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PubMed2000

Triptans in migraine: a comparative review of pharmacology, pharmacokinetics and efficacy.

Triptans are a new class of compounds developed for the treatment of migraine attacks. The first of the class, sumatriptan, and the newer triptans (zolmitriptan, naratriptan, rizatriptan, eletriptan, almotriptan and frovatriptan) display high agonist activity at mainly the serotonin 5-HT1B and 5-HT1D receptor subtypes. As expected for a class of compounds developed for affinity at a specific receptor, there are minor pharmacodynamic differences between the triptans. Sumatriptan has a low oral bioavailability (14%) and all the newer triptans have an improved oral bioavailability and for one, risatriptan, the rate of absorption is faster. The half-lives of naratriptan, eletriptan and, in particular, frovatriptan (26 to 30h) are longer than that of sumatriptan (2h). These pharmacokinetic improvements of the newer triptans so far seem to have only resulted in minor differences in their efficacy in migraine. Double-blind, randomised clinical trials (RCTs) comparing the different triptans and triptans with other medication should ideally be the basis for judging their place in migraine therapy. In only 15 of the 83 reported RCTs were 2 triptans compared, and in 11 trials triptans were compared with other drugs. Therefore, in all placebo-controlled randomised clinical trials, the relative efficacy of the triptans was also judged by calculating the therapeutic gain (i.e. percentage response for active minus percentage response for placebo). The mean therapeutic gain with subcutaneous sumatriptan 6mg (51%) was more than that for all other dosage forms of triptans (oral sumatriptan 100mg 32%; oral sumatriptan 50mg 29%: intranasal sumatriptan 20mg 30%; rectal sumatriptan 25mg 31%; oral zolmitriptan 2.5mg 32%; oral rizatriptan 10mg 37%; oral eletriptan 40mg 37%; oral almotriptan 12.5mg 26%). Compared with oral sumatriptan 100mg (32%), the mean therapeutic gain was higher with oral eletriptan 80mg (42%) but lower with oral naratriptan 2.5mg (22%) or oral frovatriptan 2.5mg (16%). The few direct comparative randomised clinical trials with oral triptans reveal the same picture. Recurrence of headache within 24 hours after an initial successful response occurs in 30 to 40% of sumatriptan-treated patients. Apart from naratriptan, which has a tendency towards less recurrence, there appears to be no consistent difference in recurrence rates between the newer triptans and sumatriptan. Rizatriptan with its shorter time to maximum concentration (tmax) tended to produce a quicker onset of headache relief than sumatriptan and zolmitriptan. The place of triptans compared with non-triptan drugs in migraine therapy remains to be established and further RCTs are required.

Animals↗
PubMed1998

Pharmacological analysis of the haemodynamic effects of 5-HT1B/D receptor agonists in the normotensive rat.

1 The receptors involved in mediating the haemodynamic effects of three 5-HT1B/D receptor agonists were investigated in pentobarbitone anaesthetized rats (n = 6-17 per group). 2 Cumulative intravenous (i.v.) infusions of rizatriptan and sumatriptan (from 0.63 to 2500 microg kg(-1); each dose over 5 min) induced dose-dependent and marked hypotension (-42+/-6 and -34+/-4 mmHg at the highest dose, respectively; both P<0.05 vs vehicle: +5+/-3 mmHg) and bradycardia (-85+/-16 and -44+/-12 beats min(-1) at the highest dose, respectively; both P<0.05 vs vehicle: +16+/-6 beats min(-1)). Zolmitriptan evoked only moderate hypotension at the highest dose (-19+/-9 mmHg; P<0.05 vs vehicle). 3 A high dose of the 5-HT1B/D receptor antagonist, GR 127935 (0.63 mg kg(-1), i.v.), failed to antagonize the hypotension and bradycardia evoked by sumatriptan (-35+/-6 mmHg and -52+/-19 beats min(-1), respectively; both not significant vs sumatriptan in untreated rats), but moderately reduced the hypotension and bradycardia evoked by rizatriptan (-20+/-5 mmHg and -30+/-17 beats min(-1), respectively; both P<0.05 vs vehicle and vs rizatriptan in untreated rats). 4 The selective 5-HT1A receptor antagonist, WAY 100635 (0.16 and 0.63 mg kg(-1), i.v.), dose-dependently attenuated the haemodynamic responses evoked by rizatriptan and sumatriptan, which were almost abolished by the higher dose of WAY 100635 (-4+/-3 mmHg and -15+/-8 beats min(-1); both not significant vs vehicle and P<0.05 vs rizatriptan in untreated rats). A slight but statistically significant reduction in mean arterial pressure (MAP) persisted at the highest dose of sumatriptan (-13+/-4 mmHg following the higher dose of WAY 100635; P<0.05 vs vehicle). 5 In pithed rats with MAP normalized by angiotensin II, rizatriptan failed to induce hypotension or bradycardia (+5+/-4 mmHg and -6+/-16 beats min(-1), respectively; both NS vs vehicle and P<0.05 vs rizatriptan in untreated rats). Similarly, sumatriptan failed to induce bradycardia in pithed rats (+5+/-6 beats min(-1); not significant vs vehicle and P<0.05 vs sumatriptan in untreated rats), whereas a slight but statistically significant reduction in MAP, compared to controls, occurred at the highest dose (-9+/-9 mmHg; P<0.05 vs both vehicle and sumatriptan in untreated rats). 6 In bilaterally vagotomized and atropine-treated (1 mg kg(-1), i.v.) rats, the reductions in MAP and heart rate evoked by rizatriptan (-31+/-4 mmHg and -64+/-9 beats min(-1), respectively; both P<0.05 vs vehicle and not significant vs rizatriptan in controls) and sumatriptan (-47+/-8 mmHg and -56+/-10 beats min(-1), respectively; both P<0.05 vs vehicle and not significant vs sumatriptan in controls) were not statistically significantly different from those observed in controls. 7 In conclusion, the 5-HT1B/D receptor agonists, rizatriptan and sumatriptan, elicit hypotension and bradycardia in the normotensive anaesthetized rat predominantly via activation of central 5-HT1A receptors, and a consequent reduction in sympathetic outflow.

