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Involvement of nitric oxide in fading of 5-hydroxytryptamine-induced vasocontraction in rat isolated vena portae smooth muscle.

PURPOSE: The aim of the present study was to investigate a nitric oxide (NO) involvement in the mediation of a 5-HT-induced vasoconstrictions response in the rat portal vein in vitro. MATERIAL AND METHODS: Isolated rat portal vein preparations obtained after dissection were placed in organ baths for isometric force measurement via a strain gauge. RESULTS: 5-hydroxytryptamine (5-HT) in concentrations ranging from 3x10(-8) M to 3x10(-4) M contracted portal vein preparations (EC50= 7x10(-7) M) in a concentration dependent manner. The vasoconstrictions induced by 5-HT was significantly increased in endothelium-denuded vessels. Pre-treatment with N(omega)-nitro-L-arginine methyl Ester (L-NAME 100 microM) enhanced the contractive response to 5-HT either in intact- or denuded endothelium vessels. Whereas, ketanserin (0.1 microM) abolished 5-HT-induced vasoconstrictions (EC50= 4.6x10(-8) M). Furthermore, a non-selective 5-HT receptors agonist, sumatriptan, (1x10(-10 )M - 1x10(-5) M) induced a reduction of spontaneous rhythmic contractions either in endothelium-intact or in endothelium -denuded vessels. However, 5-HT-induced vasoconstriction was unaffected by propranolol (10 microM). CONCLUSIONS: These findings are consistent with the hypothesis that the vasoconstrictor activity of 5-HT in vascular smooth muscle was mediated by activation of 5-HT1B/D and 5-HT2B receptors subtypes involving the endothelium (NO) dependent mechanism.

Animals↗

[Suppressing effect of the serotonin 5HT1B/D receptor agonist rizatriptan on calcitonin gene-related peptide (CGRP) concentration in migraine attacks].

Calcitonin gene-related peptide (CGRP) is one of the neuropeptides most abundant in the nervous tissue. Recent studies indicate that local cranial release of CGRP from the trigeminal nerve perivascular endings within arachnoidea plays an important role in the pathophysiology of migraine attacks and cluster headaches. Elevated CGRP levels in cranial venous blood (in the jugular vein) during an acute spontaneous migraine attack have been reported in rather few studies so far. Sumatriptan--a selective serotonin 5HT1B/D receptor agonist, highly effective in terminating migraine attacks, decreases the elevated CGRP level back to normal. The aim of our study was to determine the effect of rizatriptan (a drug from a new generation of triptans) on CGRP release in migraine attacks. In 45 patients suffering from migraine attacks with and without aura, plasma CGRP levels were assessed during an attack twice: before treatment and two hours after rizatriptan administration. In the group under study the plasma CGRP level before treatment was significantly higher than that measured two hours after rizatriptan administration. The decrease in CGRP levels was associated with subsidence of the migraine attack. There was no difference between migraine patients with and without aura. These results suggest that triptans as serotonin 5HT1B/D receptor agonists decrease CGRP plasma concentration in migraine attacks.

Adult↗

Cluster headache: the history of the Cluster Club and a review of recent clinical research.

In September 2003, a scientific meeting was held in Rome to revive the International Cluster Headache Research Group (or "Cluster Club") tradition. This group of specialists was originally formed in the late 1970s by Ottar Sjaastad in order to promote research ideas, and to generate papers and other important information in this field. Its meetings, the last of which had taken place in 1994, had been informal events at which there was ample time for lively discussion. The last decade of the 20th century brought a significant increase in clinical and experimental research into cluster headache (CH), and this review summarizes some of the results of this research. The male preponderance of CH has been shown to be progressively decreasing over the years. Revised clinical criteria and a modern classification have been presented. First-degree relatives of probands with CH have been shown to have an increased risk of suffering from CH compared with the general population. Genetic analysis suggests that an autosomal dominant gene plays a role in some families. Functional neuroimaging has contributed to a better understanding of the pathophysiology of the condition. Positron emission tomography during provoked attacks has shown activation of the ipsilateral inferior posterior hypothalamus and it has been suggested that CH might be a functional neurovascular disorder of pacemaker or circadian regions in the hypothalamic grey matter. Subcutaneously administered sumatriptan has emerged as a highly effective acute treatment, but, in our opinion, the emphasis should be on attack prevention. Deep brain stimulation of the inferior posterior hypothalamic grey matter seems to be very promising as a novel treatment targeting the presumed central origin of pain attacks.

