Preclinical studies characterizing the anti-migraine and cardiovascular effects of the selective 5-HT1D receptor agonist PNU-142633

The present study describes the preclinical pharmacology of a highly selective 5-HT1D receptor agonist PNU-142633. PNU-142633 binds with a Ki of 6 nm at the human 5-HT1D receptor and a Ki of> 18 000 nm at the human 5-HT1B receptor. The intrinsic activity of PNU-142633 at the human 5-HT1D receptor was determined to be 70% that of 5-HT in a cytosensor cell-based assay compared with 84% for that of sumatriptan. PNU-142633 was equally effective as sumatriptan and a half-log more potent than sumatriptan in preventing plasma protein extravasation induced by electrical stimulation of the trigeminal ganglion. Like sumatriptan, PNU-142633 reduced the increase in cat nucleus trigeminal caudalis blood flow elicited by electrical stimulation of the trigeminal ganglion compared with the vehicle control. The direct vasoconstrictor potential of PNU-142633 was evaluated in vascular beds. Sumatriptan increased vascular resistance in carotid, meningeal and coronary arteries while PNU-142633 failed to alter resistance in these vascular beds. These data are discussed in relation to the clinical findings of PNU-142633 in a phase II acute migraine study.     

Decreased sensitivity of 5-HT1D receptors in chronic tension-type headache

OBJECTIVE: To assess the sensitivity of 5-HT1D receptors in chronic tension-type headache using sumatriptan as a pharmacological probe. BACKGROUND: Previous studies have suggested involvement of serotonergic systems in chronic tension-type headache (CTTH), but relevant experimental data are limited. Sumatriptan, a 5-HT1B/1D receptor agonist, stimulates the release of growth hormone (GH) and inhibits the release of ACTH, cortisol, and prolactin. These effects may be used to explore the function of serotonergic systems in vivo. METHODS: We measured GH, ACTH, cortisol and prolactin (PRL) plasma concentrations in 15 patients with chronic tension-type headache and in 18 healthy controls after subcutaneous administration of sumatriptan (6 mg) or placebo. RESULTS: Placebo administration had no effect on hormone concentrations. GH and PRL secretion after sumatriptan administration was significantly (P<0.01 and <0.05) altered in CTTH patients in comparison with controls. CONCLUSION: Our results suggest that cerebral serotonergic functions mediated by 5-HT1D receptors are altered in CTTH.     

Subcutaneous Sumatriptan in the Acute Treatment of Migraine in Patients Using Dihydroergotamine as Prophylaxis

SYNOPSIS
The efficacy of sumatriptan, a 5-HT 1 receptor agonist, in patients with migraine attacks occurring despite prophylactic treatment with oral dihydroergotamine, was assessed in a double-blind placebo-controlled study involving 76 patients. Thirty-seven patients were treated with a subcutaneous injection of 6 mg sumatriptan self-administered with an auto-injector and 39 with placebo given by the same route. Patients having inadequate relief were allowed to use a second injection of test medication I hour later and rescue treatment between 2 hours and 24 hours after the first dose. Headache relief was achieved within 2 hours after sumatriptan in 26 patients (70%) compared to 8 patients (21%) in the placebo group (P<0.0001). Of these patients, 19 (51%) and 3 (8%) were, respectively, pain free at this time. A second injection of sumatriptan was used by 8 (22%) patients compared to 30 (77%) patients in the placebo group (P<0.0001), whereas rescue medication was used respectively by 13 (35%) and 22 (58%) patients (P < 0.024). The adverse event profile of sumatriptan was not affected by the concomitant use of dihydroergotamine and side-effects were all minor and transient. Patient satisfaction was significantly higher in the sumatriptan group (75%) compared to patient satisfaction with placebo (16%). These results show that the high efficacy rate of subcutaneous sumatriptan and its safety profile remain unchanged in migraine patients receiving oral dihydroergotamine as pro-phylaxis.     

