Safety and Efficacy of Riluzole in Acute Spinal Cord Injury Study (RISCIS): A Multi-Center, Randomized, Placebo-Controlled, Double-Blinded Trial.

Riluzole is a sodium-glutamate antagonist that attenuates neurodegeneration in amyotrophic lateral sclerosis (ALS). It has shown favorable results in promoting recovery in pre-clinical models of traumatic spinal cord injury (tSCI) and in early phase clinical trials. This study aimed to evaluate the efficacy and safety of riluzole in acute cervical tSCI. An international, multi-center, prospective, randomized, double-blinded, placebo-controlled, adaptive, Phase III trial (NCT01597518) was undertaken. Patients with American Spinal Injury Association Impairment Scale (AIS) A-C, cervical (C4-C8) tSCI, and <12 h from injury were randomized to receive either riluzole, at an oral dose of 100 mg twice per day (BID) for the first 24 h followed by 50 mg BID for the following 13 days, or placebo. The primary efficacy end-point was change in Upper Extremity Motor (UEM) scores at 180 days. The primary efficacy analyses were conducted on an intention to treat (ITT) and completed cases (CC) basis. The study was powered at a planned enrolment of 351 patients. The trial began in October 2013 and was halted by the sponsor on May 2020 (and terminated in April 2021) in the face of the global COVID-19 pandemic. One hundred ninety-three patients (54.9% of the pre-planned enrolment) were randomized with a follow-up rate of 82.7% at 180 days. At 180 days, in the CC population the riluzole-treated patients compared with placebo had a mean gain of 1.76 UEM scores (95% confidence interval: -2.54-6.06) and 2.86 total motor scores (CI: -6.79-12.52). No drug-related serious adverse events were associated with the use of riluzole. Additional pre-planned sensitivity analyses revealed that in the AIS C population, riluzole was associated with significant improvement in total motor scores (estimate: standard error [SE] 8.0; CI 1.5-14.4) and upper extremity motor scores (SE 13.8; CI 3.1-24.5) at 6 months. AIS B patients had higher reported independence, measured by the Spinal Cord Independence Measure score (45.3 vs. 27.3; d: 18.0 CI: -1.7-38.0) and change in mental health scores, measured by the Short Form 36 mental health domain (2.01 vs. -11.58; d: 13.2 CI: 1.2-24.8) at 180 days. AIS A patients who received riluzole had a higher average gain in neurological levels at 6 months compared with placebo (mean 0.50 levels gained vs. 0.12 in placebo; d: 0.38, CI: -0.2-0.9). The primary analysis did not achieve the predetermined end-point of efficacy for riluzole, likely related to insufficient power. However, on pre-planned secondary analyses, all subgroups of cervical SCI subjects (AIS grades A, B and C) treated with riluzole showed significant gains in functional recovery. The results of this trial may warrant further investigation to extend these findings. Moreover, guideline development groups may wish to assess the possible clinical relevance of the secondary outcome analyses, in light of the fact that SCI is an uncommon orphan disorder without an accepted neuroprotective treatment.

2022 CAS Virtual Annual Meeting

The proceedings contain 63 papers. The topics discussed include: a retrospective study to optimize post-anesthetic recovery time after ambulatory lower limb orthopedic procedures at a tertiary care hospital in Canada;a virtual airway evaluation as good as the real thing?;airway management during in hospital cardiac arrest by a consultant led airway management team during the COVID-19 pandemic: a prospective and retrospective quality assurance project;prevention of cautery induced airway fire using saline filled endotracheal tube cuffs: a study in a trachea airway fire model;smart phone assisted retrograde illumination versus conventional laryngoscope illumination for orotracheal intubation: a prospective comparative trial;time to single lung isolation in massive pulmonary hemorrhage simulation using a novel bronchial blocker and traditional techniques;cannabinoid type 2 receptor activation ameliorates acute lung injury induced systemic inflammation;bleeding in patients with end-stage liver disease undergoing liver transplantation and fibrinogen level: a cohort study;endovascular Vena Cavae occlusion in right anterior mini-thoracoscopic approach for tricuspid valve in patients with previous cardiac surgery;and mesenchymal stem cell extracellular vesicles as a novel, regenerative nanotherapeutic for myocardial infarction: a preclinical systematic review.