Biomedical Research↗

Serotonin-1D hypothesis of obsessive-compulsive disorder: an update.

Support for the serotonin-1D (5-HT(1D)) hypothesis of obsessive-compulsive disorder (OCD) and related conditions comes from a variety of sources. Some pharmacologic challenges with the 5-HT(1D) agonist sumatriptan, and case reports in which prolonged administration of 5-HT(1D) agonists was associated with a therapeutic effect, suggest that 5-HT(1D) may play a role in obsessive-compulsive symptoms. Genetic studies have also found that polymorphism of the 5-HT(1D) gene may be preferentially transmitted to those patients with OCD. However, taking into account that OCD is a heterogeneous syndrome, the 5-HT(1D) hypothesis requires further investigation in order to disentangle the role of the 5-HT(1D) receptor in this common and often severe disorder.

Humans↗

[Therapy of severe migraine attacks: practical tips].

Severe migraine attacks are treated with triptans. The forms of administration of the active substances depend on the drug profile. A standard therapy does not exist. The rate of side effects is low. Triptans are contraindicated for patients with coronary, cerebral and peripheral vascular diseases. Under no circumstances are they to be combined with ergot alkaloids. Triptans are all the more effective, the earlier they are taken. For determining the optimal time point for taking the medication, the so-called triptan threshold is helpful. Triptans are not suitable for treating status migrainosus. Sumatriptan can be administered electively and in compliance with the contraindications for the emergency treatment.

Analgesics↗

[Stabilization treatments of migraine].

Pathophysiology and principles for diagnosis of migraine, in particular ways to obtain an accurate history between attacks, are presented in the introduction. Identification of migraine triggers is an extremely important part of migraine therapy. Selected pain-relieving drugs should include primarily simple analgesics and antiemetics, while sumatriptan should be reserved mainly for severe migraine attacks. Pharmacotherapy, psychological and physical therapy are all components of a systemic approach to the treatment of migraine. To discontinue overused medication is the first step in the prevention of migraine. A number of available drugs are able to reduce the frequency and severity of migraine attacks. Several considerations should be evaluated before symptomatic and prophylactic therapies are introduced. Our strategies are based on experience collected during the treatment of 82 patients.

Analgesics↗

[Chronic cluster headache: course and outcome of treatment].

We analyze the results of treatment and the course of disease in 20 patients suffering from chronic cluster headache. Patients were followed for an average of 5 years. Sumatriptan provided the most effective relief of symptoms in those who used that medication. The results of surgical and medical prophylaxes were poor. The disease either remitted or changed to an episodic variety after several months or years in most patients. There is no evidence to suggest that these changes were related to any particular treatment.

Adrenal Cortex Hormones↗

[Present problems of migraine and similar headaches].

Headaches belong to the most frequent sufferings. According to certain most modern epidemiological studies about 20% of adults have recurrent headaches, among them particularly migraine and tension headache. In recent years the interest in these conditions had increased resulting in a great number of research works. A great role is played by the International Headache Society, and the newly formed European Federation of Headaches. In 1988 a universally accepted classification, and diagnostic criterias were elaborated and have been accepted by the Polish neurologists. Tens or research centres are studying the problems in this field. The main directions of studies are-the role of neurotransmitters, the vascular system of the head, the mechanisms of autonomic regulation, the role of neurogenic bland inflammation in the generation of pain, and the psycho-emotional factors. A number of new clinical forms of headache have been described. Therapeutic possibilities have also increased (beta-blockers, calcium blockers, serotonin receptor drugs, eg. sumatriptan, microsurgery of neuralgias etc). This opens a new period for satisfactory advances in that rather marginal, as yet, area.

Brain↗

Headache.

Headache-prone patients have many highly effective therapeutic options open to them. Used only at the time of headache, sumatriptan succinate by mouth or injection and dihydroergotamine nasal spray are novel choices now or soon to be available. The original migraine therapy, ergotamine, is highly effective in its rectal suppository formulation, when used at a subnauseating dosage. Valproate sodium is the latest addition to the many therapies available for long-term stabilization.

Anti-Inflammatory Agents, Non-Steroidal↗

[Migraine--summary of diagnostic and therapeutic strategies].

