Corticotropin-releasing Factor Type Research Articles

Phase 3 Trial of Crinecerfont in Pediatric Congenital Adrenal Hyperplasia.

Children with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency require treatment with glucocorticoids, usually at supraphysiologic doses, to address cortisol insufficiency and reduce excess adrenal androgens. However, such treatment confers a predisposition to glucocorticoid-related complications. In 2-week phase 2 trials, patients with CAH who received crinecerfont, a new oral corticotropin-releasing factor type 1 receptor antagonist, had decreases in androstenedione levels. In this phase 3, multinational, randomized trial, we assigned pediatric participants with CAH, in a 2:1 ratio, to receive crinecerfont or placebo for 28 weeks. A stable glucocorticoid dose was maintained for 4 weeks, and the dose was then adjusted to a target of 8.0 to 10.0 mg per square meter of body-surface area per day (hydrocortisone dose equivalents), provided that the androstenedione level was controlled (≤120% of the baseline level or within the reference range). The primary efficacy end point was the change in the androstenedione level from baseline to week 4. A key secondary end point was the percent change in the glucocorticoid dose from baseline to week 28 while androstenedione control was maintained. A total of 103 participants underwent randomization, of whom 69 were assigned to the crinecerfont group and 34 to the placebo group; 100 (97%) remained in the trial at 28 weeks. At baseline, the mean glucocorticoid dose was 16.4 mg per square meter per day, and the mean androstenedione level was 431 ng per deciliter (15.0 nmol per liter). At week 4, the androstenedione level was substantially reduced in the crinecerfont group (-197 ng per deciliter [-6.9 nmol per liter]) but increased in the placebo group (71 ng per deciliter [2.5 nmol per liter]) (least-squares mean difference, -268 ng per deciliter [-9.3 nmol per liter]; P<0.001); the observed mean androstenedione value, obtained before the morning glucocorticoid dose, was 208 ng per deciliter (7.3 nmol per liter) in the crinecerfont group, as compared with 545 ng per deciliter (19.0 nmol per liter) in the placebo group. At week 28, the mean glucocorticoid dose had decreased (while androstenedione control was maintained) by 18.0% with crinecerfont but increased by 5.6% with placebo (least-squares mean difference, -23.5 percentage points; P<0.001). Headache, pyrexia, and vomiting were the most common adverse events. In this phase 3 trial, crinecerfont was superior to placebo in reducing elevated androstenedione levels in pediatric participants with CAH and was also associated with a decrease in the glucocorticoid dose from supraphysiologic to physiologic levels while androstenedione control was maintained. (Funded by Neurocrine Biosciences; CAHtalyst Pediatric ClinicalTrials.gov number, NCT04806451.).

Phase 3 Trial of Crinecerfont in Adult Congenital Adrenal Hyperplasia.

Adrenal insufficiency in patients with classic 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH) is treated with glucocorticoid replacement therapy. Control of adrenal-derived androgen excess usually requires supraphysiologic glucocorticoid dosing, which predisposes patients to glucocorticoid-related complications. Crinecerfont, an oral corticotropin-releasing factor type 1 receptor antagonist, lowered androstenedione levels in phase 2 trials involving patients with CAH. In this phase 3 trial, we randomly assigned adults with CAH in a 2:1 ratio to receive crinecerfont or placebo for 24 weeks. Glucocorticoid treatment was maintained at a stable level for 4 weeks to evaluate androstenedione values, followed by glucocorticoid dose reduction and optimization over 20 weeks to achieve the lowest glucocorticoid dose that maintained androstenedione control (≤120% of the baseline value or within the reference range). The primary efficacy end point was the percent change in the daily glucocorticoid dose from baseline to week 24 with maintenance of androstenedione control. All 182 patients who underwent randomization (122 to the crinecerfont group and 60 to the placebo group) were included in the 24-week analysis, with imputation of missing values; 176 patients (97%) remained in the trial at week 24. The mean glucocorticoid dose at baseline was 17.6 mg per square meter of body-surface area per day of hydrocortisone equivalents; the mean androstenedione level was elevated at 620 ng per deciliter. At week 24, the change in the glucocorticoid dose (with androstenedione control) was -27.3% in the crinecerfont group and -10.3% in the placebo group (least-squares mean difference, -17.0 percentage points; P<0.001). A physiologic glucocorticoid dose (with androstenedione control) was reported in 63% of the patients in the crinecerfont group and in 18% in the placebo group (P<0.001). At week 4, androstenedione levels decreased with crinecerfont (-299 ng per deciliter) but increased with placebo (45.5 ng per deciliter) (least-squares mean difference, -345 ng per deciliter; P<0.001). Fatigue and headache were the most common adverse events in the two trial groups. Among patients with CAH, the use of crinecerfont resulted in a greater decrease from baseline in the mean daily glucocorticoid dose, including a reduction to the physiologic range, than placebo following evaluation of adrenal androgen levels. (Funded by Neurocrine Biosciences; CAHtalyst ClinicalTrials.gov number, NCT04490915.).

