5ht1d

OBJECTIVE: To investigate the systemic, pulmonary, and coronary artery effects of eletriptan, a new 5HT1B/1D-agonist in patients undergoing cardiac catheterization. METHODS: Ten patients (two men and eight women) without significant obstructive coronary artery disease were administered 3.33 microg/kg/min intravenous eletriptan after they were given a placebo infusion of 0.9% saline solution. Serial measurements of right heart and systemic pressures were taken at 5-minute intervals during placebo infusion, eletriptan infusion, and a 30-minute postinfusion period...

The serotonergic system has been implicated in both the aetiology and pharmacological treatment of obsessive compulsive disorder. In pharmacological challenge tests, mCPP, a 5-HT agonist, with an affinity for 5HT2C as well as 5HT1A and 5HT1D receptors, was associated with a transient exacerbation of obsessive compulsive symptoms. Chronic administration of mCPP was found to bring about some relief of these symptoms. Sumatriptan is an antimigraine agent, which interacts most potently with 5HT1D receptors. In the cases to be presented, we report the effects of chronic administration of Sumatriptan to three severe, treatment resistant, OCD patients...

New dimers of known 5HT1 ligands (5HT, 1-NP or 8-OH-DPAT) have been prepared and evaluated at human cloned 5HT1B, 5HT1D and 5HT1A receptors. Binding experiments show that all these dimers have better affinities at 5HT1B/1D receptors than their corresponding monomeric ligands. Studies of inhibition of the forskolin-stimulated c-AMP formation mediated by the human 5HT1B receptor show that hetero-bivalent ligands [combining an agonist (5HT) with an antagonist (1-NP)] behave as partial agonists while the intrinsic activity of bivalent antagonists (combining two 1-NP residues) was found to be spacer dependent...

Zolmitriptan, an oral 5HT1D agonist for the acute treatment of migraine, is cleared from the systemic circulation mainly by hepatic metabolism. Consequently, changes in hepatic function may result in changes in the pharmacokinetics of zolmitriptan. This open, parallel-group study was conducted to compare the pharmacokinetics and tolerability of a single 10-mg dose of zolmitriptan in healthy subjects and patients with hepatic impairment. A total of 37 participants entered and completed the study, including 10 healthy volunteers, 11 patients with moderate hepatic impairment, 10 patients with severe hepatic impairment without ascites, and 6 patients with severe hepatic impairment with ascites...

Heterologous expression of cloned receptor subtypes for screening programs has become a real necessity for a modern pharmaceutical company. As the expression levels obtained so far are often low or unstable, we addressed this problem by using an inducible promoter system, i.e. the interferon-inducible mouse Mxl promoter. Using the gene coding for chloramphenicol acetyltransferase (CAT) as a reporter gene, we tested the inducibility of this promoter in the murine cell line L929. We found that background expression was low and that a distinct interferon-induced expression could be obtained...

To investigate the possible role of 5HT1B and/or 5HT1D receptors in controlling neurogenic inflammation, we performed a co-localization study of the mRNA for 5HT1B and 5HT1D receptors and of substance P or calcitonin gene-related peptide (CGRP) mRNA in the guinea pig trigeminal ganglion using double labelling in situ hybridization techniques. The 5HT1D receptor mRNA is abundant whereas 5HT1B receptor mRNA is scarce. The vast majority of cells containing substance P mRNA also contained 5HT1B receptor mRNA, but very few cells expressed substance P mRNA and 5HT1D receptor mRNA...

Sumatriptan, a 5HT1B/1D-receptor agonist, is clinically effective as an antimigraine agent. Its therapeutic action may result partly from vasoconstriction of excessively dilated cranial blood vessels (a 5HT1B-receptor mediated response). The antimigraine activity of sumatriptan may also result from inhibition of the release of vasoactive neuropeptides from trigeminal sensory fibres within the meninges. The identity of the 5HT1B/1D-receptor subtype mediating this effect is unknown. Using 5HT1D- and 5HT1B-receptor-specific antibodies we have demonstrated a differential distribution of these receptor subtypes within the human trigemino-cerebrovascular system...

Spreading depression is a neurohumoral phenomenon that has been related to the pathophysiology of migraine. The recently introduced 5HT1D agonist anti-migraine compound sumatriptan blocks neurogenic extravasation and induces cerebral vasoconstriction, but the actual mechanism of action against migraine remains obscure. Retinal spreading depression (RSD) velocity has been measured in isolated chick retinas in the presence of 0.05-2.00 mM sumatriptan. This drug reversibly blocks RSD in a concentration-dependent manner...

A linkage and association analysis was made on 14 Italian families with recurrent migraine. We analyzed five chromosomal regions surrounding the candidate genes 5HT1D (1p36.3-34.3), 5HT1B (6q13), 5HT2A (13q14-21), 5HT transporter (17q11.2-12), CACNLB1 (17q11.2-22) and FHM (19p13), using 29 DNA polymorphic markers. All two-point lod scores were negative, and the chi 2 sib-pair analyses were not significant, thus indicating the probable exclusion of these regions as sites of migraine genes in our population.

Zolmitriptan (Zomig, formerly 311C90) is a novel, oral, acute treatment for migraine. In healthy volunteers it is rapidly and extensively absorbed and has favorable oral bioavailability (approximately 40%) which is not affected by concomitant food intake. On average, 75% of its eventual Cmax is achieved within 1 h of dosing. Plasma concentrations are sustained for 4 to 6 h after dosing with single or multiple peaks in the plasma concentration-time profile, reflecting continued absorption down the gastrointestinal tract...