The International Headache Society 1988 has boosted the research on and therapy of migraine by classifying the headache and operationalizing the diagnostic criteria in the recent years. The prevalence of migraine (12% in the western industrial countries) and its genetic causes are now undoubted. Numerous short-term or long-term triggers, like for instance the female hormone constellation from puberty to menopause, or prolonged stress, contribute considerably to the severity and frequency of the illness. Due to the central role of serotonin in the pathomechanism of the migraine headache and intensive research on the part of the pharmaceutical industry it was possible to develop a new, efficient drug for the treatment of migraine attacks: sumatriptan, a 5HT1-agonist. The efficiency of prophylactics has been defined and covered. For about one third of the migraine patients a long-term therapy, which is continuously adapted, is necessary, because they suffer simultaneously from a tension-type headache and a continual headache due to an abuse of pain-killers or ergotamin (analgesic or ergotamin headache), and from accompanying anxiety syndromes, depression and cervical syndromes. Only in this way can the abuse of pain-killers or ergotamin be prevented or cut back, the fear of the next attack reduced, and the ability to work maintained as well as the quality of life improved. The strategies of the therapy of migraine attacks and their prophylaxis are summed up.

Humans↗

A slow excitatory postsynaptic potential mediated by 5-HT2 receptors in nucleus prepositus hypoglossi.

Intracellular recordings were made from neurons of the nucleus prepositus hypoglossi in slices of guinea pig medulla. 5-HT (serotonin) caused a hyperpolarization followed by a late depolarization. The hyperpolarization was mediated by 5-HT1A receptor activation and could be selectively blocked by pindobind-5HT1A (PBD). 5-HT then caused a depolarization only. A selective 5-HT2 agonist, (+)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), also caused a depolarization. Ketanserin and spiperone, 5-HT2 antagonists, blocked the depolarization due to both 5-HT and DOI. Focal electrical stimulation caused an IPSP mediated by 5-HT acting upon 5-HT1A receptors and a slow EPSP (s-EPSP). PBD blocked the IPSP, leaving an isolated s-EPSP. Both spiperone and ketanserin antagonized the s-EPSP, while DOI occluded it. The s-EPSP was from 2 to 10 mV in amplitude and 35-50 sec in duration, and showed voltage dependence consistent with a decrease in potassium conductance. Both the IPSP and the s-EPSP were presynaptically inhibited by the 5-HT1D agonist sumatriptan. These data indicate that the s-EPSP is mediated by 5-HT acting upon 5-HT2 receptors. This represents strong support for the role of 5-HT as an excitatory neurotransmitter in the CNS. Further, it demonstrates that synaptic release of 5-HT can mediate opposing effects on the membrane potential of a single cell.

Amphetamines↗

[Endovascular Doppler sonography of intracranial blood vessels. Technical indications and potential applications].

Intravascular Doppler ultrasonography was initially performed with specially designed catheters and was used primarily for cardiological purposes. The recent introduction of a 0.018-in. flexible, steerable guide wire with an integrated 12-MHz piezoelectric transducer (FloWire) has made it possible to use this technique in neuroangiography. This system allows recording of Doppler spectra and determination of blood flow velocities in intracranial vessels after subselective introduction of a standard 3-F microcatheter. The measurement of blood flow velocity in an AVM feeding branch of a middle cerebral artery and the haemodynamic effects of the vasoconstrictive substance sumatriptan on the middle meningeal artery are used to illustrate potential applications of intravascular Doppler ultrasonography in neuroangiography.

Adult↗

The therapeutics of migraine.

This paper reviews the therapeutics of migraine in the context of the clinical problem and its prevalence. General principles of pharmacotherapy for symptomatic and preventive medications are provided. Two new drugs, sumatriptan (recommended for acute symptomatic therapy), and valproic acid (recommended for migraine prevention), are reviewed. The clinical effectiveness and the mechanisms of action of these drugs are discussed.

Brain↗

[Migraine--diagnosis, differential diagnosis and therapy].

Migraine is caused by intermittent brain dysfunction. Attacks result in severe unilateral headache with nausea, vomiting, photophobia, phonophobia and general weakness. The prevalence of migraine is 12 to 20% in women and 8 to 12% in man. Treatment of an acute attack is done by antiemetics in combination with analgesics. Severe migraine attacks are treated with ergotamine or sumatriptan. Parenteral treatment is performed most efficiently and safely with i.v. ASA. Frequent and severe attacks require prophylaxis. Drugs of first choice are metoprolol, propranolol, flunarizine and cyclandelate. Substances of second choice are valproic acid, DHE, pizotifen, methysergide and magnesium. Homeopathic remedies are not superior to placebo. Nonpharmacological treatment consists of sport therapy and muscle relaxation techniques.

Adrenergic beta-Antagonists↗

The way to serotonergic use and abuse in migraine.