Animals↗
PubMed1999

Rizatriptan: a review of its efficacy in the management of migraine.

UNLABELLED: Rizatriptan is an orally active serotonin 5-HT1 receptor agonist selective for the 5-HT(1B/1D) subtypes. The efficacy of oral rizatriptan (5 or 10 mg) has been demonstrated in large (n = 309 to 1746) well designed comparative trials with placebo and oral sumatriptan. Two hours postdose, rizatriptan 5 or 10 mg was more effective than placebo at producing pain relief or a pain free status, relieving migraine-associated symptoms and normalising functional ability. In general, rizatriptan 10 mg appeared to be more effective than rizatriptan 5 mg. However, recurrence rates with rizatriptan 5 and 10 mg appeared to be similar to those with placebo. Patients were significantly more likely to achieve pain relief within 2 hours after receiving rizatriptan 5 mg than sumatriptan 25 mg and after rizatriptan 10 mg than sumatriptan 50 mg. This was also observed with rizatriptan 10 mg compared with sumatriptan 100 mg according to an age-adjusted and a prespecified per-protocol analysis. In general, rizatriptan was better than sumatriptan at relieving migraine-associated symptoms, particularly nausea, and in normalising functional ability depending on which doses were compared. The incidence of headache recurrence, time to onset of recurrence and the need for escape medication in nonresponders appeared to be similar between rizatriptan and sumatriptan. Over the 24 hours after the dose, rizatriptan 10 mg improved the quality of life of patients with migraine compared with placebo. Rizatriptan 10 mg also significantly improved work function compared with placebo and with sumatriptan 50 mg. Rizatriptan appears to be well tolerated with most adverse events being mild and transient. The most commonly experienced events included general digestive complaints, general neurological complaints, dizziness, somnolence, asthenia/fatigue and pain and pressure sensations. In clinical trials, the overall incidence of adverse events with rizatriptan 5 or 10 mg was similar to that with sumatriptan 25 or 50 mg but lower than that with sumatriptan 100 mg. Chest pain was reported by 1 to 3% of rizatriptan recipients and by 3 to 6% of patients receiving sumatriptan (25, 50 or 100 mg); clinically significant effects on ECG parameters, heart rate or blood pressure were not observed with rizatriptan. CONCLUSIONS: Rizatriptan produces pain relief and a pain free status, relieves associated symptoms of migraine, normalises functional ability and improves patient quality of life. Rizatriptan 10 mg appears to be more effective than rizatriptan 5 mg. In comparison with oral sumatriptan, rizatriptan may provide better relief from pain and nausea, with some evidence of a faster onset of action. Thus, rizatriptan 5 or 10 mg is likely to establish a place as an effective and well tolerated agent for the management of acute migraine.

Administration, Oral↗
PubMed1995

Role of the serotonin receptor subtype 5-HT1D on basal and stimulated growth hormone secretion.

At present, four main types of serotonin (5-HT) receptors have been identified in the brain (5-HT1, 5-HT2, 5-HT3, and 5-HT4). In addition, the 5-HT1 have been further subclassified. We have taken advantage of a new selective 5-HT1D receptor agonist 3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulfonamide succinate, Sumatriptan, to evaluate the role of 5-HT1D receptors on GH secretion. To this end, several tests with or without sumatriptan were undertaken in normal prepubertal children. Furthermore, we assessed the effect of Sumatriptan on basal GH secretion and the GH response to GHRH in obese children. In normal children, Sumatriptan administration (3 mg, sc) resulted in an increase in basal GH levels at 30 min (7.7 +/- 1.5 micrograms/L; P < 0.05) and increased GH responses to GHRH (47.3 +/- 6.4 vs. 29.6 +/- 9.7 micrograms/L; P < 0.05). The Sumatriptan-induced increase in GH responses to GHRH was dependent on the stimulus tested. Pretreatment with Sumatriptan did not modify the GH response to clonidine or pyridostigmine, as assessed by the peak GH response and the area under the curve. In contrast, it increased the GH response to arginine. In the obese subjects, the GH response to GHRH was reduced (7.3 +/- 1.0 vs. 29.6 +/- 9.7 micrograms/L at 30 min) compared to that in control children (P < 0.05). Sumatriptan administration did not alter the basal GH value (peak GH, 1.7 +/- 0.3 micrograms/L at 30 min). However, Sumatriptan administration clearly increased the effect of GHRH, resulting in a GH peak of 14.6 +/- 3.1 micrograms/L at 30 min (P < 0.01). To assess the specificity of Sumatriptan on anterior pituitary hormone secretion, we studied its effect on TSH and PRL responses to TRH as well as LH-releasing hormone-induced LH and FSH secretion. Administration of Sumatriptan did not alter the response of any of these hormones. Our results indicate that 5-HT1D receptors have a stimulatory effect on GH secretion, possibly by inhibiting hypothalamic somatostatin release.

