Consensus Statement: Cardiovascular Safety Profile of Triptans (5‐HT<sub>1B/1D</sub> Agonists) in the Acute Treatment of Migraine

Dodick, David W.; Lipton, Richard B.; Martin, Vincent T.; Papademetriou, Vasilios; Rosamond, Wayne D.; MaassenVanDenBrink, Antoinette; Loutfi, Hassan; Welch, K. M. A.; Goadsby, Peter J.; Hahn, Steven R.; Hutchinson, Susan; Matchar, David B.; Silberstein, Stephen D.; Smith, Timothy R.; Purdy, R. Allan; Saiers, Jane

doi:10.1111/j.1526-4610.2004.04078.x

Cited by 317 publications

(221 citation statements)

References 59 publications

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“…These effects are not exclusive for the trigeminovascular system but include, in particular, the coronary circulation. The Triptan Cardiovascular Safety Expert Panel (Dodick et al, 2004) recommended their use in the absence of cardiac contraindications. Therefore, the development of CGRP receptor antagonists seemed to be an alternative perspective for antimigraine therapy.…”

Section: Introductionmentioning

confidence: 99%

The Nonpeptide Calcitonin Gene-Related Peptide Receptor Antagonist BIBN4096BS Lowers the Activity of Neurons with Meningeal Input in the Rat Spinal Trigeminal Nucleus

Fischer¹,

Koulchitsky²,

Meßlinger³

2005

J. Neurosci.

123

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Calcitonin gene-related peptide (CGRP) has been suggested to play a major role in the pathogenesis of migraines and other primary headaches. CGRP may be involved in the control of neuronal activity in the spinal trigeminal nucleus (STN), which integrates nociceptive afferent inputs from trigeminal tissues, including intracranial afferents. The activity of STN neurons is thought to reflect the activity of central trigeminal nociceptive pathways causing facial pain and headaches in humans.In a rat model of meningeal nociception, single neuronal activity in the STN was recorded. All units had receptive fields located in the exposed parietal dura mater. Heat and cold stimuli were repetitively applied to the dura in a fixed pattern of ramps and steps. The nonpeptide CGRP receptor antagonist BIBN4096BS was topically applied onto the exposed dura or infused intravenously. BIBN4096BS (300 g/kg, i.v.) reduced spontaneous activity by ϳ30%, the additional dose of 900 g/kg intravenously by ϳ50% of the initial activity, whereas saline had no effect. The activity evoked by heat ramps was also reduced after BIBN4096BS (900 g/kg, i.v.) by ϳ50%. Topical administration of BIBN4096BS (1 mM) did not significantly change the spontaneous neuronal activity within 15 min.We conclude that the endogenous release of CGRP significantly contributes to the maintenance of spontaneous activity in STN neurons. Blockade of CGRP receptors, possibly at central and peripheral sites, may therefore be an effective way to decrease nociceptive transmission. This may offer a new therapeutic strategy for the treatment of facial pain and primary headaches.

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Section: Introductionmentioning

confidence: 99%

The Nonpeptide Calcitonin Gene-Related Peptide Receptor Antagonist BIBN4096BS Lowers the Activity of Neurons with Meningeal Input in the Rat Spinal Trigeminal Nucleus

Fischer¹,

Koulchitsky²,

Meßlinger³

2005

J. Neurosci.

123

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“…Such compounds would provide a new option for migraine treatment with the potential for a differentiated profile relative to the standard of care, the 5-hydroxytryptamine 1B/1D receptor agonists, which form the triptan class of antimigraine drugs. Whereas triptans are adequately safe when used appropriately (Dodick et al, 2004), these compounds are contraindicated for patients with cardiovascular disease because they are potent vasoconstrictors (Goadsby et al, 2002). A CGRP receptor antagonist is expected to be devoid of direct vasoconstrictor activity (Doods, 2001;Edvinsson, 2003;Petersen et al, 2003) and would be a significant advance in the current standard of migraine care.…”

mentioning

confidence: 99%

Pharmacological Characterization of MK-0974 [N-[(3R,6S)-6-(2,3-Difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide], a Potent and Orally Active Calcitonin Gene-Related Peptide Receptor Antagonist for the Treatment of Migraine

