No abstract

The impact of species-dependent differences between human and rat MAO B on inhibitor screening was evidenced for two classes of compounds, coumarin and 5H-indeno[1,2-c]pyridazin-5-one derivatives. All examined compounds have shown a greater inhibitor potency toward human MAO B than toward rat MAO B. Moreover, no correlation was found between human and rat pIC(50) values. These divergences have important implications for the design and development of drugs involved in the MAO B metabolic pathway, suggesting that results obtained using rat enzyme cannot be extrapolated to human CNS, a priori. Indeed, the selection of a hit compound for lead generation could be different using human rather than rat enzyme. Moreover, the influence of substituents on the in vitro inhibition of human MAO B was markedly different between homogeneous series of coumarin and 5H-indeno[1,2-c]pyridazin-5-one derivatives, suggesting different binding modes, a hypothesis clearly supported by molecular docking simulations of inhibitors into the active site of human MAO B.

Background: insufficient feeding is frequent in the intensive care unit (ICU), which results in poor outcomes. Little is known about the nutrition pattern of patients requiring prolonged ICU stays. The aims of our study are to describe the demographic, metabolic, and nutritional specificities of chronically critically ill (CCI) patients defined by an ICU stay >2 weeks, and to identify an early risk factor. Methods: analysis of consecutive patients prospectively admitted to the CCI program, with the following variables: demographic characteristics, Nutrition Risk Screening (NRS-2002) score, total daily energy from nutritional and non-nutritional sources, protein and glucose intakes, all arterial blood glucose values, length of ICU and hospital stay, and outcome (ICU and 90-day survival). Two phases were considered for the analysis: the first 10 days, and the next 20 days of the ICU stay. Statistics: parametric and non-parametric tests. Results: 150 patients, aged 60 ± 15 years were prospectively included. Median (Q1, Q3) length of ICU stay was 31 (26, 46) days. The mortality was 18% at ICU discharge and 35.3% at 90 days. Non-survivors were older (p = 0.024), tended to have a higher SAPSII score (p = 0.072), with a significantly higher NRS score (p = 0.033). Enteral nutrition predominated, while combined feeding was minimally used. All patients received energy and protein below the ICU’s protocol recommendation. The proportion of days with fasting was 10.8%, being significantly higher in non-survivors (2 versus 3 days; p = 0.038). Higher protein delivery was associated with an increase in prealbumin over time (r2 = 0.19, p = 0.027). Conclusions: High NRS scores may identify patients at highest risk of poor outcome when exposed to underfeeding. Further studies are required to evaluate a nutrition strategy for patients with high NRS, addressing combined parenteral nutrition and protein delivery.