Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine

Ho, Tony W.; Mannix, Lisa K.; Fan, Xiaoyin; Assaid, Christopher; Furtek, Christine; Jones, Christopher J.; Lines, Christopher; Rapoport, Alan M.

doi:10.1212/01.wnl.0000286940.29755.61

Cited by 426 publications

(368 citation statements)

References 16 publications

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“…Data from a clinical proof-of-concept study demonstrate the effectiveness of olcegepant in the acute treatment of migraine, with the response rate being similar to oral triptans (Olesen et al 2004). These lines of evidence are in accordance with recent findings in a larger, ramdomized controlled trial of the orally available CGRP receptor antagonist MK-0974 (Ho et al 2008), which, similar to olcegepant, is a potent antagonist of the human CGRP receptors (Salvatore et al 2008). Since olcegepant does not induce vasoconstriction per se, this CGRP receptor antagonist has been argued to be safer than triptans, particularly in migraineurs suffering from cardiovascular pathologies.…”

Section: Cgrp Receptorssupporting

confidence: 90%

Current and prospective pharmacological targets in relation to antimigraine action

Mehrotra

Gupta

Chan

et al. 2008

Naunyn-Schmied Arch Pharmacol

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Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT 1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT 2 receptor antagonists, Ca 2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT 1-7 ), adrenergic (α 1 , α 2, and β), calcitonin gene-related peptide (CGRP 1 and CGRP 2 ), adenosine (A 1 , A 2 , and A 3 ), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon.

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Section: Cgrp Receptorssupporting

confidence: 90%

Current and prospective pharmacological targets in relation to antimigraine action

Mehrotra

Gupta

Chan

et al. 2008

Naunyn-Schmied Arch Pharmacol

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“…Drugs selectively targeting the circuits now implicated in migraine, such as glutamate, nitric oxide, triptans, 5-hydroxytryptamine (5-Ht) 1B/1D receptor agonists and calcitonin gene-related peptide (CGRP) receptor antagonists have demonstrated efficacy in both preventing (topiramate) and aborting (triptans, CGRP receptor antagonists) acute migraine attacks. Among these, CGRP receptor antagonists, such us olcegepant (BiBn4096Bs, Olesen et al 2004) and telcagepant (Ho et al 2008, Williams et al 2006 may be the closest to availability for widespread clinical use (Ho et al 2010). Novel therapeutic strategies that consider CSD and cortical hyperexcitability as key targets of preventive migraine treatment promise to improve the lives of the large number of migraine sufferers.…”

Section: Discussionmentioning

confidence: 99%

CaV2.1 voltage activated calcium channels and synaptic transmission in familial hemiplegic migraine pathogenesis

Uchitel

Inchauspe

Urbano

et al. 2012

Journal of Physiology-Paris

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“…Recently, CGRP antagonists have been developed with clinical efficacy for the treatment of acute migraine attacks [10-12]. Consequently, it is of considerable importance to clarify where the CGRP receptor is expressed which would indicate possible sites for the therapeutic effect of these antagonists.…”

Section: Introductionmentioning

confidence: 99%

Calcitonin gene-related peptide (CGRP) and its receptor components in human and rat spinal trigeminal nucleus and spinal cord at C1-level

2011

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BackgroundCalcitonin gene-related peptide (CGRP) has a key role in migraine pathophysiology and is associated with activation of the trigeminovascular system. The trigeminal ganglion, storing CGRP and its receptor components, projects peripheral to the intracranial vasculature and central to regions in the brainstem with Aδ- and C-fibers; this constitutes an essential part of the pain pathways activated in migraine attacks. Therefore it is of importance to identify the regions within the brainstem that processes nociceptive information from the trigeminovascular system, such as the spinal trigeminal nucleus (STN) and the C1-level of the spinal cord. Immunohistochemistry was used to study the distribution and relation between CGRP and its receptor components - calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1) - in human and rat STN and at the C1-level, using a set of newly well characterized antibodies. In addition, double-stainings with CGRP and myelin basic protein (MBP, myelin), synaptophysin (synaptic vesicles) or IB4 (C-fibers in general) were performed.ResultsIn the STN, the highest density of CGRP immunoreactive fibers were found in a network around fiber bundles in the superficial laminae. CLR and RAMP1 expression were predominately found in fibers in the spinal trigeminal tract region, with some fibers spanning into the superficial laminae. Co-localization between CGRP and its receptor components was not noted. In C1, CGRP was expressed in fibers of laminae I and II. The CGRP staining was similar in rat, except for CGRP positive neurons that were found close to the central canal. In C1, the receptor components were detected in laminae I and II, however these fibers were distinct from fibers expressing CGRP as verified by confocal microscopy.ConclusionsThis study demonstrates the detailed expression of CGRP and its receptor components within STN in the brainstem and in the spinal cord at C1-level, and shows the possibility of CGRP acting postjunctionally in these areas putatively involved in primary headaches.

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Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine

Abstract: The novel, orally administered calcitonin gene-related peptide (CGRP) receptor antagonist, MK-0974, was effective and generally well tolerated for the acute treatment of migraine.

Cited by 426 publications

References 16 publications

Current and prospective pharmacological targets in relation to antimigraine action

Current and prospective pharmacological targets in relation to antimigraine action

CaV2.1 voltage activated calcium channels and synaptic transmission in familial hemiplegic migraine pathogenesis

Calcitonin gene-related peptide (CGRP) and its receptor components in human and rat spinal trigeminal nucleus and spinal cord at C1-level

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