Ivabradine in the Management of COVID-19-related Cardiovascular Complications: A Perspective.

Besides acute respiratory distress syndrome, acute cardiac injury is a major complication in severe coronavirus disease 2019 (COVID-19) and is associated with a poor clinical outcome. Acute cardiac injury with COVID-19 can be of various etiologies, including myocardial ischemia or infarction and myocarditis, and may compromise cardiac function, resulting in acute heart failure or cardiogenic shock. Systemic inflammatory response increases heart rate (HR), which disrupts the myocardial oxygen supply/demand balance and worsens cardiac energy efficiency, thus further deteriorating the cardiac performance of the injured myocardium. In fact, the combination of elevated resting HR and markers of inflammation synergistically predicts adverse cardiovascular prognosis. Thus, targeted HR reduction may potentially be of benefit in cardiovascular pathologies associated with COVID-19. Ivabradine is a drug that selectively reduces HR via If current inhibition in the sinoatrial node without a negative effect on inotropy. Besides selective HR reduction, ivabradine was found to exert various beneficial pleiotropic effects, either HR-dependent or HR-independent, including anti-inflammatory, anti-atherosclerotic, anti-oxidant and antiproliferative actions and the attenuation of endothelial dysfunction and neurohumoral activation. Cardioprotection by ivabradine has already been indicated in cardiovascular pathologies that are prevalent with COVID-19, including myocarditis, acute coronary syndrome, cardiogenic shock or cardiac dysautonomia. Here, we suggest that ivabradine may be beneficial in the management of COVID-19- related cardiovascular complications.

Structure-based drug designing and immunoinformatics approach for SARS-CoV-2.

The prevalence of respiratory illness caused by the novel SARS-CoV-2 virus associated with multiple organ failures is spreading rapidly because of its contagious human-to-human transmission and inadequate globalhealth care systems. Pharmaceutical repurposing, an effective drug development technique using existing drugs, could shorten development time and reduce costs compared to those of de novo drug discovery. We carried out virtual screening of antiviral compounds targeting the spike glycoprotein (S), main protease (Mpro), and the SARS-CoV-2 receptor binding domain (RBD)-angiotensin-converting enzyme 2 (ACE2) complex of SARS-CoV-2. PC786, an antiviral polymerase inhibitor, showed enhanced binding affinity to all the targets. Furthermore, the postfusion conformation of the trimeric S protein RBD with ACE2 revealed conformational changes associated with PC786 drug binding. Exploiting immunoinformatics to identify T cell and B cell epitopes could guide future experimental studies with a higher probability of discovering appropriate vaccine candidates with fewer experiments and higher reliability.

Pilot study of extended-release lorcaserin for cocaine use disorder among men who have sex with men: A double-blind, placebo-controlled randomized trial.

OBJECTIVE: To determine if men who have sex with men (MSM) with cocaine use disorder (CUD) and actively-using cocaine could be enrolled and retained in a pharmacologic intervention trial of lorcaserin-a novel 5-HT2cR agonist-and determine the degree to which participants would adhere to study procedures. METHODS: This was a phase II randomized, double-blind, placebo-controlled pilot study with 2:1 random parallel group assignment to daily extended-release oral lorcaserin 20 mg versus placebo (clinicaltrials.gov identifier-NCT03192995). Twenty-two of a planned 45 cisgender MSM with CUD were enrolled and had weekly follow-up visits during a 12-week treatment period, with substance use counseling, urine specimen collection, and completion of audio-computer assisted self-interview (ACASI) behavioral risk assessments. Adherence was measured by medication event monitoring systems (MEMS) caps and self-report. This study was terminated early because of an FDA safety alert for lorcaserin's long-term use. RESULTS: Eighty-six percent completed the trial, with 82% of weekly study follow-up visits completed. Adherence was 55.3% (lorcaserin 51.6% vs. placebo 66.2%) by MEMS cap and 56.9% (56.5% vs. placebo 57.9%) by self-report and did not differ significantly by treatment assignment. Intention-to-treat analyses (ITT) did not show differences in cocaine positivity by urine screen between the lorcaserin and placebo groups by 12 week follow-up (incidence risk ratio [IRR]: 0.96; 95%CI = 0.24-3.82, P = 0.95). However, self-reported cocaine use in timeline follow-back declined more significantly in the lorcaserin group compared to placebo (IRR: 0.66; 95%CI = 0.49-0.88; P = 0.004). CONCLUSION: We found that it is feasible, acceptable, and tolerable to conduct a placebo-controlled pharmacologic trial for MSM with CUD who are actively using cocaine. Lorcaserin was not associated with significant reductions in cocaine use by urine testing, but was associated with significant reductions in self-reported cocaine use. Future research may be needed to continue to explore the potential utility of 5-HT2cR agonists.

Angioedema, ACE inhibitor and COVID-19.

SARS-CoV-2, the virus responsible for COVID-19, binds to the ACE2 receptors. ACE2 is thought to counterbalance ACE in the renin-angiotensin system. While presently it is advised that patients should continue to use ACE inhibitors or angiotensin receptor blockers, questions still remain as to whether adverse effects are potentiated by the virus. Here, we report a case of a 57-year-old man, unknowingly with COVID-19, who presented to the emergency department with tongue swelling, shortness of breath and difficulty in speaking following 4 months taking benazepril, an ACE inhibitor. Finally, we also describe possible pathways that exist for SARS-CoV-2 to interact with the mechanism behind angioedema.

Molecular Docking and Virtual Screening Based Prediction of Drugs for COVID-19.

AIMS: To predict potential drugs for COVID-19 by using molecular docking for virtual screening of drugs approved for other clinical applications. BACKGROUND: SARS-CoV-2 is the betacoronavirus responsible for the COVID-19 pandemic. It was listed as a potential global health threat by the WHO due to high mortality, high basic reproduction number, and lack of clinically approved drugs and vaccines. The genome of the virus responsible for COVID-19 has been sequenced. In addition, the three-dimensional structure of the main protease has been determined experimentally. OBJECTIVE: To identify potential drugs that can be repurposed for treatment of COVID-19 by using molecular docking based virtual screening of all approved drugs. METHODS: A list of drugs approved for clinical use was obtained from the SuperDRUG2 database. The structure of the target in the apo form, as well as structures of several target-ligand complexes, were obtained from RCSB PDB. The structure of SARS-CoV-2 Mpro determined from X-ray diffraction data was used as the target. Data regarding drugs in clinical trials for COVID-19 was obtained from clinicaltrials.org. Input for molecular docking based virtual screening was prepared by using Obabel and customized python, bash, and awk scripts. Molecular docking calculations were carried out with Vina and SMINA, and the docked conformations were analyzed and visualized with PLIP, Pymol, and Rasmol. RESULTS: Among the drugs that are being tested in clinical trials for COVID-19, Danoprevir and Darunavir were predicted to have the highest binding affinity for the Main protease (Mpro) target of SARS-CoV-2. Saquinavir and Beclabuvir were identified as the best novel candidates for COVID-19 therapy by using Virtual Screening of drugs approved for other clinical indications. CONCLUSION: Protease inhibitors approved for treatment of other viral diseases have the potential to be repurposed for treatment of COVID-19.