偏头痛治疗新药Sumatriptan

偏头痛是神经科临床中最常见的一种头痛。根据全国调查报告估计，我国患病率为９８５．２／１０万［１］，较美国３０００／１０万［２］为低。虽然，阐述该病的神经血管机制已提出一百余年，而且对其广泛的研究也已持续五十多年，但其发病机制迄今尚未完全明确；治疗和预防该病的药物也有数十种，均因其针对性不强，且副作用较多，病人难以耐受、自从Ｓｕｒｎａｔｒｉｐｔａｎ问世以来，偏头痛的治疗出现了新的转机。近几年，欧美国家通过多中心大规模严格的临床应用研究后得出结论；该药治疗偏头痛，具有疗效好，副作用少的特点［２－６］…     

5-HTTLPR多态性与偏头痛的关系的系统评价

目的本研究旨在使用系统评价方法评估5-HT转运体基因多态性(5-HTT gene-linkedpolymorphic region,5-HTTLPR)和偏头痛的关系。方法广泛检索中英文数据库中发现相关研究,对符合纳入标准的每个研究提取等位基因和基因型频率,使用随机或固定效应模型计算比值比(OR),使用Q检验检测研究之间的异质性,Egger’s(埃格)测试和漏斗图评估发表偏倚,对以家庭为基础的关联研究进行描述性分析。结果总共12个研究纳入meta分析,没有发现5-HTTLPR多态性与偏头痛具有相关性。结论证据未表明5-HTTLPR多态性与偏头痛患病风险有关,该结论需大样本研究进一步验证。     

偏头痛的治疗现状

偏头痛是神经系统的常见病之一。根据来自美国的报告 ,1受偏头痛影响的美国成人约为 2 80 0万 ,其中主要为 2 5～ 5 5岁、处于工作能力最强时期的成年人。每年约有 6 %的男性和18%的女性出现一次以上的偏头痛发作 ,其中女性 85 %和男性 82 %以上的患者偏头痛发作时工作能力丧失 ,1/ 3的患者需卧床休息 ,5 1%的女性和 38%的男性每年至少有 6天不能工作 ,全年因此而造成的经济损失可高达 130亿美元。 2尽管偏头痛发病率很高 ,但即使在美国仍然有超过 5 0 %的患者却未能得到正确的诊断和有效的治疗 ,3原因是这些患者认为医生目前对偏头痛也无能…     

偏头痛的新药治疗

偏头痛是神经内科的常见病之一，好发于女性，其患病率为18％，男性为6％，多发生在25～55岁的中青年人。偏头痛的发病机制仍不明了，多数人认为它是受多种因素影响的神经血管功能紊乱性疾病。五羟色胺(5-HT)、P物质、降钙素基因相关肽等神经介质的作用日益受到重视，目前用于治疗偏头痛发作期的曲坦类药物，就是5-HT受体激动剂。现介绍几种用于偏头痛急性发作期和间歇期预防性治疗的新药，对这些药物的代谢、作用方式、治疗效果和不良反应进行综述。     

偏头痛的生化研究进展

偏头痛的发病机制尚不清,生化改变很复杂。本文综述了偏头痛病人发作期及间歇期血浆、血小板、脑脊液中5—羟色胺、神经肽类诸如β—内啡肽、甲硫脑啡肽、P物质等浓度的变化及其他一些生化改变,并对它们在偏头痛中的作用及可能机制作了综述。     

偏头痛患者5-羟色胺2A受体启动子区T102C基因多态性的研究

目的 探讨5-羟色胺2A受体(5-HT2AR)基因T102C多态性与哈尔滨地区汉族人偏头痛的关系.方法 应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法,检测204例偏头痛患者及186例健康对照者5-HT2AR基因启动子区域T102C多态性.结果 偏头痛患者中T/T,T/C,C/C分布为29.9%,53.9%和16.2%,正常对照中T/T,T/C,C/C分布为35.0%,48.9%和16.1%,两组间无显著性差异(P>0.05).偏头痛患者的等位基因频率为102T 56.9%,102C 43.1%,正常对照组为102T 59.4%,102C 40.6%,两组间无显著性差异(P>0.05).结论 5-HT2AR基因启动子区域T102C基因多态性与哈尔滨地区汉族人偏头痛的发生无相关性.