Arginine↗
PubMed1998

Activation of recombinant h 5-HT1B and h 5-HT1D receptors stably expressed in C6 glioma cells produces increases in Ca2+-dependent K+ current.

The putative coupling between stably expressed recombinant h 5-HT1B or h 5-HT1D receptors and K+ channels which regulate excitability was investigated in C6 glioma cells. Outward K+ currents (IK) were examined in nontransfected C6 glioma cells and in cells expressing cloned h 5-HT1B or h 5-HT1D receptors using the patch-clamp technique in the whole-cell configuration. IK was elicited by a depolarizing step from a holding potential of -60 mV. In C6 glioma cells expressing either recombinant h 5-HT1B or h 5-HT1D receptors, sumatriptan similarly increased IK in a concentration-dependent manner (maximum increase 19.4+/-7.2%, n=8, P<0.05 and 25.1+/-3.9%, n=6, P<0.001, respectively) with EC50 values (geometric mean with 95% confidence intervals in parentheses) of 56.3 nM (7.9-140 nM) and 68.7 nM (16-120 nM), respectively. Sumatriptan failed to elicit increases in IK in non-transfected cells, confirming a specific involvement of the respective membrane h 5-HT1B and h 5-HT1D receptors in transfected C6 cells. In the presence of the mixed 5-HT1B/D receptor antagonist GR 127935 (0.1 microM), sumatriptan (1 microM) failed to significantly increase IK in C6 cells expressing h 5-HT1B receptors (-7.5+/-3.5%, P=NS, n=6), although a higher concentration of GR 127935 (1 microM) was required to significantly inhibit sumatriptan-evoked increases in IK in C6 cells expressing h 5-HT1D receptors (-1.8+/-3.5%, P=NS, n=6), confirming that sumatriptan-evoked responses were indeed mediated by h 5-HT1B and h 5-HT1D receptors, respectively. In C6 cells expressing either cloned h 5-HT1B or h 5-HT1D receptors, sumatriptan-induced increases in IK were prevented by the calcium chelator EGTA (5 mM) when included in the patch pipette (maximum increase 0.57+/-0.6%, n=3, P=NS and -2.8+/-1.6%, n=5, P=NS, respectively). In C6 cells expressing cloned h 5-HT1B receptors, sumatriptan (1 microM) similarly failed to significantly increase IK in the presence of dibutyryl cAMP (10 microM) or when a nominally Ca2+-free medium was included in the patch pipette (-19.4+/-5.1%, n=5 and -5.2+/-4.3%, n=5, respectively, P=NS in each case). In addition, the Ca2+-dependent K+ channel blockers iberiotoxin (0.1 microM) and tetraethylammonium (TEA, 1 mM) abolished sumatriptan-induced increases in IK (-0.5+/-1.0%, n=4 and -3.9+/-3.1%, n=4, respectively, P=NS in each case) in C6 cells expressing h 5-HT1B receptors, confirming the involvement of Ca2+-dependent K+ channels. In C6 cells expressing cloned h 5-HT1B receptors, sumatriptan (1 microM) similarly failed to significantly increase IK after 30-min incubation with thapsigargin (1 microM) or when heparin (2 mg/ml) was included in the patch pipette (1.1+/-0.4%, n=5 and 1.2+/-2.4%, n=5, respectively, P=NS). In conclusion, evidence is provided that both recombinant h 5-HT1B and h 5-HT1D receptors stably transfected in C6 glioma cells are positively coupled to Ca2+-dependent K+ channels, and the outward hyperpolarizing current mediated by these channels is dependent upon IP3 receptor-mediated intracellular Ca2+ release.

Animals↗
PubMed1996

Functional characterization of 5-HT1D autoreceptors on the modulation of 5-HT release in guinea-pig mesencephalic raphe, hippocampus and frontal cortex.