The phe-124-Cys and A-161T variants of the human 5-HT1B receptor gene are not major determinants of the clinical response to sumatriptan

BACKGROUND: The 5-HT(1B/1D) receptor agonist sumatriptan is highly effective in the treatment of migraine. However, some patients do not respond to sumatriptan or experience recurrence of the headache after initial relief. In addition, some patients report chest symptoms after the use of sumatriptan. OBJECTIVE: To assess whether 2 genetic variants (F124C changing a phenylalanine for a cysteine and polymorphism A/T at nucleotide position -161 in the 5' regulatory region) of the 5-HT(1B) receptor play a major role in the therapeutic response to sumatriptan. The 5-HT(1B) receptor most likely mediates the therapeutic action and coronary side effects of sumatriptan, and both F124C and A-161T have relevant functional consequences on either the affinity of sumatriptan to bind to the 5-HT(1B) receptor or on receptor expression level itself, respectively. METHOD: Genomic DNA of a relatively small but very well-characterized set of migraine patients with consistently good response to sumatriptan (n = 14), with no response (n = 12), with recurrence of the headache (n = 12), with chest symptoms (n = 13), and patients without chest symptoms (n = 27) was available for the genetic analyses and screened for the F124C variant and the A-161T polymorphism in the human 5-HT(1B) receptor gene. RESULTS: F124C was not detected in any of the patients studied. In addition, we did not observe drastic changes in allele frequencies of the A-161T polymorphism that might hint to a causal relation with the therapeutic effect of sumatriptan. CONCLUSION: We have not obtained any evidence that variants F124C and A-161T of the 5-HT(1B) receptor are major determinants in the clinical response to sumatriptan.     

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.     

Subcutaneous Sumatriptan in the Treatment of Headache During Withdrawal From Drug-Induced Headache

In a pilot study (5 patients) we investigated the effects of subcutaneous sumatriptan, a 5-HT1-like receptor agonist, on headache experienced during the withdrawal period of drug-induced headache. The pilot study indicated that the substance was effective mostly in patients who originally suffered from migraine. In a patient with tension headache the substance was less effective. In a second double-blind study on six migraine patients with severe drug-induced headache, the drug was highly effective in ameliorating headache and autonomic disturbances. Blood flow velocities measured in extracranial parts of internal and external carotid arteries by duplex-sonography and in middle cerebral and basilar arteries by transcranial Doppler showed no changes after administration of sumatriptan or placebo. This result suggests sumatriptan does not act primarily via constriction of the large cerebral arteries.     

Oral and subcutaneous sumatriptan in the acute treatment of migraine: an open randomized cress-over study

In an open, randomized cross-over study in 124 patients, we compared the efficacy, safety and patient preference of oral and subcutaneous sum triptan in the acute treatment of migraine. Patients were treated for 3 attacks or 3 months and then crossed over. Primary clinical efficacy was defined as a reduction in headache severity on a four-point self-rating scale from severe (3) or moderate (2) to mild (1) or none (0), or mild (1) to none (0). Efficacy was evaluated 2 h after the administration of subcutaneous and 4h after the administration of oral sumatriptan. Subcutaneous sumatriptan was significantly more effective than oral sumatriptan in relieving headache (over all three attacks 78% vs 61% improvement), improving clinical disability (55% vs 41 % improvement) and relieving nausea (69% vs 53%), vomiting (72% vs 32%) and phono- or photophobia (67% vs 49%). Median time to recurrence was shorter after subcutaneous (12.5 h) than after oral sumatriptan (18 h); the number of patients experiencing a recurrence was similar Patients reported more adverse events after subcutaneous sumatriptan (1.32 per attack) than after the oral form (0.85 per attack), but all adverse events were mild to moderate in intensity and of short duration. Patient opinion was more often positive after subcutaneous sumatriptan. These results may be useful in counselling patients to choose between the available marketed formulations of sumatriptan.     

