Gene-related Peptide Antagonist Research Articles

THE EFFICACY OF CGRP ANTAGONISTS IN THE TREATMENT OF MIGRAINE (Review Article)

Migraine is one of the most common and disabling diseases in the world. The usage of Calcitonin Gene-Related Peptide (CGRP) antagonist drugs has been on the horizon and looks to be a promising treatment option. Growing evidence suggests that CGRP plays a key role in the development of peripheral sensitization and associated enhanced pain. CGRP is involved in the development of neurogenic inflammation and is upregulated in inflammatory and neuropathic pain conditions. Drugs like Erenumab, Rimegepant, Olcegepant and others of the same category have shown significantly fewer side effects along with high therapeutic effects, which makes this group of drugs a useful addition to the existing therapeutic options.

Retracted: Calcitonin Gene‐Related Peptide (CGRP) Antagonists: A comprehensive review of safety, efficacy and prescribing information

Migraine is a disabling disorder that affects individuals of all ages. To date, there are multiple limitations to using guidelines-recommended treatments and preventive therapies. The goal of this review was to provide a comprehensive clinical review of the safety, efficacy and prescribing information of the emerging calcitonin gene-related peptide (CGRP) antagonists. Agents in this new pharmacologic class were approved by the US Food and Drug Administration (FDA) for the treatment of acute migraine attack pain and the management of episodic and chronic migraine. A total of 12 randomized, placebo-controlled clinical trials were identified and included in the review utilizing databases such as clinicaltrial.gov, PubMed and EMBASE. The trials collectively evaluated six CGRP antagonists starting from the orally administered CGRPs such as rimegepant and ubrogepant, to the quarterly IV administered CGRP such as eptinezumab, and the monthly/quarterly subcutaneously administered agents such as erenumab, fremanezumab and galcanezumab. All agents displayed significant efficacy compared with placebo, measured by reduction in mean monthly migraine days (MMD). In addition, CGRP antagonists displayed a great tolerability profile with few adverse effects. These medications were neither associated with any cardiovascular-related adverse effects, nor do they currently have specific contraindications to pre-existing cardiovascular conditions. This can present a safe alternative to a wide range of patients who cannot be appropriately treated with first-line treatments such as triptans. No treatment-related death was reported in any of the clinical trials outlined and discussed. Calcitonin gene-related peptide antagonists are safe and efficacious medications both in treating acute migraine headache pain and the management of episodic and chronic migraine. Head-to-head comparative studies with current guideline-recommended treatments are needed. However, CGRP antagonists are promising agents that present an alternative solution for patients living with migraine.

Rimegepant for Migraine Prophylaxis

Rimegepant, an oral calcitonin gene-related peptide (CGRP) antagonist drug, was approved by the FDA in February 2020 for the acute treatment of

Achievements of Recent Decades in the Diagnosis and Study of Migraine Pathogenesis

Significant advances have been made in recent decades in the study of migraine, which have changed our understanding of its neurobiology. Migraine is currently considered a neurovascular disorder, characterized by recurrent attacks consisting of consecutive phases of prodrome, aura, headache, and postdrome. Assessment of their clinical features has enabled us to classify the types of migraine—with aura, without aura, chronic, and its concomitant symptoms, to standardize the diagnostic algorithm and present them as criteria for headache classification. A leading role in attack onset is thought to be an imbalance in the interaction between central and peripheral nervous system structures involved in the transmission of pain and inflammation, and the vascular wall. The cause of these disturbances is thought to be primary neuronal dysfunction and related sensory processing disorders, spreading cortical depression, and decreased excitability threshold of the trigeminovascular system. Activation of the latter leads to the release of neuropeptides, development of aseptic inflammation in the vascular wall, pain and related non-pain symptoms. There is growing evidence that recently developed calcitonin gene-related peptide (CGRP) antagonists may lead the way in the treatment and prevention of migraines. A better understanding of the key molecules and mechanisms involved in various stages of migraine will help establish new therapeutic targets, ensuring qualitative improvements in the care for this common and disabling disease.

Therapy of migranes

In migraine attack treatment analgesics such as nonsteroidal anti-inflammatory drugs and triptans can be utilized. The efficacy of acute attack treatment is relevant to prevent migraine chronification. For prophylactic treatment β‑blockers, tricyclic antidepressants, flunarizine, antiepileptics and onabotulinumtoxinA are available. There is evidence that some other substances (e. g. sartans) are also efficacious in this regard. Furthermore, nondrug approaches are essential in migraine therapy. Early education and prophylactic treatment of patients at risk may prevent from medication overuse headache. Noninvasive neuromodulatory approaches as supraorbital or vagal nerve stimulation are emerging methods for prophylactic treatment. Ongoing clinical trials investigate an oral calcitonin gene-related peptide (CGRP) antagonist for acute treatment and several prophylactic monoclonal CGRP or CGRP receptor-antibodies regarding safety, side effects and efficacy as new therapeutic options.

Biphasic relaxation of the opossum lower esophageal sphincter: roles of NO., VIP, and CGRP.

Vasoactive intestinal polypeptide (VIP) and nitric oxide (NO.) are thought to mediate lower esophageal sphincter (LES) relaxation. Transverse muscle strips from the opossum LES were used to test this hypothesis. Electrical field stimulation (EFS) produced a biphasic LES relaxation: a rapid component during the stimulus was more prominent at lower stimulus frequencies, and a sustained component was more prominent at higher frequencies. N(omega)-nitro-L-arginine and hemoglobin inhibited the rapid component but affected the sustained component less. Exogenous VIP decreased LES tone. A number of purported VIP antagonists blocked neither VIP-induced nor EFS-induced relaxation of the LES. The calcitonin gene-related peptide (CGRP) antagonist CGRP-(8-37) did not alter EFS-induced LES relaxation. EFS-induced relaxation of opossum LES muscle is biphasic, and the initial, rapid component of the relaxation is mediated primarily by NO. The mediator of the sustained component was not identified.

