Eicosapentaenoic acid incorporation in membrane phospholipids modulates receptor-mediated phospholipase C and membrane fluidity in rat ventricular myocytes in culture

The influence of increased incorporation of linoleic acid (18:2n-6) and eicosapentaenoic acid (20:5n-3) in membrane phospholipids on receptor-mediated phospholipase Cβ (PLC-β) activity in cultured rat ventricular myocytes was investigated. For this purpose, cells were grown for 4 days in control, stearic acid (18:0)/oleic acid (18:1n-9), 18:2n-6 and 20:5n-3 enriched media, and subsequently assayed for the basal- and phenylephrine- or endothelin-1-induced total inositol phosphate formation. The various fatty acid treatments resulted in the expected alterations of fatty acid composition of membrane phospholipids. In 18:2n-6-treated cells, the incorporation of this 18:2n-6 in the phospholipids increased from 17.1 mol % in control cells to 38.9 mol %. In 20:5n-3-treated cells, incorporation of 20: 5n-3 and docosapentaenoic acid (22:5n-3) in the phospholipids increased from 0.5 and 2.7 mol % in control cells to 23.2 and 9.7 mol %, respectively. When 20:5n-3-treated cells were stimulated with phenylephrine or endothelin-1, the inositolphosphate production decreased by 33.2% and increased by 43.4%, respectively, as compared to cells grown in control medium. No efffects were seen in 18:2n-6-treated cells. When 18:0/18:1n-9-treated cells were stimulated with endothelin-1, inositolphosphate formation increased by 26.4%, whereas phenylephrine-stimulated inositolphosphate formation was not affected. In saponin-permeabilized cells, that were pre-treated with 20:5n-3, the formation of total inositolphosphates after stimulation with GTPγS, in the presence of Ca2+, was inhibited 19.3%. This suggests that the 20:5n-3 effect on intact cardiomyocytes could be exerted either on the level of agonist-receptor, receptor-GTP-binding-protein coupling or GTP-binding-protein-PLC-β interaction. Investigation of the time course of saponin-induced permeabilization of the cardiomyocytes, measured by the release of lactate dehydrogenase, unmasked a slight decrease in the rate of permeabilization by 20:5n-3 pretreatment, indicating a protective effect. This led the authors to measure the cholesterol/phospholipid molar ratio, the double bond index of membrane phospholipids, and the membrane fluidity; the latter by using a diphenylhexatriene probe. In 20: 5n-3-pretreated cells, a strong increase in the cholesterol/phospholipid molar ratio (from 0.23 to 0.39), a marked increase in the double bond index (from 1.76 to 2.33), and a slight decrease in fluidity (steady-state anisotropy r(ss) of the diphenylhexatriene probe increased from 0.196 to 0.217) were observed. Thus, treatment of cardiomyocytes for 4 days with 20:5n-3, but not with 18:2n-6, causes alterations of receptor-mediated phospholipase Cβ activity. A causal relationship may exist between the 20:5 n-3-induced alterations of the physicochemical properties in the bilayer and of the agonist-stimulated phosphatidylinositol cycle activity

Adverse drug events caused by three high-risk drug–drug interactions in patients admitted to intensive care units:A multicentre retrospective observational study

Aims: Knowledge about adverse drug events caused by drug–drug interactions (DDI-ADEs) is limited. We aimed to provide detailed insights about DDI-ADEs related to three frequent, high-risk potential DDIs (pDDIs) in the critical care setting: pDDIs with international normalized ratio increase (INR+) potential, pDDIs with acute kidney injury (AKI) potential, and pDDIs with QTc prolongation potential. Methods: We extracted routinely collected retrospective data from electronic health records of intensive care units (ICUs) patients (≥18 years), admitted to ten hospitals in the Netherlands between January 2010 and September 2019. We used computerized triggers (e-triggers) to preselect patients with potential DDI-ADEs. Between September 2020 and October 2021, clinical experts conducted a retrospective manual patient chart review on a subset of preselected patients, and assessed causality, severity, preventability, and contribution to ICU length of stay of DDI-ADEs using internationally prevailing standards. Results: In total 85 422 patients with ≥1 pDDI were included. Of these patients, 32 820 (38.4%) have been exposed to one of the three pDDIs. In the exposed group, 1141 (3.5%) patients were preselected using e-triggers. Of 237 patients (21%) assessed, 155 (65.4%) experienced an actual DDI-ADE; 52.9% had severity level of serious or higher, 75.5% were preventable, and 19.3% contributed to a longer ICU length of stay. The positive predictive value was the highest for DDI-INR+ e-trigger (0.76), followed by DDI-AKI e-trigger (0.57). Conclusion: The highly preventable nature and severity of DDI-ADEs, calls for action to optimize ICU patient safety. Use of e-triggers proved to be a promising preselection strategy.</p

Adverse drug events caused by three high-risk drug–drug interactions in patients admitted to intensive care units:A multicentre retrospective observational study

Aims: Knowledge about adverse drug events caused by drug–drug interactions (DDI-ADEs) is limited. We aimed to provide detailed insights about DDI-ADEs related to three frequent, high-risk potential DDIs (pDDIs) in the critical care setting: pDDIs with international normalized ratio increase (INR+) potential, pDDIs with acute kidney injury (AKI) potential, and pDDIs with QTc prolongation potential. Methods: We extracted routinely collected retrospective data from electronic health records of intensive care units (ICUs) patients (≥18 years), admitted to ten hospitals in the Netherlands between January 2010 and September 2019. We used computerized triggers (e-triggers) to preselect patients with potential DDI-ADEs. Between September 2020 and October 2021, clinical experts conducted a retrospective manual patient chart review on a subset of preselected patients, and assessed causality, severity, preventability, and contribution to ICU length of stay of DDI-ADEs using internationally prevailing standards. Results: In total 85 422 patients with ≥1 pDDI were included. Of these patients, 32 820 (38.4%) have been exposed to one of the three pDDIs. In the exposed group, 1141 (3.5%) patients were preselected using e-triggers. Of 237 patients (21%) assessed, 155 (65.4%) experienced an actual DDI-ADE; 52.9% had severity level of serious or higher, 75.5% were preventable, and 19.3% contributed to a longer ICU length of stay. The positive predictive value was the highest for DDI-INR+ e-trigger (0.76), followed by DDI-AKI e-trigger (0.57). Conclusion: The highly preventable nature and severity of DDI-ADEs, calls for action to optimize ICU patient safety. Use of e-triggers proved to be a promising preselection strategy.</p