active endogenous peptides able to significantly decrease the rate of human plasmatic aminopeptidase (AP) leucine-enkephalin (LEU) degradation. Bacitracin, bestatin, fluvoxamine, and each of 4 peptides tested significantly increased, in a dose-dependent manner (10-10 M), LEU degradation half-life (t1/2) in each of 5 plasma samples studied. Each sample was obtained by pooling equal volume of 6 randomly selected, individual plasmas (4 male and 2 female healthy, drug-free volunteers). Thirty subjects (20 females and 10 males) participated in this study. With the exception of fluvoxamine, this inhibitory effect was lacking in various other commonly used drugs with widely different chemical structures and pharmacological profiles, eg, antidepressants (SSRIs, imipramine-like tricyclics, MAOIs), acute antimigraine agents (triptan class drugs), the nonselective beta-adrenergic antagonist propranolol, and serotonin receptor agonists and antagonists. Agents (concentration 10 M used as illustration), listed in decreasing order of LEU-AP inhibitory activity: substance P > angiotensin III > methionine-enkephalin > angiotensin II > fluvoxamine > bestatin gave t1/2 values (+/- SD) of 39.3 +/- 1.1, 29.4 +/- 0.8, 28.3 +/- 0.8, 27.4 +/- 0.7, 24.5 +/- 1.5, and 23.6 +/- 0.9 minutes, respectively. Control, bacitracin, and fluphenazine (known LEU-AP inhibitors were used for comparison) values of 11.8 +/- 1.0, 31.3 +/- 0.7, and 19.6 +/- 1.0 minutes, respectively. As expected, these drugs significantly decreased the initial velocity of peptide degradation; Iv values (+/- SD) of: 0.17 +/- 0.1 (0.02 +/- 0.01), 0.23 +/- 0.2 (0.02 +/- 0.01), 0.25 +/- 0.2 (0.02 +/- 0.01), 0.26 +/- 0.2 (0.03 +/- 0.01), 0.31 +/- 0.1 (0.03 +/- 0.01), and 0.33 +/- 0.1 (0.03 +/- 0.01), respectively; control, bacitracin, and fluphenazine: 1.10 +/- 0.3 (0.12 +/- 0.03), 0.20 +/- 0.1 (0.02 +/- 0.01), and 0.82 +/- 0.2 (0.08 +/- 0.02) pg LEU/min (pg LEU/mg protein/min), respectively. Results emphasize the selective nature of chemical structures required to significantly inhibit AP activity and provided information that could help the rational design of agents with high specificity in a biologic milieu containing multiple peptidases. In this case, targeted modulation of the bioavailability of LEU and other endogenous AP-degraded hormonal and nonhormonal peptides could be useful in the treatment of the pathophysiology associated with various disease conditions. Whether their development could find useful pharmacological applications remains to be explored.

QT prolongation and fatal arrhythmias: a review of clinical implications and effects of drugs.

A long QT interval due to prolonged repolarization may be associated with a polymorphic ventricular tachycardia known as torsades de pointes. During marked prolongation of the action potential (long QT) early after depolarizations may occur, which when propagated may trigger an arrhythmia. The duration of QTc interval is the major determinant of the risk of drug-induced torsades. Congenital long QT syndrome, female gender, hypokalemia and use of sympathomimetics increase the risk of torsades, and potentiate the QT prolonging effects of drugs. Antiarrhythmics that block the potassium channel prolong the QT and increase the risk for torsades (amiodarone, sotalol, quinidine, procainamide, ibutilide, disopyramide). Additionally, some macrolide and fluoroquinolone antibiotics, antipsychotic and antidepressant drugs, serotonin agonists of the triptan class, cisapride, dolasetron and others have been reported to be associated with QT prolongation or cases of torsades. Drug-induced effects on the QT interval with the associated possibility of inducing fatal arrhythmias have become a new challenge for the practitioner, the drug development process and the regulatory agencies.

Tolerability and safety of eletriptan in the treatment of migraine: a comprehensive review.