5-HT is currently indicated to play a role in migraine (M). Previously evidenced 5-HT supersensitivity which characterizes M is insufficient to compensate for a possible deficit in 5-HT bioavailability. Inducing a further up-regulation of 5-HT receptor can yield improvement of M syndrome. Chronic treatments of methysergide and propranolol, drugs exerting antagonist action at 5-HT receptors, induced a significant amelioration in 256M sufferers. On the contrary, chronic treatments of ergotamine and sumatriptan, both provided with a 5-HT1 agonist activity, induced a worsening of M in 134 M sufferers. The M worsening was paralleled by an increase in consumption of analgesic drugs. Discussion concerns the effects of the chronically given 5-HT agonists and antagonists as well as the possible receptor mechanism underlying "craving for serotonin" in severe M. The increase of 5-HT supersensitivity evidenced at the end of M attacks is also discussed and its role in determining the interruption of the attack is here suggested.

Adult↗

[Unusual varieties of cluster headache].

Atypical forms of cluster headache (CH) are characterized by the association of CH to other headaches and facial neuralgias. Cluster-tic syndrome causes headaches similar to CR and pains similar to trigeminal neuralgia. The disorder is usually of unknown nature and its course is either episodic or chronic. Carbamazepine together with medication for CH is the treatment of choice. A characteristic sensory aura usually develops immediatedly before the attacks of headache in CH-Migraine (CHM). These attacks respond dramatically to subcutaneous sumatriptan and the prophylaxis of CHM is that of CH. CH variant comprises different types of pain and responds to indomethacin. Other unusual varieties of CH are the subchronic and the combined forms, probably related to chronic CH. Finally, the characteristics of CH may be modified by its treatment and chronic abuse of steroids may change the evolution of an episodic CH into a chronic unilateral paroxysmal headache with resembles to but is different from chronic CR. This headache could be called transformed CH (TCH) and to the best of our knowledge the disorder has not been reported up to now. TCH goes undiagnosed and does not respond to the usual treatments of CH. Patients suffering from TCH are frequently sent for surgical treatment which is absolutely contraindicated. Withdrawal of steroids, which is difficult to accomplish, changes TCH into a the former and typical episodic CH, which can now be treated in the usual way.

Adolescent↗

[Zolmitriptan].

One of the outstanding therapeutic revolutions of this last decade has been the introduction of selective serotonin agonists in the acute treatment of migraine. After sumatriptan, introduced in Belgium in 1992, other "triptans" are emerging. The efficacy and the pharmacoeconomic profile of zolmitriptan, the second "triptan" now available in Belgium, are reviewed and the arrival of a third triptan, naratriptan is announced.

Chemistry, Pharmaceutical↗

Effectiveness of intranasal zolmitriptan in acute cluster headache: a randomized, placebo-controlled, double-blind crossover study.

BACKGROUND: Cluster headache is a form of primary headache in which attacks are rapid in onset with very severe pain. The mainstays of acute therapy are inhaled oxygen and sumatriptan succinate injection. OBJECTIVE: To evaluate zolmitriptan nasal spray in the acute treatment of cluster headache. METHODS: Ninety-two patients, aged 40 +/- 10 years (mean +/- SD) (80 men and 12 women), with International Headache Society-defined cluster headache were randomized into a placebo-controlled, double-blind crossover study. Patients treated 3 headache attacks using placebo for 1 attack, 5 mg of zolmitriptan nasal spray (ZNS5) for 1 attack, and 10 mg of zolmitriptan nasal spray for 1 attack. The primary end point was headache relief at 30 minutes, defined as reduction from moderate, severe, or very severe pain to no or mild pain. The study was approved by the appropriate ethics committees. RESULTS: Sixty-nine patients were available for an intention-to-treat analysis. The 30-minute headache relief rates were placebo, 21%; ZNS5, 40%; and ZNS10, 62%. Modeling the response as a binary outcome, the Wald test was significant for the overall regression (chi(2)(1) = 29.4; P<.001), with both ZNS5 and ZNS10 giving significant effects against placebo. Headache relief rates for patients with episodic cluster headache were 30% for placebo, 47% for ZNS5, and 80% for ZNS10, while corresponding rates for patients with chronic cluster headache were 14%, 28%, and 36%, respectively. Zolmitriptan was also well tolerated. CONCLUSION: Five-milligram and 10-mg doses of zolmitriptan intranasal spray are effective within 30 minutes and well tolerated in the treatment of acute cluster headache. Trial Registration controlled-trials.com Identifier ISCRTN27362692.

Acute Disease↗