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PubMed1996

Evidence for receptor subtype cross-talk in the mitogenic action of serotonin on human small-cell lung carcinoma cells.

We previously reported a significant mitogenic effect of serotonin (5-hydroxytryptamine, 5-HT) on human small-cell lung carcinoma cells (SCLC, GLC-8), mediated by both 5-HT1D and 5-HT1A receptors. Here we investigate possible interactions between the two receptor subtypes. Dose-effect curves obtained by simultaneously applying equipotent concentrations of the selective 5-HT1A agonist 8-OH-DPAT and the selective 5-HT1D receptor agonist sumatriptan are shifted to the right, although maximal effects are additive. The nonselective 5-HT antagonist metergoline displays higher potency when both receptor subtypes are activated. The 5-HT1D receptor antagonist GR127935 is markedly more potent against sumatriptan than against the sensitive portion of 5-HT effect. Indeed, both GR127935 and the 5-HT1A antagonist spiperone shift the EC50 for the residual effect of 5-HT from approximately 300 to 120-150 nM, suggesting that blocking one receptor subtype may facilitate activation of the other. Preincubation with either 8-OH-DPAT or sumatriptan suppresses the mitogenic response to the other specific receptor agonist; suppression is complete within 10 min at 37 degrees C, and is not observed when the preincubation is done at 4 degrees C. Measurements of adenylate cyclase activity do not help in interpreting the results. Conversely, measurements of MAP kinase activity reveals biphasic activation with a delayed activation at 1 h, and reproduce the suppression of the effect of the second drug by 15 min preincubation. These findings constitute the first evidence of a reciprocal negative interference between human 5-HT1A and 5-HT1D receptors, and indicate that SCLC GLC-8 cells simultaneously express both receptor subtypes. Mere reciprocal antagonism of the drugs employed cannot account for these data. We suggest that in this cell system cross-talk occurs in the transduction pathways of the two receptor subtypes.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1998

The role of central 5-HT receptors in the bronchoconstriction evoked by inhaled capsaicin in anaesthetised guinea-pigs.

The effects of intracisternal (i.c) injections of the 5-HT1A receptor agonists, buspirone and 8-OH-DPAT, and the antagonists WAY-100635; and (-)-pindolol, the 5-HT1B/1D receptor agonist sumatriptan and antagonist GR127935, the 5-HT2 receptor agonist DOI and the antagonist cinanserin, the 5-HT3 receptor antagonist granisetron, the alpha-adrenoceptor agonist clonidine and the antagonist idazoxan, the D2 receptor antagonists (-)-sulpiride and the 5-HT uptake inhibitor fluoxetine on capsaicin-evoked increase in tracheal inflation pressure (bronchoconstriction) were investigated in alpha-chloralose anaesthetised, neuromuscularly blocked, artificially ventilated guinea-pigs. Buspirone, 8-OH-DPAT and fluoxetine significantly potentiated while WAY-100635 (-)-pindolol and sumatriptan attenuated the evoked bronchoconstriction when applied i.c. Granisetron attenuated the response when applied i.v. but not when given i.c. The 5-HT2, alpha2-adrenoceptor and D2 dopamine receptor ligands did not have any significant effect on the evoked bronchoconstriction. Pretreatment i.v. with WAY-100635 alone had no effect on the capsaicin-evoked bronchoconstriction but blocked the potentiating action of i.c. buspirone. The effects of sumatriptan could be completely blocked by pretreatment i.v. with GR127935. Only DOI, in the presence (i.v.) of the peripheral acting 5-HT2 receptor antagonist BW501C67, caused a significant increase in baseline tracheal inflation pressure. It is concluded that activation of central 5-HT1A and 5-HT1B/1D receptors have opposing roles, facilitation and inhibition respectively, on the reflex activation of bronchoconstrictor vagal preganglionic neurones.

Administration, Inhalation↗
PubMed1999

Symptomatic pharmacotherapy of migraine.

