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GW280430A is an ultrashort-acting neuromuscular blocking agent targeted at muscle relaxation to facilitate surgical intubation. The objective of this work was to study the buffer and cosolvent effects on the solution stability of GW280430A. The buffer catalytic effect was examined in citrate, malate, tartrate, and glycine by measuring the rate of degradation of GW280430A (0.2 mg/mL) at constant pH (3), ionic strength (0.15 M), and various buffer concentrations (0.01-0.05 M). The temperature dependence of the buffer catalytic effect and the degradation of the GW280430A in cosolvent (ethanol, propylene glycol, polyethylene glycol 400, N,N-dimethylacetamide)/water mixtures were studied at 40, 50, and 60 C. The loss of parent drug was monitored by reverse-phase high-performance liquid chromatography. The degradation of GW280430A followed first-order kinetics in all buffer solutions. Significant buffer-catalyzed hydrolysis of GW280430A was observed with citrate, tartrate, and malate buffers, but not in glycine-buffered solutions. The activation energies in all buffered drug solutions ranged from 70 to 80 kJ/mol and decreased with increasing buffer concentration. GW280430A degradation was primarily through ester hydrolysis and followed first-order kinetics in aqueous solutions. In cosolvent/water mixtures, new degradation products were observed, indicating a chemical reaction between GW280430A and cosolvents. The reaction activation energies in the cosolvent/water mixtures ranged from 75 to 85 kJ/mol, with the longest t 0.9 at 5 C equal to approximately 12 months and at 25 C equal to Drug Dev Ind Pharm Downloaded from informahealthcare.com by University of Mississippi on 11/03/14For personal use only. ORDER REPRINTS 36 days. Consideration should be given to the incorporation of glycine or a low concentration of citrate, malate, or tartrate buffer in the parenteral formulation development of GW280430A. Cosolvents prolonged the predicted t 0.9 for GW280430A in solution, but the enhancement was not significant enough to pursue a liquid formulation.

Background Alcohol use is a major global healthcare burden that contributes to numerous adverse health outcomes, including liver disease. Many factors influence individual susceptibility to alcohol‐associated diseases, including nutritional factors. The objective of the current study was to examine inter‐relations among alcohol, dietary micronutrients and macronutrient consumption, and liver health by analyzing data from the 2017–2018 National Health and Nutrition Examination Survey (NHANES). Methods Based on self‐reported alcohol consumption, NHANES respondents were assigned to one of four categories: never drinkers (lifetime abstainers), non‐drinkers (past‐year abstainers), moderate drinkers (1/2 drinks per day for females/males, respectively), and heavy drinkers (>1/>2 drinks per day for females/males, respectively, and/or frequent binge drinking). Survey‐weighted regression analyses (adjusted for gender, age, race, education, and body mass index) were performed to examine associations between alcohol intake, dietary, and liver health characteristics. Results Individuals categorized as heavy drinkers were significantly younger, most often well‐educated males with low incidences of diabetes and other comorbidities. They consumed the most overall calories and various micronutrients, indicating a diet that was not necessarily nutrient poor. Neither moderate nor heavy drinkers had liver steatosis or fibrosis as measured by liver elastography, although heavy drinkers had modestly elevated plasma biomarkers of liver injury, including ALT, AST, and GGT, compared with the other groups. Conclusions Our findings suggest that the category of heavy drinkers in the 2017–2018 NHANES consisted of generally healthy individuals with high‐energy intake and no evidence of liver steatosis or fibrosis. However, slightly increased plasma liver markers may indicate a risk of future progression to more advanced stages of liver disease over time in some individuals. Several limitations should be considered when interpreting these data, including the potential misclassification of drinking categories and the lack of standardized cutoff scores for fatty liver as assessed by elastography, among others.

The psychotic illness of a 16-year-old girl is described from both the professionals' viewpoint and that of the adolescent. The article discusses issues raised during a community-based intervention which prioritized the prevention of hospitalization. Atypical features of the psychosis are used to highlight issues arising from such an intensive community approach.

Alcohol-associated liver disease (ALD) is the most common chronic liver disease and carries a significant healthcare burden. ALD has no long-term treatment options aside from abstinence, and the mechanisms that contribute to its pathogenesis are not fully understood. This study aimed to investigate the role of formyl peptide receptor 2 (FPR2), a receptor for immunomodulatory signals, in the pathogenesis of ALD. WT and Fpr2−/− mice were exposed to chronic–binge ethanol administration and subsequently assessed for liver injury, inflammation, and markers of regeneration. The differentiation capacity of liver macrophages and the oxidative burst activity of neutrophils were also examined. Compared to WT, Fpr2−/− mice developed more severe liver injury and inflammation and had compromised liver regeneration in response to ethanol administration. Fpr2−/− mice had fewer hepatic monocyte-derived restorative macrophages, and neutrophils isolated from Fpr2−/− mice had diminished oxidative burst capacity. Fpr2−/− MoMF differentiation was restored when co-cultured with WT neutrophils. Loss of FPR2 led to exacerbated liver damage via multiple mechanisms, including abnormal immune responses, indicating the crucial role of FPR2 in ALD pathogenesis.