牛痘疫苗致炎兔皮提取物治疗三叉神经痛的作用机制研究

目的:观察牛痘疫苗致炎兔皮提取物(analgecine)对于三叉神经痛的效果及镇痛机制.方法:将大鼠制成单侧缩窄性三叉神经痛模型,在痛觉超敏期随机分为两组.牛痘疫苗致炎兔皮提取物组:腹腔内注入牛痘疫苗致炎兔皮提取物100u/kg;生理盐水组:腹腔内注入生理盐水10ml/kg.2周后,观察大鼠疼痛阚值(PT)变化及缩窄环区域神经组织的改变.结果:(1)术后2周,动物出现痛觉过敏,PT明显减低;牛痘疫苗致炎兔皮提取物组PT逐渐升高,与治疗前及生理盐水组相比存在显著差异性(P<0.01).(2)痛觉超敏期大量神经纤维肿胀变性、髓鞘脱失.2周后,生理盐水组髓鞘脱失明显,无髓纤维数目增多;牛痘疫苗致炎兔皮提取物组神经纤维肿胀消失,髓鞘板层结构致密,与正常结构类似.结论:动物实验表明,牛痘疫苗致炎兔皮提取物对于三叉神经痛的镇痛效果肯定,其作用机制部分是通过促进受损变性的神经纤维修复实现.     

Neurogenic dural protein extravasation induced by meta-chlorophenylpiperazine (mCPP) involves nitric oxide and 5-HT2B receptor activation

The compound m-chlorophenylpiperazine (mCPP), which is known to trigger migraine-like head pain in some subjects, was evaluated for its ability to induce dural plasma protein extravasation (PPE) in guinea pigs. Intravenous mCPP dose-dependently increased PPE. This effect was inhibited by non-selective 5-HT2 receptor antagonists (methysergide, LY53857, LY215840), by a peripherally restricted 5-HT2 receptor antagonist (xylamidine) and by a 5-HT2B selective receptor antagonist (LY202146). These data suggests that peripheral 5-HT2B receptors mediate mCPP-induced PPE. The nitric oxide synthase inhibitor L-NAME and 5-HT1 agonist sumatriptan also blocked mCPP-induced PPE, suggesting a role for nitric oxide (NO) and the trigeminal system, respectively. NO release has been linked to activation of the 5-HT2B receptor on the vascular endothelium. However, LY202146 did not block PPE induced by electrical stimulation of the trigeminal ganglion. These data are consistent with activation of peripheral 5-HT2B receptors initiating PPE and the theory that selective 5-HT2B antagonists might be effective prophylactic therapies for migraine.     

Continuous administration of the 5-hydroxytryptamine1A agonist (3-Chloro-4-fluoro-phenyl)-[4-fluoro-4-[[(5-methyl-pyridin-2-ylmethyl) -amino]-methyl]piperidin-1-yl]-methadone (F 13640) attenuates allodynia-like behavior in a rat model of trigeminal neuropathic pain

(3-Chloro-4-fluoro-phenyl)-[4-fluoro-4-[[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl]piperidin-1-yl]-methadone (F 13640) is a recently discovered high-efficacy 5-hydroxytryptamine (HT)1A receptor agonist that produces central analgesia through the neuroadaptive mechanisms of inverse tolerance and cooperation. In a rat model of trigeminal neuropathic pain, the chronic constriction injury of the infraorbital nerve causes allodynia-like behavior that develops within 2 weeks and remains stable thereafter. We report that early after surgery, during which time allodynia develops, the continuous 2-week infusion of 0.63 mg/day F 13640 inhibited the allodynia-like behavior, whereas 5 mg/day morphine showed no significant effect. When F 13640 infusion was initiated late after surgery, when allodynia was well established, it produced an antiallodynic effect that was apparent during the entire infusion period. In contrast, morphine infusion caused an initially marked antiallodynic effect to which tolerance developed within the 2-week infusion period. The GABA-B receptor agonist baclofen (1.06 mg/day) that has a recognized usefulness in the treatment of trigeminal neuralgia, demonstrated effectiveness in both conditions. The data are consistent with a theory of nociceptive signal transduction, as well as with previous data, in demonstrating the neuroadaptive mechanisms of inverse tolerance and cooperation. That is, in contrast with morphine, the antiallodynic effect induced by 5-HT1A receptor activation does not decay, but, if anything, grows with chronicity. Also, 5-HT1A receptor activation seemed to cooperate with nociceptive stimulation in, paradoxically, inducing an antiallodynic effect. The data presented here suggest that F 13640 may perhaps offer a lasting treatment of trigeminal neuralgia.     

