Potential therapeutic use of melatonin in migraine and other headache disorders

There is increasing evidence that headache disorders are connected with melatonin secretion and pineal function. Some headaches have a clearcut seasonal and circadian pattern, such as cluster and hypnic headaches. Melatonin levels have been found to be decreased in both migraine and cluster headaches. Melatonin mechanisms are related to headache pathophysiology in many ways, including its anti-inflammatory effect, toxic free radical scavenging, reduction of pro-inflammatory cytokine upregulation, nitric oxide synthase activity and dopamine release inhibition, membrane stabilisation, GABA and opioid analgesia potentitation, glutamate neurotoxicity protection, neurovascular regulation, 5-HT modulation and the similarity in chemical structure to indometacin. The treatment of headache disorders with melatonin and other chronobiotic agents, such as melatonin agonists (ramelteon and agomelatin), is promising and there is a great potential for their use in headache treatment.     

Recent developments in melatonin receptor ligands

In recent years, many physiological properties of melatonin have been described resulting in much interest in the development of synthetic compounds possessing agonist or antagonist properties for melatonin receptors. These compounds have structural similarity to melatonin, being derivatives of either substituted tryptamines or of bioisosteric moieties of the indole ring such as benzothiophene, indene and naphthalene. Research to determine the structural parameters of the melatonergic pharmacophore led to the synthesis of potent constrained, polycyclic compounds. The important roles of substitutions on the 2 position of the indole ring and of the alkyl chain of the acyl group have been highlighted. The ethylamido chain seems to prefer the flexible conformation and a folded conformer has been shown to be the active conformation. Almost all of the compounds described have been patented. They have been claimed to be useful for the treatment of depression, sleep disorders and disturbances of circadian rhythm. Some patents have claimed also anti-ovulatory or antiproliferative properties. No compounds developed so far discriminate between the different melatonin receptor subtypes and few compounds have been described as antagonists for melatonin receptors.     

Physiology and pharmacology of melatonin in relation to biological rhythms

Melatonin is an evolutionarily conserved molecule that serves a time-keeping function in various species. In vertebrates, melatonin is produced predominantly by the pineal gland with a marked circadian rhythm that is governed by the central circadian pacemaker (biological clock) in the suprachiasmatic nuclei of the hypothalamus. High levels of melatonin are normally found at night, and low levels are seen during daylight hours. As a consequence, melatonin has been called the “darkness hormone”. This review surveys the current state of knowledge regarding the regulation of melatonin synthesis, receptor expression, and function. In particular, it addresses the physiological, pathological, and therapeutic aspects of melatonin in humans, with an emphasis on biological rhythms.     

儿童原发性头痛研究进展

儿童原发性头痛主要包括偏头痛、紧张性头痛及丛集性头痛等,是儿童神经内科常见病。通常认为其发 病机制是遗传因素及环境因素共同作用所致。头痛反复发作严重影响了患儿的身心健康,给患儿、家庭、学校和社 会带来极大的负担。部分患儿可能发展为慢性每日头痛,甚至可能迁延至成年。因此,对患儿原发性头痛的正确诊 断及治疗极为重要。儿童原发性头痛需要生理和心理的共同关注,需要联合药物、心理、社会学等多学科治疗,需要 改善生活方式、避免诱发因素,多方面共同推进才能达到好的效果。本文就儿童原发性头痛的临床表现、诊断以及 治疗管理进行综述。     

Effect of melatonin on endogenous circadian rhythm

Objective To further authenticate the role of melatonin on endogenous biologic clock system.Methods Pinealectomized mice were used in the experiments,a series of circadian rhythm of physiology index,such as glucocorticoid,amino acid neurotransmitter,immune function,sensitivity of algesia and body temperature were measured.Results Effects of melatonin on endogenous circadian rhythm roughly appeared four forms:1)The model of inherent rhythm was invariant,but midvalue was removed.2)Pacing function:pinealectomy and melatonin administration changed amplitude of the circadian vibration of aspartate,peripheral blood WBC and serum hemolysin.3)Phase of rhythm changed,such as the effects on percentage of lymphocyte and sensitivity of algesia.4)No effect,the circadian rhythm of body temperature belong to this form.Conclusions Melatonin has effects some circadian rhythm,and it can adjust endogenous inherent rhythm and make the rhythm keep step with environmental cycle.Melatonin may be a kind of Zeitgeber,Pineal gland might being a rhythm bearing organ to some circadian rhythm.     

