Efficacy of Remdesivir and Neutralizing Monoclonal Antibodies in Monotherapy or Combination Therapy in Reducing the Risk of Disease Progression in Elderly or Immunocompromised Hosts Hospitalized for COVID-19: A Single Center Retrospective Study.

INTRODUCTION: Remdesivir (REM) and monoclonal antibodies (mAbs) could alleviate severe COVID-19 in at-risk outpatients. However, data on their use in hospitalized patients, particularly in elderly or immunocompromised hosts, are lacking. METHODS: All consecutive patients hospitalized with COVID-19 at our unit from 1 July 2021 to 15 March 2022 were retrospectively enrolled. The primary outcome was the progression to severe COVID-19 (P/F < 200). Descriptive statistics, a Cox univariate-multivariate model, and an inverse probability treatment-weighted (IPTW) analysis were performed. RESULTS: Overall, 331 subjects were included; their median (q1-q3) age was 71 (51-80) years, and they were males in 52% of the cases. Of them, 78 (23%) developed severe COVID-19. All-cause in-hospital mortality was 14%; it was higher in those with disease progression (36% vs. 7%, p < 0.001). REM and mAbs resulted in a 7% (95%CI = 3-11%) and 14% (95%CI = 3-25%) reduction in the risk of severe COVID-19, respectively, after adjusting the analysis with the IPTW. In addition, by evaluating only immunocompromised hosts, the combination of REM and mAbs was associated with a significantly lower incidence of severe COVID-19 (aHR = 0.06, 95%CI = 0.02-0.77) when compared with monotherapy. CONCLUSIONS: REM and mAbs may reduce the risk of COVID-19 progression in hospitalized patients. Importantly, in immunocompromised hosts, the combination of mAbs and REM may be beneficial.

Teriflunomide and COVID-19: A Friend or Foe?!

Unfortunately, the coronavirus disease 2019 (COVID-19) pandemic has become an irritating universal crisis. Thus, the discovery/identification of prospective drug candidates to disband the branched health issues caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become urgent. This current research sheds light on the repositioning possibility of the potent antirheumatic drug teriflunomide to act as an efficient anti-SARS-CoV-2/anti-COVID-19 remedy. Herein, a motivating in silico molecular docking/modeling study of teriflunomide explores its potential inhibitory actions on the novel coronaviral-2 RNA-dependent RNA polymerase (nCoV-RdRp) enzyme/protein was reported. Interestingly, the computational analysis of the teriflunomide superior inhibitory binding mode in the binding cavity of one of the active sites of the nCoV-RdRp detected that teriflunomide molecule shows considerably stronger inhibitory binding interactions and better inhibitory binding affinities (it shows lower binding energies which reached-9.70 kcal/mol) than both used references. It was reported that teriflunomide potently impairs viral replication/reproduction by employing two distinct action mechanisms. Thus, the existing study's findings surprisingly uphold teriflunomide's double mode of action. In conclusion, the presented research work paves the way to biologically and clinically begin exploring the promising properties of teriflunomide to strongly hit the SARS-CoV-2 particles of the different strains and inhibit their pathogenic replication in an integrative triple mode of action. Hopingly, the potential sextet COVID-19 attacker teriflunomide can be rapidly subjected to the various in vitro/in vivo/clinical anti-COVID-19 assays/trials in a serious attempt to assess its comprehensive bioactivities against COVID-19 to be effectively used in SARS-CoV-2 infections therapy soon. © 2022 by the authors.

Is There a Need to Widely Prescribe Antibiotics in Patients with COVID-19?