To provide a comprehensive review of the tolerability and safety of eletriptan. Background.-Eletriptan is a potent and selective 5-HT1B/1D agonist that has demonstrated significant efficacy in the acute treatment of migraine in doses of 20 mg, 40 mg, and 80 mg. This review reports the tolerability and safety of eletriptan across a broad spectrum of preclinical studies and clinical trials that collectively included treatment of more than 11 000 subjects and more than 74 000 migraine attacks. In clinical trials, eletriptan was well tolerated and safe across its dosing range of 20 mg to 80 mg. The adverse event profile of eletriptan 20 mg was similar to placebo, while the most commonly used dose, eletriptan 40 mg, has an adverse event profile that is only marginally higher than placebo. Eletriptan was safe and well tolerated regardless of age or gender, and for both short- and long-term treatment. Eletriptan is metabolized primarily by the CYP3A4 enzyme. Coadministration of potent CYP3A4 inhibitors was not associated with clinically meaningful change in eletriptan tolerability or safety in the population included in these clinical trials. The margin of cardiovascular safety for eletriptan was also confirmed by a well-controlled clinical study in which intravenous eletriptan in excess of an 80-mg dose was rapidly infused in patients undergoing coronary angiography; nonetheless, it is recommended that eletriptan not be coadministered with a limited list of 7 potent CYP3A4 inhibitors; in addition, the triptan class in general (including eletriptan) is contraindicated in patients with symptoms or findings consistent with ischemic heart disease or other significant underlying cardiovascular disease. This comprehensive review found that eletriptan is safe and well tolerated, and that relatively large changes in dose and plasma concentration result in minimal changes in tolerability.

Frovatriptan: a review

Frovatriptan is a potent 5-HT1B/1D receptor agonist and has the highest 5HT1B potency in the triptan class. preclinical pharmacology studies demonstrated that frovatriptan is apparently cerebro-selective. In clinical pharmacology studies, frovatriptan was shown to have a long-terminal elimination half-life of 26 h and to be well-tolerated across a broad dose range of 1 – 100 mg. Frovatriptan has no inhibiting or inducing effects on cytochrome P450 isoenzymes and is only slightly bound to plasma proteins; thus it has a low potential for drug interactions. No dosage adjustments are necessary based on age or renal or hepatic impairment. Efficacy studies show significantly higher response rates compared with placebo and the lowest reported range of headache recurrence rates in the triptan class. Safety studies show a side effect profile similar to placebo. The combination of cerebro-selectivity, long half-life, reliable efficacy, low recurrence rates and good tolerability make frovatriptan a valuable new choice for acute treatment of migraine. Frovatriptan may be particularly well suited to patients with migraine of long duration, those prone to recurrence and those troubled by ‘triptan-type’ side effects.

Frovatriptan: a review

Frovatriptan is a potent 5-HT1B/1D receptor agonist and has the highest 5HT1B potency in the triptan class. preclinical pharmacology studies demonstrated that frovatriptan is apparently cerebro-selective. In clinical pharmacology studies, frovatriptan was shown to have a long-terminal elimination half-life of 26 h and to be well-tolerated across a broad dose range of 1 – 100 mg. Frovatriptan has no inhibiting or inducing effects on cytochrome P450 isoenzymes and is only slightly bound to plasma proteins; thus it has a low potential for drug interactions. No dosage adjustments are necessary based on age or renal or hepatic impairment. Efficacy studies show significantly higher response rates compared with placebo and the lowest reported range of headache recurrence rates in the triptan class. Safety studies show a side effect profile similar to placebo. The combination of cerebro-selectivity, long half-life, reliable efficacy, low recurrence rates and good tolerability make frovatriptan a valuable new choice for acute treatment of migraine. Frovatriptan may be particularly well suited to patients with migraine of long duration, those prone to recurrence and those troubled by ‘triptan-type’ side effects.

Safety of sumatriptan in pregnancy: a review of the data so far.