普瑞巴林联合神经阻滞在老年人头面颈部带状疱疹后神经痛中的应用

目的观察不同剂量普瑞巴林联合神经阻滞治疗老年人头面部带状疱疹后神经痛的有效性和安全性。方法头面部带状疱疹后神经痛老年患者54例,随机分为低剂量组和高剂量组。高剂量组采用三叉神经分支阻滞和皮损区皮内注射治疗每星期一次,治疗1个月,并从治疗开始时口服普瑞巴林300 mg/d,bid直至第10周,低剂量组采用相同的神经阻滞疗法并从治疗开始时口服普瑞巴林150 mg/d,bid直至第10周。用视觉模拟评分(visual analoguescale,VAS)和睡眠质量评分(quality of sleep,QS)评价治疗效果,并观察治疗后的不良反应。结果与治疗前比较,两组治疗后第1～10w,VAS和QS评分均显著下降(P<0.05);与低剂量组相比,高剂量组治疗后第5w和第4w开始VAS评分和QS评分分别降低,且差异有统计学意义(P<0.05);两组患者治疗后10周,不良反应无明显差别。结论普瑞巴林300 mg/d联合神经阻滞可迅速缓解老年头面部带状疱疹后神经痛,改善睡眠质量,且无明显不良反应,值得临床推广。     

Activation of the 5-HT1B/D receptor reduces hindlimb neurogenic inflammation caused by sensory nerve stimulation and capsaicin

Activation of the 5-HT(1B/D) receptor inhibits cerebrovascular neurogenic inflammation (NI). The aim of this study was to determine if the 5-HT(1B/D) receptor agonist sumatriptan can also inhibit NI in other regions of the body. NI was assessed by measuring plasma extravasation (PE) and changes in blood flow in the rat hindpaw. Sumatriptan was administered locally (20 microl, 50 or 100 nM, s.c.) into the dorso-medial region of one hindpaw. The other paw was pre-treated with vehicle (20 microl of 0.9% saline) and served as a control. NI was induced after treatment with sumatriptan/vehicle by injecting capsaicin (15 microl, 1%, s.c.) into each paw or by electrically stimulating the saphenous nerve (4 Hz, 30s). Sumatriptan administered locally or systemically (300 microg/kg, i.v.) significantly reduced saphenous nerve and capsaicin-induced PE and vasodilation. The systemic and local inhibitory actions of sumatriptan are mediated by the 5-HT(1B/D) receptor as pre-treatment with the 5-HT(1B/D) antagonist GR127935 (GR; 15 microl, 1 microM, s.c. or 0.2 micromol/kg, i.v.) completely blocked the inhibitory effect of sumatriptan on capsaicin-induced vasodilation and reduced the inhibitory effect of sumatriptan on capsaicin and electrically induced-PE. Neither PE induced by local injection of substance P (SP) (20 pmol, 20 microl, s.c.) nor vasodilation induced by local CGRP injection was affected by pre-treatment with sumatriptan. These findings indicate that both local and systemic activation of the 5-HT(1B/D) receptor by sumatriptan reduce NI induced by nerve stimulation or capsaicin presumably by inhibiting neuropeptide release. 5-HT(1B/D) receptor agonists may be useful for the treatment of non-trigeminal pain conditions involving NI.     

