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

Neurotransmitter receptors in three rodent models of Parkinson's disease : a quantitative multireceptor study

Parkinson’s disease (PD) is the second most common neurodegenerative disorder. Despite ongoing efforts, the knowledge of the etiology and underlying mechanisms resulting in the neurodegenerative processes (e.g., loss of dopaminergic neurons) remains incomplete. Since therapeutic intervention is still limited to symptomatic relief and mainly focused on the dopamine system, the understanding of the role of other, non-dopaminergic systems during pathogenesis of PD has to be improved for identifying new targets for treatment. Neurotransmitter receptors are major targets for pharmaceutical interventions in numerous neurological and psychiatric disorders, since distinct changes of receptors are often found in such diseases. In case of PD, the dominant role of changes in dopaminergic neurotransmission is well known. The possible involvement of other transmitter systems and their receptors, however, is not well understood. Therefore, the aim of this study was the analysis of the density and distribution of neurotransmitter receptors for glutamate, GABA, acetylcholine, adrenaline, serotonin, dopamine and adenosine in the brains of three well established mouse models of PD. The Pitx3 aphakia mouse served as a model exhibiting crucial hallmarks of PD on the neuropathological, symptomatic and pharmacological level. Additionally, Parkin and DJ-1 knockout mice were analyzed as models for hereditary parkinsonism by exhibiting PD associated gene mutations. Quantitative receptor autoradiography was used to comprehensively investigate the density and distribution of glutamate, GABA, acetylcholine, adrenaline, serotonin, dopamine and adenosine receptors in eleven different brain regions (i.e., the olfactory bulb, the motor, somatosensory, piriform and visual cortices, the hippocampal regions CA1, CA2/3 and dentate gyrus, the striatum, the substantia nigra and the cerebellum). Differential quantitative changes of neurotransmitter receptor densities were demonstrated for the three different animal models of PD compared to controls. In general, receptor density changes were similar between Parkin and DJ-1 knockout mice, indicating pathologic mechanisms occurring likewise in both models. GABAB receptor densities were increased in several regions of all investigated PD models (i.e., the piriform cortex, the dentate gyrus, the visual cortex and the substantia nigra). Thus, the increase in GABAB receptors seems to be a common reaction during pathogenesis of PD. The densities of nicotinic acetylcholine, serotonergic 5-HT1A and 5-HT2 receptors were demonstrated to be considerably reduced in Pitx3 aphakia mouse brains (i.e., the nicotinic acetylcholine receptor in the striatum, CA2/3 and the dentate gyrus; the serotonergic 5-HT1A receptor in the olfactory bulb, CA1 and the dentate gyrus; the 5-HT2 receptor in the striatum). A complex pattern of receptor changes in the striatum of Pitx3 aphakia, Parkin and DJ-1 knockout mice, respectively, correlates with the behavioral findings in these mice, and indicates differential interactions and dependencies between the different receptor systems in PD. Taken together, the present findings of neurotransmitter receptor density changes in Pitx3 aphakia, Parkin and DJ-1 knockout mice, respectively, provide novel data on the up- and down-regulation of GABA, acetylcholine, and 5-HT receptor expression in animal models of PD, and thereby highlight the often neglected impact of non-dopaminergic systems in the molecular pathology of Parkinson’s disease

Developmental Changes of Glutamate and GABA Receptor Densities in Wistar Rats

Neurotransmitters and their receptors are key molecules of signal transduction and subject to various changes during pre- and postnatal development. Previous studies addressed ontogeny at the level of neurotransmitters and expression of neurotransmitter receptor subunits. However, developmental changes in receptor densities to this day are not well understood. Here, we analyzed developmental changes in excitatory glutamate and inhibitory γ-aminobutyric acid (GABA) receptors in adjacent sections of the rat brain by means of quantitative in vitro receptor autoradiography. Receptor densities of the ionotropic glutamatergic receptors α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate and N-methyl-D-aspartate (NMDA) as well as of the ionotropic GABAA and metabotropic GABAB receptors were investigated using specific high-affinity ligands. For each receptor binding site, significant density differences were demonstrated in the investigated regions of interest [olfactory bulb, striatum, hippocampus, and cerebellum] and developmental stages [postnatal day (P) 0, 10, 20, 30 and 90]. In particular, we showed that the glutamatergic and GABAergic receptor densities were already present between P0 and P10 in all regions of interest, which may indicate the early relevance of these receptors for brain development. A transient increase of glutamatergic receptor densities in the hippocampus was found, indicating their possible involvement in synaptic plasticity. We demonstrated a decline of NMDA receptor densities in the striatum and hippocampus from P30 to P90, which could be due to synapse elimination, a process that redefines neuronal networks in postnatal brains. Furthermore, the highest increase in GABAA receptor densities from P10 to P20 coincides with the developmental shift from excitatory to inhibitory GABA transmission. Moreover, the increase from P10 to P20 in GABAA receptor densities in the cerebellum corresponds to a point in time when functional GABAergic synapses are formed. Taken together, the present data reveal differential changes in glutamate and GABA receptor densities during postnatal rat brain development, which may contribute to their specific functions during ontogenesis, thus providing a deeper understanding of brain ontogenesis and receptor function

Effect of Antiplatelet Therapy on Survival and Organ Support–Free Days in Critically Ill Patients With COVID-19

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