Mechanisms mediating gastric hyperemic and acid responses to central TRH analog at a cytoprotective dose.

Gastric hyperemic and acid responses to the stable thyrotropin-releasing hormone (TRH) analog RX-77368 injected intracisternally at a cytoprotective dose were investigated, as well as the underlying mechanisms of the responses. Gastric acid secretion (GAS), mucosal blood flow (GMBF; measured by the hydrogen gas clearance technique), and mucosal vascular resistance (GMVR) and mean arterial pressure (MAP) were assessed simultaneously for 30 min before and after RX-77368 (1.5 ng) administration in urethan-anesthetized rats. RX-77368 increased GMBF from 46.8 +/- 5.3 to 100.6 +/- 20.9 ml.min-1.100 g-1 and MAP from 70.3 +/- 2.1 to 84.3 +/- 5.9 mmHg and decreased GMVR from 1.50 +/- 0.33 to 0.84 +/- 0.08 mmHg.ml-1.min.100 g, whereas GAS was not significantly altered (1.8 +/- 0.4 vs. 4.7 +/- 1.7 mumol/30 min) in vehicle-pretreated rats. The GMBF, MAP, and GMVR responses to RX-77368 were not modified by indomethacin (5 mg/kg ip), whereas GAS was increased. In rats pretreated with capsaicin (125 mg/kg sc) or calcitonin gene-related peptide (CGRP) antagonist hCGRP-(8-37), intracisternal RX-77368 did not increase GMBF or decrease GMVR but did stimulate GAS. These data show that vagal stimulation by the TRH analog RX-77368 injected intracisternally at a nonacid secretory dose increases GMBF. Gastric hyperemia is mediated by CGRP contained in capsaicin-sensitive afferent fibers, whereas acid secretion is under the inhibitory influence of prostaglandins and CGRP.

Modulation of adrenergic coronary vasoconstriction via ATP-sensitive potassium channel

We examined humoral and/or locally produced vasoactive factors involved in modulating sympathetic coronary vasoconstriction via the ATP-sensitive K (KATP) channel in 42 anesthetized dogs. Glibenclamide (30 micrograms.kg-1.min-1 ic or 0.6 mg.kg-1.min-1 left atrial injection) augmented coronary vascular resistance (CVR) at baseline and during cardiac sympathetic nerve stimulation (2-20 Hz), with a greater increase seen in the subepicardial region than in the subendocardial region both during beta-adrenergic receptor blockade and alpha- and beta-receptor blockade [P < 0.05 and P < 0.05 (n = 6 and 18 dogs), analysis of variance]. In contrast, pinacidil (10 micrograms.kg-1.min-1; n = 8 dogs) suppressed CVR. Glibenclamide enhanced CVR response to locally administered norepinephrine of 0.001-0.1 microgram.kg-1.min-1 (P < 0.05, analysis of covariance; n = 5 dogs) but did not enhance norepinephrine or neuropeptide Y overflow (n = 18 dogs). CVR was not modified by calcitonin gene-related peptide (CGRP) antagonist [CGRP-(8-37)], 8-phenyltheophylline, or N omega-nitro-L-arginine (n = 11 dogs). Thus sympathetic coronary vasoconstriction is modified by coronary vascular KATP channels with a transmural difference. However, CGRP, adenosine, and endothelial nitric oxide production are not involved in the modulation.

Effect of CGRP antagonist, alpha-CGRP 8-37, on acid secretion in the dog.

The recently synthesized calcitonin gene-related peptide (CGRP) antagonist, human alpha-CGRP 8-37, was used to study its effects on gastric acid secretion. Four dogs with gastric fistula were used to measure the antagonist's physiologic effects in the stomach. All dogs received a bactopeptone dextrose meal (intragastric titration to pH 5.5) with either continuous CGRP 8-37 (1000 pmol/kg/hr) or saline (control). Additionally, intravenous bombesin (75-600 ng/kg/hr) and bethanechol (12.5-100 micrograms/kg/hr) was tested in the presence of the antagonist. Plasma gastrin levels also were measured via radioimmunoassay (RIA) in control and CGRP 8-37-stimulated animals. Gastric acid secretion increased by 100% with infusion of 1000 pmol/kg/hr CGRP 8-37 when compared to the control. Acid output increased 98% with both intravenous antagonist and 600 ng/kg/hr bombesin when compared to bombesin alone. However, no augmentation of acid secretion by CGRP 8-37 was shown with 25 micrograms/kg/hr bethanechol. RIA of plasma gastrin demonstrated no effect with the antagonist when given alone and did not increase bombesin-stimulated gastrin release. We conclude that CGRP 8-37 blocks native CGRP inhibitory effects on gastric acid secretion. Our findings of potentiation of acid secretion by bombesin as well as no change in gastrin levels in the presence of the antagonist is likely due to a blockage in a noncholinergic neuron to the somatostatin cell. Furthermore, CGRP 8-37 did not increase bethanechol-stimulated acid secretion, most likely due to bethanechol's (acetylcholine) nearly ubiquitous positive effects on acid secretion.