Treatment of migraine attacks with subcutaneous sumatriptan: first placebo-controlled study

The results of the very first large-scale placebo-controlled dose-response trial with the novel selective 5-hydroxytryptamine1-like (5HT1-like) receptor agonist sumatriptan are presented. We studied the efficacy and tolerability of subcutaneous injections of 1 mg, 2 mg and 3 mg of sumatriptan in alleviating migraine attacks in a double-blind, placebo-controlled, parallel-group, multicentre clinical trial. Six-hundred and ninety patients were randomized and 685 received study medication. At 30 min, reduction of headache severity to mild or none (primary efficacy endpoint) was achieved in 22% (95% CI: 15-28%) of placebo-treated patients and in 39% (CI: 31-46%) of patients treated with 1 mg sumatriptan, 44% (CI: 36-51%) treated with 2 mg sumatriptan and 55% (CI: 48-63%) treated with 3 mg sumatriptan. Differences from placebo were 17% (CI: 8-27%) for 1 mg sumatriptan, 22% (CI: 13-32%) for 2 mg sumatriptan and 34% (CI: 24-44%) for 3 mg sumatriptan (p < 0.001 for all three comparisons). Other migraine symptoms were also more effectively treated by sumatriptan than by placebo. Subsequently, an open-label 3 mg dose subcutaneous sumatriptan was given to partial or non-responders. Thirty minutes after this open dose the response rate to sumatriptan had improved to between 70 and 80%. Adverse events after sumatriptan were minor and short-lived. We conclude that subcutaneous sumatriptan is well tolerated in doses up to 3 + 3 mg and may rapidly abort migraine attacks.     

Crossover comparison of rizatriptan 5 mg and 10 mg versus sumatriptan 25 mg and 50 mg in migraine. Rizatriptan Protocol 046 Study Group

Rizatriptan is a selective 5-HT1B/1D receptor agonist with rapid oral absorption and early onset of action in the acute treatment of migraine. This double-blind, placebo-controlled, crossover study compared rizatriptan 5 mg versus sumatriptan 25 mg, and rizatriptan 10 mg versus sumatriptan 50 mg. A total of 1329 patients were allocated to one of five groups for treatment of two attacks: rizatriptan 5 mg/sumatriptan 25 mg; sumatriptan 25 mg/rizatriptan 5 mg; rizatriptan 10 mg/sumatriptan 50 mg; sumatriptan 50 mg/rizatriptan 10 mg; placebo/placebo. For each attack, patients rated headache severity, presence of associated symptoms, and functional disability prior to dosing and at intervals through 4 hours thereafter. Patients also rated their satisfaction with medication. Rizatriptan 5 mg and 10 mg provided faster relief of headache pain and greater relief of migraine symptoms than the 25-mg and 50-mg doses of sumatriptan, respectively. The response to rizatriptan was better than sumatriptan on additional measures including functional disability and satisfaction with medication. All active treatments were highly effective compared to placebo and acted as early as 30 minutes after dosing. All active treatments were well-tolerated and showed comparable safety profiles.     

Sumatriptan for the treatment of migraine attacks-a review of controlled clinical trials

Sumatriptan, a 5HT₁-like receptor agonist, is a completely new treatment principle for migraine. In an extensive international programme of controlled clinical trials, sumatriptan, 6 mg subcutaneously and 100 mg orally, was superior to placebo in reducing headache and associated symptoms. The response rate for subcutaneous sumatriptan (70–84% after 1 h and 81–87% after 2 h) was higher than for oral sumatriptan (50–67% after 2 h). Additional doses did not increase efficacy. Oral sumatriptan was superior to Cafergot (2 mg ergotamine plus 200 mg caffeine) and somewhat better than aspirin (900 mg) plus metoclopramide (10 mg). Recurrence of migraine occurred in approximately 40% of attacks. Side effects were generally mild and short-lived in the controlled clinical trials. However, in clinical practice sumatriptan has subsequently caused rare cases of heart ischemia and sumatriptan is contraindicated in patients with a history of ischemic heart disease.     