1. The aims of the present study were (i) to characterize further the pharmacology of 5-HT1D autoreceptors modulating 5-HT release in guinea-pig mesencephalic raphe, hippocampus and frontal cortex; (ii) to determine whether 5-HT1D receptors in the mesencephalic raphe are located on 5-HT neurones; (iii) to determine whether 5-HT1D autoreceptors are coupled to G proteins; and (iv) to assess their sensitivity following long-term 5-HT reuptake blockade and inhibition of type-A monoamine oxidase. 2. In mesencephalic raphe, hippocampus and frontal cortex slices, the 5-HT1D/1B receptor agonist, sumatriptan and the 5-HT1 receptor agonist, 5-methoxytryptamine (5-MeOT) but not the 5-HT1B receptor agonist, CP93129, inhibited electrically the evoked release of [3H]-5-HT in a concentration-dependent manner. This effect was antagonized by the 5-HT1D/1B receptor antagonist GR127935 in the three structures, but not by the 5-HT1A receptor antagonist, (+)-WAY100635 in mesencephalic raphe slices. These results confirm the presence of functional 5-HT1D autoreceptors controlling 5-HT release within the mesencephalic raphe as well as in terminal regions. 3. The inhibitory effect of sumatriptan on K(+)-evoked release of [3H]-5-HT was not reduced by the addition of the Na+ channel blocker, tetrodotoxin to the superfusion medium, suggesting that these 5-HT1D receptors in the mesencephalic raphe are located on 5-HT neurones and may be considered autoreceptors. 4. The in vitro treatment with the alkylating agent N-ethylmaleimide (NEM) was used to determine whether these 5-HT1D autoreceptors are coupled to G proteins. The inhibitory effect of sumatriptan on electrically evoked release of [3H]-5-HT was attenuated in NEM-pretreated slices from mesencephalic raphe, hippocampus and frontal cortex, indicating that the 5-HT1D autoreceptors activated by sumatriptan are coupled to G proteins in these three structures. Taken together with our previous results, this suggests that, in addition to the 5-HT1D autoreceptor activated by sumatriptan, another subtype of 5-HT autoreceptor is activated by 5-MeOT in the hippocampus. 5. Following a 3-week treatment with the selective 5-HT reuptake inhibitor, paroxetine (10 mg kg-1 day-1) and a 48 h washout period, the electrically evoked release of [3H]-5-HT was enhanced in mesencephalic raphe, hippocampus and frontal cortex slices. There was an attenuation of the capacity of sumatriptan to inhibit the evoked release of [3H]-5-HT from mesencephalic raphe slices but not from frontal cortex and hippocampus slices. Only in the latter structure was the suppressant effect of 5-MeOT attenuated. After a 3-week treatment with the reversible type-A monoamine oxidase inhibitor, befloxatone (0.75 mg kg-1 day-1) and 48 h washout period, the effectiveness of sumatriptan and 5-MeOT on the evoked release of [3H]-5-HT was unaltered in the same brain structures. 6. The enhancement of [3H]-5-HT release by long-term paroxetine treatment is possibly due to a desensitization of 5-HT1D autoreceptors activated by sumatriptan in mesencephalic raphe and by terminal 5-HT autoreceptors activated by 5-MeOT in hippocampus. In the case of the frontal cortex, it appears that 5-MeOT and sumatriptan may act on the same 5-HT1D autoreceptor which is not desensitized either after paroxetine or befloxatone treatment, as previously reported.

Animals↗
PubMedDate not supplied

Characterization of 5-hydroxytryptamine receptors in rabbit isolated iliac artery.

To characterize the 5-hydroxytryptamine (5-HT) receptors, the contractile effects of both 5-HT and the 5-HT1-like receptor agonist sumatriptan were investigated in isolated open ring preparations of the rabbit common iliac artery. 5-HT induced concentration-dependent contractions. Sumatriptan did not induce any contraction of unstimulated preparations, whereas it elicited concentration-dependent contractions in preparations given a moderate tone with a threshold concentration of prostaglandin F2 alpha. In vessel segments precontracted with prostaglandin F2 alpha, Emax values for 5-HT and sumatriptan reached about 85% and 30% of the phenylephrine maximal effect, respectively. The mean EC50 values for sumatriptan and 5-HT were 3.34 microM and 1.5 microM, respectively. Pargyline, cocaine or normetanephrine were without significant effect on the contractions induced by 5-HT or sumatriptan. The 5-HT3 receptor antagonist tropisetron (1 microM) had no effect on 5-HT- and sumatriptan-induced contractions. The 5-HT2 receptor antagonist ketanserin (0.1-1 microM) produced parallel displacements to the right of the 5-HT and phenylephrine concentration-effect curves, without significant reduction in the maximum responses. The pA2 values were 7.85 +/- 0.19 and 7.9 +/- 0.16, respectively. Ketanserin had no effect on the sumatriptan concentration-effect curves. The nonselective 5-HT receptor antagonists methysergide (0.3 microM) and methiothepin (0.01 microM) shifted the concentration-response curve to sumatriptan to the right (mean pKB values of 6.91 and 8.68, respectively). The pA2 value for prazosin against 5-HT (9.98 +/- 0.43) was not significantly different from the value against phenylephrine (9.27 +/- 0.20). These results suggest that the sumatriptan-induced contraction is mediated by a 5-HT1-like receptor, whereas an additional mechanism, probably an alpha 1-adrenoceptor stimulation, plays a role in the contraction induced by 5-HT in the rabbit iliac artery.

Animals↗
PubMed2000

Efficacy of naratriptan tablets in the acute treatment of migraine: a dose-ranging study. Naratriptan S2WB2004 Study Group.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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%. CONCLUSIONS: 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.

Dose-Response Relationship, Drug↗
PubMed1998

Effects of the novel antimigraine agent, frovatriptan, on coronary and cardiac function in dogs.

