Targeting the Arginine Vasopressin V1b Receptor System and Stress Response in Depression and Other Neuropsychiatric Disorders.

A healthy stress response is critical for good mental and overall health and promotes neuronal growth and adaptation, but the intricately balanced biological mechanisms that facilitate a stress response can also result in predisposition to disease when that equilibrium is disrupted. The hypothalamic-pituitary-adrenal (HPA) axis neuroendocrine system plays a critical role in the body's response and adaptation to stress, and vasopressinergic regulation of the HPA axis is critical to maintaining system responsiveness during chronic stress. However, exposure to repeated or excessive physical or emotional stress or trauma can shift the body's stress response equilibrium to a "new normal" underpinned by enduring changes in HPA axis function. Exposure to early life stress due to adverse childhood experiences can also lead to lasting neurobiological changes, including in HPA axis function. HPA axis impairment in patients with depression is considered among the most reliable findings in biological psychiatry, and chronic stress has been shown to play a major role in the pathogenesis and onset of depression and other neuropsychiatric disorders. Modulating HPA axis activity, for example via targeted antagonism of the vasopressin V1b receptor, is a promising approach for patients with depression and other neuropsychiatric disorders associated with HPA axis impairment. Despite favorable preclinical indications in animal models, demonstration of clinical efficacy for the treatment of depressive disorders by targeting HPA axis dysfunction has been challenging, possibly due to the heterogeneity and syndromal nature of depressive disorders. Measures of HPA axis function, such as elevated cortisol levels, may be useful biomarkers for identifying patients who may benefit from treatments that modulate HPA axis activity. Utilizing clinical biomarkers to identify subsets of patients with impaired HPA axis function who may benefit is a promising next step in fine-tuning HPA axis activity via targeted antagonism of the V1b receptor.

Correction to: Safety and Efficacy of 0.5% Carbomer 980 Gel for Treatment of Symptoms of Common Cold: Results of 2 Randomized Trials.

The original publication of the article contained the following errors.

Safety and Efficacy of 0.5% Carbomer 980 Gel for Treatment of Symptoms of Common Cold: Results of 2 Randomized Trials.

BACKGROUND: Two studies of intranasal 0.5% carbomer 980 gel were conducted evaluating nasal tolerability in healthy volunteers and safety and efficacy in adults with common cold symptoms. METHODS: Study 1 randomly assigned healthy adults to 0.5% carbomer 980 gel (n = 20) or placebo (n = 10) administered intranasally four times daily for 7 days. Nasal examinations were conducted at baseline and daily throughout the study. The primary endpoint was local nasal tolerability. Study 2 randomly assigned adults with an investigator-confirmed diagnosis of symptomatic common cold to 0.5% carbomer 980 gel (n = 87) or placebo (n = 81), administered intranasally four times daily for 7 days (except for day 1, where subjects who received their first dose mid-day administered only three doses). The primary efficacy endpoint was the average nasal symptom score over days 1‒4 (ANSS1-4). Secondary efficacy endpoints included ANSS over days 1‒7 and average total symptom score (ATSS). Adverse events (AEs) were recorded throughout the study. RESULTS: In study 1, subjects assigned to 0.5% carbomer 980 gel had no mucosal grading higher than grade 1B (superficial nasal mucosal erosion) and low incidences of mucosal bleeding and crusting. In study 2, there were no statistically significant differences between treatments for any efficacy endpoints. Active treatment was well-tolerated; the most commonly reported AEs were headache, myalgia, and cough. CONCLUSION: While 0.5% carbomer 980 gel nasal spray demonstrated good local nasal tolerability in healthy volunteers, the spray did not significantly impact the course of infection or resolution of cold symptoms in subjects with common cold.

Bioequivalence Evaluation of Two Oral Formulations of Acetaminophen in Healthy Subjects: Results From a Randomized, Single-Blind, Crossover Study.

Despite widespread availability of acetaminophen in Mexico, data on its pharmacokinetic properties in Mexican populations are limited. This single-center, single-blind, randomized, 2-period, 2-treatment, crossover, single-dose-per-period, 2-sequence study evaluated the bioequivalence of a test acetaminophen product available in Mexico compared with a reference 500-mg acetaminophen product in 28 healthy adults under fasting conditions. Blood samples were collected predose and at specified intervals across a 16-hour period following administration and were analyzed for acetaminophen using a validated reverse-phase high-performance liquid chromatography method. Drug products were considered to be bioequivalent if confidence intervals of natural log-transformed Cmax , AUC0-t , and AUC0-∞ data were within the range of 80% to 125%. Results were inconclusive for Cmax due to high levels of intrasubject variability with this parameter. However, criteria for bioequivalence were met for AUC0-t and AUC0-∞ . All measured acetaminophen concentrations in this study were within a safe therapeutic range, and no adverse events were reported. The level of Cmax intrasubject variability observed in this study does not have any apparent clinical implications that could affect either safety or efficacy.