Baseline characteristics of children and adolescents with classic congenital adrenal hyperplasia enrolled in CAHtalyst pediatric, a phase 3 Study of Crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist

Baseline characteristics of children and adolescents with classic congenital adrenal hyperplasia enrolled in CAHtalyst pediatric, a phase 3 Study of Crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist

Baseline characteristics of adults with classic congenital adrenal hyperplasia enrolled in CAHtalyst, a phase 3 study of Crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist

Baseline characteristics of adults with classic congenital adrenal hyperplasia enrolled in CAHtalyst, a phase 3 study of Crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist

Musclin prevents depression-like behavior in male mice by activating urocortin 2 signaling in the hypothalamus.

Physical activity is recommended as an alternative treatment for depression. Myokines, which are secreted from skeletal muscles during physical activity, play an important role in the skeletal muscle-brain axis. Musclin, a newly discovered myokine, exerts physical endurance, however, the effects of musclin on emotional behaviors, such as depression, have not been evaluated. This study aimed to access the anti-depressive effect of musclin and clarify the connection between depression-like behavior and hypothalamic neuropeptides in mice. We measured the immobility time in the forced swim (FS) test, the time spent in open arm in the elevated-plus maze (EPM) test, the mRNA levels of hypothalamic neuropeptides, and enumerated the c-Fos-positive cells in the paraventricular nucleus (PVN), arcuate nucleus (ARC), and nucleus tractus solitarii (NTS) in mice with the intraperitoneal (i.p.) administration of musclin. Next, we evaluated the effects of a selective corticotropin-releasing factor (CRF) type 1 receptor antagonist, selective CRF type 2 receptor antagonist, melanocortin receptor (MCR) agonist, and selective melanocortin 4 receptor (MC4R) agonist on changes in behaviors induced by musclin. Finally we evaluated the antidepressant effect of musclin using mice exposed to repeated water immersion (WI) stress. We found that the i.p. and i.c.v. administration of musclin decreased the immobility time and relative time in the open arms (open %) in mice and increased urocortin 2 (Ucn 2) levels but decreased proopiomelanocortin levels in the hypothalamus. The numbers of c-Fos-positive cells were increased in the PVN and NTS but decreased in the ARC of mice with i.p. administration of musclin. The c-Fos-positive cells in the PVN were also found to be Ucn 2-positive. The antidepressant and anxiogenic effects of musclin were blocked by central administration of a CRF type 2 receptor antagonist and a melanocortin 4 receptor agonist, respectively. Peripheral administration of musclin also prevented depression-like behavior and the decrease in levels of hypothalamic Ucn 2 induced by repeated WI stress. These data identify the antidepressant effects of musclin through the activation of central Ucn 2 signaling and suggest that musclin and Ucn 2 can be new therapeutic targets and endogenous peptides mediating the muscle-brain axis.

Traumatic Stress-Induced Increases in Anxiety-like Behavior and Alcohol Self-Administration Are Mediated by Central Amygdala CRF1 Neurons That Project to the Lateral Hypothalamus.

