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There is an urgent need to identify optimal antiviral therapies for COVID-19 caused by SARS-CoV-2. We have conducted a rapid and comprehensive review of relevant pharmacological evidence, focusing on (1) the pharmacokinetics (PK) of potential antiviral therapies; (2) coronavirus-specific pharmacodynamics (PD); (3) PK and PD interactions between proposed combination therapies; (4) pharmacology of major supportive therapies; and (5) anticipated drug–drug interactions (DDIs). We found promising in vitro evidence for remdesivir, (hydroxy)chloroquine and favipiravir against SARS-CoV-2; potential clinical benefit in SARS-CoV-2 with remdesivir, the combination of lopinavir/ritonavir (LPV/r) plus ribavirin; and strong evidence for LPV/r plus ribavirin against Middle East Respiratory Syndrome (MERS) for post-exposure prophylaxis in healthcare workers. Despite these emerging data, robust controlled clinical trials assessing patient-centred outcomes remain imperative and clinical data have already reduced expectations with regard to some drugs. Any therapy should be used with caution in the light of potential drug interactions and the uncertainty of optimal doses for treating mild versus serious infections., SCOPUS: re.j, info:eu-repo/semantics/published

Objective: To describe our experience performing ED procedural sedation in a country where emergency medicine (EM) is a relatively new specialty. Methods: This is a prospective observational study of adult patients undergoing procedural sedation by emergency physicians (EPs) or EM residents in eight hospitals in the Netherlands. Data were collected on a standardised form, including patient characteristics, sedative and analgesic used, procedural success, adverse events (classified according to World SIVA) and rescue interventions. Results: 1711 adult cases were included from 2006 to 2013. Propofol, midazolam and esketamine (S+ enantiomer of ketamine) were the most used sedatives (63%, 29% and 8%). We had adverse event data on all patients. The overall adverse event rate was 11%, mostly hypoxia or apnoea. There was no difference in adverse event rate between EPs and EM residents. However, there was a significantly higher success rate of the procedure when EPs did the procedural sedation (92% vs 84%). No moderate (unplanned hospital admission or escalation of care) or sentinel SIVA outcomes occurred ( pulmonary aspiration syndrome, death or permanent neurological deficit). Conclusion: Adverse events during procedural sedation occurred in 11% of patients. There were no moderate or sentinel outcomes. All events could be managed by the sedating physician. In a country where EM is a relatively new specialty, procedural sedation appears to be safe when performed by EPs or trained EM residents and has comparable adverse event rates to international studies.

Anesthetics may induce specific changes that alter the balance of activity within neural networks. Here we describe the effects of the GABAAreceptor potentiating anesthetic etomidate on sensory processing, studied in a cerebellum-like structure, the electrosensory lateral line lobe (ELL) of mormyrid fish, in vitro. Previous studies have shown that the ELL integrates sensory input and removes predictable features by comparing reafferent sensory signals with a descending electromotor command-driven corollary signal that arrives in part through parallel fiber synapses with the apical dendrites of GABAergic interneurons. These synapses show spike timing–dependent depression when presynaptic activation is associated with postsynaptic backpropagating dendritic action potentials. Under etomidate, almost all neurons become tonically hyperpolarized. The threshold for action potential initiation increased for both synaptic activation and direct intracellular depolarization. Synaptically evoked inhibitory postsynaptic potentials (IPSPs) were also strongly potentiated and prolonged. Current source density analysis showed that backpropagation of action potentials through the apical dendritic arborization in the molecular layer was reduced but could be restored by increasing stimulus strength. These effects of etomidate were blocked by bicuculline or picrotoxin. It is concluded that etomidate affects both tonic and phasic inhibitory conductances at GABAAreceptors and that increased shunting inhibition at the level of the proximal dendrites also contributes to increasing the threshold for action potential backpropagation. When stimulus strength is sufficient to evoke backpropagation, repetitive association of synaptic excitation with postsynaptic action potential initiation still results in synaptic depression, showing that etomidate does not interfere with the molecular mechanism underlying plastic modulation.