This review summarizes data on the effectiveness of various symptomatic migraine pharmacotherapies and makes recommendations for treatment. A wide variety of agents are available for the symptomatic treatment of migraine headache, including over-the-counter analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), combination products, opiates, ergot alkaloids, corticosteroids, dopamine antagonists, and triptans. In the stepped-care approach, simple analgesics and NSAIDs are the recommended first step for the treatment of mild-to-moderate migraine headaches. Patients who do not respond to first-step treatments may be given ergots, combination products, dopamine antagonists, or triptans as the second step. Corticosteroids or opiates may be used as rescue treatment in patients who do not respond to second-step treatment. A stratified approach to care individualizes treatment based on the severity of the headache and other patient-specific factors. In a stratified approach, dihydroergotamine or triptans may be the first-step treatment for patients who present with a history of severe migraines that have responded poorly to previous treatments. Sumatriptan was the first triptan approved for the symptomatic treatment of migraine headache; newer triptans include zolmitriptan, naratriptan, and rizatriptan. Since sumatriptan is rapidly absorbed by the subcutaneous route, its time to onset of effect is shortest. Among triptan drugs that are administered orally, the relative time to onset may be shorter with rizatriptan than sumatriptan. Naratriptan has a longer time to onset but is associated with a lower rate of migraine recurrence than other triptans. graine headache, ergot alkaloids, triptans,

Clinical Trials as Topic↗
PubMed2002

Use of rescue medication in trials of almotriptan versus placebo in the treatment of acute migraine.

BACKGROUND: Almotriptan malate is a recently marketed triptan for the treatment of acute migraine. Results from controlled clinical trials demonstrate efficacy superior to placebo and an adverse event rate comparable to that with placebo. OBJECTIVE: The goal of this study was to assess the effect of oral almotriptan on the use of rescue medication in the treatment of acute migraine attacks. METHODS: Three Phase II and III, placebo-controlled, randomized, double-blind studies of almotriptan used as the basis for regulatory approval of the drug were included in the analysis. Two studies (1 single dose, 1 multiple dose) assessed almotriptan 6.25 mg and 12.5 mg and a third compared almotriptan 12.5 mg and sumatriptan 100 mg. Primary results from all 3 trials were previously published. Rescue medication was permitted if migraine pain had not decreased to mild severity or to no pain at 2 hours after study medication. The primary end point of this analysis was use of rescue medication. RESULTS: A total of 1777 patients were included in the analysis. Mean patient age ranged from 39.4 to 44.0 years; approximately 87% were women, and >98% were white. Patients were well matched for demographic characteristics. Overall, use of rescue medication was significantly lower with almotriptan 6.25 mg and 12.5 mg compared with placebo (P < or = 0.05 for each group). No significant difference was noted between the almotriptan 12.5-mg and sumatriptan 100-mg groups. In 2 of the studies, patients with moderate or severe baseline pain used significantly less rescue medication in the almotriptan groups compared with placebo. CONCLUSIONS: Oral almotriptan 6.25 mg or 12.5 mg significantly reduced use of rescue medication compared with placebo among patients with acute migraine. Use of rescue medication was comparable with almotriptan 12.5 mg and sumatriptan 100 mg.

Acute Disease↗
PubMed2003

A review of the effects of almotriptan and other triptans on clinical trial outcomes that are meaningful to patients with migraine.