Avoidance stress coping, defined as persistent internal and/or external avoidance of stress-related stimuli, is a key feature of anxiety- and stress-related disorders, and contributes to increases in alcohol misuse after stress exposure. Previous work using a rat model of predator odor stress avoidance identified corticotropin-releasing factor (CRF) signaling via CRF Type 1 receptors (CRF1) in the CeA, as well as CeA projections to the lateral hypothalamus (LH) as key mediators of conditioned avoidance of stress-paired contexts and/or increased alcohol drinking after stress. Here, we report that CRF1-expressing CeA cells that project to the LH are preferentially activated in male and female rats that show persistent avoidance of predator odor stress-paired contexts (termed Avoider rats), and that chemogenetic inhibition of these cells rescues stress-induced increases in anxiety-like behavior and alcohol self-administration in male and female Avoider rats. Using slice electrophysiology, we found that prior predator odor stress exposure blunts inhibitory synaptic transmission and increases synaptic drive in CRF1 CeA-LH cells. In addition, we found that CRF bath application reduces synaptic drive in CRF1 CeA-LH cells in Non-Avoiders only. Collectively, these data show that CRF1 CeA-LH cells contribute to stress-induced increases in anxiety-like behavior and alcohol self-administration in male and female Avoider rats.SIGNIFICANCE STATEMENT Stress may lead to a variety of behavioral and physiological negative consequences, and better understanding of the neurobiological mechanisms that contribute to negative stress effects may lead to improved prevention and treatment strategies. This study, performed in laboratory rats, shows that animals that exhibit avoidance stress coping go on to develop heightened anxiety-like behavior and alcohol self-administration, and that these behaviors can be rescued by inhibiting the activity of a specific population of neurons in the central amygdala. This study also describes stress-induced physiological changes in these neurons that may contribute to their role in promoting increased anxiety and alcohol self-administration.

Corticotropin-releasing factor signaling and its potential role in the prefrontal cortex-dependent regulation of anxiety.

A large body of literature has highlighted the significance of the corticotropin-releasing factor (CRF) system in the regulation of neuropsychiatric diseases. Anxiety disorders are among the most common neuropsychiatric disorders. An increasing number of studies have demonstrated that the CRF family mediates and regulates the development and maintenance of anxiety. Thus, the CRF family is considered to be a potential target for the treatment of anxiety disorders. The prefrontal cortex (PFC) plays a role in the occurrence and development of anxiety, and both CRF and CRF-R1 are widely expressed in the PFC. This paper begins by reviewing CRF-related signaling pathways and their different roles in anxiety and related processes. Then, the role of the CRF system in other neuropsychiatric diseases is reviewed and the potential role of PFC CRF signaling in the regulation of anxiety disorders is discussed. Although other signaling pathways are potentially involved in the process of anxiety, CRF in the PFC primarily modulates anxiety disorders through the activation of corticotropin-releasing factor type1 receptors (CRF-R1)and the excitation of the cAMP/PKA signaling pathway. Moreover, the main signaling pathways of CRF involved in sex differentiation in the PFC appear to be different. In summary, this review suggests that the CRF system in the PFC plays a critical role in the occurrence of anxiety. Thus, CRF signaling is of great significance as a potential target for the treatment of stress-related disorders in the future.

Network Pharmacology Study on the Mechanism of Gastrodin Reversing Depressive Symptoms in Traumatically Stressed Rats.

Depression is a typical outcome of the repair of posttraumatic stress disorder (PTSD). Based on network pharmacology and neuropharmacology experiments, this study aimed to explore how gastrodin (GAS) reverses depressive symptoms in traumatically stressed rats. GAS-related targets were predicted by SwissTargetPrediction; depression-related targets were collected from GeneCards and therapeutic target database (TTD); protein-protein interaction (PPI) network was constructed with its action mechanism being predicted by gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. The animal model of PTSD was replicated by single prolonged stress (SPS). The antidepressant effect of GAS was investigated by the forced swim test (FST) and tail suspension test (TST). The levels of tyrosine hydroxylase (TH) and corticotropin-releasing factor type I receptor (CRF1) in locus ceruleus (LC) and the expression of corticotropin-releasing factor (CRF) in the paraventricular nucleus of the hypothalamus (PVN) and central amygdala (CeA) were measured by immunofluorescence. GAS significantly shortened the tail suspension and swimming immobility in SPS rats in TST and FST experiments (p < 0.05 or p < 0.01). The network analysis showed that the critical antidepressant targets of GAS were 86 targets such as GAPDH, CASP3 MMP9, HRAS, DPP4, and TH, which were significantly enriched in the pathways such as pathways neuroactive ligandreceptor interaction. High doses of GAS could significantly reduce the level of TH and CRF in CEA in the brain of rats with depressive symptoms (p < 0.01) and, at the same time, lower the expression of CRF in PVN (p < 0.05). The effect of GAS on depressive symptoms in SPS rats may be closely related to its reduction of CRF expression in PVN and CeA and inhibition of neuron (NE) synthesis in LC.

Crinecerfont, a CRF1 Receptor Antagonist, Lowers Adrenal Androgens in Adolescents With Congenital Adrenal Hyperplasia.

Crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist, has been shown to reduce elevated adrenal androgens and precursors in adults with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), a rare autosomal recessive disorder characterized by cortisol deficiency and androgen excess due to elevated adrenocorticotropin. To evaluate the safety, tolerability, and efficacy of crinecerfont in adolescents with 21OHD CAH. This was an open-label, phase 2 study (NCT04045145) at 4 centers in the United States. Participants were males and females, 14 to 17 years of age, with classic 21OHD CAH. Crinecerfont was administered orally (50 mg twice daily) for 14 consecutive days with morning and evening meals. The main outcomes were change from baseline to day 14 in circulating concentrations of ACTH, 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone. 8 participants (3 males, 5 females) were enrolled; median age was 15 years and 88% were Caucasian/White. After 14 days of crinecerfont, median percent reductions from baseline to day 14 were as follows: ACTH, -57%; 17OHP, -69%; and androstenedione, -58%. In female participants, 60% (3/5) had ≥50% reduction from baseline in testosterone. Adolescents with classic 21OHD CAH had substantial reductions in adrenal androgens and androgen precursors after 14 days of oral crinecerfont administration. These results are consistent with a study of crinecerfont in adults with classic 21OHD CAH.

Stress-related neuropeptide systems as targets for treatment of alcohol addiction: A clinical perspective.

Alcohol use is a major cause of disability and death globally. These negative consequences disproportionately affect people who develop alcohol addiction, a chronic relapsing condition characterized by increased motivation to use alcohol, choice of alcohol over healthy, natural rewards, and continued use despite negative consequences. Available pharmacotherapies for alcohol addiction are few, have effect sizes in need of improvement, and remain infrequently prescribed. Research aimed at developing novel therapeutics has in large part focused on attenuating pleasurable or "rewarding" properties of alcohol, but this targets processes that primarily play a role as initiation factors. As clinical alcohol addiction develops, long-term changes in brain function result in a shift of affective homeostasis, and rewarding alcohol effects become progressively reduced. Instead, increased stress sensitivity and negative affective states emerge in the absence of alcohol and create powerful incentives for relapse and continued use through negative reinforcement, or "relief." Based on research in animal models, several neuropeptide systems have been proposed to play an important role in this shift, suggesting that these systems could be targeted by novel medications. Two mechanisms in this category, antagonism at corticotropin-releasing factor type 1, and neurokinin 1/substance P receptors, have been subject to initial evaluation in humans. A third, kappa-opioid receptor antagonism, has been evaluated in nicotine addiction and could soon be tested for alcohol. This paper discusses findings with these mechanisms to date, and their prospects as future targets for novel medications.

OR18-4 Crinecerfont (NBI-74788), a Novel CRF1 Receptor Antagonist, Lowers Adrenal Androgens and Precursors in Adolescents with Classic Congenital Adrenal Hyperplasia

Abstract Introduction Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is a rare autosomal recessive disease characterized by deficiency of cortisol and oftentimes aldosterone, with elevated adrenocorticotropic hormone (ACTH) and steroid precursors that are then shunted toward excess androgen production. A phase 2 study of adults with classic 21OHD demonstrated that crinecerfont—an oral, non-steroidal, selective corticotropin-releasing factor type 1 (CRF1) receptor antagonist—substantially reduced elevated hormone markers after 14 days of treatment [1]. The current study evaluated the effect of crinecerfont in adolescents with classic 21OHD, who may be especially challenging to manage for multiple reasons including the hormonal changes associated with puberty [2]. Methods Eligible adolescents (14─17 years of age) with classic 21OHD received open-label crinecerfont (50 mg BID) for 14 days. ACTH, 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone were assessed over 24 hours prior to (baseline) and after 14 days of crinecerfont treatment. Morning window values were defined as the average of samples collected at 0700h and 1000h, before the morning glucocorticoid dose. The participants’ glucocorticoid and fludrocortisone regimens were maintained stable during crinecerfont treatment. Results In 8 participants (3 males, 5 females, ages 14-16 years), baseline median hormone concentrations (based on morning window) were as follows: plasma ACTH, 226.2 pg/mL; serum 17OHP, 7703.7 ng/dL; serum androstenedione, 367.9 ng/dL; and in females, serum testosterone, 63.5 ng/dL. After 14 days of crinecerfont treatment, median percent reductions from baseline were: ACTH, -57.1%; 17OHP, -69.5%; androstenedione, -58.3%; and in females, testosterone, -76.2%. A ≥50% reduction from baseline to Day 14 in ACTH, 17OHP, and androstenedione was observed in 62.5%, 75.0%, and 50.0% of participants, respectively. Furthermore, 60% (3/5) of females had ≥50% reduction from baseline in testosterone. Thirteen treatment-emergent adverse events (TEAEs) were reported; all but 1 (bruising) were assessed as mild. The majority of TEAEs were assessed as unrelated by the investigator, with the most common being headache (n=2). There were no serious AEs, discontinuations due to AEs, or safety concerns related to routine laboratory tests, vital signs, or electrocardiograms. Conclusions In adolescents with classic 21OHD, substantial median reductions (57-76%) in adrenal androgens and androgen precursors were observed after 14 days of crinecerfont treatment, consistent with reported results from a similar study of adults with classic 21OHD. Further studies are warranted to evaluate whether longer-term treatment with crinecerfont can allow for lower, more physiologic glucocorticoid dosing by directly reducing adrenal androgens, and thereby improving clinical outcomes (weight, metabolic risk, growth/development, fertility, etc.), via antagonism of the CRF1 receptor.

