Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Examining the Uptake of Central Nervous System Drugs and Candidates across the Blood-Brain Barrier s

ABSTRACT Assessing the equilibration of the unbound drug concentrations across the blood-brain barrier (K p,uu ) has progressively replaced the partition coefficient based on the ratio of the total concentration in brain tissue to blood (K p ). Here, in vivo brain distribution studies were performed on a set of central nervous system (CNS)-targeted compounds in both rats and P-glycoprotein (P-gp) genetic knockout mice. Several CNS drugs are characterized by K p,uu values greater than unity, inferring facilitated uptake across the rodent blood-brain barrier (BBB). Examples are shown in which K p,uu also increases above unity on knockout of P-gp, highlighting the composite nature of this parameter with respect to facilitated BBB uptake, efflux, and passive diffusion. Several molecules with high K p,uu values share common structural elements, whereas uptake across the BBB appears more prevalent in the CNS-targeted drug set than the chemical templates being generated within the current lead optimization paradigm. Challenges for identifying high K p,uu compounds are discussed in the context of acute versus steady-state data and cross-species differences. Evidently, there is a need for better predictive models of human brain K p,uu

A new environmental sciences AMS laboratory in Scotland

A new Scottish AMS laboratory complements existing local facilities for radiocarbon and other cosmogenic isotope environmental research. A 5 MV Pelletron based accelerator mass spectrometer has been installed in a purpose-built building. The instrument is intended for routine <sup>10</sup>Be,<sup>14</sup>C,<sup>26</sup>Al,<sup>36</sup>Cl and <sup>129</sup>I-AMS as well as for developing CO<sub>2</sub> sample measurement and science