Continuous infusion of physostigmine in patients with perioperative septic shock: A pharmacokinetic/pharmacodynamic study with population pharmacokinetic modeling

Background In the context of the cholinergic anti-inflammatory pathway, the clinical trial Anticholium® per Se (EudraCT Number: 2012-001650-26, ClinicalTrials.gov NCT03013322) addressed the possibility of taking adjunctive physostigmine salicylate treatment in septic shock from bench to bedside. Pharmacokinetics (PK) are likely altered in critically ill patients; data on physostigmine PK and target concentrations are sparse, particularly for continuous infusion. Our objective was to build a population PK (popPK) model for physostigmine, and further evaluate pharmacodynamics (PD) and concentration-response relationship in this setting. Methods In the randomized, double-blind, placebo-controlled trial, 20 patients with perioperative septic shock either received an initial dose of 0.04 mg/kg physostigmine salicylate, followed by continuous infusion of 1 mg/h for up to 120 h, or equivalent volumes of 0.9% sodium chloride (placebo group). Physostigmine plasma concentrations and acetylcholinesterase (AChE) activity were measured; concentration-response associations were evaluated, and popPK and PD modeling was performed with NONMEM. Results Steady state physostigmine plasma concentrations reached 7.60 ± 2.81 ng/mL (mean ± standard deviation [SD]). PK was best described by a two-compartment model with linear clearance. Significant covariate effects were detected for body weight and age on clearance, as well as a high inter-individual variability of the central volume of distribution. AChE activity was significantly reduced to 30.5%–50.6% of baseline activity during physostigmine salicylate infusion. A sigmoidal direct effect PD model best described enzyme inhibition by physostigmine, with an estimated half maximal effective concentration (EC50) of 5.99 ng/mL. Conclusions PK of physostigmine in patients with septic shock displayed substantial inter-individual variability with body weight and age influencing the clearance. Physostigmine inhibited AChE activity with a sigmoidal concentration-response effect

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Isomere 1,2,4-Triazolcarbaldehyde Synthese und Eigenschaften

SIGLEAvailable from TIB Hannover: DW 4821 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

Medication errors in intravenous drug preparation and administration: a multicentre audit in the UK, Germany and France

Background: Previous studies have identified medication errors in preparing and administering intravenous medicines of 13–84% in hospitals in individual countries. Objective: To compare the effect of the design and implementation of systems for the preparation and administration of intravenous therapy in hospitals in three European countries on the number of observed medication errors. To gain a better understanding of these risks and the methods used in each country to manage them. Design: Prospective audit. Setting: Six hospital departments in the UK, Germany and France willing to participate in the audit as part of a quality improvement programme. Methods: Direct observation of the preparation and the administration of intravenous drugs made by a single observer in each country. Main outcome measures: Medication process errors. Results: 824 doses were prepared and 798 doses administered. The product was either not labelled or incorrectly labelled in 43%, 99%, and 20% of doses administered in the UK, German and French hospitals, respectively. The wrong diluent was used in 1%, 49% and 18% of cases, respectively, and the wrong rate of administration was selected for 49%, 21% and 5% of doses observed, respectively. At least one deviation from aseptic technique was observed among 100%, 58%, and 19% of cases in the three countries. Conclusion: Uncontrolled risks in the intravenous systems studied were observed in all three countries. Intravenous therapy must be regarded as a high risk activity where the use of risk management procedures to minimise risk to patients is seen as a high priority by all those involved with these duties. There is a requirement to develop better national (possibly international) procedures for safe intravenous practice