BACKGROUND: Traditional end points in clinical trials of migraine therapy, such as 2-hour pain response, may not fully address the outcomes patients consider most important: rapid and sustained freedom from pain over 24 hours, and a low, placebo-like incidence of adverse events. A composite efficacy measure such as the sustained pain-free rate (no pain by 2 hours after dosing, no recurrence, no use of rescue medication from 2 to 24 hours after dosing) may be more appropriate. OBJECTIVE: Clinically relevant differences between almotriptan and other triptans were reviewed in the context of the attributes of acute migraine treatment that patients consider most important. METHODS: This review was based on published reports of open-label and placebo-controlled clinical trials of almotriptan, results of a survey concerning the attributes patients consider most important in a migraine medication, and a published meta-analysis of 53 placebo-controlled clinical trials of triptans involving >24,000 patients. RESULTS: Almotriptan was effective and well tolerated in the placebo-controlled clinical trials; results of the 6- and 12-month open-label studies supported its good tolerability profile. A respective 87% and 86% of respondents to the patient survey indicated that they considered complete freedom from pain and no recurrence among the most important attributes of migraine treatment, both of which are included in the sustained pain-free rate. In the meta-analysis, almotriptan had a favorable efficacy and tolerability profile compared with other triptans, particularly with respect to sustained pain-free rate, which was significantly higher with almotriptan 12.5 mg compared with sumatriptan 100 mg (25.9% vs 20.0%, respectively; P < 0.05). In addition, the placebo-subtracted rate of adverse events was significantly lower with almotriptan compared with sumatriptan (1.8% vs 4.4%, respectively; P < 0.05). Results of a head-to-head placebo-controlled trial of almotriptan 12.5 mg and sumatriptan 100 mg supported the balance of efficacy and tolerability observed for almotriptan in the meta-analysis. CONCLUSIONS: Data from clinical trials suggest that almotriptan is effective and well tolerated in the treatment of acute migraine pain. Based on a sustained pain-free rate that is among the highest and an adverse-event rate that is among the lowest for the triptans, almotriptan represents a therapeutic option for the initial treatment of acute migraine with or without aura.

Clinical Trials as Topic↗
PubMed2002

Pharmacological treatments for acute migraine: quantitative systematic review.

We wanted to compare the analgesic efficacy and adverse effects of pharmacological treatments for acute migraine through a systematic review of randomised controlled trials in patients with acute migraine pain of moderate to severe intensity. Trials were identified from systematic searching of bibliographic databases. For eletriptan information from all trials was supplied by Pfizer Inc. Outcomes sought were headache relief at 1 and 2h, patients pain free at 2h and sustained relief over 24h for treatments compared with placebo. Numbers-needed-to-treat (NNTs) were calculated, together with relative benefit. Information on adverse effects was also collected. Comparisons of relative efficacy used the same definition of headache, the same degree of pain at the start of treatment and the same definitions of outcomes, and always compared with placebo. Forty-eight publications reporting on 54 trials were included in the meta-analyses, with 79 placebo comparisons for the primary outcome of headache relief at 2h. Information on any outcome was available for nine oral medications, two intranasal medications and subcutaneous sumatriptan in 21,022 patients. For headache relief at 2h NNTs ranged from 2.0 for subcutaneous sumatriptan 6mg to 5.4 for naratriptan 2.5mg. For patients pain free at 2h NNTs ranged from 2.1 for subcutaneous sumatriptan 6mg to 8.6 for aspirin 900mg plus metoclopramide 10mg. For sustained relief over 24h NNTs ranged from 2.8 for eletriptan 80mg to 8.3 for rizatriptan 5mg. It was not possible to systematically review adverse effects data. Most interventions are effective. There is considerable information on relative efficacy for a number of outcomes.

Acute Disease↗
PubMed1998

Glutamate release in human cerebral cortex and its modulation by 5-hydroxytryptamine acting at h 5-HT1D receptors.

1. The release of glutamic acid and its modulation by 5-hydroxytryptamine (5-HT) in the human brain has been investigated in synaptosomal preparations from fresh neocortical samples obtained from patients undergoing neurosurgery to reach deeply sited tumours. 2. The Ca2+-dependent K+ (15 mM)-evoked overflow of glutamate was inhibited by 5-HT in a concentration-dependent manner (EC50 = 2.9 nM; maximal effect approximately 50%). The inhibition caused by 5-HT was antagonized by the 5-HT1/5-HT2 receptor antagonist methiothepin. The 5-HT1B/5-HT1D receptor agonist sumatriptan mimicked 5-HT (EC50 = 6.4 nM; maximal effect approximately 50%); the effect of sumatriptan was also methiothepin-sensitive. Selective 5-HT1A receptor antagonists could not prevent the inhibition of glutamate release by 5-HT. 3. The 5-HT1B/5-HT1D receptor ligand GR 127935 and the 5-HT2C/5-HT1B/5-HT1D receptor ligand metergoline were unable to prevent the 5-HT effect; instead they inhibited glutamate release, their effects being abolished by methiothepin. Some 5-HT1A receptor antagonists also displayed intrinsic agonist activity. 4. The effect of sumatriptan was prevented by ketanserin, a drug known to display much higher affinity for recombinant h 5-HT1D than for h 5-HT1B receptors. 5. We propose that neocortical glutamatergic nerve terminals in human brain cortex possess release-inhibiting presynaptic heteroreceptors that appear to belong to the h 5-HT1D subtype.