The effects of frovatriptan (VML 251/SB-209509) on coronary artery function were investigated in isolated coronary arteries from beagle dogs. Low concentrations of frovatriptan produced contraction with -logEC50 7.55 +/- 0.08 (n = 11). The maximal observed contraction attained was 56 +/- 7% of the control 5-hydroxytryptamine (5-HT; 10 microM) response. At high concentrations of frovatriptan (>6 microM), reversal of sumatriptan (10 microM)-induced contractions was noted. In arteries precontracted with the thromboxane mimetic, U46619, frovatriptan produced a bell-shaped concentration-response relation with a maximal response at 600 nM. Concentrations of frovatriptan >2 microM produced marked reversal of tone, with full relaxation of precontracted tissues at 200 microM. In anesthetized, open-chest mongrel dogs, intravenous (n = 5) or intracoronary (n = 5) artery administration of frovatriptan (0.0001-1 mg/kg) had no consistent effect on left ventricular end-diastolic pressure, left end-systolic pressure, cardiac contractility, aortic blood flow, systemic peripheral resistance, coronary blood flow, coronary vascular resistance, mean arterial blood pressure, or heart rate when compared with vehicle (n = 3). Intravenous sumatriptan produced minor effects on blood pressure and heart rate. Intracoronary artery administration of sumatriptan (0.0003 mg/kg) produced an increase in systemic peripheral resistance to 120.5 +/- 8.2% compared with vehicle (97.8 +/- 5.4%; p < 0.05). This dose of sumatriptan also produced a significant increase in coronary blood flow and decrease in coronary vascular resistance. Intravenous administration of sumatriptan produced a dose-related reduction in left ventricular diastolic pressure with a reduction to 58.3 +/- 8.3% and 41.7 +/- 25% of control values observed at 0.3 and 1 mg/kg, respectively; however, administration of sumatriptan by an intracoronary route had no effect. In a model of myocardial infarction, comparable doses of sumatriptan (1.0 mg/kg) or frovatriptan (0.1 mg/kg), in terms of their effect on carotid vascular resistance, had no significant effect on infarct size. Frovatriptan had no effect on coronary blood flow after reperfusion; however, sumatriptan produced a significant reduction in coronary blood flow for < or =3 h. These studies show that frovatriptan has the capability of relaxing coronary arteries in vitro, has no overall effect on cardiac function at rest with no effect on coronary hemodynamics after myocardial infarction, and has a profile superior to that of sumatriptan.

Animals↗
PubMed2003

Triptans for treatment of acute pediatric migraine: a systematic literature review.

The purpose of this article is to evaluate the effectiveness and safety of triptans for the treatment of acute migraine in children and adolescents. Randomized and open label trials of triptans in acute pediatric patients (ages 6-18 years) were identified by Medline (1966-2002) and PubMed (1991-2002). Additional reports were identified from the reference list of the retrieved studies. To study effectiveness, only randomized controlled trials were included, but open label studies were also included to study adverse effects. Pharmacokinetic studies of triptans in pediatric patients were also searched. Four randomized controlled trials were identified. One study reported oral sumatriptan, another oral rizatriptan, and two studies reported nasal spray sumatriptan. Rizatriptan is well tolerated but not clearly beneficial when used in adolescents. Effectiveness of nasal spray sumatriptan in acute pediatric migraine where other medications had failed was supported. Effectiveness of oral sumatriptan was not established. Adverse effects were minor for oral sumatriptan and rizatriptan and nasal sumatriptan. Pharmacokinetics of sumatriptan in pediatric patients has not been established. In conclusion, nasal spray sumatriptan should be considered in acute pediatric migraine in patients not experiencing adequate relief with other interventions.

Acute Disease↗
PubMed1997

Characterization of 5-HT receptors on human pulmonary artery and vein: functional and binding studies.

1. This study aimed to investigate the 5-hydroxytryptamine (5-HT) receptors mediating contraction of ring preparations isolated from human pulmonary arteries and veins. In functional studies, the responses to 5-HT, sumatriptan, ergotamine, serotonin-O-carboxymethyl-glycyl-tyrosinamide (SCMGT), alpha-methyl 5-HT (alpha-Me) and 2-methyl 5-HT (2-Me) were studied with WAY100635, GR127935, ritanserin, zacopride and SB204070 as antagonists. 2. All agonists produced concentration-dependent contractions of human pulmonary artery and vein preparations. The order of potency (-log ECS0 values) was ergotamine (6.88) > 5-HT (6.41) > or = SCMGT (6.20) = sumatriptan (6.19) > or = alpha-Me (6.04) in the artery, and ergotamine (7.84) > 5-HT (6.96) > sumatriptan (6.60) = alpha-Me (6.56) > SCMGT (6.09) in the vein. The potency of each agonist, except for SCMGT, was greater in vein than in artery preparations. Contractile responses to 5-HT were similar in intact and endothelium-denuded preparations but responses to sumatriptan were enhanced in artery rings without endothelium. 3. GR127935 (1 nM to 0.5 microM) produced an unsurmountable antagonism of the response to 5-HT, sumatriptan, ergotamine and SCMGT. Ritanserin (1 nM to 1 microM) also reduced the maximum contractile responses to 5-HT, ergotamine and alpha-Me in artery and vein preparations without affecting those to sumatriptan and SCMGT. In endothelium-denuded preparations, surmountable antagonism of sumatriptan by GR127935 (in the presence of ritanserin) and of alpha-Me by ritanserin (in the presence of GR127935) allowed for the calculation of the apparent pK(B) values of GR127935 (9.17+/-0.11 in artery and 9.11+/-0.05 in vein) and ritanserin (8.82+/-0.09 in artery and 8.98+/-0.12 in vein). 4. WAY100635 (1 nM to 1 microM), zacopride (1 nM to 1 microM), or SB204070 (1 nM) did not significantly alter the concentration-response curves for 5-HT, sumatriptan, ergotamine, SCMGT or 2-Me in human pulmonary artery or vein thus indicating that 5-HT1A, 5-HT3 and 5-HT4 receptors are presumably not involved in the contractile response to these agonists. 5. Binding studies using selective radioligands for different 5-HT receptors could not detect the presence of 5-HT1A receptor binding in human pulmonary blood vessels whereas the 5-HT(1B/1D) radioligand [3H]-5CT significantly labelled a population of specific binding sites in both vessel types. The presence of 5-HT2A receptors could also be inferred from the level of binding of [3H]-ketanserin to membranes obtained from human pulmonary vessels, although significance could not be reached for arteries. 5-HT4 specific receptor binding was scarce in veins and absent in the case of arteries. 6. These findings indicate that the human pulmonary artery and vein have a mixed functional population of 5-HT(1B/1D) and 5-HT2A receptors mediating the contractile response to 5-HT which is consistent with results of the binding studies.