Abstract：

Objective To investigate the association between 5-HT2A receptor (5-HT2AR) promoter T102C gene polymorphism and migraine in Han nationality, Harbin. Methods Polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP)analysis were applied to determine the genotypes at the promoter 102 of 5-HT2AR gene in 204 migraine patients and 186 controls. The genotype distribution and allele frequencies among different groups were compared. Results The genotype T/T,T/C,C/C distribution of the 5-HT2AR were 29.9% ,53.9% and 16.2% in migraine patients,and were 35.0% ,48.9% and 16.1% in controls (P > 0.05). The allele frequencies of 5-HT2AR in migraine patients were 56.9% for 102T,43.1% for 102C,and 59.4% for 102T,40.6% for 102C in controls (P > 0.05 ).Conclusion The polymorphism of 5-HT2AR promoter T102C gene was not significantly associated with migraine among Han nationality,in Harbin, China.     

5-HT1D受体调节大鼠偏头痛模型三叉神经二级神经元兴奋性

目的探索5-HT1D受体在偏头痛发病中的中枢角色.方法应用大鼠电刺激偏头痛模型,观察给予佐米曲普坦和BRL15572后三叉神经脊束核尾段和上颈髓背角的c-fos表达变化.结果佐米曲普坦明显抑制电刺激诱发的三叉神经脊束核尾段和上颈髓背角浅层神经元c-fos表达,BRL15572可拮抗佐米曲普坦的大部分抑制效应,单独BRL15572对c-fos表达无影响.结论5-HT1D受体在偏头痛模型中是调节三叉神经二级神经元兴奋的主要受体,曲坦类药物通过5-HT1D受体抑制该神经元伤害性兴奋.     

STin2基因多态性与偏头痛关联性研究

目的 探讨中国东北地区汉族人群中5-羟色胺转运体基因STin2多态性与偏头痛遗传易感性关系.方法 研究对象包括150例偏头痛患者(其中无先兆偏头痛M0 111例,有先兆偏头痛MA 39例)及105例正常对照.详细记录临床资料,提取DNA.运用多聚酶链式反应和电泳分析技术,检测偏头痛组及对照组STin2基因多态性,并比较两组基因型及等位基因频率.结果 偏头痛组STin2基因型总体分布与对照组相比无显著性差异(x2=5.509,df =2,P=0.064),但MO患者STin2.12/12基因型频率为45.9％,对照组为31.4％,两者比较有统计学意义(x2 =4.785,df=1,P=0.036),STin2.9等位基因在MA患者中有增加的趋势(MA组为5.1％,而对照组为0.9％).结论 STin2.12/ 12基因型可能增加偏头痛发病风险.     

偏头痛与5-羟色胺转运体基因多态性的相关性研究

目的研究5-羟色胺转运体(5-hydroxytryptamine transporter,5-HTT)基因多态性频率在汉族偏头痛人群的分布,探讨该基因多态性与偏头痛的相关性。方法采集40例偏头痛患者(实验组)和40例健康成人(对照组)的肘静脉血,通过DNA-PCR扩增等分子生物学技术,观察5-HTT基因多态性的基因型和等位基因频率在两组中的分布特点。结果5-HTT基因多态性的基因型和等位基因频率在实验组和对照组中的分布无统计学差异(P>0.05),在偏头痛各临床特征中的分布也无统计学差异(P>0.05)。结论5-HTT基因是否在汉族人群偏头痛发病中起作用,有待进一步研究。     

无先兆偏头痛患者血浆及血小板5-HT、5-HIAA含量的变化

目的　了解 5 -羟色胺 (5 - HT)、5 -羟吲哚乙酸 (5 - HIAA)在无先兆偏头痛发病中的作用。方法　用荧光分光光度法检测 2 0例无先兆偏头痛患者 (病例组 )和 2 3名正常人 (对照组 )血浆及血小板 5 - HT、5 - HI-AA的含量。结果　病例组发作期血浆 5 - HT含量低于对照组 (P<0 .0 5 ) ,而 5 - HIAA高于对照组 (P<0 .0 5 ) ;间歇期血浆 5 - HT高于发作期 (P<0 .0 5 ) ,而 5 - HIAA含量低于发作期 (P<0 .0 5 )。发作期血小板 5 - HT含量显著高于间歇期和对照组 (P<0 .0 1) ,而 5 - HIAA含量显著低于间歇期和对照组 (P<0 .0 1)。病例组 (含发作期和间歇期 )血小板 5 - HT含量高于对照组 (P<0 .0 5 ) ,而 5 - HIAA含量显著低于对照组 (P<0 .0 5 )。结论　无先兆偏头痛患者不同时期其血浆和血小板 5 - HT、5 - HIAA含量发生不同变化     