Over the past two years, the SARS-CoV-2 pandemic has dominated all aspects of health care around the world, often leaving other long-term public health problems in the background. Despite the fact that COVID-19 is a viral disease, the use of antibiotics in these patients was common practice, especially at the beginning of the pandemic. The use of antibiotics (ABs) in patients with the novel coronavirus infection (NCI) reaches over 70% cases. Suspected concomitant bacterial infection, lack of effective means of treating NCI, terminological problems associated with the definition of «pneumonia» may have been the motivating factor for such widespread use. The data of the conducted studies indicate that there is currently insufficient evidence for the widespread empirical use of antibiotics in the majority of hospitalized patients, as the total proportion of bacterial infections in COVID-19 is quite low. Thus, according to most researchers, combined bacterial infection is rare and is less than 10%. Unjustified prescription of ABs to patients with COVID-19 can lead to complications that could otherwise have been avoided, including increased bacterial resistance, Clostridioides difficile infection, kidney failure, and much more. The article provides information on the frequency of AB therapy at various stages of medical care. The analysis of data on the nature of antibiotics prescribed to inpatients and outpatients with COVID-19 in different countries was carried out. Recommendations from different countries on AB therapy in patients with COVID-19 are presented. Conclusion. The data reviewed confirm the discrepancy between the unjustified and excessive prescribing of antibiotics to patients with COVID-19 and the small number of evidence of associated bacterial infections. © Team of Authors, 2022.

The role of peroxisome proliferator-activated receptors in the modulation of hyperinflammation induced by SARS-CoV-2 infection: A perspective for COVID-19 therapy.

Coronavirus disease 2019 (COVID-19) is a severe respiratory disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that affects the lower and upper respiratory tract in humans. SARS-CoV-2 infection is associated with the induction of a cascade of uncontrolled inflammatory responses in the host, ultimately leading to hyperinflammation or cytokine storm. Indeed, cytokine storm is a hallmark of SARS-CoV-2 immunopathogenesis, directly related to the severity of the disease and mortality in COVID-19 patients. Considering the lack of any definitive treatment for COVID-19, targeting key inflammatory factors to regulate the inflammatory response in COVID-19 patients could be a fundamental step to developing effective therapeutic strategies against SARS-CoV-2 infection. Currently, in addition to well-defined metabolic actions, especially lipid metabolism and glucose utilization, there is growing evidence of a central role of the ligand-dependent nuclear receptors and peroxisome proliferator-activated receptors (PPARs) including PPARα, PPARß/δ, and PPARγ in the control of inflammatory signals in various human inflammatory diseases. This makes them attractive targets for developing therapeutic approaches to control/suppress the hyperinflammatory response in patients with severe COVID-19. In this review, we (1) investigate the anti-inflammatory mechanisms mediated by PPARs and their ligands during SARS-CoV-2 infection, and (2) on the basis of the recent literature, highlight the importance of PPAR subtypes for the development of promising therapeutic approaches against the cytokine storm in severe COVID-19 patients.

Mucoadhesive drug delivery systems: a promising noninvasive approach to bioavailability enhancement. Part II: formulation considerations.

INTRODUCTION: Mucoadhesive drug delivery systems (MDDS) are specifically designed to interact and bind to the mucosal layer of the epithelium for localized, prolonged, and/or targeted drug delivery. Over the past 4 decades, several dosage forms have been developed for localized as well as systemic drug delivery at different anatomical sites. AREAS COVERED: The objective of this review is to provide a detailed understanding of the different aspects of MDDS. Part II describes the origin and evolution of MDDS, followed by a discussion of the properties of mucoadhesive polymers. Finally, a synopsis of the different commercial aspects of MDDS, recent advances in the development of MDDS for biologics and COVID-19 as well as future perspectives are provided. EXPERT OPINION: A review of the past reports and recent advances reveal MDDS as highly versatile, biocompatible, and noninvasive drug delivery systems. The rise in the number of approved biologics, the introduction of newer highly efficient thiomers, as well as the recent advances in the field of nanotechnology have led to several excellent applications of MDDS, which are predicted to grow significantly in the future.