Adult↗
PubMed1998

Characterization of 5-HT receptors mediating constriction of porcine carotid arteriovenous anastomoses; involvement of 5-HT1B/1D and novel receptors.

1. It was previously shown that porcine cranial arteriovenous anastomoses (AVAs) constrict to 5-hydroxytryptamine (5-HT), ergotamine, dihydroergotamine, as well as sumatriptan and that sumatriptan acts exclusively via 5-HT1B/1D receptors. The present study was devoted to establish the contribution of 5-HT1B/1D receptors in the constriction of AVAs elicited by 5-HT (in presence of 0.5 mg kg(-1) ketanserin), ergotamine and dihydroergotamine in anaesthetized pigs. 2. Intracarotid infusion of 5-HT (2 microg kg(-1) min(-1)) and intravenous doses of ergotamine (2.5-20 microg kg(-1)) and dihydroergotamine (3-100 microg kg(-1)) reduced AVA and increased nutrient blood flows and vascular conductances. The vasodilator response to 5-HT, observed mainly in the skin and ear, was much more prominent than that of the ergot alkaloids. 3. Treatment with the 5-HT1B/1D receptor antagonist GR127935 (0.5 mg kg(-1), i.v.) significantly attenuated both ergot-induced AVA constriction and arteriolar dilatation, whereas GR127935 only slightly affected the carotid vascular effects of 5-HT. 4. The results suggest that 5-HT constricts carotid AVAs primarily via receptors, which seem to differ from those (5-HT1B/1D) stimulated by sumatriptan. The ergot alkaloids produce AVA constriction for a substantial part via 5-HT1B/1D receptors, but also stimulate unidentified receptors. Both these non-5-HT1B/1D receptors may be targets for the development of novel antimigraine drugs. 5. The moderate vasodilator response to the ergot derivatives seems to be mediated, at least in part, by 5-HT1B/1D receptors, whereas the arteriolar dilatation caused by 5-HT may be mediated by other, possibly 5-HT7 receptors.

Animals↗
PubMed1998

5-hydroxytryptamine receptors mediating vasoconstriction and vasodilation in perinatal and adult rabbit small pulmonary arteries.

1. Vasoconstrictor responses to 5-HT, 5-carboxamidotryptamine (5-CT, 5-HT1 receptor agonist), alpha-methyl-5-HT (5-HT2 receptor agonist) and sumatriptan (5-HT1D/1B receptor agonist) were studied in fetal, 0-24 h, 4 day, 7 day and adult rabbit pulmonary resistance arteries (PRAs), alone and in the presence of the NO synthase inhibitor Nomega-nitro-L-arginine methylester (L-NAME). The effect of the selective 5-HT receptor antagonists ketanserin (5-HT2A receptor) and GR55562 (5-HT1B/1D receptor) on vasoconstrictor responses to 5-HT were studied in the presence of L-NAME. Vasodilator responses to 5-CT were also studied in pre-contracted PRAs. 3. 5-HT and alpha-methyl-5-HT were equipotent in causing contraction in the PRAs at each age (e.g. pEC50s for 5-HT and alpha-methyl-5-HT were 6.74+/-0.13 and 6.63+/-0.22 respectively in adult vessels). In the perinatal PRAs, sumatriptan and 5-CT produced negligible contractions, but in adult PRAs, 5-CT and sumatriptan were potent agonists with pEC50s of 6.05+/-0.3 and 5.70+/-0.20 respectively. 4. L-NAME markedly increased the maximum response to 5-HT in the 0-24 h, 4 day and 7 day vessels and increased 5-HT potency in the 4-, 7-day-old and adult rabbit vessels. 5. In perinatal vessels, responses to 5-HT, with L-NAME present, were antagonized by ketanserin (30 nM and 0.1 microM) but not GR55562 (1 microM). A small ketanserin-resistant, GR55562-sensitive component was observed at 0-24 h. In adult vessels, both ketanserin and GR55562 inhibited 5-HT-induced responses. 7. Vasodilator responses to 5-CT were observed in pre-contracted PRAs from 4- and 7-day-old rabbits but not in the fetus, 0-24 h old or adult rabbit vessels. At 4 days the vasodilator response was inhibited both by L-NAME and GR55562. At 7 days the response was only partly blocked by L-NAME and resistant to GR55562. The L-NAME resistant component was antagonized by the 5-HT7 receptor antagonist spiperone (1 microM). 8. The results suggest that 5-HT2A-receptors mediate vasoconstriction in perinatal vessels whilst the 5-HT1D or 5-HT1B receptor contributes in adult rabbit vessels. The 5-HT1D or 5-HT1B receptor mediates NO-dependent vasodilation in vessels from rabbits at 4 days of age whilst 5-HT7 receptors mediate NO-independent vasodilation by 7 days.