5-HT1 receptors in migraine pathophysiology and treatment

Migraine is a frequent paroxysmal headache disorder of unknown aetiology. Genetic factors may control attack frequency and possibly attack severity. Serotonin_1D (5-HT_1Dβ) receptors have a prominent position within the final common pathway of the mechanisms involved in the headache and associated symptoms. Stimulation of these receptors by selective 5-HT_1Dβ receptor agonists such as sumatriptan and newer compounds including MK-462 and 311C90, rapidly and fully blocks the symptoms of the headache phase. The efficacy depends on factors such as timing of administration during or before the headache, speed of initial rise of drug plasma levels, and possibly degree of brain penetration. All agonists at S-HT_1Dβ receptors share a short duration of action resulting in recurrence of the headache symptoms within 24 h in about one-third of attacks in clinical trials. The risk for headache recurrence seems patient dependent: about 10% of patients treating multiple attacks experience headache recurrence in every treated attack, whereas 40% never experience recurrence. These differences are not related to simple pharmacokinetic differences between patients or drugs. Increasing plasma half-life of the drug will most likely not reduce the risk of recurrence. “Breakthrough of peripheral suppressive effect” with an ongoing “central migraine generator”, rather than the occurrence of a new attack, seems to be the most likely underlying mechanism for headache recurrence. In a minority of, possibly predisposed, patients, use of sumatriptan may induce increase of attack frequency. Four mechanisms have been suggested for the antimigraine action of 5-HT_1Dβ receptor agonists: (1) vasoconstriction of cranial, most likely meningeal and dural blood vessels; (2) inhibition of release of vasoactive neuropeptides from perivascular trigeminal nerve terminals within dura mater and meninges; (3) blockade of trigeminal nerve terminal depolarization; and (4) central inhibition within the trigeminal nucleus caudatus in the brainstem. Which of these mechanisms is the most important, and whether or not vasoconstrictor action is necessary for antimigraine efficacy, is currently under extensive investigation. At this point all drugs with proven antimigraine efficacy share the ability to contract blood vessels and thus all feature also the potential risk of causing vasoconstriction of coronary vessels. In relation herewith, major efforts are put into the search for “the antimigraine receptor” and which receptor subtype mediates which action of sumatriptan-like drugs. At this point, the 5-HT_1Dβ receptor subtype is thought to mediate vasoconstriction. Some investigators feel that the 5-HT_1Dα receptor subtype mediates the neuronal effects of sumatriptan, while others are much less convinced about the physiological role of this subtype of receptor. Further research into receptor subtype specificity and affinity of compounds may promote the development of even better antimigraine drugs.     

Oral sumatriptan compared with placebo in the acute treatment of migraine

This multicentre, doubleblind, parallel-group study compared the efficacy, safety and tolerability of oral sumatriptan, given as a new film-coated tablet, with placebo in the acute treatment of migraine. Patients were randomised unequally (1:2) to receive placebo or sumatriptan. Eighty-eight patients received placebo (plus an optional dose 2 h later if the headache persisted plus a further optional dose for recurrence within 24 h) and 162 patients received sumatriptan 100 mg (plus an optional 100 mg dose at 2 h and an optional 100 mg dose within 24 h). Sumatriptan was significantly more effective than placebo at relieving headache (defined as reduction in severity from severe or moderate pain to mild or no pain) at 2 h (51% versus 31%,P = 0.003) and 4 h (71% versus 35%,P < 0.001). Fewer sumatriptan-treated patients required a second dose compared with placebo-treated patients (49% versus 74%,P < 0.001). More sumatriptan-treated patients were completely pain free compared with placebo-treated patients at both 2 h (24% versus 12%) and 4 h (48% versus 18). Patients receiving sumatriptan reported earlier onset of headache relief than patients receiving placebo. Headache relief in sumatriptan-treated patients was similar, irrespective of the type of migraine (with or without aura) or the time of treatment 4 h or > 4 h after onset of migraine). Sumatriptan was more effective than placebo at relieving nausea, vomiting and photophobia/phonophobia. Few patients were evaluable for treatment of headache recurrence, and statistical analysis was not possible. More sumatriptan-treated patients than placebo-treated patients reported adverse events (29% versus 16%) but the difference was not significant at the 5% level. Most of these events were mild to moderate in severity, of short duration and resolved without treatment. Sumatriptan had no clinically significant effect on blood pressure, heart rate, electrocardiogram or laboratory test results. It is concluded that oral sumatriptan 100 mg, given as a film-coated tablet, provides an effective and well-tolerated acute treatment for migraine.     

