New Agents for Acute Treatment of Migraine: CGRP Receptor Antagonists, iNOS Inhibitors

Department of Neurology, University of California, San Francisco, 1701 Divisadero Street, Suite 480, San Francisco, CA, 94115, USA.
Current Treatment Options in Neurology (Impact Factor: 1.94). 11/2011; 14(1):50-9. DOI: 10.1007/s11940-011-0155-4
Source: PubMed


OPINION STATEMENT: The treatment of migraine was advanced dramatically with the introduction of triptans in the early 1990s. Despite the substantial improvement in the quality of life that triptans have brought to many migraineurs, a substantial cohort of patients remain highly disabled by attacks and need new therapeutic approaches, which ideally should be quick-acting, have no vasoconstrictor activity, and have a longer duration of action and be better tolerated than current therapies. The calcitonin gene-related peptide (CGRP) receptor antagonists (gepants)-olcegepant (BIBN 4096 BS), telcagepant (MK-0974), MK3207, and BI 44370 TA-are effective in treating acute migraine. They have no vasoconstrictive properties, fewer adverse effects, and may act longer than triptans. Their development has been complicated by liver toxicity issues when used as preventives. Results from studies with BI 44370 TA do not support broad concern about a class effect, and further studies are ongoing in this respect. Many experimental studies and clinical trials suggest that nitric oxide may have a role in the pathophysiology of migraine. Therefore, the inhibition of nitric oxide synthase (NOS) for the acute or prophylactic treatment of migraine offered a feasible approach; as inducible NOS (iNOS) is involved in several pain states, such as inflammatory pain, it appeared to be an attractive target. However, despite high selectivity and potency, the iNOS inhibitor GW274150 was not effective for acute treatment or prophylaxis of migraine, suggesting that iNOS is very unlikely to be a promising target.

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    • "Four chemically unrelated CGRP receptor (CGRP-R) antagonists (olcegepant, telcagepant, MK-3207 and BI 44370 TA) have displayed efficacy in the treatment of migraine [192]. They have fewer adverse effects, and act for a longer period than triptans [193]. Their development has been slowed by a liver toxicity when used as preventives. "
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    ABSTRACT: Spreading depression (SD) is a slowly propagating wave of neuronal and glial depolarization lasting a few minutes, that can develop within the cerebral cortex or other brain areas after electrical, mechanical or chemical depolarizing stimulations. Cortical SD (CSD) is considered the neurophysiological correlate of migraine aura. It is characterized by massive increases in both extracellular K+ and glutamate, as well as rises in intracellular Na+ and Ca2+. These ionic shifts produce slow direct current (DC) potential shifts that can be recorded extracellularly. Moreover, CSD is associated with changes in cortical parenchymal blood flow. CSD has been shown to be a common therapeutic target for currently prescribed migraine prophylactic drugs. Yet, no effects have been observed for the antiepileptic drugs carbamazepine and oxcarbazepine, consistent with their lack of efficacy on migraine. Some molecules of interest for migraine have been tested for their effect on CSD. Specifically, blocking CSD may play an enabling role for novel benzopyran derivative tonabersat in preventing migraine with aura. Additionally, calcitonin gene-related peptide (CGRP) antagonists have been recently reported to inhibit CSD, suggesting the contribution of CGRP receptor activation to the initiation and maintenance of CSD not only at the classic vascular sites, but also at a central neuronal level. Understanding what may be lying behind this contribution, would add further insights into the mechanisms of actions for “gepants”, which may be pivotal for the effectiveness of these drugs as anti-migraine agents. CSD models are useful tools for testing current and novel prophylactic drugs, providing knowledge on mechanisms of action relevant for migraine.
    Full-text · Article · Jul 2013 · The Journal of Headache and Pain
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    • "The neuropeptide calcitonin gene-related peptide (CGRP) is hypothesized to play an important role in migraine pathology (Durham, 2008; Ho et al., 2010). Serum levels of CGRP are increased during migraine attack (Goadsby et al., 1990) (however, see Tvedskov et al., 2005); migraine patients infused with CGRP develop a delayed headache, fulfilling the criteria of a migraine (Lassen et al., 2002); and infusion of CGRP receptor antagonists have been shown to effectively treat migraine pain (Durham and Vause, 2010; Fischer, 2010; Hoffmann and Goadsby, 2011). Importantly, treatment of migraine headache pain with sumatriptan has been shown to correlate with normalization of CGRP levels e an effect that paralleled migraine resolution (Edvinsson and Ho, 2010; Goadsby and Edvinsson, 1993; Sarchielli et al., 2006; Stepien et al., 2003). "
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    ABSTRACT: The selective 5-HT₁ receptor agonist sumatriptan is an effective therapeutic for migraine pain yet the antimigraine mechanisms of action remain controversial. Pain-responsive fibres containing calcitonin gene-related peptide (CGRP) densely innervating the cranial dura mater are widely believed to be an essential anatomical substrate for the development of migraine pain. 5-HT₁ receptors in the dura colocalize with CGRP fibres in high density and thus provide a possible peripheral site of action for sumatriptan. In the present study, we used high-resolution optical imaging selectively within individual mouse dural CGRP nociceptive fibre terminations and found that application of sumatriptan caused a rapid, reversible dose-dependent inhibition in the amplitude of single action potential evoked Ca²⁺ transients. Pre-application of the 5-HT₁ antagonist GR 127935 or the selective 5-HT(1D) antagonist BRL 15572 prevented inhibition while the selective 5-HT(1B) antagonist SB 224289 did not, suggesting this effect was mediated selectively through the 5-HT(1D) receptor subtype. Sumatriptan inhibition of the action potential evoked Ca²⁺ signaling was mediated selectively through N-type Ca²⁺ channels. Although the T-type Ca²⁺ channel accounted for a greater proportion of the Ca²⁺ signal it did not mediate any of the sumatriptan inhibition. Our findings support a peripheral site of action for sumatriptan in inhibiting the activity of dural pain fibres selectively through a single Ca²⁺ channel subtype. This finding adds to our understanding of the mechanisms that underlie the clinical effectiveness of 5-HT₁ receptor agonists such as sumatriptan and may provide insight for the development of novel peripherally targeted therapeutics for mitigating the pain of migraine.
    Full-text · Article · Apr 2012 · Neuropharmacology
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    ABSTRACT: The first edition of the Italian diagnostic and therapeutic guidelines for primary headaches in adults was published in J Headache Pain 2(Suppl. 1):105-190 (2001). Ten years later, the guideline committee of the Italian Society for the Study of Headaches (SISC) decided it was time to update therapeutic guidelines. A literature search was carried out on Medline database, and all articles on primary headache treatments in English, German, French and Italian published from February 2001 to December 2011 were taken into account. Only randomized controlled trials (RCT) and meta-analyses were analysed for each drug. If RCT were lacking, open studies and case series were also examined. According to the previous edition, four levels of recommendation were defined on the basis of levels of evidence, scientific strength of evidence and clinical effectiveness. Recommendations for symptomatic and prophylactic treatment of migraine and cluster headache were therefore revised with respect to previous 2001 guidelines and a section was dedicated to non-pharmacological treatment. This article reports a summary of the revised version published in extenso in an Italian version.
    Full-text · Article · May 2012 · The Journal of Headache and Pain
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