Cardiovascular System and COVID-19

Objective Different hypotheses suggest a contradictory association of statins, angiotensin receptor blockers(ARBs) or angiotensin-converting enzyme(ACE) inhibitors with potential adverse or favorable effects in patients with Coronavirus disease 2019(COVID-19). This study aimed to compare the association of statins, ARB, and ACE inhibitors in COVID-19 and in pneumonia. Design and Method All patients with laboratory-confirmed COVID-19 through April 16, 2020, in Korea were retrieved. We evaluated the association of statins, ARBs, and ACE inhibitors on COVID-19-related mortality within 60 days. Furthermore, a comparison of hazard ratio (HR) was performed between COVID-19 patients and a retrospective cohort of patients hospitalized with pneumonia between January and June 2019 in Korea. Lastly, meta-analysis was performed to compare the results of this study and other reports. Results The median age of the 10,448 COVID-19 patients was 45 years, and statins, ARBs and ACE inhibitors were prescribed in 533 (5.1%), 1,231(11.8%) and 47(0.4%) patients, respectively. As of April 24, 228 patients (2.2%) succumbed to death. After adjusting age, sex, residential area, the history of comorbidities, Cox regression showed significant decrease in HR by 36% associated with statin use (HR 0.635, 95% CI 0.424 - 0.951, p = 0.0274). However, ARBs group showed neutral association (HR 1.034, 95% CI 0.765 - 1.399, p = 0.8270) and ACE inhibitor groups showed insignificant results mainly due to small sample size (HR 0.736, 95% CI 0.314 - 1.726, p = 0.4810). When comparing the HR between COVID-19 patients and a retrospective cohort of patients hospitalized with pneumonia between January and June 2019, the trend of statins and ACE inhibitors showed similar benefit, whereas the protective effect of ARBs observed in the retrospective cohort was lost in the COVID-19 patients. Meta-analysis including the results of this study showed significant benefit of statins and ACE inhibitors, whereas neutral association with ARBs and the mortality. Conclusions Statins were associated with significantly lower mortality of COVID-19, consistent with usual pneumonia patients. While ARBs or ACE inhibitors were not associated with fatal outcome, the possible beneficial effect of ARBs observed in usual pneumonia was attenuated in COVID-19.

Therapeutic uses of Antihistamines in the Management of COVID-19: A Narrative Review

Background: The first case of COVID-19 emerged in China in 2019 and spread rap-idly worldwide. Therefore, all researchers worldwide sought ways to treat and prevent the dis-ease. Since the production of vaccines and new drugs is time-consuming, a good way is to look at existing drugs to find new effects. Objective(s): Due to the pathogenic mechanism of COVID-19, most of its symptoms, including anosmia, ageusia, and cytokine storm, are dependent on the release of histamine and its activities. Therefore, one category of drugs that may be effective in treating and improving the symptoms of COVID-19 is antihistamines. This paper reviewed studies that have been done so far on the effects of antihistamines, specially famotidine, in COVID-19. Method(s): A literature search was performed using scientific databases such as PubMed, Web of Science, Scopus, and Google Scholar from the beginning up to December 2021. The most rele-vant articles considering the potential impacts of antihistamines against COVID-19 were col-lected. Result(s): In addition to the current medications prescribed for the treatment of SARS-CoV-2, H1 and H2 blockers are promising drugs for repurposing in the COVID-19 remedy. Several studies on famotidine were performed using virtual screening to determine whether they are effective. Many studies have shown that famotidine use improved COVID-19 symptoms and reduced the need for intubation and mortality. However, few studies concluded that famotidine is ineffective. Conclusion(s): Antihistamines, and specifically famotidine, are effective in reducing COVID-19 symptoms. Therefore, they are a good choice for combination therapy with other drugs to treat COVID-19.Copyright © 2023 Bentham Science Publishers.