Drug-induced respiratory system toxicity

During current COVID-19 pandemic health care professionals as well as general communities all over the world have become much more aware about the importance of such basic physiological functions as breathing and the essential nature of intact respiratory system for our proper functioning and survival. Treatment of severe forms of respiratory failure puts enormous personal, material as well as financial strains on health care systems even in countries of the developed world. Since the beginning of COVID-19 pandemic scientists and physicians alike are putting vast efforts into developing effective treatment plans to fight this new disease, yet many times with dubious effect. With repurposing old drugs and development of new ones, concerns of potential lung toxicity as a side effect of medication use pose a serious concern. Currently there are several hundred medications known to us which can exert various toxic effects on the respiratory system. As such, in every day clinical practice it is extremely important to identify and minimize the chances of morbidity and mortality induced by medications used in treatment of pulmonary diseases as well as non-pulmonary illnesses. In most cases the diagnosis of drug induced pulmonary toxicity is done by exclusion after all other etiologies of lung compromise have been eliminated. Transbronchial or even open surgical lung biopsy is in many times only of limited value on changing the treatment strategy, however it frequently poses a significant risk of developing pre and post-operative complications. It has to be cautiously considered on individual basis after evaluating potential risks and benefits of the intervention. Apart from affecting the pulmonary parenchyma drugs can exert their toxic effects on pulmonary vascular system, pleura, mediastinal structures as well as on the neuromuscular system driving and executing the respiratory effort. In conclusion, prior to initiating any medication therapy it is paramount to estimate the potential risks and benefits on the pulmonary system and notify the patient in order to make an adequate informed decision regarding starting or declining specific medical intervention (Tab. 3, Ref. 45). Text in PDF www.lekarsky.herba.sk. (http://www.lekarsky.herba.sk.) © 2022, Lekarsky Obzor.All Rights Reserved.

Patients' Experiences With Therapeutic Approaches for Post-COVID Syndrome: Results of a Crowdsourced Research Survey.

Some patients develop multiple protracted sequelae after infection with SARS-CoV-2, collectively known as post-COVID syndrome or long COVID. To date, there is no evidence showing benefit of specific therapies for this condition, and patients likely resort to self-initiated therapies. We aimed to obtain information about therapies used by and needs of this population via inductive crowdsourcing research. Patients completed an online questionnaire about their symptoms and experiences with therapeutic approaches. Responses of 499 participants suggested few approaches (eg, mind-body medicine, respiratory therapy) had positive effects and showed a great need for patient-centered communication (eg, more recognition of this syndrome). Our findings can help design clinical studies and underscore the importance of the holistic approach to care provided by family medicine.

The Role of Viral and Host miRNAs in The Control, Progression and Possible Treatment of Covid-19 Disease

Background and Aim: Previous studies have shown that viral and host miRNAs play a role in the process of controlling or progressing the disease and can even be considered as therapeutic targets. Accordingly, the present review study was designed to evaluate the role of host miRNAs and Covid-19 virus in the disease process. Materials and Methods: The current study was a review study that was conducted during 2012-2022. Studies were extracted from PubMed, Google Scholar, Web of Science and Scopus scientific databases. The researchers selected relevant resources and a summary of them was presented in this review. Results: The present review study showed that some host miRNAs such as miR-23b-5p, miR-200c, and miR-125a-5p had an inhibitory effect on ACE2 receptor, while miR-3909, miR-4677, and miR-133a had a stimulatory effect on this receptor. Furthermore, host miR-98-5p had an inhibitory effect on TMPRSS2 gene expression. On the other hand, host miR-146a, miR-21, and miR-142 induced inflammation through MAPK and NF-Ƙβ signaling. While, host miR-124, miR-410, and miR-1336 inhibited factor STAT3 and prevented inflammation. Furthermore, host miR-302b and miR-372 targeted the mitochondrial antiviral signaling protein (MAVS), resulting in silencing of type 1 interferon signaling. It has also been established that host exosomal miR-7-5p, miR-24-3p, miR-145-5p, and miR-223-3p inhibited the replication of SARS-CoV-2 and the expression of S protein and their decreased expression in elderly and Diabetic subjects was associated with decreased inhibition of SARS-CoV-2 replication. Moreover, viral miR-359-5p regulated the expression of MYH9 (non-muscle myosin heavy chain 9), which caused virus invasion and release in the host cell. Conclusion: This study showed that many miRNAs play a role in controlling or progressing the disease of Covid-19 and it is possible to treat the disease of Covid-19 by changing the expression of viral and host miRNA. However, more research is needed in this regard. © 2022 the Authors. Published by Tehran University of Medical Sciences.

Convalescent or standard plasma versus standard of care in the treatment of COVID-19 patients with respiratory impairment: short and long-term effects. A three-arm randomized controlled clinical trial.