Rationale for the use of 5-HT1-like agonists in the treatment of migraine

Migraine headache is thought to be associated with a dilatation of cranial blood vessels, particularly those in the dura mater, and an accompanying localized sterile inflammatory response. Sumatriptan is a highly selective 5-HT₁-like receptor agonist which selectively constricts cranial blood vessels (including those in the dura mater). It also inhibits neurogenically-mediated plasma protein extravasation in the dura mater. Haemodynamic studies in anaesthetized animals have shown that sumatriptan selectively constricts the carotid arterial circulation and this effect appears to be restricted to an effect on carotid arteriovenous anastomoses. Sumatriptan has a much more selective pharmacological profile than ergot preparations which are also used in the acute treatment of migraine. The development of sumatriptan has been based on a vascular theory of migraine and its high degree of efficacy in the treatment of migraine strengthens the argument that dilatation of cranial blood vessels is the cause of vascular headache.     

Inhibition of NMDA-receptor mediated response in the rat medial prefrontal cortical pyramidal cells by the 5-HT3 receptor agonist SR 57227A and 5-HT: Intracellular studies

The techniques of intracellular recording and single-electrode voltage-clamp were used to study the effect of serotonin (5-HT) and the selective 5-HT₃ receptor agonist SR 57227A on N-methyl-D-aspartic acid (NMDA)-evoked responses in pyramidal cells of the rat medial prefrontal cortex (mPFC) in in vitro brain slice preparations. Bath application of 5-HT or SR 57227A produced a concentration-dependent inhibition of NMDA-induced membrane depolarization, action potentials, and inward current. The depressant action of 5-HT and SR 57227A had a slow onset and showed no signs of receptor desensitization. This action was markedly attenuated or completely blocked by the selective 5-HT₃ receptor antagonists granisetron and BRL 46470A, but not other receptor antagonists. In addition to inhibiting NMDA-evoked responses, SR 57227A also depressed significantly pharmacologically isolated, NMDA receptor-mediated, monosynaptic excitatory postsynaptic currents (EPSCs) elicited by electrical stimulation of the forceps minor; this inhibitory action was blocked by BRL 46470A but not other 5-HT receptor antagonists. Perfusion of Ca²⁺-free or low Ca²⁺ plus Cd²⁺ artificial cerebrospinal fluid prevented electrical stimulation-induced EPSCs, but did not affect the inhibitory action of 5-HT and SR 57227A. In conclusion, we demonstrate for the first time that 5-HT and SR 57227A interact with 5-HT₃-like receptors to produce a direct inhibitory action on NMDA receptor-mediated response in pyramidal cells of the mPFC. Synapse 29:257–268, 1998. © 1998 Wiley-Liss, Inc.     

Subcutaneous sumatriptan in the acute treatment of migraine

Two double-blind, randomized, placebo-controlled multicentre studies were carried out to assess the efficacy and tolerability of subcutaneous (s. c.) injections of 1-3 mg and 1-8 mg sumatriptan, respectively, in the acute treatment of migraine. Data are presented from a total of 519 patients. In both studies, the primary endpoint of efficacy was a reduction in headache severity from severe or moderate to mild or no headache. All doses of sumatriptan were significantly more effective than placebo in relieving symptoms, and the response appeared to be dose-related; an effective response to treatment was achieved within 30 min in 73% of patients treated with 6 mg sumatriptan and 80% of patients treated with 8 mg sumatriptan s. c., compared with 22% for placebo. Sumatriptan was well tolerated and the majority of adverse events were mild and transient. The most frequent complaint was irritation and pain at the site of injection. No changes in laboratory values were noted and ECG readings were unaltered by treatment. On the basis of these results, the 6 mg subcutaneous dose has been selected for further evaluation in large-scale studies.     