Biomarkers of COVID-19 and technologies to combat SARS-CoV-2.

Due to the unprecedented public health crisis caused by COVID-19, our first contribution to the newly launching journal, Advances in Biomarker Sciences and Technology, has abruptly diverted to focus on the current pandemic. As the number of new COVID-19 cases and deaths continue to rise steadily around the world, the common goal of healthcare providers, scientists, and government officials worldwide has been to identify the best way to detect the novel coronavirus, named SARS-CoV-2, and to treat the viral infection - COVID-19. Accurate detection, timely diagnosis, effective treatment, and future prevention are the vital keys to management of COVID-19, and can help curb the viral spread. Traditionally, biomarkers play a pivotal role in the early detection of disease etiology, diagnosis, treatment and prognosis. To assist myriad ongoing investigations and innovations, we developed this current article to overview known and emerging biomarkers for SARS-CoV-2 detection, COVID-19 diagnostics, treatment and prognosis, and ongoing work to identify and develop more biomarkers for new drugs and vaccines. Moreover, biomarkers of socio-psychological stress, the high-technology quest for new virtual drug screening, and digital applications are described.

Beta-Blocker and Calcium Channel Blocker Toxicity With BRASH Syndrome: A Case Report.

Atrioventricular (AV) nodal blockers have a wide variety of medical uses, including the management of hypertension and cardiac arrhythmias. Like any other drug, they can carry side effects and toxicity. We present a case of a patient with a constellation of findings consistent with bradycardia, renal failure, AV nodal blockade, shock, and hyperkalemia (BRASH) syndrome. A 75-year-old female with a history of paroxysmal atrial fibrillation and heart failure with preserved ejection fraction presented to the hospital with shortness of breath. She was discharged two weeks prior to the presentation from another hospital after being treated for atrial fibrillation with a rapid ventricular response. She was discharged on metoprolol and diltiazem. Upon presentation to the hospital, the patient was noted to be bradycardic and hypotensive with blood work notable for acute kidney injury and hyperkalemia, consistent with BRASH syndrome. She received a dose of intravenous (IV) glucagon followed by infusion and received epinephrine infusion. Once clinically stable, she was discharged with her home dose of metoprolol and a reduced dose of diltiazem with a close follow-up with cardiology. Early recognition of BRASH syndrome as a unique clinical entity rather than different pathologic conditions is important to improve morbidity and mortality in these patients.

Potential antiviral peptides targeting the SARS-CoV-2 spike protein.

BACKGROUND: The coronavirus disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection became an international pandemic and created a public health crisis. The binding of the viral Spike glycoprotein to the human cell receptor angiotensin-converting enzyme 2 (ACE2) initiates viral infection. The development of efficient treatments to combat coronavirus disease is considered essential. METHODS: An in silico approach was employed to design amino acid peptide inhibitor against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. The designed inhibitor (SARS-CoV-2 PEP 49) consists of amino acids with the α1 helix and the ß4 - ß5 sheets of ACE2. The PEP-FOLD3 web tool was used to create the 3D structures of the peptide amino acids. Analyzing the interaction between ACE2 and the RBD of the Spike protein for three protein data bank entries (6M0J, 7C8D, and 7A95) indicated that the interacting amino acids were contained inside two regions of ACE2: the α1 helical protease domain (PD) and the ß4 - ß5 sheets. RESULTS: Molecular docking analysis of the designed inhibitor demonstrated that SARS-CoV-2 PEP 49 attaches directly to the ACE2 binding site of the Spike protein with a binding affinity greater than the ACE2, implying that the SARS-CoV-2 PEP 49 model may be useful as a potential RBD binding blocker.