唾液中游离皮质醇和松果体素水平昼夜节律性变化与夜间哮喘相关性研究

目的　探讨唾液中游离皮质醇和松果体素水平昼夜节律性变化与夜间哮喘发病机制和昼夜肺功能变化的关系。方法　采用放射免疫分析方法测定 15例正常人和 15例夜间哮喘病人唾液中游离皮质醇和松果体素水平 ,哮喘病人中急性发作期 8例 ,缓解期 7例。 2 4h内按 12个时间点采集唾液样本 ,夜间取样时光照强度控制在 5 0lx之内。结果　 3组间游离皮质醇水平差异具有显著性 (P <0 0 1)。与对照组比较 ,急性发作期和缓解期病人游离皮质醇 2 4h平均水平均降低 (P <0 0 1) ;振幅减小 (P <0 0 5 ) ;峰值相位(acrophase)延迟 (P <0 0 1,P <0 0 5 )。 3组间游离松果体素水平差异亦具有显著性 (P <0 0 1)。与对照组比较 ,急性发作期和缓解期病人松果体素水平基线值 ,振幅和峰值皆降低(P <0 0 5orP <0 0 1) ;急性发作期峰值相位延迟 (P <0 0 5 )。凌晨 4点游离皮质醇水平分别与占FEV1预计值 %和占PEF预计值 %正相关 (r =0 5 3 ,P <0 0 5 ;r =0 5 5 ,P<0 0 5 ) ,游离松果体素水平与占PEF预计值 %呈正相关 (r=0 5 2 ,P <0 0 5 )。昼夜占PEF预计值 %差值和夜间出现症状或憋醒次数呈正相关 (r =0 62 5 ,P <0 0 5 )。结论　唾液中游离皮质醇和松果体素水平的昼夜节律性改变参与夜间哮喘的发病过程 ,且与病人     

Alterations in circadian rhythms of melatonin and cortisol in patients with bronchial asthma

INTRODUCTIONBronchial asthma is a characteristic circadianrhythm disease in many aspects. Patients with asthmaoften experience a nocturnal worsening of pulmonaryfunction[1], asthmatic symptoms[2,3], and sleep quality[4].Asthma patients also show a diurnal variation in deathwith the peak occurring during the early morning hours[5].The mechanisms involved in circadian rhythms ofasthma are multiple, interactive, and presently not fullyunderstood[6].Cortisol exhibits a circadian rhythm, reac…     

Investigating prophylactic botulinum toxin type A for chronic headache disorders

There is an increasing number of studies on botulinum toxin A in the treatment of idiopathic and symptomatic headache; however, many studies can hardly be compared with each other because of different end points and different trial designs. For the prophylactic treatment of tension-type headache, migraine and cervicogenic headache, no sufficient positive evidence for a successful treatment can be obtained from the randomised, double-blind and placebo-controlled trials performed so far. For the treatment of chronic daily headache (including medication-overuse headache), there is inconsistent positive evidence for subgroups (e.g., patients without other prophylactic treatment). This means that most of the double-blind and placebo-controlled studies do not confirm the assumption that botulinum toxin A is efficacious in the treatment of idiopathic headache disorders; however, it is possible that some subgroups of patients with chronic migraine benefit from a long-term treatment for ≥ 6 months.     

褪黑素对睡眠的调节作用及与脑内氨基酸递质的关系

目的：研究褪黑素促眠、昼夜节律作用有 与脑内氨基酸递质的关系。方法：以翻正反射为指标研究褪黑素对小鼠睡眠及其昼夜节律的影响。采用纸电泳－双波长扫描法,测定褪黑素对小鼠不同脑区中γ-氨基丁酸（GABA）和谷氨酸（Glu)含量的影响。结果：褪黑素能明显促进小鼠睡眠,其药效强度依赖于给药的时辰。褪黑素可使小鼠下丘脑内γ-氨基丁酸含量明显升高。但对谷氨酸水平无明显影响。结论：褪黑素促眠作用可能与小鼠下丘脑中γ-氨基丁酸含量升高有关。     

褪黑素对睡眠的调节作用及与脑内氨基酸递质的关系

目的 :研究褪黑素促眠、昼夜节律作用及其与脑内氨基酸递质的关系。方法 :以翻正反射为指标研究褪黑素对小鼠睡眠及其昼夜节律的影响。采用纸电泳 双波长扫描法 ,测定褪黑素对小鼠不同脑区中γ 氨基丁酸 (GABA)和谷氨酸 (Glu)含量的影响。结果 :褪黑素能明显促进小鼠睡眠 ,其药效强度依赖于给药的时辰。褪黑素可使小鼠下丘脑内γ 氨基丁酸含量明显升高。但对谷氨酸水平无明显影响。结论 :褪黑素促眠作用可能与小鼠下丘脑中γ 氨基丁酸含量升高有关     

