Reduced oxycodone brain delivery in rats due to lipopolysaccharide-induced inflammation: microdialysis insights into brain disposition and sex-specific pharmacokinetics.

Background: Oxycodone, a widely used opioid analgesic, has an unbound brain-to-plasma concentration ratio (K) greater than unity, indicating active uptake across brain barriers associated with the putative proton-coupled organic cation (H/OC) antiporter system. With this study, we aimed to elucidate oxycodone's CNS disposition during lipopolysaccharide (LPS)-induced systemic inflammation in Sprague-Dawley rats.

Methods: Using brain microdialysis, we dynamically and simultaneously monitored unbound oxycodone concentrations in blood, striatum, lateral ventricle, and cisterna magna following intravenous administration of oxycodone post-LPS challenge.

Ceftazidime-avibactam (CAZ-AVI) pharmacokinetics in critically ill patients undergoing continuous venovenous hemodiafiltration (CVVHDF).

Purpose: To investigate the pharmacokinetics (PK) of ceftazidime-avibactam (CAZ-AVI) in critically ill patients undergoing continuous venovenous hemodiafiltration (CVVHDF), and compare with a general phase III trial population.

Methods: A prospective PK study was conducted in critically ill patients who received CVVHDF for acute kidney injury, treated with CAZ-AVI (1000/250 mg or 2000/500 mg q8h). Plasma and CVVHDF-circuit samples were collected to determine CAZ-AVI concentrations.

Formulation-dependent differences in paclitaxel distribution to anatomical sites relevant to chemotherapy-induced peripheral neuropathy.

Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting adverse event observed in patients receiving paclitaxel, associated with initial pathological changes in the peripheral nervous system, i.e., distal nerves and dorsal root ganglia (DRG).

The challenge to identify sensitive safety biomarkers of peripheral neurotoxicity in the rat: A collaborative effort across industry and academia (IMI NeuroDeRisk project).

Peripheral nervous system (PNS) toxicity assessment in non-clinical safety studies is challenging and relies mostly on histopathological assessment. The present work aims to identify blood-based biomarkers that could detect peripheral neuropathy in rats upon exposure to neurotoxic compounds. Three anticancer agents (oxaliplatin, cisplatin, paclitaxel) and a developmental compound (NVS-1) were assessed in male rats (Wistar Han).

Region-independent active CNS net uptake of marketed H/OC antiporter system substrates.

The pyrilamine-sensitive proton-coupled organic cation (H/OC) antiporter system facilitates the active net uptake of several marketed organic cationic drugs across the blood-brain barrier (BBB). This rare phenomenon has garnered interest in the H/OC antiporter system as a potential target for CNS drug delivery. However, analysis of pharmacovigilance data has uncovered a significant association between substrates of the H/OC antiporter and neurotoxicity, particularly drug-induced seizures (DIS) and mood- and cognitive-related adverse events (MCAEs).