Investigating the Effects of Maternal Separation on Hypothalamic-Pituitary-Adrenal Axis and Glucose Homeostasis under Chronic Social Defeat Stress in Young Adult Male Rat Offspring

Introduction: Given the suggested metabolic regulatory effects of stress-responsive genes and based on the impacts of early-life stress on HPA axis development, this study aimed to characterize the maternal separation (MS) impact on the communication between glucose metabolism and HPA axis dysregulations under chronic social defeat stress (CSDS). Methods: During the first 2 weeks of life, male Wistar rats were either exposed to MS or left undisturbed with their mothers (Std). Starting on postnatal day 50, the animals of each group were either left undisturbed in the standard group housing (Con) or underwent CSDS for 3 weeks. There were four groups (n = 10/group): Std-Con, MS-Con, Std-CSDS, and MS-CSDS. Results: Early and/or adult life adversity reduced β-cell number, muscular FK506-binding protein 51 (FKBP51) content, and BMI in adulthood. The reduction of β-cell number and BMI in the MS-CSDS rats were more profound than MS-Con group. CSDS either alone or in combination with MS reduced locomotor activity and increased and decreased corticotropin-releasing factor type 1 receptor (CRFR1) content, respectively, in hypothalamus and pancreas. Although, under CSDS, MS intensified HPA axis overactivity and reduced isolated islets’ insulin secretion, it could promote resilience to depression symptoms. No differences were observed in hypothalamic Fkbp5 gene DNA methylation and glucose tolerance among groups. Conclusion: MS exacerbated HPA axis overactivity and the endocrine pancreas dysfunctions under CSDS. The intensified corticosterone secretion and the diminished content of pancreatic CRFR1 protein could be involved in the reduced β-cell number and islets’ insulin secretion under CSDS. The decreased muscular FKBP51 content might be a homeostatic response to slow down insulin resistance development under chronic stress.

Generation of a CRF1-Cre transgenic rat and the role of central amygdala CRF1 cells in nociception and anxiety-like behavior.

Corticotropin-releasing factor type-1 (CRF1) receptors are critical to stress responses because they allow neurons to respond to CRF released in response to stress. Our understanding of the role of CRF1-expressing neurons in CRF-mediated behaviors has been largely limited to mouse experiments due to the lack of genetic tools available to selectively visualize and manipulate CRF1+ cells in rats. Here, we describe the generation and validation of a transgenic CRF1-Cre-tdTomato rat. We report that Crhr1 and Cre mRNA expression are highly colocalized in both the central amygdala (CeA), composed of mostly GABAergic neurons, and in the basolateral amygdala (BLA), composed of mostly glutamatergic neurons. In the CeA, membrane properties, inhibitory synaptic transmission, and responses to CRF bath application in tdTomato+ neurons are similar to those previously reported in GFP+ cells in CRFR1-GFP mice. We show that stimulatory DREADD receptors can be targeted to CeA CRF1+ cells via virally delivered Cre-dependent transgenes, that transfected Cre/tdTomato+ cells are activated by clozapine-n-oxide in vitro and in vivo, and that activation of these cells in vivo increases anxiety-like and nocifensive behaviors. Outside the amygdala, we show that Cre-tdTomato is expressed in several brain areas across the brain, and that the expression pattern of Cre-tdTomato cells is similar to the known expression pattern of CRF1 cells. Given the accuracy of expression in the CRF1-Cre rat, modern genetic techniques used to investigate the anatomy, physiology, and behavioral function of CRF1+ neurons can now be performed in assays that require the use of rats as the model organism.

