Intranasal naloxone rapidly occupies brain mu-opioid receptors in human subjects.

Nasal spray formulations of naloxone, a mu-opioid receptor (MOR) antagonist, are currently used for the treatment of opioid overdose. They may have additional therapeutic utility also in the absence of opioid agonist drugs, but the onset and duration of action at brain MORs have been inadequately characterized to allow such projections. This study provides initial characterization of brain MOR availability at high temporal resolution following intranasal (IN) naloxone administration to healthy volunteers in the absence of a competing opioid agonist. Fourteen participants were scanned twice using positron emission tomography (PET) and [11C]carfentanil, a selective MOR agonist radioligand. Concentrations of naloxone in plasma and MOR availability (relative to placebo) were monitored from 0 to 60 min and at 300-360 min post naloxone. Naloxone plasma concentrations peaked at ~20 min post naloxone, associated with slightly delayed development of brain MOR occupancy (half of peak occupancy reached at ~10 min). Estimated peak occupancies were 67 and 85% following 2 and 4 mg IN doses, respectively. The estimated half-life of occupancy disappearance was ~100 min. The rapid onset of brain MOR occupancy by IN naloxone, evidenced by the rapid onset of its action in opioid overdose victims, was directly documented in humans for the first time. The employed high temporal-resolution PET method establishes a model that can be used to predict brain MOR occupancy from plasma naloxone concentrations. IN naloxone may have therapeutic utility in various addictions where brain opioid receptors are implicated, such as gambling disorder and alcohol use disorder.

Pharmacological investigations on adaptation in rats subjected to cold water immersion stress.

The present study was designed to investigate whether adaptogenic factors may be transferred from stress adapted rats to naïve rats and to explore the nature of endogenous adaptogens by pharmacological modulation. The rats were subjected to cold water immersion stress by placing them individually in a tank of water (depth=15.5cm; temperature=16±2°C) for 5min. The rats were subjected to single episode of cold water immersion stress for acute stress; while for adaptation, the rats were subjected to repeated episodes of same stressor for 5 consecutive days. The plasma of stress adapted rats was administered to naïve rats before subjecting to acute stress. The stress related behavioral alterations were assessed using the actophotometer, the hole board, the open field and the social interaction tests. Acute stress with single episode of cold water immersion was associated with behavioral alterations. However, the behavioral alterations were significantly restored on subjecting repeated episodes of cold water immersion. Administration of plasma of stress adapted rats also attenuated acute stress associated behavioral alterations. Administration of naltrexone abolished the restoration of behavioral changes as a part of adaptive process in repeated stress subjected rats as well as the anti-stress effects of plasma of stress adapted rat. It may be concluded that opioids may be the potential endogenous adaptogens that tend to restore the homeostasis during repeated episodes of stress. Furthermore, the endogenous adaptogens may be transferred in the form of plasma from repeated stress subjected rats to the naïve rats to confer the anti-stress properties.

Effects of rosiglitazone maleate when added to a sulfonylurea regimen in patients with type 2 diabetes mellitus and mild to moderate renal impairment: a post hoc analysis.

BACKGROUND: Patients with type 2 diabetes mellitus (DM) and renal impairment whose disease is inadequately controlled on a sulfonylurea (SU) have limited oral combination treatment options. OBJECTIVE: This post hoc analysis assesses the efficacy and tolerability of the insulin sensitizer rosiglitazone maleate (RSG) when added to an SU treatment regimen in patients with type 2 DM with mild to moderate renal impairment that is inadequately controlled by SU monotherapy. METHODS: Data were pooled from 3 randomized, double-blind, placebo-controlled, parallel-group studies in which RSG or placebo was added to an SU (glibenclamide, gliclazide, or glipizide) treatment regimen for a period of 6 months. Patients were subcategorized as having mild to moderate renal impairment or normal renal function based on a baseline creatinine clearance rate of 30 to 80 mL/min or >80 mL/min, respectively, as estimated by the Cockcroft-Gault equation. RESULTS: The population studied comprised 824 patients, 62% men and 38% women, aged 32 to 81 years, of whom 301 had mild to moderate renal impairment and 523 had normal renal function. In patients with and without renal impairment, glycemia was improved in the SU + RSG-treated group compared with the SU + placebo-treated group. The observed treatment differences between the groups were -2.6 mmol/L for fasting plasma glucose and -1.1% for glycosylated hemoglobin (for both renally impaired and nonimpaired patients). For patients receiving SU + RSG, little difference in the safety profile was found between patients with and without renal impairment. CONCLUSION: RSG was effective and well tolerated when added to SU therapy in this population of patients with mild to moderate renal impairment.