Hunting for protective drugs at the break of a pandemic: Causal inference from hospital data.

At the break of a pandemic, the protective efficacy of therapeutic interventions needs rapid evaluation. An experimental approach to the problem will not always be appropriate. An alternative route are observational studies, whether based on regional health service data or hospital records. In this paper, we discuss the use of methods of causal inference for the analysis of such data, with special reference to causal questions that may arise in a pandemic. We apply the methods by using the aid of a directed acyclic graph (DAG) representation of the problem, to encode our causal assumptions and to logically connect the scientific questions. We illustrate the usefulness of DAGs in the context of a controversy over the effects of renin aldosterone system inhibitors (RASIs) in hypertensive individuals at risk of (or affected by) severe acute respiratory syndrome coronavirus 2 disease. We consider questions concerning the existence and the directions of those effects, their underlying mechanisms, and the possible dependence of the effects on context variables. This paper describes the cognitive steps that led to a DAG representation of the problem, based on background knowledge and evidence from past studies, and the use of the DAG to analyze our hospital data and assess the interpretive limits of the results. Our study contributed to subverting early opinions about RASIs, by suggesting that these drugs may indeed protect the older hypertensive Covid-19 patients from the consequences of the disease. Mechanistic interaction methods revealed that the benefit may be greater (in a sense to be made clear) in the older stratum of the population.

A Synergistic Broad-Spectrum Viral Entry Blocker: In-Silico Approach

Increasing victims of viral attacks is a serious concern of the current time as well as soon. The story of virulence was started with the origin of the Spanish flu pandemic of 1918, later severe other viral infections like SARS, MARS, and many others took the life of many people. Currently, the situation is locked in the world because of the unprecedented arrival of the COVID-19 from the Wuhan, city of China. The current need turned to make suitable candidates with the existing safety data, to get the molecule in a limited period. Because of that, the quinolone 3-carboxy derivatives were docked with many targets enzyme, but the interaction with gp-41 was found interactive, which is represented with interactive binding energy scores. In this regard, the validated target of the virus likes HIV. COVID-19 and other viruses were utilized to see the beneficial interactions. The present research is based on the Quinoline-3carboxy derivatives and their interaction with gp41. The gp41 has been found with the highest similarity with the S2 protein of the Coronavirus;targeting this protein will inhibit the interaction of cells and viruses. The in silico results were found encouraging with the suitable interactions with the amino acid residues. The results give us the hope to develop a lead for the inhibition of viral infection, including HIV, flu, and Coronavirus. The result is summarized with all the in silico docking and residual interaction with the reasonable concept of lead to go further in the drug discovery process. © 2022 by the authors.

Synthesis and Crystal Structure of Adamantylated 4,5,6,7-Tetrahalogeno-1H-benzimidazoles Novel Multi-Target Ligands (Potential CK2, M2 and SARS-CoV-2 Inhibitors); X-ray/DFT/QTAIM/Hirshfeld Surfaces/Molecular Docking Study.