Activation CRF-R2 augments cerebellar climbing fiber-Purkinje cell synaptic transmission via presynaptic PKA pathway in mice

Corticotropin releasing factor (CRF) type 2 receptor (CRF-R2) is present in climbing fiber (CF) afferents, which involves in modulating the CF-Purkinje cell (PC) synaptic transmission in cerebellar cortex. However, the role of CRF-R2 in regulating CF-PC synaptic transmission is unclear. We here investigate the role of CRF-R2 in modulating PC complex spikes (CSs) activity and CF-PC synaptic transmission using electrophysiological recording techniques and pharmacological methods. Cerebellar surface application of a selective CRF-R2 agonist, urocortin III (UCN III; 300 nM) induced an enhancement of CSs activity, which expressed an increase in number of CSs spikelets and pause of simple spike firing of cerebellar PCs in urethane anesthetized mice. The CSs activity was also enhanced by CRF (300 nM) in the presence of CRF-R1 antagonist, which was abolished by CRF-R2 antagonist. Under in vitro conditions, bath application of UCN III increased CF-PC synaptic transmission, which exhibited a time-dependent increase in amplitude of excitatory postsynaptic currents (EPSCs), accompanied by a decrease in paired-pulse ratio (PPR). In addition, bath application of CRF (100 nM) induced an increase in amplitude of EPSCs and a decrease in PPR in the absence of CRF-R1 activity. UCN-induced enhancement of CF-PC synaptic transmission was abolished by bath application of protein kinase A (PKA) inhibitor, KT5720 (100 nM), but it was not prevented by inhibiting intracellular PKA with PKI (5 μM). These results indicate that activation of CRF-R2 augments CF-PC synaptic transmission through a presynaptic PKA signaling pathway in the mouse cerebellar cortex.

Intervensi Farmakologi Sindrom Putus Obat pada Penyalahguna Opioid

Opioid withdrawal syndrome appears after abrupt discontinuation of opioids characterized by watery eyes, runny nose, muscle pain, anxiety, yawning, gooseflesh, mydriasis, gastrointestinal discomfort, and rapid heartbeat. Globally, opioid abuse remains a significant problem, necessitating adequate treatment of drug syndrome in opioid addicts, particularly pharmaceutical therapy. Therefore, this study aimed to identify, evaluate, and analyze pharmacological management in opioid abusers. The articles used were retrieved based on specific limitations using the main keywords "opioid withdrawal syndrome treatment" and additional keywords "heroin, fentanyl, morphine" that were published in PubMed, ScienceDirect, and SpringerLink. From the 21 articles included, heroin abuse was the most prevalent. The primary treatment for opioid abuse is substitution therapy of opioid or non-opioid such as lofexidine, naltrexone, buprenorphine, dronabinol, methadone, pregabalin, oxytocin, antagonist corticotropin-releasing factor type 1 (CRF1), tramadol, clonidine, and pioglitazone. Additionally, the patient received symptomatic therapy based on the condition. The drugs used for treatment and willingness to obtain therapy are the factors for the withdrawal completion rate. The results were evaluated using opioid withdrawal assessment, either from a subjective, objective, or clinical perspective.

Clinical advances in the pharmacotherapy of congenital adrenal hyperplasia.

BackgroundPatients with 21-hydroxylase deficiency congenital adrenal hyperplasia (21OHD-CAH) have poor health outcomes with increased mortality, short stature, impaired fertility, and increased cardiovascular risk factors such as obesity. To address this, there are therapies in development that target the clinical goal of treatment, which is to control excess androgens with an adrenal replacement dose of glucocorticoid.MethodsNarrative review of publications on recent clinical developments in the pharmacotherapy of congenital adrenal hyperplasia.SummaryTherapies in clinical development target different levels of the hypothalamo–pituitary–adrenal axis. Two corticotrophin-releasing factor type 1 (CRF1) receptor antagonists, Crinecerfont and Tildacerfont, have been trialled in poorly controlled 21OHD-CAH patients, and both reduced ACTH and androgen biomarkers while patients were on stable glucocorticoid replacement. Improvements in glucocorticoid replacement include replacing the circadian rhythm of cortisol that has been trialled with continuous s.c. infusion of hydrocortisone and Chronocort, a delayed-release hydrocortisone formulation. Chronocort optimally controlled 21OHD-CAH in 80% of patients on an adrenal replacement dose of hydrocortisone, which was associated with patient-reported benefits including restoration of menses and pregnancies. Adrenal-targeted therapies include the steroidogenesis-blocking drug Abiraterone acetate, which reduced adrenal androgen biomarkers in poorly controlled patients.ConclusionsCRF1 receptor antagonists hold promise to avoid excess glucocorticoid replacement in patients not controlled on standard or circadian glucocorticoid replacement such as Chronocort. Gene and cell therapies are the only therapeutic approaches that could potentially correct both cortisol deficiency and androgen excess.