Animals↗
PubMed1999

Trigeminal nerve ganglion stimulation-induced neurovascular reflexes in the anaesthetized cat: role of endothelin(B) receptors in carotid vasodilatation.

1. The effects of intravenous administration of endothelin (ET) receptor antagonists SB-209670 (0.001-10.0 mg kg(-1)), SB-217242, SB-234551 (0.01-10.0 mg kg(-1)) and BQ-788 (0.001-1.0 mg kg(-1)) were investigated on trigeminal nerve ganglion stimulation-induced neurovascular reflexes in the carotid vasculature of the anaesthetized cat. Comparisons were made with sumatriptan (0.003-3.0 mg kg(-1)) and alpha-CGRP8-37 (0.001-0.1 mg kg(-1)). 2. Trigeminal nerve ganglion stimulation produced frequency related increases in carotid blood flow, reductions in carotid vascular resistance and non-frequency related increases in blood pressure. Guanethidine (3 mg kg(-1), i.v.) blocked trigeminal nerve ganglion-induced increases in blood pressure but had no effect on changes in carotid flow or resistance. Maximal reductions in carotid vascular resistance was observed at 10 Hz, and this frequency was selected to investigate the effects of drugs on trigeminal nerve ganglion stimulation-induced responses in guanethidine treated cats. 3. Saline, alpha-CGRP8-37 SB-209670 and BQ-788 had little or no effect on resting haemodynamic parameters. SB-217242 (10 mg kg(-1), n=3) produced a 56% reduction in arterial blood pressure whereas SB-233451 (10 mg kg(-1), n=3) produced a 30% reduction in carotid vascular resistance. Sumatriptan produced dose-related reductions in resting carotid flow and increases (max. 104% at 0.3 mg kg(-1), n = 5) in vascular resistance. 4. SB-209670 (n=6-7), SB-217242 (n=3) and BQ-788 (n=3) produced inhibition of trigeminal nerve ganglion stimulation-induced reductions in carotid vascular resistance. Saline, SB-234551, alpha-CGRP8-37 and sumatriptan had no effect. 5. These data demonstrate ET(B) receptor blockade attenuates the vasodilator effects of trigeminal nerve ganglion stimulation in the carotid vascular bed of guanethidine pretreated anaesthetized cats.

Anesthesia↗
PubMed1997

Intensity dependence of the cortical auditory evoked potentials as a surrogate marker of central nervous system serotonin transmission in man: demonstration of a central effect for the 5HT1B/1D agonist zolmitriptan (311C90, Zomig).

