[Clinical aspects of the use of imidazopyridine derivatives in the treatment of sleep disorders associated with post-COVID syndrome]. / Klinicheskie aspekty primeneniya preparatov gruppy imidazopiridinov v terapii narushenii sna, assotsiirovannykh s postkovidnym sindromom.

In 2019, a pandemic caused by the SARS-CoV-2 virus began. The fight against COVID-19 required the introduction of a number of restrictive measures, in particular the introduction of quarantine for the population and isolation of the sick, which, along with the direct effect of the virus on the nervous system, led to a significant spread of sleep disorders. In this regard, questions have become relevant about the choice of drugs for the correction of sleep disorders, about which sleeping pills will be safe in conditions of acute illness and during the recovery period after COVID-19. The article discusses the prevalence and therapy of insomnia in patients with acute COVID-19 and in patients with postcovid syndrome. The pharmacological effects and safety of zolpidem, a non-benzodiazepine short-acting hypnotic drug belonging to the class of imidazopyridines, which is used in short courses for both acute and transient insomnia and chronic insomnia, are described. The data on the ability of zolpidem to improve memory after a night's sleep are given. The possibility of its use in acute COVID-19 and postcovid syndrome is being evaluated.

Propofol directly binds to and inhibits TLR7.

Sedatives/anesthetics are important medical tools to facilitate medical care and increase patients' comfort. Increasingly, there is recognition that sedatives/anesthetics can modulate immune functions. Toll-like receptors (TLRs) are major pattern recognition receptors involved in the recognition of microbial components. TLR7 recognizes single-strand RNA virus such as influenza and SARS-CoV2 viruses and initiates interferon (IFN) responses. IFN production triggered by TLR7 stimulation is a critical anti-viral response. For example, patients with TLR7 variants including loss-of- function variants were associated with severe COVID-19. Taken together, it is important to determine if sedatives/anesthetics mitigate TLR7 function. We have previously showed that TLR7-mediated activation was not affected by volatile anesthetics. However, we found that propofol attenuated TLR7 activation among intravenous sedatives in the reporter assay. TLR7 agonist R837 stimulation increased TNF-α, IL-1ß, IL-6, IL-10, and IFN-ß mRNA levels in bone marrow-derived dendritic cells, while these levels were attenuated by propofol. Our murine lung slice experiments showed that propofol attenuated IFN production. R837 increased IFN-ß expression in the lungs, and propofol attenuated IFN-ß expression in an in vivo model of R837 intranasal instillation. We also found that propofol directly bound to and hindered its association of TLR7 with MyD88. Our analysis using fropofol, propofol derivative showed that the hydroxyl group in propofol was important for propofol-TLR7 interaction.

Efficacy comparison of intraperitoneal anaesthesia and post-operative analgesia regimens in laboratory rats.

INTRODUCTION: Effective and safe anesthesia for rodents has long been a leading concern among biomedical researchers. Intraperitoneal injection constitutes an alternative to inhalant anesthesia. PURPOSE: The aim of this study was to identify a safe, reliable, and effective anesthesia and postoperative analgesia protocol for laboratory rats exposed to painful procedures. MATERIAL AND METHODS: Twenty-seven female Wistar rats in an ongoing study that required surgery were randomized into groups for three different intraperitoneal anesthesia protocols and three different analgesia regimens. The anesthesia groups were (1) medetomidine + ketamine (MK), (2) ketamine + xylacine (KX), and (3) fentanyl + medetomidine (FM). Three analgesia groups were equally distributed among the anesthesia groups: (1) local mepivacaine + oral ibuprofen (MI), (2) oral tramadol + oral ibuprofen (TI), and (3) local tramadol + oral tramadol + + oral ibuprofen (TTI). A core was assigned to measure anesthesia (0-3) and analgesia (0-2) effectiveness; the lower the score, the more effective the treatment. RESULTS: The mean MK score was 0.44 versus 2.00 for FM and 2.33 for KX. Mean score for analgesia on the first postoperative day was TTI (4.66) TI (9.13), and MI (10.14). Mean score 48 hours after surgery was TTI (3.4), TI (6.71), and MI (9.5). These differences were statistically significant. CONCLUSION: MK was shown to be a reliable, safe, and effective method of anesthesia. The TTI analgesia regimen is strongly recommended in light of these results.

Design of Clinical Trials Evaluating Sedation in Critically Ill Adults Undergoing Mechanical Ventilation: Recommendations From Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research (SCEPTER) Recommendation III.

OBJECTIVES: Clinical trials evaluating the safety and effectiveness of sedative medication use in critically ill adults undergoing mechanical ventilation differ considerably in their methodological approach. This heterogeneity impedes the ability to compare results across studies. The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research Recommendations convened a meeting of multidisciplinary experts to develop recommendations for key methodologic elements of sedation trials in the ICU to help guide academic and industry clinical investigators. DESIGN: A 2-day in-person meeting was held in Washington, DC, on March 28-29, 2019, followed by a three-round, online modified Delphi consensus process. PARTICIPANTS: Thirty-six participants from academia, industry, and the Food and Drug Administration with expertise in relevant content areas, including two former ICU patients attended the in-person meeting, and the majority completed an online follow-up survey and participated in the modified Delphi process. MEASUREMENTS AND MAIN RESULTS: The final recommendations were iteratively refined based on the survey results, participants' reactions to those results, summaries written by panel moderators, and a review of the meeting transcripts made from audio recordings. Fifteen recommendations were developed for study design and conduct, subject enrollment, outcomes, and measurement instruments. Consensus recommendations included obtaining input from ICU survivors and/or their families, ensuring adequate training for personnel using validated instruments for assessments of sedation, pain, and delirium in the ICU environment, and the need for methodological standardization. CONCLUSIONS: These recommendations are intended to assist researchers in the design, conduct, selection of endpoints, and reporting of clinical trials involving sedative medications and/or sedation protocols for adult ICU patients who require mechanical ventilation. These recommendations should be viewed as a starting point to improve clinical trials and help reduce methodological heterogeneity in future clinical trials.