BACKGROUND: The efficacy of early treatment with convalescent plasma in patients with COVID-19 is debated. Nothing is known about the potential effect of other plasma components other than anti-SARS-CoV-2 antibodies. METHODS: To determine whether convalescent or standard plasma would improve outcomes for adults in early phase of Covid19 respiratory impairment we designed this randomized, three-arms, clinical trial (PLACO COVID) blinded on interventional arms that was conducted from June 2020 to August 2021. It was a multicentric trial at 19 Italian hospitals. We enrolled 180 hospitalized adult patients with COVID-19 pneumonia within 5 days from the onset of respiratory distress. Patients were randomly assigned in a 1:1:1 ratio to standard of care (n = 60) or standard of care + three units of standard plasma (n = 60) or standard of care + three units of high-titre convalescent plasma (n = 60) administered on days 1, 3, 5 after randomization. Primary outcome was 30-days mortality. Secondary outcomes were: incidence of mechanical ventilation or death at day 30, 6-month mortality, proportion of days with mechanical ventilation on total length of hospital stay, IgG anti-SARS-CoV-2 seroconversion, viral clearance from plasma and respiratory tract samples, and variations in Sequential Organ Failure Assessment score. The trial was analysed according to the intention-to-treat principle. RESULTS: 180 patients (133/180 [73.9%] males, mean age 66.6 years [IQR 57-73]) were enrolled a median of 8 days from onset of symptoms. At enrollment, 88.9% of patients showed moderate/severe respiratory failure. 30-days mortality was 20% in Control arm, 23% in Convalescent (risk ratio [RR] 1.13; 95% confidence interval [CI], 0.61-2.13, P = 0.694) and 25% in Standard plasma (RR 1.23; 95%CI, 0.63-2.37, P = 0.544). Time to viral clearance from respiratory tract was 21 days for Convalescent, 28 for Standard plasma and 23 in Control arm but differences were not statistically significant. No differences for other secondary endpoints were seen in the three arms. Serious adverse events were reported in 1.7%, 3.3% and 5% of patients in Control, Standard and Convalescent plasma arms respectively. CONCLUSIONS: Neither high-titer Convalescent nor Standard plasma improve outcomes of COVID-19 patients with acute respiratory failure. Trial Registration Clinicaltrials.gov Identifier: NCT04428021. First posted: 11/06/2020.

The Impact of Inflammation and Drug Interactions on Covid-19 Pharmacotherapy. A Mini-Review

The pandemic induced by the SARS-CoV-2 virus, named COVID-19, produced in addition to the severity of the symptoms in some of the patients also a series of challenges regarding their treatment. The pathogenesis of the virus is mediated mainly by the structural proteins of the envelope, membrane and nucleocapsid, as well as by the spike glycoprotein that facilitates the entry into cells. It was pointed out, that there is a disorder caused by the inflammatory syndrome that influences the severity of COVID-19 and its unfavourable prognosis. The inflammatory process is responsible for the transient phenoconversion, characterized by the deviation between the function encoded in the genotype and the expression of the phenotype. Systemic inflammation and the immune response are an important element in many acute and chronic diseases, being strongly involved in changing the pharmacokinetics of the drug. Existing medical comorbidities in elderly patients requires multiple drug therapies, making them the most vulnerable group for both drug-drug interactions and disease-drug interactions. In the following, a series of data will be provided on the interactions that occur in the main classes of drugs used so far in COVID-19 therapy. Copyright © 2022, Romanian Society for Pharmaceutical Sciences. All rights reserved.

Efficacy and Safety of Direct Hemoperfusion Using Polymyxin B-Immobilized Polystyrene Column for Patients With COVID-19: Protocol for an Exploratory Study.