Salvatore¹,

Hershey²,

Corcoran³

et al. 2007

J Pharmacol Exp Ther

135

111

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Calcitonin gene-related peptide (CGRP) is a potent neuropeptide that plays a key role in the pathophysiology of migraine headache. CGRP levels in the cranial circulation are increased during a migraine attack, and CGRP itself has been shown to trigger migraine-like headache. The correlation between CGRP release and migraine headache points to the potential utility of CGRP receptor antagonists as novel therapeutics in the treatment of migraine. Indeed, clinical proof-of-concept in the acute treatment of migraine was demonstrated with an intravenous formulation of the CGRP receptor antagonist BIBN4096BS (olcegepant). Here we report on the pharmacological characterization of the first orally bioavailable CGRP receptor antagonist in clinical development, MK-MK-0974 is a potent antagonist of the human (K i ϭ 0.77 nM) and rhesus (K i ϭ 1.2 nM) CGRP receptors but displays Ͼ1500-fold lower affinity for the canine and rat receptors as determined via 125 I-human CGRP competition binding assays. A rhesus pharmacodynamic assay measuring capsaicin-induced changes in forearm dermal blood flow via laser Doppler imaging was utilized to determine the in vivo activity of CGRP receptor antagonism. MK-0974 produced a concentration-dependent inhibition of dermal vasodilation, generated by capsaicininduced release of endogenous CGRP, with plasma concentrations of 127 and 994 nM required to block 50 and 90% of the blood flow increase, respectively. In conclusion, MK-0974 is a highly potent, selective, and orally bioavailable CGRP receptor antagonist, which may be valuable in the acute treatment of migraine.CGRP is a 37 amino acid neuropeptide produced by tissuespecific alternative mRNA splicing of the calcitonin gene (Amara et al., 1982) and is a member of the calcitonin family of peptides, which includes calcitonin, amylin, and adrenomedullin. CGRP activity is mediated by the coexpression of a G-protein-coupled receptor, calcitonin receptor-like receptor, a single transmembrane-spanning protein designated receptor activity-modifying protein (RAMP) 1 (McLatchie et al., 1998), and an intracellular protein, receptor component proArticle, publication date, and citation information can be found at

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“…6 Moreover, there are important contraindications to their use in the setting of cardiovascular and cerebrovascular disease. 7 Against this background, both new formulations of current medicines and altogether new approaches to treatment are being developed. The articles in this issue of Neurotherapeutics address a common theme: better treatment of patients with headache disorders.…”

Section: Introductionmentioning

confidence: 99%

Headache

Goadsby

2010

Neurotherapeutics

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Consensus Statement: Cardiovascular Safety Profile of Triptans (5‐HT_1B/1D Agonists) in the Acute Treatment of Migraine

Cited by 317 publications

References 59 publications

The Nonpeptide Calcitonin Gene-Related Peptide Receptor Antagonist BIBN4096BS Lowers the Activity of Neurons with Meningeal Input in the Rat Spinal Trigeminal Nucleus

The Nonpeptide Calcitonin Gene-Related Peptide Receptor Antagonist BIBN4096BS Lowers the Activity of Neurons with Meningeal Input in the Rat Spinal Trigeminal Nucleus

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Consensus Statement: Cardiovascular Safety Profile of Triptans (5‐HT1B/1D Agonists) in the Acute Treatment of Migraine

Cited by 317 publications

References 59 publications

The Nonpeptide Calcitonin Gene-Related Peptide Receptor Antagonist BIBN4096BS Lowers the Activity of Neurons with Meningeal Input in the Rat Spinal Trigeminal Nucleus

The Nonpeptide Calcitonin Gene-Related Peptide Receptor Antagonist BIBN4096BS Lowers the Activity of Neurons with Meningeal Input in the Rat Spinal Trigeminal Nucleus

Headache

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Consensus Statement: Cardiovascular Safety Profile of Triptans (5‐HT_1B/1D Agonists) in the Acute Treatment of Migraine