Abortifacient Agents, Nonsteroidal↗
PubMed2001

Effect of rizatriptan and other triptans on the nausea symptom of migraine: a post hoc analysis.

OBJECTIVE: To compare the effects of oral rizatriptan, sumatriptan, naratriptan, and zolmitriptan on the relief and emergence of nausea during a migraine attack. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Administration, Oral↗
PubMed1991

Vascular 5-HT1-like receptors that mediate contraction of the dog isolated saphenous vein and carotid arterial vasoconstriction in anaesthetized dogs are not of the 5-HT1A or 5-HT1D subtype.

1. There is controversy about whether 5-HT1A receptors mediate contraction of isolated cerebral blood vessels. We have therefore compared the vascular actions of the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propyl-amino)-tetralin (8-OH-DPAT) with those of the 5-HT1-like receptor agonist, sumatriptan, on the dog isolated saphenous vein, which contains a 5-HT1-like receptor similar to those on cerebral blood vessels, and in the carotid circulation of the anaesthetized dog. 2. 5-Hydroxytryptamine (5-HT), sumatriptan and 8-OH-DPAT each caused contraction of dog isolated saphenous vein with a rank order of agonist potency of 5-HT greater than sumatriptan greater than 8-OH-DPAT and EC50 values (95% confidence limits) of 0.06 (0.04-0.08), 0.3 (0.1-0.8) and 3.9 (2.0-7.5) microM respectively. The maximum contractile effect produced by each agonist was similar. 3. The contractile effects of 5-HT, sumatriptan and 8-OH-DPAT in the dog isolated saphenous vein were resistant to antagonism by the 5-HT1A receptor antagonists spiperone, spiroxatrine and pindolol (all 1 microM). The 5-HT1D receptor ligands, metergoline (0.1 microM) rauwolscine (1 microM) and yohimbine (1 microM) had little or no antagonist activity. In contrast, the non-selective 5-HT1-like receptor blocking drug, methiothepin (0.03-0.3 microM) potently antagonized the contractile effects of 5-HT, sumatriptan and 8-OH-DPAT to a similar degree, suggesting that all three agonists act at the same receptor. 4. In ganglion-blocked, anaesthetized dogs, intra-carotid administration of 8-OH-DPAT (0.3-3 pggkg-1) and sumatriptan (0.1l-1 pgkg -), caused dose-dependent carotid arterial vasoconstriction. The two agonists were approximately equipotent in this respect. 5. The carotid arterial vasoconstrictor actions of 8-OH-DPAT and sumatriptan were not modified by spiperone (1 mgkg- , i.v.) but were antagonized to a similar extent by the subsequent administration of methiothepin (1 mgkg- 1, i.v.). 6. These results suggest that 8-OH-DPAT contracts the dog isolated saphenous vein and constricts the carotid arterial circulation of anaesthetized dogs by activation of 5-HT1-like receptors which are not of the 5-HTlA subtype, nor, on the basis of data with metergoline in the dog isolated saphenous vein, of the 5-HTID subtype. The receptor involved in these actions appears to be the same as that mediating the vasoconstrictor effects of sumatriptan. This receptor does not appear to be like any known 5-HT1 ligand binding site; hence the current description, 5-HT1-like, remains the most appropriate.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1995

Ketanserin-sensitive depressant actions of 5-HT receptor agonists in the neonatal rat spinal cord.