褪黑激素治疗偏头痛的作用机制和临床应用的研究进展

偏头痛是一种临床常见的原发性头痛疾病,其发病率、致残率逐年升高,给患者、家庭和社会带来沉重负担.目前偏头痛发病机制尚不明确.有研究表明压力、睡眠障碍等与偏头痛周期性发作有密切联系.褪黑激素在临床上广泛应用,尤其在其节律性减少或失调有关的疾病中,如昼夜节律性睡眠障碍、阿尔茨海默病等.偏头痛患者被证明存在时间生物学功能障碍...     

Pregnancy and chronic headache

Headache patterns in women change in relation to fluctuations in oestrogen levels. Increasing oestrogen levels in early pregnancy offer a protective effect against headache, particularly for women with migraine. However, some women continue to experience troublesome headache throughout pregnancy. Headache persisting at the end of the first trimester will usually continue without improvement for the remainder of pregnancy and should be treated. Safe and effective acute care treatment options include paracetamol, opioids and anti-emetics. The use of triptans during pregnancy is controversial and not broadly recommended. Safe and effective preventive treatments include relaxation, biofeedback, β-blockers, some antidepressants and gabapentin in early pregnancy.     

Sex hormones and chronic headache in women

Women experience changes in headache pattern in relation to changes in their reproductive cycles. Menarche, menses, pregnancy, menopause and the use of exogenous oestrogen-containing medications frequently alter baseline headache patterns. Changing patterns of headache in women may be linked to alterations in levels of sex hormones. Sex hormones directly influence headache by affecting the activity of a variety of neurochemicals important for headache, including serotonin (5HT). Treating headache alterations in women may include therapies that modify sex hormones or neurochemicals.     

An investigation of the effect of immediate and extended release venlafaxine on nocturnal melatonin and cortisol release in healthy adult volunteers

The secretion of the hormone melatonin is particularly robust to the effect of pharmacological agents. Medications may alter melatonin levels through either altering adrenergic activity or affecting liver enzymes involved in melatonin metabolism. The aim of this study was to investigate the effect of venlafaxine, a third generation antidepressant with known adrenergic properties on melatonin secretion. A further aim of the study was to investigate the correlation between plasma and salivary measures on this medication. Eight healthy adult participants (four males, four females) took part in this double blind placebo controlled randomised trial. Participants were tested on 3 nights after taking venlafaxine XR (75 mg), venlafaxine IR (75 mg) or placebo. Participants were placed in a darkened room between 1900 and 0300 h and regular temperature readings, blood and saliva samples were drawn to assess melatonin and cortisol secretion in each condition. There was no significant effect of venlafaxine IR or XR on melatonin concentrations in plasma or saliva and no effects on other circadian parameters including cortisol and temperature. It was notable that the correlation between plasma and salivary melatonin levels became poor after drug treatment. These results indicate that at low doses the mixed serotonergic and noradrenergic drug venlafaxine has no effect on nocturnal melatonin concentrations.     

Treatment of paediatric headache

Headaches are very common during childhood and become increasingly frequent during adolescence. The diagnosis of primary headache disorders (e.g., migraine and tension-type headache) rests principally on clinical criteria as set forth by the International Headache Society. Treatment options include acute or episodic measures, prophylactic agents and non-pharmacological or behavioural interventions. From review of available evidence, the most efficacious acute treatments of paediatric migraine include the non-steroidal anti-inflammatory agent ibuprofen at 7.5 – 10 mg/kg/dose or nasal sumatriptan at doses of 5 or 20 mg. For those patients with headaches that occur with sufficient frequency and severity to warrant daily prophylaxis, controlled data are limited. Agents which are likely to be beneficial include amitriptyline, flunarizine (not available in the US) and cyproheptadine. Clinical experience with the anti-epileptic agents topiramate and valproate suggests an expanding role for the prevention of paediatric migraine in the future.     