The study of serotonin (5-HT) receptors from the points of view of their anatomical localization and pharmacological characterization has been linked to the availability of highly selective radioligands exhibiting high affinity for their targets. This is particularly so in the case of serotonin receptors, since many different subtypes with overlapping pharmacological profiles have been described. Of these, the serotonin 5-HT1 receptor family appears to be the most complex in terms of molecular diversity and pharmacological properties...

AIMS: Two open studies in healthy volunteers were conducted to determine the absolute bioavailability and metabolic disposition of zolmitriptan (311C90), a novel 5HT1D agonist for the acute treatment of migraine. METHODS: After an initial test i.v. infusion, bioavailability was assessed by comparison of AUC after an i.v. infusion (3.5 mg) and an oral tablet (10 mg), in six men and six women using a randomised, crossover design. Disposition was studied by administration of a 25 mg capsule, labelled with 100 microCi [14C]-zolmitriptan, to five men and one woman on a single occasion...

The biological profile of naratriptan (N-methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethane-sulphonamide), a novel 5HT1B/1D receptor agonist, was investigated in a variety of experimental models of relevance to migraine. Naratriptan has high affinity for human recombinant 5HT1B and 5HT1D receptors (pKi = 8.7 +/- 0.03 and 8.3 +/- 0.1, respectively) and causes contractions of dog isolated basilar and middle cerebral artery (EC50 values of 0.11 and 0.07 microM, respectively). Naratriptan causes small contractions of human isolated coronary arteries (EC50 value of 0...

The novel antimigraine drug 311C90 (Zomig; zolmitriptan) has a high selectivity for serotonin (5HT)1 receptors, mainly 5HT1B and 5HT1D subtypes, and in preclinical studies it has been shown to act on four different sites within the trigemino-vascular system (blockade of neurogenic inflammation by inhibition of peptide release, vasoconstriction, inhibition of neuronal depolarization at peripheral sites, and effects at central sites). Oral 311C90 has a favorable pharmacokinetic profile. It is rapidly absorbed, with 75% of maximal plasma concentration (Cmax) attained within 1 hour and good absolute oral bioavailability (approximately 40%)...

Alniditan is a new 5HT1D receptor agonist, belonging to a different chemical class from sumatriptan and other indole derivatives used or being developed for the treatment of acute migraine. In a multinational double-blind randomized parallel-groups dose-finding trial, alniditan was given subcutaneously in hospital to patients with migraine headache of moderate or severe intensity at doses of 0.8 mg (n = 44), 1.0 mg (n = 42), 1.2 mg (n = 46) and 1.4 mg (n = 39). Efficacy, tolerability and safety of each dose were compared with those of placebo (n = 41)...

The 5HT1D agonist sumatriptan is efficacious in the treatment of migraines. MK-462 is a drug of the same class which is under development in our laboratories. Bioanalytical methods of high efficiency, specificity and sensitivity were required to support the preclinical and clinical programs. These assays were based on HPLC with tandem MS-MS detection. MK-462 and sumatriptan were extracted using an automated solid-phase extraction technique on a C2 Varian Bond-Elut cartridge. The n-diethyl analogues of MK-462 and sumatriptan were used as internal standards...

The anatomical distribution of [3H]sumatriptan-binding sites was analysed in brain tissue sections from 11 subjects. Relevant concentrations of [3H]sumatriptan-binding sites were seen in areas such as visual cortex > locus niger > globus pallidus > layers IV-V of the frontal cortex > subiculum > entorhinal cortex > nucleus tractus solitarius > nucleus trigeminalis caudalis. This distribution of [3H]sumatriptan-binding sites in the human brain shows some differences when compared with that of 5HT1D receptors, confirming that, besides 5HT1D, sumatriptan also binds to 5HT1F receptor subtype...

5-Hydroxytryptamine (serotonin, 5-HT), essentially known as a neurotransmitter and vasoactive agent, also functions as a mitogen in various cell types through several different second messenger systems. Stimulation of cloned human 5-HT1D receptor sites by sumatriptan in stably transfected rat C6-glial/5-HT1D cells promotes cell growth (Pauwels et al. (1996) Naunyn-Schmiedeberg's Arch Pharmacol 353:144-156). In the present study, the pharmacology of this growth response was investigated using a broad series of 5-HT receptor ligands...

In the 1990s, the Decade of the Brain, significant progress has been made in our understanding of the pathophysiological events that take place during a migraine attack. Simultaneously, a big step forward has been made as regards drug therapy. The development of the 5-Hydroxy Tryptamine ID (5HT1D)-agonist sumatriptan has changed the lives of many migraine sufferers. This review describes attack management with analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), ergotamines and sumatriptan. Adverse events associated with ergotamines and use of sumatriptan are focused upon, with special attention to the pharmacokinetic and pharmacodynamic aspects of both these drugs...

The oral absorption of a 10-mg oral dose of the novel 5-hydroxytryptamine (5HT1D) agonist, 311C90, was compared during a moderate or severe migraine headache and in a migraine-free period in an open, two-period study. The safety and efficacy of 311C90 in acute migraine were also assessed. Twenty patients attended the clinics during a moderate or severe migraine attack and 18 patients returned for a second dose in a migraine-free period. 311C90 was less rapidly absorbed during a migraine attack compared to the migraine-free period, consistent with gastric stasis during a migraine attach...