A series of new congeners, 1-[2-(1-adamantyl)ethyl]-1H-benzimidazole (AB) and 1-[2-(1-adamantyl)ethyl]-4,5,6,7-tetrahalogeno-1H-benzimidazole (Hal=Cl, Br, I; tClAB, tBrAB, tIAB), have been synthesized and studied. These novel multi-target ligands combine a benzimidazole ring known to show antitumor activity and an adamantyl moiety showing anti-influenza activity. Their crystal structures were determined by X-ray, while intermolecular interactions were studied using topological Bader's Quantum Theory of Atoms in Molecules, Hirshfeld Surfaces, CLP and PIXEL approaches. The newly synthesized compounds crystallize within two different space groups, P-1 (AB and tIAB) and P21/c (tClAB and tBrAB). A number of intramolecular hydrogen bonds, C-H⋯Hal (Hal=Cl, Br, I), were found in all halogen-containing congeners studied, but the intermolecular C-H⋯N hydrogen bond was detected only in AB and tIAB, while C-Hal⋯π only in tClAB and tBrAB. The interplay between C-H⋯N and C-H⋯Hal hydrogen bonds and a shift from the strong (C-H⋯Cl) to the very weak (C-H⋯I) attractive interactions upon Hal exchange, supplemented with Hal⋯Hal overlapping, determines the differences in the symmetry of crystalline packing and is crucial from the biological point of view. The hypothesis about the potential dual inhibitor role of the newly synthesized congeners was verified using molecular docking and the congeners were found to be pharmaceutically attractive as Human Casein Kinase 2, CK2, inhibitors, Membrane Matrix 2 Protein, M2, blockers and Severe Acute Respiratory Syndrome Coronavirus 2, SARS-CoV-2, inhibitors. The addition of adamantyl moiety seems to broaden and modify the therapeutic indices of the 4,5,6,7-tetrahalogeno-1H-benzimidazoles.

What do we know about the renin angiotensin system and inflammatory bowel disease?

INTRODUCTION: The renin-angiotensin system (RAS) is an important homeostatic pathway, with emerging evidence for the impact of its components on inflammation and fibrosis in gastrointestinal tissues. This review aims to review current knowledge of the physiological mechanism of RAS in inflammatory bowel disease (IBD), and potential therapeutic implications. AREAS COVERED: An extensive online literature review including Pubmed, Medline, and Google Scholar was undertaken. Discussion on the components of the RAS, localization, and physiological functions in the gastrointestinal tract, preclinical, and clinical data in IBD, and the relation with SARS-Cov-2 are covered in this review. EXPERT OPINION: RAS inhibition may have a role as anti-fibrotic adjunct therapy. Targeting the local gastrointestinal RAS with novel modes of delivery may be a target for future therapeutics for IBD, given the widespread availability and safety of current options as utilized in other diseases. Further insight into the mechanism and downstream effects of gastrointestinal ACE2 may lead to a better understanding of the pathogenesis of IBD.

Impact of angiotensin receptor blocker as antihypertensive in assessing mortality in patients of COVID-19: A single tertiary care center study.

BACKGROUND: The angiotensin-converting enzyme 2 (ACE2) receptor, a membrane receptor present in the respiratory system, the gastrointestinal tracts, the heart, and the kidney is the entry point for SARS-CoV-2 to enter human cells. Concerns were raised about the influence of using antihypertensive drugs like angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in individuals with COVID-19 due to its tight relationship with the ACE2 receptor. The aim of this study was to investigate the impact of being on an Angiotensin Receptor Blockers (ARB) on mortality in patients consecutively diagnosed with COVID-19. MATERIAL AND METHODS: This is the retrospective observational study done in all patients consecutively diagnosed with COVID-19 from January 2021 to June 2021. All related patient information and clinical data was retrieved from the hospitals electronic medical record system. RESULTS: In this study, out of 500 patients, 51 died, having mean age of 66.92 ± 10.85 years. 144 (28.8%) patients were on angiotensin receptor blockers as antihypertensive treatment, 142 (28.4%) having other antihypertensive and 214 (42.8%) were not on any treatment. Out of 51 Death 7 (4.9) patients were on ARBs, 15 ± 10.6 were on other medication [OR 2.31 (0.94-6.22, P = 0.077) univariable; OR 2.57 (1.00-7.23, P = 0.058) multivariable] and 29 ± 13.6 had no treatment at all [OR 3.07 (1.38-7.80, P = 0.010) univariable; OR 3.36 (1.41-9.08, P = 0.010) multivariable]. CONCLUSION: Use of ARB medications for the hypertensive patients who acquire COVID-19 infection has shown protective effects of such medications on COVID-19 disease severity in the term of mortality and the mortality rate among hypertensive patients on COVID-19 with ARBs/ACE inhibitors showed significant differences as compared to other antihypertensives.

