Gepants

Migraine is a highly prevalent, complex neurological disorder. The burden of disease and the direct/indirect annual costs are enormous. Thus far, treatment options have been inadequate and mostly based on trial and error, leaving a significant unmet need for effective therapies. While the underlying pathophysiology of migraine is incompletely understood, blocking the calcitonin gene-related peptide (CGRP) using monoclonal antibodies targeting CGRP or its receptor and small molecule CGRP receptor antagonists (gepants) have emerged as a promising therapeutic opportunity for the management of migraine...

The neuropeptide calcitonin gene-related peptide is well established as a key player in the pathogenesis of migraine. Clinical studies show calcitonin gene-related peptide levels correlate with migraine attacks, and decreases in this neuropeptide can indicate antimigraine therapy effectiveness. Research has revealed a wide distribution of expression sites for calcitonin gene-related peptide in the central and peripheral nervous system. Of these, the calcitonin gene-related peptide receptor, which binds calcitonin gene-related peptide with high affinity, has attracted growing interest as a viable target for antimigraine therapies...

Background A better understanding of the mechanisms underlying the migraine attack has reinforced the concept that migraine is a complex brain disease, and has paved the way for the development of new migraine specific acute treatments. In recent years, targeting the calcitonin gene-related peptide and its receptors has been one of the most promising pharmacological strategies for both acute and preventive treatment of migraine. Findings Randomized double-blind placebo-controlled trials have demonstrated the superiority of small molecule calcitonin gene-related peptide receptor antagonists (gepants) over placebo in treating acute migraine attacks measured as the two-hour pain free endpoint...

Migraine varies in its frequency, severity, and impact; treatment should consider these variations and the patient's needs and goals. Migraine pharmacologic treatment may be acute (abortive) or preventive (prophylactic), and patients often require both. New medication devices are available or in development, including an intracutaneous, microneedle system of zolmitriptan and sumatriptan, and breath-powered powder sumatriptan intranasal treatment. Lasmiditan, a 5-HT1F receptor agonist, is in development for acute treatment, as are small molecule calcitonin gene-related peptide (CGRP) receptor antagonists (Gepants) for acute and preventive treatment...

Migraine is a neurovascular disorder. Current acute specific antimigraine pharmacotherapies target trigeminovascular 5-HT1B/1D , 5-HT1F and CGRP receptors but, unfortunately, they induce some cardiovascular and central side effects that lead to poor treatment adherence/compliance. Therefore, new antimigraine drugs are being explored. Areas covered: This review considers the adverse (or potential) side effects produced by current and prospective antimigraine drugs, including medication overuse headache (MOH) produced by ergots and triptans, the side effects observed in clinical trials for the new gepants and CGRP antibodies, and a section discussing the potential effects resulting from disruption of the cardiovascular CGRPergic neurotransmission...

Premise The brain and the sensory nervous system contain a rich supply of calcitonin gene-related peptide (CGRP) and CGRP receptor components. Clinical studies have demonstrated a correlation between CGRP release and acute migraine headache that led to the development of CGRP-specific drugs that either abort acute attacks of migraine (gepants) or are effective as prophylaxis (antibodies). However, there is still much discussion concerning the site of action of these drugs. Problem Here we describe the most recent data related to CGRP in the trigeminal ganglion and its connections to the CNS, putative key regions involved in migraine pathophysiology...

The trigeminovascular system plays a key role in the pathophysiology of migraine. The activation of the trigeminovascular system causes release of various neurotransmitters and neuropeptides, including serotonin and calcitonin gene-related peptide (CGRP), which modulate pain transmission and vascular tone. Thirty years after discovery of agonists for serotonin 5-HT1B and 5-HT1D receptors (triptans) and less than fifteen after the proof of concept of the gepant class of CGRP receptor antagonists, we are still a long way from understanding their precise site and mode of action in migraine...

Migraine is the most prevalent neurological disorder worldwide and it has immense socioeconomic impact. Currently, preventative treatment options for migraine include drugs developed for diseases other than migraine such as hypertension, depression and epilepsy. During the last decade, however, blocking calcitonin gene-related peptide (CGRP) has emerged as a possible mechanism for prevention of migraine attacks. CGRP has been shown to be released during migraine attacks and it may play a causative role in induction of migraine attacks...

Headache disorders are common worldwide and often disabling. Until recently, treatments were borrowed from other branches of neurology and medicine. Monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) ligand and receptor, small molecule CGRP receptor antagonist gepants, serotonin1F agonists, new devices to deliver currently available drugs, and neuromodulation devices have recently been in the forefront of headache treatments that are rather specific for various headache disorders. These novel therapies are changing the field of headache medicine...