BACKGROUND: Polymyxin B-immobilized fiber column (PMX; Toraymyxin column) was approved for the relief of systemic inflammatory response syndrome caused by bacterial infection or endotoxemia. PMX reduces lung damage by removing leukocytes and cytokines in addition to endotoxin removal in the setting of idiopathic pulmonary fibrosis. Acute exacerbation of interstitial pneumonia pathologically presents with diffuse alveolar damage (DAD). PMX direct hemoperfusion (PMX-DHP) demonstrated efficacy, improving oxygenation. The SARS-CoV-2 virus causes COVID-19, which emerged in December 2019. The condition may become severe about 1 week after onset, and respiratory failure rapidly develops, requiring intensive care management. A characteristic of COVID-19-related severe pneumonia is ground-glass opacities rapidly progressing in both lungs, which subsequently turn into infiltrative shadows. This condition could be classified as DAD. As for the congealing fibrinogenolysis system, D-dimer, fibrin/fibrinogen degradation product quantity, and prolonged prothrombin time were significant factors in nonsurviving COVID-19 cases, associated with aggravated pneumonia. Clinical trials are being conducted, but except for remdesivir and dexamethasone, no treatments have yet been approved. COVID-19 aggravates with the deterioration of oxygen saturation, decrease in lymphocytes, and the occurrence of an abnormal congealing fibrinogenolysis system, leading to diffuse lung damage. Once the condition transitions from moderate to severe, it is necessary to prevent further exacerbation by providing treatment that will suppress the aforementioned symptoms as soon as possible. OBJECTIVE: This study aims to access treatment options to prevent the transition from acute exacerbation of interstitial pneumonia to DAD. The mechanism of action envisioned for PMX-DHP is to reduce congealing fibrinogenolysis system abnormalities and increase oxygenation by removing activated leukocytes and cytokines, which are risk factors for the aggravation of COVID-19-related pneumonia. METHODS: We will conduct a multicenter, prospective, intervention, single-group study to evaluate the efficacy and safety of direct hemoperfusion using PMX-DHP for patients with COVID-19. Efficacy will be evaluated by the primary end point, which is the rate of Ordinal Scale for Clinical Improvement after PMX-DHP of at least 1 point from a status of 4, 5, or 6 on day 15. The effect of PMX-DHP will be estimated by setting a control group with background factors from non-PMX-DHP patients enrolled in the COVID-19 registry. This study will be carried out as a single-group open-label study and will be compared with a historical control. The historical control will be selected from the COVID-19 registry according to age, gender, and severity of pneumonia. RESULTS: The study period is scheduled from September 28, 2020, through April 30, 2023. Patient enrollment was scheduled from the Japan Registry of Clinical Trials publication for March 31, 2022. Data fixation is scheduled for October 2022, with the publication of the results by March 2023. CONCLUSIONS: From a clinical perspective, PMX-DHP is expected to become an adjunctive therapy to address unmet medical needs and prevent the exacerbation from moderate to severe acute respiratory distress syndrome in COVID-19 cases. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/37426.

Bionanomaterials for diagnosis and therapy of SARS-CoV-2

Coronavirus disease 2019 (COVID-19) was first detected in December 2019 in China and has caused a global pandemic affecting 202 nations around the world. It is caused by a new pathogen of the Betacoronavirus B genetic group, severe acute respiratory syndrome virus 2 (SARS-CoV-2). This new virus shares 96% similarity in RNA with bat coronavirus and 80% similarity with SARS virus but is severely more transmissible. SARS-CoV-2 has inflicted more than 4.29 million fatalities around the globe, has devastated the global economy, and continues to spread. There has been a tremendous scientific thrust for diagnostics, therapy, and vaccines for SARS-CoV-2. The SARS-CoV-2 virion has a nanoscale structure consisting of four protein components. Therefore, bionanomaterials are key candidates for engineering a therapy and diagnostic to combat this disease. This chapter reviews the advances in bionanomaterial-based disinfectants, therapy, vaccine, and diagnostics for SARS-CoV-2. We will also highlight the key material properties of these novel nanostructures. © 2022 Elsevier Inc. All rights reserved.

Putative COVID-19 therapies imatinib, lopinavir, ritonavir, and ivermectin cause hair cell damage: A targeted screen in the zebrafish lateral line.