The atypical ß-blocker S-oxprenolol reduces cachexia and improves survival in a rat cancer cachexia model.

BACKGROUND: Beta-blockers and selected stereoisomers of beta-blockers, like bisoprolol and S-pindolol (ACM-001), have been shown to be effective in preclinical cancer cachexia models. Here, we tested the efficacy of stereoisomers of oxprenolol in two preclinical models of cancer cachexia-the Yoshida AH-130 rat model and the Lewis lung carcinoma (LLC) mouse model. METHODS AND RESULTS: In the Yoshida AH130 hepatoma rat cancer cachexia model and compared with placebo, 50 mg/kg/d S-oxprenolol (HR: 0.49, 95% CI: 0.28-0.85, P = 0.012) was superior to 50 mg/kg/d R-oxprenolol (HR: 0.83, 95% CI 0.38-1.45, P = 0.51) in reducing mortality (= reaching ethical endpoints). Combination of the three doses (12.5, 25 and 50 mg/kg/d) that had a significant effect on body weight loss in the S-oxprenolol groups vs the same combination of the R-oxprenolol groups lead to a significantly improved survival of S-oxprenolol vs R-oxprenolol (HR: 1.61, 95% CI: 1.08-2.39, P = 0.0185). Interestingly, there is a clear dose dependency in S-oxprenolol-treated (5, 12.5, 25 and 50 mg/kg/d) groups, which was not observed in groups treated with R-oxprenolol. A dose-dependent attenuation of weight and lean mass loss by S-oxprenolol was seen in the Yoshida rat model, whereas R-oxprenolol had only had a significant effect on fat mass. S-oxprenolol also non-significantly reduced weight loss in the LLC model and also improved muscle function (grip strength 428 ± 25 and 539 ± 37 g/100 g body weight for placebo and S-oxprenolol, respectively). However, there was only a minor effect on quality of life indicators food intake and spontaneous activity in the Yoshida model (25 mg/kg/S-oxprenolol: 11.9 ± 2.5 g vs placebo: 4.9 ± 0.8 g, P = 0.013 and also vs 25 mg/kg/d R-oxprenolol: 7.5 ± 2.6 g, P = 0.025). Both enantiomers had no effects on cardiac dimensions and function at the doses used in this study. Western blotting of proteins involved in the anabolic/catabolic homoeostasis suggest that anabolic signalling is persevered (IGF-1 receptor, Akt) and catabolic signalling is inhibited (FXBO-10, TRAF-6) by S-pindolol, but not he R-enantiomer. Expression of glucose transporters Glut1 and Glut 4 was similar in all groups, as was AMPK. CONCLUSIONS: S-oxprenolol is superior to R-oxprenolol in cancer cachexia animal models and shows promise for a human application in cancer cachexia.

Inhibition of SARS-CoV-2 Viral Channel Activity Using FDA-Approved Channel Modulators Independent of Variants.

BACKGROUND: SARS-CoV-2 has undergone mutations, yielding clinically relevant variants. HYPOTHESIS: We hypothesized that in SARS-CoV-2, two highly conserved Orf3a and E channels directly related to the virus replication were a target for the detection and inhibition of the viral replication, independent of the variant, using FDA-approved ion channel modulators. METHODS: A combination of a fluorescence potassium ion assay with channel modulators was developed to detect SARS-CoV-2 Orf3a/E channel activity. Two FDA-approved drugs, amantadine (an antiviral) and amitriptyline (an antidepressant), which are ion channel blockers, were tested as to whether they inhibited Orf3a/E channel activity in isolated virus variants and in nasal swab samples from COVID-19 patients. The variants were confirmed by PCR sequencing. RESULTS: In isolated SARS-CoV-2 Alpha, Beta, and Delta variants, the channel activity of Orf3a/E was detected and inhibited by emodin and gliclazide (IC50 = 0.42 mM). In the Delta swab samples, amitriptyline and amantadine inhibited the channel activity of viral proteins, with IC50 values of 0.73 mM and 1.11 mM, respectively. In the Omicron swab samples, amitriptyline inhibited the channel activity, with an IC50 of 0.76 mM. CONCLUSIONS: We developed an efficient method to screen FDA-approved ion channel modulators that could be repurposed to detect and inhibit SARS-CoV-2 viral replication, independent of variants.