The high prevalence of migraine in women during their reproductive years means that new drug treatments for migraine, such as the serotonin 5-HT(1B/1D) receptor agonists (the 'triptans'), are likely to be widely used by women of childbearing potential. Scrutiny of these agents in an effort to detect any signal of teratogenicity is thus important. A systematic review of the medical literature was conducted to identify information regarding the safety of sumatriptan during pregnancy. This agent was chosen to be investigated because it has been available for the longest and is the most widely used of the triptan class. Information was obtained regarding the impact of migraine on pregnancy outcome, and data on sumatriptan use in pregnancy were obtained from animal studies, preclinical drug trials, postmarketing surveillance efforts, prospective pregnancy registries, national birth registries and teratogen information services. Synthesis of information from these sources is sufficient to rule out a large increase in birth defects from sumatriptan use during pregnancy and is reassuring for cases where inadvertent exposure to sumatriptan during pregnancy has occurred. However, current information is not sufficient to rule out small increases in the risk for birth defects. For this reason, caution should be exercised in making a positive recommendation for the use of sumatriptan during pregnancy.

Triptans for migraine management in adolescents.

To review triptan efficacy and tolerability data for adolescent migraine sufferers to assist clinicians in selecting triptans for this age group. Migraine is a common cause of headache among adolescents. To date, no medications, including those with proven headache relief in adults, have been approved for treatment of migraine in adolescents. Recent triptan clinical trials conducted in adolescent migraine sufferers 12 to 17 years of age were reviewed and results were summarized. The success of individual triptan clinical trials conducted in adolescent appears related to time to treatment (1.9 to 6 hours), placebo response (25% to 57%), and day of the week (weekday versus weekend). Overall, triptan tolerability in adolescents is similar to that reported in adults. Study results suggest that the triptan class of antimigraine drugs may effectively alleviate migraine in adolescents. Future research should address placebo response and earlier treatment paradigms.

The anti-migraine 5-HT(1B/1D) agonist rizatriptan inhibits neurogenic dural vasodilation in anaesthetized guinea-pigs.

These studies investigated the pharmacology of neurogenic dural vasodilation in anaesthetized guinea-pigs. Following introduction of a closed cranial window the meningeal (dural) blood vessels were visualized using intravital microscopy and the diameter constantly measured using a video dimension analyser. Dural blood vessels were constricted with endothelin-1 (3 microg kg(-1), i.v.) prior to dilation of the dural blood vessels with calcitonin gene-related peptide (CGRP; 1 microg kg(-1), i.v.) or local electrical stimulation (up to 300 microA) of the dura mater. In guinea-pigs pre-treated with the CGRP receptor antagonist CGRP((8-37)) (0.3 mg kg(-1), i.v.) the dilator response to electrical stimulation was inhibited by 85% indicating an important role of CGRP in neurogenic dural vasodilation in this species. Neurogenic dural vasodilation was also blocked by the 5-HT(1B/1D) agonist rizatriptan (100 microg kg(-1)) with estimated plasma levels commensurate with concentrations required for anti-migraine efficacy in patients. Rizatriptan did not reverse the dural dilation evoked by CGRP indicating an action on presynaptic receptors located on trigeminal sensory fibres innervating dural blood vessels. In addition, neurogenic dural vasodilation was also blocked by the selective 5-HT(1D) agonist PNU-142633 (100 microg kg(-1)) but not by the 5-HT(1F) agonist LY334370 (3 mg kg(-1)) suggesting that rizatriptan blocks neurogenic vasodilation via an action on 5-HT(1D) receptors located on perivascular trigeminal nerves to inhibit CGRP release. This mechanism may underlie one of the anti-migraine actions of the triptan class exemplified by rizatriptan and suggests that the guinea-pig is an appropriate species in which to investigate the pharmacology of neurogenic dural vasodilation.

Naratriptan

SUMMARYNaratriptan is a selective 5-HT1B/1D receptor agonist, with a high affinity at the 5-HT1B, 5-HT1D and 5-HT1F 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, with 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 with 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.