As shown in animal studies, 5HT1B/D agonists can inhibit activity in the trigeminal nucleus caudalis, which may be advantageous for their antimigraine effect. To demonstrate a possible central nervous system (CNS) action of these compounds in man we studied their effect on the intensity dependence of the cortical auditory evoked potentials (IDAPs), thought to be inversely related to central serotonergic transmission. An amplitude/stimulus intensity function (ASF) slope was computed in healthy volunteers and migraine patients between attacks before and 2 h after oral 311C90 (zolmitriptan "Zomig") 10 mg (n=14), 311C90 5 mg (n=7), sumatriptan 100 mg (n=14), dexfenfluramine 15 mg (n=4), lorazepam 1.25 mg (n=4) and placebo (n=14). 311C90 10 mg and, to a lesser degree, 5 mg significantly increased the mean ASF slope (p=0.007 and 0.05 vs placebo). There was a significant positive correlation between plasma levels of 311C90 and ASF slope changes. Sumatriptan and lorazepam had little effect, but dexfenfluramine produced a significant ASF slope decrease. 311C90 is able to modify a CNS activity that is modulated by serotonin, i.e. the IDAP. This effect is probably the consequence of its superior lipophilicity compared to sumatriptan and of activation of prejunctional 5HT1B/D autoreceptors, which lowers central serotonin release and thus the preactivation level of sensory cortices.

Adult↗
PubMed2003

5-HT(1B/1D) serotonin receptor agonist attenuates nitroglycerin-evoked nitric oxide synthase expression in trigeminal pathway.

This study was conducted to investigate the effect of 5-HT(1B/1D) receptor activation on nitroglycerin (NTG)-induced cerebral hyperaemia and neuronal nitric oxide synthase (nNOS) expression in trigeminovascular neurones. NTG (10 mg/kg) was infused intravenously to adult male Wistar rats with or without pretreatment with 5-HT(1B/1D) receptor agonist, sumatriptan (0.4 mg/kg, intravenously). Cortical blood flow and expression of nNOS enzyme in trigeminal ganglia, trigeminal nucleus caudalis and perivascular nerve fibre surrounding superior sagittal sinus were measured. The results showed that pretreatment with sumatriptan could significantly shorten the period of NTG-induced cerebral hyperaemia without compromising the magnitude of hyperaemic peak. Sumatriptan pretreatment also attenuated the NTG-evoked expression of nNOS in all studied areas. Based on these findings, we suggest that 5-HT(1B/1D) receptor has an important role in stabilizing the trigeminovascular system by attenuating the expression of nNOS enzyme, hence reducing nitric oxide production.

Animals↗
PubMed2002

Efficacy and safety of almotriptan malate for migraine.

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of almotriptan are reviewed. Migraine is a common disorder with a serious impact on quality of life. Newer serotonin-receptor agonists have been developed with the aim of improving pharmacokinetic characteristics. Almotriptan, a selective agonist of serotonin receptors 1B and 1D, carries FDA-approved labeling for use in the management of migraine with or without aura in adults. The efficacy and receptor affinity resemble those of sumatriptan, but almotriptan has a more favorable pharmacokinetic profile. It has a rapid onset of action, an oral bioavailability of 70-80%, and a longer half-life than sumatriptan. In clinical trials, almotriptan has been significantly more effective than placebo and as effective as sumatriptan. However, it has been associated with better tolerability and greater patient satisfaction. In clinical trials, the most commonly reported adverse effects were nausea, dry mouth, dizziness, somnolence, fatigue, vomiting, and paresthesia. Almotriptan is contraindicated in patients with known ischemic heart disease, coronary vasospasm, and other significant cardiovascular disorders. Almotriptan has a lower acquisition cost than other triptans and possibly lower overall health care costs because of a lower frequency of cardiovascular adverse effects. The recommended dose of almotriptan is one 6.25- or 12.5-mg tablet given at the onset of symptoms. Almotriptan is effective for the management of migraine and offers the potential for fewer adverse effects than other agents in its class.

Biological Availability↗
PubMed1994

Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies.