Pre-Admission Beta-Blocker Therapy and Outcomes of Coronavirus Disease 2019 (COVID-19): A Systematic Review, Meta-Analysis, and Meta-Regression.

BACKGROUND: Hypertension and heart failure are known risk factors for coronavirus disease 2019 (COVID-19) severity and mortality outcomes. Beta-blocker is one of the drugs of choice to treat these conditions. The purpose of this study is to explore the relationship between preadmission beta-blocker use and COVID-19 outcomes. METHODS: PubMed and Europe PMC were used as the database for our search strategy by using combined keywords related to our aims until December 10th, 2020. All articles related to COVID- 19 and beta-blocker were retrieved. Review Manager 5.4 and Comprehensive Meta-Analysis 3 software were used to perform statistical analysis. RESULTS: A total of 43 studies consisting of 11,388,556 patients were included in our analysis. Our meta-analysis showed that the use of beta-blocker was associated with increased risk of COVID-19 [OR 1.32 (95% CI 1.02 - 1.70), p = 0.03, I2 = 99%, random-effect modelling], clinical progression [OR 1.37 (95% CI 1.01 - 1.88), p = 0.04, I2 = 89%, random-effect modelling], and mortality from COVID-19 [OR 1.64 (95% CI 1.22 - 2.19), p = 0.0009, I2 = 94%, random-effect modelling]. Metaregression showed that the association with mortality outcome were influenced by age (p = 0.018) and hypertension (p = 0.005). CONCLUSION: The risk and benefits of using beta-blocker as a drug of choice to treat hypertensive patients should be considered and reviewed individually, case by case, knowing their association with higher incidence and severity of COVID-19 infections. Other first-line antihypertensive drugs may be considered as an alternative therapy if the risk of administering beta blockers outweighs the benefits of COVID-19 infection. REGISTRATION DETAILS: PROSPERO (CRD42021260455).

Topical timolol for treatment of pyogenic granulomas in children: A case series

Background: Pyogenic granuloma (PG) is benign vascular tumour presenting as small, friable, reddish papule or nodule. Bleeding tendency of PGs warrants their removal.Various available treatment options require local anesthesia, cause pain, local side effects, scarring and become undesirable for treating children. Hence, topical beta blocker (timolol 0.5%) becomes a valuable option for treating PG in children. Method(s): We enrolled 3 healthy children aged less than 14 years with clinical diagnosis of PG for the case series. Patients with any cardiopulmonary abnormalities were not enrolled. All the patients were prescribed 0.5% ophthalmic solution, topically twice a day for 6 weeks. Due to the prevailing COVID-19 pandemic, patients were called for follow up visits every three weeks. At the end of 6 weeks, patients were evaluated for the improvement and followed up for one year after treatment to look for any recurrences or any long-term side effects of timolol. Result(s): All three patients enrolled in the study showed partial improvement at 6weeks and complete improvement in two patients after one year. No recurrence or any long-term side effects with timolol were noted in any patient. Conclusion(s): Topical beta blocker (Timolol) is easy to administer, safe and noninvasive. It appears to have a promising role in children with no recurrences or any associated long-term side effects. Copyright © 2022 Ubiquity Press. All rights reserved.