The trigeminal ganglion plays a key role in primary headache pathophysiology. Calcitonin gene-related peptide (CGRP) and CGRP receptors are expressed in trigeminal neurons that form C-fibers and A-fibers, respectively. In acute migraine and cluster headache attacks, there is release of CGRP into the cranial venous outflow. In addition, intravenous CGRP can induce migraine-like symptoms in migraine patients. These findings led to the development of anti-migraine therapies that inhibit CGRP action. Currently, CGRP receptor antagonists, the gepants, and monoclonal antibodies towards CGRP and the CGRP receptor are all showing positive relief of acute and chronic migraine in clinical trials...

Migraine is a common brain disorder with high disability rates which involves a series of abnormal neuronal networks, interacting at different levels of the central and peripheral nervous system. An increase in the interest around migraine pathophysiology has allowed researchers to unravel certain neurophysiological mechanisms and neurotransmitter involvement culminating in the recent development of novel therapies, which might substantially change the clinical approach to migraine patients. The present review will highlight the current aspects of migraine pathophysiology, covering an understanding of the complex workings of the migraine state and the brain regions responsible for them...

AIM: The neuropeptide calcitonin gene-related peptide (CGRP) is found in afferent sensory nerve fibers innervating the resistance arteries and plays a pivotal role in a number of neurovascular diseases such as migraine and subarachnoid bleedings. The present study investigates the binding and antagonistic characteristics of small non-peptide CGRP receptor antagonists (i.e. gepants) in isolated rat brain and mesenteric resistance arteries. METHODS: The antagonistic behavior of gepants was investigated in isolated rat mesenteric arteries using a wire myograph setup while binding of gepants to CGRP receptors was investigated in rat brain membranes using a radioligand competitive binding assay...

Plaguing humans for more than two millennia, manifest on every continent studied, and with more than one billion patients having an attack in any year, migraine stands as the sixth most common cause of disability on the planet. The pathophysiology of migraine has emerged from a historical consideration of the "humors" through mid-20th century distraction of the now defunct Vascular Theory to a clear place as a neurological disorder. It could be said there are three questions: why, how, and when? Why: migraine is largely accepted to be an inherited tendency for the brain to lose control of its inputs...

BACKGROUND: Migraine is a paroxysmal, disabling primary headache that affects 16 % of the adult population. In spite of decades of intense research, the origin and the pathophysiology mechanisms involved are still not fully known. Although triptans and gepants provide effective relief from acute migraine for many patients, their site of action remains unidentified. It has been suggested that during migraine attacks the leakiness of the blood-brain barrier (BBB) is altered, increasing the passage of anti-migraine drugs...

Recently developed calcitonin gene-related peptide (CGRP) receptor antagonistic molecules have shown promising results in clinical trials for acute treatment of migraine attacks. Drugs from the gepant class of CGRP receptor antagonists are effective and do not cause vasoconstriction, one of the major limitations in the use of triptans. However their use had to be discontinued because of risk of liver toxicity after continuous exposure. As an alternative approach to block CGRP transmission, fully humanized monoclonal antibodies towards CGRP and the CGRP receptor have been developed for treatment of chronic migraine (attacks >15 days/month)...

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...

This short review aims to give a focus on news in the migraine attack treatment and discusses the CGRP receptor antagonists (gepants), the 5-HT1F receptors agonists (ditans), the transcranial magnetic stimulation for the treatment of migraine attack with aura, innovative delivery systems for sumatriptan and the oral inhalation of dihydroergotamine.

While triptans, the 5-HT1B/1D agonists, are effective and generally well-tolerated in many patients up to one-third of migraine patients either may not respond well to triptans, may not tolerate their side effects, or may have contraindications that preclude their use. Recurrence, triptan-related side effects, and cardiovascular constriction effects are demerits for acute migraine treatment. CGRP receptor antagonists, the so-called gepants, were clearely designed and expected to be better than triptans. CGRP is located in sensory nerve endings around cranial blood vessels...

INTRODUCTION: Migraine afflicts approximately 11% of the population worldwide producing substantial disability, resulting in loss of productivity both at home and at the workplace. Calcitonin gene-related peptide (CGRP) is closely involved in the cascade of molecular events leading to migraine painful crisis. AREAS COVERED: Acute treatment of migraine is actually based on the use of triptans, class drug which presents a clear limitation due to its cardiovascular side effects...

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...