Cluster headache is a rare very severe disorder that is clinically well characterized with a relatively poorly understood pathophysiology. In this study patients with episodic cluster headache fulfilling the criteria of the International Headache Society were examined during an acute spontaneous attack of headache to determine the local cranial release of neuropeptides. Blood was sampled from the external jugular vein ipsilateral to the pain before and after treatment of the attack. Samples were assayed for calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP), substance P and neuropeptide Y. Attacks were treated with either oxygen inhalation, sumatriptan or an opiate. Thirteen patients were studied of whom 10 were male and three female. All had well-established typical attacks of cluster headache when blood was sampled. During the attacks external jugular vein blood levels of CGRP and VIP were raised while there was no change in neuropeptide Y or substance P. Calcitonin gene-related peptide levels rose to 110 +/- 7 pmol/l (normal: < 40) while VIP levels rose to 20 +/- 3 pmol/l (normal: < 7). Treatment with both oxygen and subcutaneous sumatriptan reduced the CGRP level to normal, while opiate administration did not alter the peptide levels. These data demonstrate for the first time in vivo human evidence for activation of the trigeminovascular system and the cranial parasympathetic nervous system in an acute attack of cluster headache. Furthermore, it is shown that both oxygen and sumatriptan abort the attacks and terminate activity in the trigeminovascular system.

Adult↗
PubMed1997

5-Hydroxytryptamine contracts human uterine artery smooth muscle predominantly via 5-HT2 receptors.

Serotonergic receptors were classified in the isolated human uterine artery with intact endothelium, using agonists and antagonists for 5-hydroxytryptamine (5-HT) receptors. The efficacy for different agonists rated: alpha-methyl-5-HT (5-HT2) = 5-HT (non-selective) = 2-methyl-5-HT (5-HT3) >> sumatriptan (5-HT1), and the potency as: sumatriptan = 5-HT > 5-HT > alpha-methyl-5-HT > 2-methyl-5-HT. The contractile effects of 5-HT and alpha-methyl-5-HT were antagonized by the 5-HT2 receptor antagonist ketanserin and the non-selective antagonist methiothepin. The efficacy of sumatriptan was comparatively low. No interaction was encountered between 2-methyl-5-HT and MDL72222, suggesting an absence of 5-HT3 receptors. The results indicate that the contractile serotonergic receptor population in the human uterine artery mainly comprises 5-HT2 receptors, although a minor contribution of contractile 5-HT1 receptors cannot be excluded.

Dose-Response Relationship, Drug↗
PubMedDate not supplied

Effect of hyperoxia on neurogenic plasma protein extravasation in the rat dura mater.

OBJECTIVE: We aimed to study the effect of normobaric hyperoxia on neurogenic inflammation of the rat dura mater. BACKGROUND: Inhalation of 100% oxygen is a first-line therapy for the treatment of acute cluster headache (CH). However, the mechanisms underlying the antinociceptive effect of oxygen are poorly understood. Sumatriptan, which is also effective in aborting CH attacks, is known to inhibit neurogenic inflammation of the dura mater. We hypothesized that hyperoxia reduces dural plasma protein extravasation in the model of electrically stimulating the rat trigeminal ganglion. METHODS: Unilateral stimulation of the trigeminal ganglion was performed in anesthetized male Sprague-Dawley rats. We assessed plasma protein extravasation (PPE) in the ipsilateral dura mater under normoxic (group 1) and hyperoxic conditions (group 2: pO(2) 200 mmHg; group 3: pO(2) 300 mmHg; group 4: pO(2) 400 mmHg). The study results were compared to the effect of sumatriptan (300 microg/kg) on dural PPE. RESULTS: Under normoxic conditions, the calculated extravasation ratio was 1.72 +/- 0.2. Hyperoxic treatment (groups 2, 3, 4) significantly attenuated dural PPE. At oxygen levels of 400 mmHg, the PPE ratio was 1.14 +/- 0.2 (P < .01). After IV application of sumatriptan (300 microg/kg), PPE was nearly abolished (PPE ratio: 1.06 +/-0.17). CONCLUSION: Our findings demonstrate that hyperoxia is able to inhibit dural PPE. Hyperoxia may play an anti-inflammatory role in neurogenic inflammation, but further studies are needed to clarify whether this effect is either caused by prejunctional mechanisms or by modulation of the vascular permeability at postcapillary venules.

Animals↗
PubMed2002

The proximal stomach and postprandial symptoms in functional dyspeptics.