Urocortin3 in the Posterodorsal Medial Amygdala Mediates Stress-induced Suppression of LH Pulsatility in Female Mice.

Psychosocial stress disrupts reproduction and interferes with pulsatile LH secretion. The posterodorsal medial amygdala (MePD) is an upstream modulator of the reproductive axis and stress. Corticotropin-releasing factor type 2 receptors (CRFR2s) are activated in the presence of psychosocial stress together with increased expression of the CRFR2 ligand Urocortin3 (Ucn3) in the MePD of rodents. We investigate whether Ucn3 signalling in the MePD is involved in mediating the suppressive effect of psychosocial stress on LH pulsatility. First, we administered Ucn3 into the MePD and monitored the effect on LH pulses in ovariectomized mice. Next, we delivered Astressin2B, a selective CRFR2 antagonist, intra-MePD in the presence of predator odor, 2,4,5-trimethylthiazole (TMT) and examined the effect on LH pulses. Subsequently, we virally infected Ucn3-cre-tdTomato mice with inhibitory designer receptor exclusively activated by designer drugs (DREADDs) targeting MePD Ucn3 neurons while exposing mice to TMT or restraint stress and examined the effect on LH pulsatility as well as corticosterone release. Administration of Ucn3 into the MePD dose-dependently inhibited LH pulses and administration of Astressin2B blocked the suppressive effect of TMT on LH pulsatility. Additionally, DREADDs inhibition of MePD Ucn3 neurons blocked TMT and restraint stress-induced inhibition of LH pulses and corticosterone release. These results demonstrate for the first time that Ucn3 neurons in the MePD mediate psychosocial stress-induced suppression of the GnRH pulse generator and corticosterone secretion. Ucn3 signalling in the MePD plays a role in modulating the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes, and this brain locus may represent a nodal center in the interaction between the reproductive and stress axes.

Regulation of maternal care by corticotropin-releasing factor receptors in the dorsal raphe nucleus in mice.

We previously reported that the dorsal raphe nucleus (DRN) was involved in the regulation of maternal care in lactating female mice. The DRN receives multiple innervations from a variety of the brain regions. Corticotropin-releasing factor (CRF) Type 1 and Type 2 receptors are distributed in the DRN. Both receptors have been implicated in regulating negative aspects including stress, fear, and anxiety. However, it remains unknown how CRF receptors in the DRN regulate maternal care. In the present study, we investigated how CRF receptors in the DRN is involved in regulating maternal care in lactating female mice. Injection of antalarmin or antisauvagine-30, which is an antagonist of CRF Type 1 or Type 2 receptor, respectively, into the DRN increased the latency to retrieving pups into the nest and to crouching over pups, and decreased the duration of crouching over pups, indicating that blockage of CRF receptor signaling in the DRN decreased maternal care. Each treatment did not affect anxiety-related behaviors, which were assayed using the hole-board test. These results suggest that CRF receptor signaling in the DRN positively regulates maternal care in lactating female mice. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Dose Escalating and Bioavailability Phase 1 Studies Assessing Safety and Tolerability and Pharmacokinetics of Tildacerfont, a Small-Molecule CRF1 Receptor Antagonist