Action of serotonin in the medial prefrontal cortex: mediation by serotonin3-like receptors.

In the present study, we investigated the effects of various serotonin (5-HT) antagonists on 5-HT's action on medial prefrontal cortical cells (mPFc) using the techniques of single cell recording and microiontophoresis. The microiontophoretic application of 5-HT (10-80 nA) produced a current-dependent suppression of mPFc cell firing and this effect was blocked by the selective 5-HT3 receptor antagonists (+/-)-zacopride, ICS 205930 and granisetron at currents of 5-20 nA. Furthermore, the intravenous (i.v.) administration of (+/-)-zacopride (5-50 micrograms/kg) markedly attenuates the suppressive action of 5-HT on mPFc cell firing. In contrast, the microiontophoresis of 5-HT1 and 5-HT2 receptor antagonists such as (+/-)-pindolol, spiperone, metergoline, and ritanserin (10-20 nA) failed to block 5-HT's effect. In fact, in some cells, spiperone and ritanserin potentiated 5-HT's action and prolonged neuronal recovery. In addition, the intravenous administration of either ritanserin (5-2,000 micrograms/kg) or metergoline (4-2,400 micrograms/kg) failed to alter 5-HT's action. The electrical stimulation of the caudal linear raphe nucleus (CLi) suppressed the spontaneous activity of 83% of the mPFc cells tested by 45 +/- 2%. This suppression was significantly attenuated by the iontophoresis of granisetron (2.5-5 nA) but not by the 5-HT2 and 5-HT1C receptor antagonist ritanserin or the relatively selective 5-HT2 receptor antagonist (+)-MDL 11,939 (10-40 nA). However, the i.v. administration of ritanserin (0.5-1.5 mg/kg) or S-zacopride (0.1 mg/kg) significantly blocked the suppression of mPFc cell firing produced by CLi stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Electrophysiological evidence for a functional interaction between 5-HT1A and 5-HT2A receptors in the rat medial prefrontal cortex: An lontophoretic study

In this study, we examined the interaction of 5-HT_1A and 5-HT_2A receptors in the rat medial prefrontal cortex (mPFc) using the techniques of extracellular single unit recording and microiontophoresis. The iontophoresis of the selective 5-HT_1A receptor agonist (±)-8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT) produced a current-dependent suppression (2.5-20 nA) of the basal firing rate of spontaneously active mPFc cells. The iontophoretic (5-10 nA) and systemic administration (0.1-0.5 mg/kg, i.v. ) of the 5-HT_2A/5-HT_2C receptor antagonist ritanserin and the selective 5 HT_2A receptor antagonist MDL 28727 significantly potentiated and prolonged 8-OHDPATs suppressant action. In addition, the systemic administration of another selective 5-HT_2A antagonist MDL 100907, but not its less active enantiomer MDL 100009, also potentiated and prolonged 8-OHDPATs action. The potentiating effect of the 5-HT_2A receptor antagonists on the action of 8-OHDPAT is specific in that neither the iontophoresis of ritanserin nor MDL 28727 altered the suppressant action produced by the iontophoresis of the 5-HT₃ receptor agonist 2-methylserotonin onto mPFc cells. Moreover, the suppressant action of 8-OHDPAT was not altered by the systemic administration of the selective 5-HT₃ receptor antagonist granisetron (0.1-0.5 mg/kg, i.v.). On the other hand, the iontophoresis of a low current (0.5 nA) of the 5-HT_2A,2C receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) potentiated the excitation induced by the iontophoresis of 1-glutamate on quiescent mPFc cells. The iontophoresis of 8-OHD-PAT at a current that had no effect on the firing rate of 1-glutamate activated when administered alone significantly attenuated the excitatory action produced by the iontophoresis of DOI. Overall these results confirm and extend the hypothesis that there is an interaction between 5-HT_1A and 5-HT_2A receptors in the mPFc at the neuronal level. © 1994 Wiley-Liss, Inc.     