OBJECTIVES: It remains unclear whether postprandial symptom profiles in patients with visceral hypersensitivity and in those with impaired fundic accommodation differ. Therefore, we evaluated the postprandial symptoms in functional dyspepsia (FD) patients classified according to proximal stomach function. In addition, the effect of gastric relaxation induced by sumatriptan on postprandial symptoms was studied in FD patients with impaired fundic accommodation. METHODS: Twenty-five healthy volunteers (HVs) and 44 FD patients filled out a disease-specific questionnaire (Nepean Dyspepsia Index) and underwent a gastric barostat study to evaluate visceral sensitivity, meal-induced fundic relaxation, and postprandial symptoms. Postprandial symptoms evoked by a drink test or reported during the barostat study were compared between FD patients subdivided according to the underlying pathophysiological mechanism. Finally, the effect of sumatriptan on postprandial symptoms evoked by a drink test was investigated in HVs and in FD patients with impaired fundic accommodation. RESULTS: There was no clear relationship between any of the 15 Nepean Dyspepsia Index symptoms and proximal stomach function. Postprandial symptoms evoked during the barostat study or after the drink tests were significantly higher in FD patients than in HVs; however, no clear differences in symptom profile could be demonstrated between the different subclasses of FD. Sumatriptan did not affect the maximal ingested volume or the postprandial symptoms in HVs or FD patients after a drink test. CONCLUSIONS: No clear relationship could be demonstrated between postprandial symptoms and proximal stomach function.

Adult↗
PubMed1997

Pre-clinical pharmacology of zolmitriptan (Zomig; formerly 311C90), a centrally and peripherally acting 5HT1B/1D agonist for migraine.

Zolmitriptan (Zomig; formerly 311C90) is a novel 5-hydroxytryptamine (5HT)1B/1D receptor agonist with proven efficacy in the acute treatment of migraine with or without preceding aura. The drug differs from presently available members of this drug class in that it combines 5HT1B/1D receptor partial agonist activity with robust oral pharmacokinetics and an ability to inhibit trigeminovascular activation centrally as well as peripherally in preclinical studies. Consistent with its selectivity for 5HT1B/1D receptors, zolmitriptan produces constriction of various isolated blood vessels, most notably cranial arteries. In anaesthetized animals, these vascular effects manifest as a selective constriction of cranial arterio-venous anastomoses resulting in a redistribution of carotid arterial blood flow. This effect is produced without significant effects on heart rate, blood pressure or blood flow to the brain, heart or lungs. Zolmitriptan also inhibits trigeminal-evoked increases in cerebral blood flow in anaesthetized cats and blocks trigeminal-evoked plasma protein extravasation in the dura of guinea-pigs. These actions are consistent with a pre-junctional inhibition of neuropeptide release from perivascular afferents of the trigeminal nerve, as confirmed by independent studies showing that zolmitriptan blocks elevations of calcitonin-gene-related peptide in jugular venous blood during electrical stimulation of the trigeminal ganglion. In all of these effects, zolmitriptan is three to four times more potent than sumatriptan, but produces the same maximum response. Zolmitriptan crosses the intact blood-brain barrier to inhibit trigeminovascular activation in the brainstem. This was shown initially by the ability of the drug to block a brainstem reflex provoking vasoactive intestinal peptide release from the VIIth cranial (facial) nerve during trigeminal stimulation. Subsequent ex vivo autoradiography confirmed that intravenously injected [3H]zolmitriptan labels a discrete population of cells in the trigeminal nucleus caudalis (TNC) and nucleus tractus solitarius. Direct evidence for a central neuromodulatory effect of zolmitriptan was provided by electrophysiological experiments which clearly demonstrated that the drug inhibits the excitability of cells in the TNC after systemic administration. This novel pre-clinical profile not only distinguishes zolmitriptan from sumatriptan, but raises intriguing questions about the clinical relevance of a dual action. Studies to date show that zolmitriptan indeed modulates cranial sensory processing in humans, yet central side-effects are no different from sumatriptan. This property may account for the remarkable consistency in clinical efficacy observed in clinical trials.

Administration, Oral↗