Recommendations for the safe use of direct oral anticoagulants in patients with cirrhosis based on a systematic review of pharmacokinetic, pharmacodynamic and safety data.

PURPOSE: The popularity of direct oral anticoagulants (DOACs) is increasing among patients with cirrhosis. Cirrhosis has a major impact on the pharmacokinetics of drugs, potentially increasing adverse events. Safe use of drugs in cirrhosis requires a diligent risk-benefit analysis. The aim of this study is to develop practice recommendations for safe use of DOACs in cirrhosis based on a systematic review of pharmacokinetic, pharmacodynamic and safety data. METHODS: We conducted a systematic literature search to identify studies on pharmacokinetics, pharmacodynamics and safety of DOACs in cirrhosis. Data were collected and presented in summary tables by severity of cirrhosis using the Child-Turcotte-Pugh (CTP) classification. A multidisciplinary expert panel evaluated the results and classified the DOACs according to safety. RESULTS: Fifty four studies were included. All DOACs were classified as 'no additional risks known' for CTP A. For CTP B, apixaban, dabigatran and edoxaban were classified as 'no additional risks known'. Apixaban and edoxaban showed fewer adverse events in patients with cirrhosis, while dabigatran may be less impacted by severity of cirrhosis based on its pharmacokinetic profile. Rivaroxaban was classified as 'unsafe' in CTP B and C based on significant pharmacokinetic alterations. Due to lack of data, apixaban, dabigatran and edoxaban were classified as 'unknown' for CTP C. CONCLUSION: DOACs can be used in patients with CTP A cirrhosis, and apixaban, dabigatran and edoxaban can also be used in CTP B. It is recommended to avoid rivaroxaban in CTP B and C. There is insufficient evidence to support safe use of other DOACs in CTP C cirrhosis.

Evaluation of the importance of mixing during preparation of antibiotic infusions.

BACKGROUND: The mixing step after medication addition to the infusion bag is frequently omitted during the preparation of drug infusions. However, the importance of mixing when preparing antibiotic infusions is still unknown. METHODS: The primary aim of this study was to assess the importance of the mixing step by comparing the concentrations of unmixed antibiotic infusions (cefuroxime, flucloxacillin, meropenem, and vancomycin) with the declared concentration at regular intervals during infusion. The secondary aim was to compare concentrations between preparation sites (hospital pharmacy versus clinical ward). Infusion bags were run through electronic infusion pumps. For cefuroxime, flucloxacillin, and meropenem, samples were collected 1, 15, and 20 min after starting the administration (infusion duration: 30 min). For vancomycin, samples were collected after 1, 60, and 110 min (infusion duration: 120 min). Vancomycin concentrations were measured using the Architect c4000 analyser and other concentrations using a validated UPC2-MS-MS multimethod. RESULTS: The median concentrations of the four antibiotics were comparable to the declared concentration at all three time points. No significant differences were found between preparation sites. CONCLUSIONS: Spontaneous mixing occurred in the examined antibiotic solutions during normal handling.

A yeast-based phenotypic screen for aquaporin inhibitors.

Aquaporins mediate transport of water or small, uncharged solutes across cellular membranes according to the prevailing osmotic and chemical gradients. Because of their implication in human diseases and pathophysiological states, aquaporins are considered as potential drug targets. Yet, specific aquaporin inhibitors for in vivo studies are not available. Common functional aquaporin assays that monitor biophysical parameters related to volume changes, such as light scattering or fluorescence quenching, are time consuming and require costly equipment. Hence, they are not well geared for screening large numbers of compounds. In this paper, we describe a less demanding phenotypic yeast-based assay on 96-well microplates. The assay uses a methylamine-sensitive yeast strain in which a methylamine-permeable test aquaporin is expressed to rescue proliferation on selection plates. Specific inhibition of the aquaporin directly correlates to reduced cell proliferation.