养血清脑颗粒预防和治疗偏头痛的临床研究

目的研究养血清脑颗粒(主要成分为当归、川芎、白芍、细辛等)治疗偏头痛的疗效及其不良反应.方法112例偏头痛患者,男性42例,女性70例,年龄19～75岁,平均年龄为(38.1±9.8)岁,进行了多中心、随机、双盲、安慰剂对照研究.结果(1)养血清脑颗粒对偏头痛的治疗中治疗组比安慰剂组较明显地减少总发作次数(分别为3.1±2.5和4.2±2.7,Z=2.16,P=0.03)和总发作时间(h)分别为31.0±48.0和51.2±73.8,Z=2.86,P=0.004.(2)治疗组和安慰剂组总发作次数减少率(%)分别为4.9±0.3和3.0±0.5,两组比较差异有显著意义(Z=5.76,P<0.001).(3)治疗组和安慰剂组中偏头痛伴随症状,如恶心、呕吐、畏光、怕声的观察表明无明显差异.(4)治疗组发生不良反应3例(5.4%),安慰剂组1例(1.8%).(5)血尿常规和血生化检查治疗前后无特殊改变.结论养血清脑颗粒可用于治疗偏头痛,可减少偏头痛的发作次数和缩短发作时间,但对偏头痛发作过程中出现的伴随症状的作用不明显.     

Depression of mGluR-mediated IPSCs by 5-HT in dopamine neurons of the rat substantia nigra pars compacta

Dopamine neurons of the substantia nigra pars compacta receive a prominent serotonin (5-HT) projection from the dorsal raphe nucleus and important functional interactions between the serotonergic and the dopaminergic system have been postulated. In the present report we examined the role of 5-HT in the modulation of the metabotropic glutamate receptor-mediated inhibitory postsynaptic current (mGluR-IPSC) in midbrain dopamine neurons, and we found a reversible depression of this synaptic response at concentrations of 5-HT ranging from 100 nm to 30 microm (EC50 1.06 microm). This resulted in a shift towards excitation of the overall dopamine neuron response to glutamatergic synaptic input. This effect was not because of a direct modulation of the Ca2+-sensitive K+ conductances underlying the mGluR-IPSC, but was associated with a decrease in the intracellular calcium signal triggered by mGluR stimulation. Similar results were obtained with alpha-methyl-5-hydroxytryptamine and 5-methoxytryptamine, but not with 5-carboxamidotryptamine or 1-(3-chlorophenyl) piperazine. No significant depression of the mGluR-IPSC by 5-HT was observed in the presence of the 5-HT2 antagonist cinanserin or the 5-HT4 receptor antagonist RS 23597-190, whereas the 5-HT2C antagonist RS 102221 was ineffective. Our results demonstrate a powerful inhibition of the mGluR-IPSC by 5-HT in midbrain dopamine neurons, most probably through stimulation of 5-HT2A and 5-HT4 receptors.     

Different regulation of serotonin receptors following adrenal hormone imbalance in the rat hippocampus and hypothalamus

Summary Adrenal influence on serotonin (5-HT) transmission in the hippocampal and hypothalamic areas was studied in adrenalectomized rats receiving or not corticosterone replacement. After adrenalectomy, the 5-HT presynaptic receptors were desensitized both in hippocampus and hypothalamus: a significant increase in 5-HT 1 and 5-HT 2 receptor binding numbers took place in membranes from the hippocampus, but not in hypothalamus, while no changes in affinity of receptors to radioligands were observed in either brain area. Corticosterone treatment restored the adrenalectomy-impaired 5-HT autoreceptor sensitivity in hippocampus and hypothalamus and 5-HT density receptor sites in the hippocampus. Serotonin autoreceptor down-regulation following adrenalectomy may increase 5-HT release to maintain the constancy of serotonergic transmission in the brain and 5-HT modulated CRH-ACTH release to compensate the plasma corticosteroid drop. Corticosterone seems to display a distinct tonic control on serotonin transmission in both hippocampus and hypothalamus, the diversity being due to the different roles played by the hormone in these brain regions.