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Corticotropin-releasing factor (CRF) processes in acute and chronic anxiety
Published in Philip N. Murphy, The Routledge International Handbook of Psychobiology, 2018
Paula S. M. Yamashita, James E. Hassell, Christopher A. Lowry
A clinical trial, using a more recently discovered CRFR1 antagonist, Pexacerfont, investigated if this drug would treat symptoms of generalized anxiety disorder, but no differences were observed compared with placebo in patients with generalized anxiety disorder (Coric et al., 2010).
Pharmacological Treatment of Generalised Anxiety Disorder: Current Practice and Future Directions
Published in Expert Review of Neurotherapeutics, 2023
Harry A. Fagan, David S. Baldwin
Corticotropin-releasing factor/hormone (CRF/CRH) is a peptide hormone secreted by the hypothalamus in response to stress. It stimulates secretion of adrenocorticotropic hormone (ACTH) by the anterior pituitary and is a component of the hypothalamic-pituitary-adrenal (HPA) axis. CRF binds two different GPCR (CRF1 and CRF2 receptors) which are expressed in the hypothalamus and other brain regions [117]. An anxiogenic (and pro-depressive) role of CRF1 receptors was identified in animal studies, leading to the development of several CRF1 receptor antagonists [117,118]. However, clinical studies of CRF1 receptor antagonists have not shown promise in anxiety disorders [118]. To date, only one RCT has been published in GAD, which showed that the CRF1 receptor antagonist pexacerfont did not differentiate from placebo treatment after 8 weeks of treatment [119].
Novel investigational therapeutics for generalized anxiety disorder (GAD)
Published in Expert Opinion on Investigational Drugs, 2019
Bella Schanzer, Ana Maria Rivas-Grajales, Aamir Khan, Sanjay J Mathew
Pexacerfont is one of the number of novel pyrazines that were developed to serve as CRF-1 receptor antagonists. In addition, it was found to have a favorable metabolic profile including its absorption, distribution, metabolism, and excretion and it appears that a low dose would yield an adequate plasma level. In terms of its use in anxiety, brain and pituitary CRF1 are involved with physiological stress-response with the resultant belief that a CRF1 receptor antagonist that can cross the blood-brain barrier might have utility in treating stress-related conditions like anxiety and, in animal models, CRF1 receptor antagonists show an anxiolytic effect. The anxiolytic effect of a CRF1 receptor antagonist occurs without the development of tolerance and without sedation or cognitive impairment [62–64]. Despite these findings, a multicenter, randomized, double-blind, placebo-controlled trial of Pexacerfont in 2010 was negative with no significant difference between Pexacerfont and placebo in the treatment of GAD [65].
New approved and emerging pharmacological approaches to alcohol use disorder: a review of clinical studies
Published in Expert Opinion on Pharmacotherapy, 2021
Kirsten C Morley, Christina J Perry, Joshua Watt, Tristan Hurzeler, Lorenzo Leggio, Andrew J Lawrence, Paul Haber
Kwako et al. [96] trialed pexacerfont in 55 inpatients including 49 males and reported no effects on the primary outcome measure of craving for alcohol. Using a similar design, verucerfont was subsequently trialed in 44 female inpatients [97]. This second study was limited to females, given previous reports indicating an inhibitory effect of verucerfont on sperm production [98]. Based on the results of pexacerfont study, the investigators conducted an interim analysis before completing the verucerfont study. Results did not indicate any potential for superiority over placebo and thus the study was terminated.