Sumatriptan reduces exercise capacity in healthy males: a peripheral effect of 5-hydroxytryptamine agonism?

5-Hydroxytryptamine (5-HT; serotonin) has been implicated in the perception of exercise-induced fatigue. Sumatriptan is a selective 5-HT(1B/D) receptor agonist which does not cross the blood-brain barrier. The aim of the present study was to determine the effect of sumatriptan on exercise capacity. Ten healthy male subjects (mean age 28.4+/-10.8 years) performed a maximal treadmill exercise test according to the Bruce protocol with expired gas analysis on two occasions. Either 6 mg of sumatriptan or placebo was administered subcutaneously in a randomized, double-blind, placebo-controlled, cross-over design. Exercise time was greater after placebo compared with sumatriptan [914 and 879 s respectively; 95% confidence interval (CI) of difference 12.1 s, 59.1 s; P = 0.008]. There was no significant effect on peak oxygen consumption (placebo, 50.6+/-6.3 ml.min(-1).kg(-1); sumatriptan, 51.7+/-7.6 ml.min(-1).kg(-1)). Sumatriptan administration resulted in decreases in both heart rate (sumatriptan, 188+/-14 beats/min, placebo, 196+/-12 beats/min; 95% CI of difference 12.6, 2.6; P = 0.008) and respiratory exchange ratio (sumatriptan, 1.23+/-0.06; placebo, 1.26+/-0.07; 95% CI of difference 0.05, 0.01; P = 0.01) at peak exercise. There were no significant differences in blood pressure, heart rate or submaximal oxygen consumption between sumatriptan and placebo treatments at any stage of exercise. Thus sumatriptan reduces maximal exercise capacity in normal males. The failure to demonstrate any haemodynamic or cardiorespiratory effect suggests that sumatriptan enhances perception of fatigue by a peripheral mechanism affecting 5-HT modulation.     

Extracellular recordings of membrane potential from guinea-pig isolated trigeminal ganglion: lack of effect of sumatriptan

The aim of this study was to investigate the effect of the anti-migraine drug and selective 5-HT₁ receptor agonist, sumatriptan, on membrane potential of guinea-pig isolated trigeminal ganglion. Ganglia were divided into three longitudinally, placed in two-compartment baths and the d.c. potential between compartments was recorded extracellularly. Drugs were applied to the Krebs superfusion fluid of one compartment. KCl (3 mmol/1) and GABA (0.1 mmol/l) caused depolarization (0.30 ± 0.05 and 0.55± 0.08 mV respectively, n = 11–19). 5-HT (1–10 mmol/1) caused small depolarizations (0.06 ± 0.02. mV, n = 8) but sumatriptan (0.1–10 mmol/l) had no effect on trigeminal ganglion membrane potential. Collagenase pretreatment, to enhance desheathing, or modification of the composition of the Krebs solution failed to reveal any effect of sumatriptan. These data provide no evidence to suggest that sumatriptan inhibits neurotransmission in trigeminal ganglion. However, 5-HT₁ receptors may be present in insufficient numbers in the trigeminal ganglion to elicit a change in membrane potential. Further studies are required to investigate the effect of sumatriptan at the level of the sensory nerve terminals within the intracranial vasculature, where 5-HT₁ receptors may be concentrated.     

难治性三叉神经痛的药物联合治疗

目的：观察应用新型抗焦虑药物黛力新与抗惊厥药物联合治疗难治性三又神经痛的临床效果。方法：应用视觉模拟评分和情绪评分分别对疼痛和情绪进行评估并比较治疗前后的结果。结果：联合治疗对难治性三叉神经痛的止痛效果明显，并且能很好地改善病人情绪。结论：联合药物治疗是一种非常有效和安全的治疗方法。