1. The monosynaptic reflex (MSR), recorded in vitro from the neonatal rat spinal cord, was depressed by 5-hydroxytryptamine (5-HT), 5-carboxamidotryptamine (5-CT), methysergide and R(+)-8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), and also by the selective 5-HT1D agonists, sumatriptan and N-methyl-3-(1-methyl-1-piperidinyl)-1H-indole-5-ethane sulphonamide (GR 85548). 2. Ketanserin (1 microM) and methiothepin (1 microM) reduced the duration of depressions elicited by 5-CT, but not those produced by 5-HT, sumatriptan, GR 85548, methysergide or 8-OH-DPAT. 3. The IC50 for MSR depression by 5-CT was 3.6, 2.1-6.2 nM (n = 4), by sumatriptan was 15.2, 12.9-18.0 nM (n = 32), by GR 85548 was 18.4, 11.7-29.1 nM (n = 12), by methysergide was 29.8, 10.2-87.1 nM (n = 4) and by 8-OH-DPAT was 0.21, 0.11-0.43 microM (n = 3) (geometric means and 95% confidence limits). 4. Ketanserin (0.1 or 1 microM) antagonized competitively responses to sumatriptan (apparent pA2 7.8 +/- 0.1, n = 5), GR 85548 (apparent pA2 7.6, unpaired data, n = 5), methysergide (apparent pA2 7.9 +/- 0.12, n = 4) and 8-OH-DPAT (apparent pA2 8.3 +/- 0.1, n = 3). Concentration-response curves to 5-CT showed a smaller, parallel shift to the right (apparent pA2 6.8 +/- 0.1, n = 4), but responses to 5-HT were unaffected by ketanserin (1 microM) (n = 4). 5. Methiothepin (1 microM) antagonized competitively responses to GR 85548 (apparent pA2 7.7, unpaired data, n = 5). 6. Mianserin (0.3 microM), a concentration sufficient to cause substantial block of 5-HT2C-mediated responses but have only a small effect on 5-HT1D-mediated actions, caused a small, non-parallel shift of the concentration-response curve to sumatriptan. 7. Depression of the MSR by sumatriptan was not blocked by (+/-)-cyanopindolol (0.1 microM), (+/-)-propranolol (0.5 or 1 microM) or spiroxatrine (0.1 microM), and depression of MSR by 8-OH-DPAT was not blocked by spiroxatrine (0.1 microM). (+/-)-Cyanopindolol (0.1 and 1 microM) itself induced a slow depression of the MSR. 8. The novel 5-HT1D antagonist, N-[4-methyl-1-piperazinyl) phenyl]2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl) [1,1-biphenyl]-4-carboxamide (GR 127935, 30 nM to 1 microM) caused a concentration-related depression of the reflex (up to 50%) usually slow in onset. Neither with these concentrations nor with concentrations in the range 1-3 nM was there any unequivocal blockade of responses to sumatriptan. 9. It is concluded that sumatriptan, GR 85548, methysergide and 8-OH-DPAT depress the MSR in the neonate rat spinal cord via ketanserin-sensitive receptors, which have some similarities to 5-HT1D alpha receptors but which are not blocked by GR 127935. 5-HT released by tryptaminergic pathways may act via the same receptors to depress the MSR. 5-HT applied to the cord probably acts via a different, possibly novel 5-HT receptor to depress the MSR.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1994

The 5-HT1-like receptor mediating the increase in canine external carotid blood flow: close resemblance to the 5-HT1D subtype.

1. It has recently been shown that the increase in external carotid blood flow induced by 5-hydroxy-tryptamine (5-HT) in the anaesthetized dog, being mimicked by 5-carboxamidotryptamine (5-CT), inhibited by methiothepin, vagosympathectomy and sympatho-inhibitory drugs, and resistant to blockade by ritanserin and MDL 72222, is mediated by stimulation of prejunctional 5-HT1-like receptors leading to an inhibitory action on carotid sympathetic nerves; these 5-HT1-like receptors are unrelated to either the 5-HT1A, 5-HT1B or 5-HT1C (now 5-HT2C) receptor subtypes. Inasmuch as 5-CT, 5-methoxytryptamine, sumatriptan and metergoline display high affinity, amongst other 5-HT binding sites, for the 5-HT1D subtype, in the present study we have used these drugs in an attempt to determine whether the above inhibitory prejunctional 5-HT1-like receptors correlate with the 5-HT1D subtype. 2. One-minute intracarotid (i.c.) infusions of 5-HT (0.3, 1, 3 and 10 micrograms), 5-CT (0.01, 0.03, 0.1 and 0.3 micrograms), 5-methoxytryptamine (1, 3, 10 and 30 micrograms) and sumatriptan (1, 3, 10, 30 and 100 micrograms) resulted in dose-dependent increases in external carotid blood flow (without changes in mean arterial blood pressure or heart rate) with the following rank order of agonist potency: 5-CT >> 5-HT > 5-methoxytryptamine > or = sumatriptan. Interestingly, sumatriptan-induced vasodilatation was followed by a more pronounced vasoconstriction. 3. The external carotid vasodilator effects of 5-HT, 5-CT, 5-methoxytryptamine and sumatriptan were dose-dependently and specifically antagonized by metergoline (10, 30 and/or 100 micrograms kg-1, i.v.). In addition, 5-methoxytryptamine- and sumatriptan-induced vasodilator effects were, respectively, markedly inhibited or abolished after vagosympathectomy, as previously shown for 5-CT and 5-HT.4. Sumatriptan showed tachyphylaxis in its vasodilator component and antagonized 5-HT-induced external carotid vasodilatation in a specific manner, suggesting that a common site of action may be involved.5. Taken together, the above results support our contention that 5-HT, 5-CT, 5-methoxytryptamine and sumatriptan produce external carotid vasodilatation in the dog by an action that might primarily involve a prejunctional inhibition on carotid sympathetic nerves; a secondary component of this vasodilator response may be postsynaptic (endothelium-dependent and/or even directly on the vasculature).Based on the rank order of agonist potency, inhibition by vagosympathectomy and blockade by metergoline, we suggest that the inhibitory prejunctional 5-HT1-like receptors mediating external carotid vasodilatation in the dog closely resemble the 5-HTID receptor subtype. The pharmacological profile of these receptors is similar (sympathetic nerves of the rat kidney and human saphenous vein, as well as porcine coronary endothelium) to other putative 5-HTID receptors mediating vascular responses.

Animals↗
PubMed2004

Analgesic triptan action in an animal model of intracranial pain: a race against the development of central sensitization.