Background: Tildacerfont (SPR001; LY2371712), a second generation, potent, selective, nonsteroidal, oral small-molecule antagonist of corticotropin-releasing factor type-1 (CRF1) receptors in the pituitary gland, is in late stage development as a potential treatment for adults with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD). We report the results of 3 randomized Phase 1 studies of safety, tolerability, and pharmacokinetics (PK) of tildacerfont in healthy adults and compare the relative bioavailability of 2 tildacerfont formulations. Methods: Two Phase 1 studies were double-blind, placebo-controlled and evaluated escalating doses (2–800 mg QD) as single doses (SAD; n=18) and 50-200mg as multiple doses (MAD; n=47). The studies also included pilot food effect and drug-drug interaction sub studies, respectively. A randomized, balanced, open-label, crossover study (n=42) examined the relative bioavailability (BA) of single oral doses of 2 tildacerfont formulations, 200 mg powder-in-capsule (PIC) compared to 200 mg low-drug load tablet. Results: In the SAD and MAD studies, the most common, non-procedural adverse events were headache and cough. In the BA study, the most common, non-procedural adverse events were constipation and headache. There were no study drug-related serious adverse events (SAEs) in any study. In the SAD and MAD (PIC formulation), tildacerfont concentrations declined in a multi-exponential manner with Cmax occurring moderately late, ~5 hours post dose, and a high degree of variability was observed in AUC and Cmax (CV range: 54–122%). A food effect was observed in the SAD. Fourteen days of dosing achieved near steady state exposure with an AUC accumulation ratio of 2.51 to 3.65 in the MAD study. Midazolam, a sensitive probe substrate for CYP3A4 exhibited ~2-fold increase in AUC and a 1.8 increase in Cmax when co-administered with tildacerfont suggesting moderate CYP3A4 inhibition. The tablet formulation reduced the variability (AUC and Cmax CV range: 69–72%) compared to the PIC formulation resulting in a more predictable pharmacokinetic profile. The half-life of the tablet was ~60 hrs. Bioequivalence in AUC was established with the tablet and PIC formulations (fed state) with Cmax ~20% higher for tablet than PIC due to a reduction in and more consistent Tmax, median [range], from 6 [4.5, 24] hours to 3 [2, 6] hours. Conclusions: These results suggest that tildacerfont is safe and generally well-tolerated in healthy adults and suitable for further study in patients with CAH. The tablet formulation provided a more consistent pharmacokinetic profile with reduced variability in all parameters and is being evaluated in late stage studies of tildacerfont in adult CAH.

Tildacerfont for the Treatment of Patients With Classic Congenital Adrenal Hyperplasia: Results From a 12-Week Phase 2 Clinical Trial in Adults With Classic CAH

Background: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is an autosomal recessive disorder characterized by insufficient cortisol production resulting in excess adrenocorticotropic hormone (ACTH) and adrenal androgen production. Standard-of-care therapy with glucocorticoids (GC) is suboptimal due to the difficulty of balancing control of the ACTH-driven androgen excess against the serious long-term side effects associated with chronic supraphysiologic GC exposure. Tildacerfont, a second-generation corticotropin-releasing factor type-1 (CRF1) receptor antagonist, lowers excess ACTH, and thus has the potential to reduce adrenal androgen production and to allow for GC dosing closer to physiologic doses. A prior study demonstrated that tildacerfont was effective in reducing ACTH, 17-hydroxyprogesterone (17-OHP) and androstenedione (A4) after 2 weeks of therapy. Here we report results from an open-label 12-week extension study. Methods: Subjects met either of the following criteria: 1) completion of prior study or 2) treatment naïve to tildacerfont with 17-OHP >800 ng/dL while on a stable GC regimen (excluding dexamethasone). Subjects were treated with oral tildacerfont at 400 mg once daily for 12 weeks. Efficacy and safety parameters were assessed at baseline through Week 12. Results: Subject characteristics (n=8) are as follows: median (range) age was 44.5 years (26-67 years; 5 females), median (range) body mass index 30.8 kg/m2 (22-41 kg/m2). In month 3, in the participants with poor control of disease at baseline (elevations in all key biomarkers: ACTH, 17-OHP, and A4) (n=5), maximum mean percentage reductions for ACTH, 17-OHP and A4 were 84%, 82%, and 79%, respectively. In this subgroup, 60% of subjects achieved ACTH normalization and 40% achieved A4 normalization during treatment. Tildacerfont treatment maintained, and did not suppress, biomarkers in participants with good control of disease at baseline (A4 below upper limit of normal) (n=3). Overall, tildacerfont was well tolerated with no serious adverse events. Conclusions: This is the first study of 12 weeks’ duration for a novel, non-steroidal mechanism-of-action agent for the treatment of 21-OHD. Results of this study show that tildacerfont was generally well-tolerated and effective in achieving meaningful reductions in ACTH and A4 in poorly controlled patients over 12 weeks. In addition, this is the first, non-steroidal therapeutic to show evidence of ACTH and A4 normalization over 12 weeks of therapy. Longer term future studies will evaluate whether treatment with tildacerfont can achieve further clinical benefits and allow reduction of GC doses while controlling relevant disease biomarkers.