Severe Toxic Epidermal Necrolysis and Drug Reaction with Eosinophilia and Systemic Symptoms Overlap Syndrome Treated with Benralizumab: A Case Report

TEN/DRESS overlap syndrome can be difficult to diagnose, especially if it is masked by comorbidities in critically ill patients in intensive care units. The existing therapy for the two conditions is also a major challenge for the treating team. A possible alternative, especially for refractory cases, is benralizumab as an IL-5-receptor alpha-chain-specific humanized monoclonal antibody (IgG1k). We are able to show a successful treatment in this case report.

Drugs acting on the renin-angiotensin-aldosterone system (RAAS) and deaths of COVID-19 patients: a systematic review and meta-analysis of observational studies.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) are two of the most commonly used antihypertensive drugs acting on the renin-angiotensin-aldosterone system (RAAS). Previous research has shown that RAAS inhibitors increase the expression of angiotensin-converting enzyme, a cellular receptor for the severe acute respiratory syndrome coronavirus 2, raising concerns that the use of ACEi and ARBs in hypertensive patients may increase COVID-19 patient mortality. Therefore, the main aim of the current study was to find out the role of drugs acting on RAAS, particularly ACEi/ARBs in the deaths of COVID-19 patients. RESULTS: In total, 68 studies were found to be appropriate, reporting a total of 128,078 subjects. The odds ratio was found to be 1.14 [0.95, 1.36], which indicates the non-significant association of ACEi/ARBs with mortality of COVID-19 patients. Further, the association of individual ACEi/ARBs with mortality of COVID-19 patients was also found non-significant. The sensitivity analysis results have shown no significant effect of outliers on the outcome. CONCLUSIONS: Based on available evidence, ACEi/ARB were not significantly associated with deaths of COVID-19 patients.

COVIDMED - An early pandemic randomized clinical trial of losartan treatment for hospitalized COVID-19 patients.

Objectives: To assess the efficacy and safety of losartan for COVID-19 patients. Methods: COVIDMED was a double-blinded, placebo-controlled platform RCT. Enrollees were randomized to standard care plus hydroxychloroquine, lopinavir/ritonavir, losartan, or placebo. Hydroxychloroquine and lopinavir/ritonavir arms were discontinued early. We report losartan data vs. combined (lopinavir-ritonavir and placebo) and prespecified placebo-only controls. The primary endpoint was the mean COVID-19 Ordinal Severity Score (COSS) slope of change. Slow enrollment prompted early termination. Results: Fourteen patients were included in our final analysis (losartan [N = 9] vs. control [N = 5] [lopinavir/ritonavir [N = 2], placebo [N = 3]]). Most baseline parameters were balanced. Losartan treatment was not associated with a difference in mean COSS slope of change vs. combined (p = 0.4) or placebo-only control (p = 0.05) (trend favoring placebo). 60-day mortality and overall AE/SAE rates were insignificantly higher with losartan. Conclusion: In this small RCT in hospitalized COVID-19 patients, losartan did not improve outcome and was associated with adverse safety signals.

SAR-based approach to explore in silico ferrocene analogues as the potential inhibitors of major viral proteins of SARS-CoV-2 virus and human Ca2+-channel blocker

Amid the pandemic COVID-19, there is a desperate and urgent need for a therapeutic solution for COVID-19. Our present studies have adapted the SAR-based approach to explore in silico several selected ferrocene-based complexes as the potential inhibitors of the major viral proteins (Spike, RdRp, M-pro, N protein) of the SARS-CoV-2 virus. The SAR-based molecular docking studies have revealed that compound 1 is the strongest inhibitor of the major viral proteins with a binding energy of >9.0 kcal/mol. Compound 1 is also able to inhibit the human Ca2+ channel and thereby potentially able to prevent the strong inflammatory signalling cascades causing severe respiratory distress to the COVID-19 patients. Overall, our computational studies explored ferrocene-based compounds as the emerging multi-targeting therapeutic solution for COVID-19 by inhibiting viral replication as well as modulating the inflammatory signalling cascades.