Hemodynamic and respiratory effects of dexmedetomidine sedation in critically ill Covid-19 patients: A retrospective cohort study.

INTRODUCTION: Dexmedetomidine has been suggested to be a promising sedative for patients with Covid-19 infection (CV19). However, use of dexmedetomidine is limited by its heart rate (HR) and arterial blood pressure lowering effects. Moreover, CV19 is associated with cardiac manifestations including bradyarrythmias. The hemodynamic effects of dexmedetomidine have not been previously studied in CV19 patients. We evaluated the effects of dexmedetomidine on hemodynamic and respiratory parameters of CV19 patients. METHODS: In this single center study, all CV19 patients receiving dexmedetomidine for sedation during a one year period were included. Our primary outcomes included changes in HR, mean arterial pressure (MAP), respiratory rate (RR), partial oxygen pressure of arterial blood/fraction of inspired oxygen-ratio (PF-ratio), and Richmond Agitation and Sedation Score (RASS) during dexmedetomidine administration. RESULTS: We identified 39 patients with a mean (SD) age of 58.3 (12.7) years. After initiation of dexmedetomidine, HR decreased by 16.9 (3.3) beats/min (95% CI 9.5-22.4; p < 0.001). During the 12-hour follow-up period, HR decrease was significant at 2 to 12 h. Incident bradycardia (<45/min) was reported in 12 (30.8%) patients and it was associated with lower plasma C-reactive protein, Pro-calcitonin, and troponin T levels. There was no change in MAP compared to baseline. Dexmedetomidine administration was associated with improvement of PF-ratio (p < 0.001) and with decrease of RASS (p = 0.004). CONCLUSIONS: Dexmedetomidine is an effective sedative for CV19 patients and may improve their oxygenation. However, dexmedetomidine administration is associated with marked decline in HR and with a high incidence of bradycardia in patients with CV19.

High sedation needs of critically ill COVID-19 ARDS patients-A monocentric observational study.

BACKGROUND: Therapy of severely affected coronavirus patient, requiring intubation and sedation is still challenging. Recently, difficulties in sedating these patients have been discussed. This study aims to describe sedation practices in patients with 2019 coronavirus disease (COVID-19)-induced acute respiratory distress syndrome (ARDS). METHODS: We performed a retrospective monocentric analysis of sedation regimens in critically ill intubated patients with respiratory failure who required sedation in our mixed 32-bed university intensive care unit. All mechanically ventilated adults with COVID-19-induced ARDS requiring continuously infused sedative therapy admitted between April 4, 2020, and June 30, 2020 were included. We recorded demographic data, sedative dosages, prone positioning, sedation levels and duration. Descriptive data analysis was performed; for additional analysis, a logistic regression with mixed effect was used. RESULTS: In total, 56 patients (mean age 67 (±14) years) were included. The mean observed sedation period was 224 (±139) hours. To achieve the prescribed sedation level, we observed the need for two or three sedatives in 48.7% and 12.8% of the cases, respectively. In cases with a triple sedation regimen, the combination of clonidine, esketamine and midazolam was observed in most cases (75.7%). Analgesia was achieved using sufentanil in 98.6% of the cases. The analysis showed that the majority of COVID-19 patients required an unusually high sedation dose compared to those available in the literature. CONCLUSION: The global pandemic continues to affect patients severely requiring ventilation and sedation, but optimal sedation strategies are still lacking. The findings of our observation suggest unusual high dosages of sedatives in mechanically ventilated patients with COVID-19. Prescribed sedation levels appear to be achievable only with several combinations of sedatives in most critically ill patients suffering from COVID-19-induced ARDS and a potential association to the often required sophisticated critical care including prone positioning and ECMO treatment seems conceivable.

Pharmacokinetics/Pharmacodynamics of Antiviral Agents Used to Treat SARS-CoV-2 and Their Potential Interaction with Drugs and Other Supportive Measures: A Comprehensive Review by the PK/PD of Anti-Infectives Study Group of the European Society of Antimicrobial Agents.

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.

Dexmedetomidine and worsening hypoxemia in the setting of COVID-19: A case report.

Emergency department management of hypoxemia in the setting of COVID-19 is riddled with uncertainty. The lack of high-quality research has translated to an absence of clarity at the bedside. With disease spread outpacing treatment consensus, provider discretion has taken on a heightened role. Here, we report a case of dexmedetomidine use in the setting of worsening hypoxemia, whereby oxygenation improved and intubation was avoided. Well known pharmacologic properties of the drug, namely the lack of respiratory depression and its anti-delirium effects, as well as other possible physiologic effects, suggest potential benefit for patients being managed with a delayed intubation approach. If dexmedetomidine can improve compliance with non-invasive oxygen support (the current recommended first-line therapy) while promoting better oxygenation, it may also decrease the need for mechanical ventilation and thus improve mortality.