昼夜节律睡眠-觉醒障碍与恶性肿瘤发生发展的关系

昼夜节律睡眠-觉醒障碍是指睡眠-觉醒周期与人体24 h生物节律失调所致的一类睡眠疾病,它可以影响人体的认知功能和代谢等过程,还能促进恶性肿瘤的发生发展——通过改变时钟基因表达直接促进肿瘤增殖,并通过抑制褪黑素的分泌等内分泌机制间接加速肿瘤发展。本文阐述了昼夜节律睡眠-觉醒障碍的定义、它导致的病理状态以及它对恶性肿瘤发生发展的影响,以期为昼夜节律性睡眠-觉醒障碍影响的肿瘤发生发展的防治提供可能的治疗措施。     

Role of melatonin in mood disorders and the antidepressant effects of agomelatine

Introduction: Disturbances of circadian rhythms and sleep play an important role in various types of mood disorders like major depressive disorder (MDD), bipolar depressive disorder (BPD) and seasonal affective disorder (SAD). Malfunctioning of the SCN–pineal–melatonin link has been suggested as the main cause for these disorders. As a rhythm-regulating factor and as a hormone involved in the regulation of sleep, melatonin is essential for the control of mood and behavior.

Areas covered: Melatonin's involvement in various mood disorders is reviewed based on studies undertaken in patients with MDD, BPD and SAD. The chemistry and metabolism of the newly introduced antidepressant, agomelatine, a MT1/MT2 melatonin receptor agonist and 5-HT2c antagonist in brain areas involved in mood regulation are also discussed. Its clinical role in mood regulation, agomelatine's efficacy, safety and tolerability are also reviewed.

Expert opinion: Agomelatine, a melatonergic antidepressant with a rapid onset of action, has been shown effective in various types of mood disorders (e.g., MDD, BPD, SAD). Some studies find it superior to other common antidepressants (SSRIs, SNRIs) that are in clinical use today. Agomelatine's efficacy, good tolerability and safety profile suggest that it may become a preferred antidepressant in the near future.     

Recent advances in the development of melatonin MT1 and MT2 receptor agonists

Importance of the field: Increasing clinical evidences suggest that melatonin receptor agonists can represent a novel therapeutic approach for the treatment of sleep disturbances and depression. A variety of studies also revealed a role of melatonin and its receptors in different patho-physiological conditions. Due to the multiple effects of this hormone, the design of new agents able to interact selectively with melatonin receptors has become an area of great interest during the last decade.

Areas covered in this review: An extensive inspection of patents and scientific literature about MT₁ and MT₂ melatonin receptor agonists reported from 1999 to early 2010.

What the reader will gain: A comprehensive review of structures recently claimed as melatonin receptor agonists and a broad overview of structure–activity relationships for these ligands.

Take home message: After 5 decades of research, the field of melatonin receptor agonists comprises a variety of chemical entities, belonging to structurally different classes. Patents filed since 1999 claim new melatonin receptor agonists, characterized either by improved pharmacokinetic or pharmacodynamic properties, compared to those of melatonin receptor agonists already approved for clinical uses. The results of preclinical studies on animal models show that melatonin receptor agonists can be considered promising agents for the treatment of CNS-related pathologies.     

对偏头痛临床现状的一些思考

偏头痛被公认为一种家族高聚集性神经系统疾病。基础和临床、西医和中医的深入结合,进一步明确偏头痛的根本发病机制、探索临床的有效乃至根治偏头痛治疗手段是研究的最终目标。本文综述偏头痛的中国现代史,中国人群偏头痛的患病率及局部注射治疗难治性偏头痛进展。     

Emerging drugs in migraine treatment

Ergot alkaloids have been the mainstay of acute migraine therapy for most of the 20th century. They have been supplanted by sumatriptan-like drugs (‘triptans’), which, while keeping some of the ergots’ mechanisms of action, show improved safety profiles due to their increased receptor selectivity. However, triptans are still far from being perfect drugs: they can constrict human coronary arteries at therapeutic doses and, therefore, are contra-indicated in the presence of cardiovascular disease. Another problem with these agents is recurrence of moderate-to-severe pain within 24 h of initial headache relief. While mechanism-driven drug design has led to the development of various novel, albeit still imperfect, acute antimigraine medications, only a few new prophylactic agents have been made available to migraine clinicians. The efficacy of most, if not all of them has been discovered serendipitously. This is probably due to the fact that, while the pathophysiology of a migraine attack is now reasonably understood, the mechanisms leading to an attack are still mostly unknown. This update analyses the profile of some antimigraine drugs in clinical trials, their mode of action and their potential advantages or drawbacks over already available agents.