We have shown that the development of cutaneous allodynia (exaggerated skin sensitivity) during migraine is detrimental to the anti-migraine action of the 5HT(IB/ID) receptor agonists known is triptans. Because cutaneous allodynia is a manifestation of sensitization of central trigeminovascular neurons, we examined whether triptan treatment can intercept such sensitization before its initiation or after its establishment in our rat model for cutaneous allodynia induced by intracranial pain. Single-unit recordings were obtained from spinal trigeminal neurons that proved to received convergent inputs from the dura and facial skin. The effects of sumatriptan (300 microg/kg i.v.) on central sensitization induced by topical application of inflammatory soup (IS) on the dura were determined when the drug was administered either 2 h after IS (late intervention) or at the same time as IS (early intervention). Late sumatriptan intervention counteracted two aspects of central sensitization: dural receptive fields, which initially expanded by IS, shrunk back after treatment; neuronal response threshold to dural indentation, which initially decreased after IS, increased after sumatriptan. On the other hand, late sumatriptan intervention did not reverse other aspects of central sensitization: spontaneous firing rate and neuronal response magnitude to skin brushing which initially increased after IS, remained elevated after sumatriptan; response threshold to heating of the skin, which initially dropped after IS, remained low after sumatriptan. Early sumatriptan intervention effectively blocked the development of all aspects of central sensitization expected to be induced 2 h after IS application: dural receptive fields did not expand; neuronal response threshold to dural indentation and skin stimulation did not decrease; spontaneous firing rate did not increase. The early treatment results suggest that triptan action provides a powerful means of preventing the initiation of central sensitization triggered by chemical stimulation of meningeal nociceptors. The late treatment results suggest that triptan action is insufficient to counteract an already established central sensitization. Thus, triptan action appears to be exerted directly on peripheral rather than central trigeminovascular neurons.

Animals↗
PubMed1999

Characterisation of the contractile activity of eletriptan at the canine vascular 5-HT1B receptor.

The functional activity of eletriptan ((R)-3-(1-methyl-2-pyrrolidinylmethyl)-5-[2-(phenylsulphonyl )ethyl]- 1 H-indole) at the contractile serotonin (5-hydroxytryptamine; 5-HT) '1B-like' receptor in dog isolated saphenous vein and basilar artery was investigated. Eletriptan, like 5-HT and sumatriptan potently contracted saphenous vein (pEC50: 6.3, 6.9 and 6.1, respectively) and basilar artery (pEC50 7.2, 7.5 and 6.8, respectively). The maximum responses evoked by eletriptan was, unlike sumatriptan, significantly lower than that to 5-HT (intrinsic activity saphenous vein: eletriptan 0.57, 5-HT 1.0, sumatriptan 0.85; basilar artery: eletriptan 0.77, 5-HT 0.98, sumatriptan 0.89). Contractions evoked by eletriptan were antagonised by the 5-HT1B/1D receptor antagonist GR125743 (N-[4-methoxy-3-(4-methyl piperazin-1-yl)phenyl]-3-methyl-4-(4-pyridyl)benzamide) with pA2 values of 9.1 in saphenous vein and 9.4 in basilar artery. Affinity estimates (pKA) for 5-HT and sumatriptan determined from receptor alkylation studies in saphenous vein were 6.6 and 6.3, respectively, compared to the apparent equilibrium dissociation constant (pKp) for eletriptan of 6.8. The rank order of relative intrinsic efficacies (epsilon) was 5-HT > sumatriptan > eletriptan. Thus, eletriptan required greater receptor occupancy (4.4-fold) to evoke an equivalent contraction to 5-HT and sumatriptan in dog isolated saphenous vein. These data demonstrate that eletriptan is a potent partial agonist at the canine vascular 5-HT1B receptor.

Alkylation↗
PubMed1999

Vasoconstriction in human isolated middle meningeal arteries: determining the contribution of 5-HT1B- and 5-HT1F-receptor activation.

AIMS: Sumatriptan is a 5-HT1B/1D-receptor agonist which also has affinity for 5-HT1F-receptors. The vasoconstrictor effects of sumatriptan are thought to be 5-HT1B-receptor mediated and these receptors have been shown to be expressed in human cranial blood vessels. However, in the same tissue mRNA coding for 5-HT1F-receptors has also been identified and this study addresses the possibility of whether 5-HT1F-receptor activation contributes to vasoconstriction. METHODS: The ability of two selective 5-HT1B/1D-receptor antagonists (GR125,743 and GR127,935) with no affinity for 5-HT1F-receptors, to inhibit sumatriptan evoked contractions in human isolated middle meningeal artery was investigated. Using a series of 5-HT1B/1D-receptor agonists (sumatriptan, zolmitriptan, CP122,288, L-741,519 and L-741,604), some with high affinity for 5-HTIF-receptors and the non-selective 5-HT-receptor agonists 5-HT and 5-CT, we compared the vasoconstrictor potency of these drugs in human isolated middle meningeal artery with their affinities at cloned human 5-HT1B-, 5-HT1D-and 5-HT1F-receptors expressed in CHO cell lines. RESULTS: GR125,743 antagonized sumatriptan evoked contractions in a competitive manner (apparent pA2 9.1) and GR127,935 antagonized sumatriptan-induced responses in a non-competitive manner (reducing the maximum contraction to 27%). There was a significant correlation between vasoconstrictor potency and 5-HT1B-receptor affinity (r=0.93, P=0.002) but not with 5-HT1D- or 5-HT1F-receptor affinity (r=0.74, P=0.06; r= 0.31, P= 0.49, respectively). CONCLUSIONS: These experiments show that in human middle meningeal artery vasoconstriction to sumatriptan-like agents is 5-HT1B-receptor mediated with little if any contribution from 5-HT1F-receptor activation.

Animals↗