The biomedical community is rapidly developing COVID-19 drugs to bring much-need therapies to market, with over 900 drugs and drug combinations currently in clinical trials. While this pace of drug development is necessary, the risk of producing therapies with significant side-effects is also increased. One likely side-effect of some COVID-19 drugs is hearing loss, yet hearing is not assessed during preclinical development or clinical trials. We used the zebrafish lateral line, an established model for drug-induced sensory hair cell damage, to assess the ototoxic potential of seven drugs in clinical trials for treatment of COVID-19. We found that ivermectin, lopinavir, imatinib, and ritonavir were significantly toxic to lateral line hair cells. By contrast, the approved COVID-19 therapies dexamethasone and remdesivir did not cause damage. We also did not observe damage from the antibiotic azithromycin. Neither lopinavir nor ritonavir altered the number of pre-synaptic ribbons per surviving hair cell, while there was an increase in ribbons following imatinib or ivermectin exposure. Damage from lopinavir, imatinib, and ivermectin was specific to hair cells, with no overall cytotoxicity noted following TUNEL labeling. Ritonavir may be generally cytotoxic, as determined by an increase in the number of TUNEL-positive non-hair cells following ritonavir exposure. Pharmacological inhibition of the mechanotransduction (MET) channel attenuated damage caused by lopinavir and ritonavir but did not alter imatinib or ivermectin toxicity. These results suggest that lopinavir and ritonavir may enter hair cells through the MET channel, similar to known ototoxins such as aminoglycoside antibiotics. Finally, we asked if ivermectin was ototoxic to rats in vivo. While ivermectin is not recommended by the FDA for treating COVID-19, many people have chosen to take ivermectin without a doctor's guidance, often with serious side-effects. Rats received daily subcutaneous injections for 10 days with a clinically relevant ivermectin dose (0.2 mg/kg). In contrast to our zebrafish assays, ivermectin did not cause ototoxicity in rats. Our research suggests that some drugs in clinical trials for COVID-19 may be ototoxic. This work can help identify drugs with the fewest side-effects and determine which therapies warrant audiometric monitoring.

Therapeutic Repurposing of Antiviral Drugs Available for COVID-19 Therapy: A Mini Review

The impact of repurposing drugs that now in vitro inhibit significant chronic respiratory illness corona virus type 2 was indeed underestimated or ignored during the early phases of the COVID-19 virus. Recent clinical data, however, suggest that remdesivir and favipiravir may hasten to heal, but lopinavir/ritonavir had minimal impact on very ill patients. The interferon appears to be the primary impact of triple therapy with ribavirin, lopinavir and interferon-1b. The role of hydroxychloroquine, marketed as Plaquenil® or chloroquine, marketed as Aralen®, in the treatment and prevention of COVID-19 is presently unknown due to the small sample size research. Anti-cytokine drugs may not benefit persons with mild disease or severe illness. Traditional Chinese medicine (TCM) is commonly used for COVID-19 patients in China and has antiviral and immunomodulatory effects on SARS-CoV-2. This review outlines existing COVID-19 therapeutic options and advocates for clinical trials for children, persons with mild disease and those in the early stages of COVID-19. © 2022 Chemical Publishing Co.. All rights reserved.

In silico investigation of oxindole alkaloids from Uncaria perrottetii and Uncaria lanosa f. philippinensis for COVID-19 therapy: A ligand affinity and characterization study

The biological origin of COVID-19 is linked to three pathophysiological conditions: immunosuppression, viral infection, and inflammation. In the Philippines, nine alkaloids with potential antiviral and anti-inflammatory effects have been isolated from two plants, Uncaria perrottetii and Uncaria lanosa f. philippinensis, and their potential for COVID-19 therapy were investigated. Results showed that mitraphylline (L5) and uncarine B (L6) are two potential candidates as they exhibited the best binding energy score, lowest binding interaction energies, and lowest RMSD score. MMPBSA analysis indicated that complex binding energies of -128.295 ± 16.787 kJ/mol and -44.940 ± 10.918 for A2AR-5 and 3CL-6, suggesting that mitraphylline is a potential competitive antagonist in A2AR of caffeine, which is a known antagonist and inhibitor of the receptors, and uncarine B is a candidate inhibitor of 3CL protease. © 2022 ACM.

In silico investigation of oxindole alkaloids from Uncaria perrottetii and Uncaria lanosa f. philippinensis for COVID-19 therapy: Binding site prediction and molecular docking

On January 31, 2020, WHO declared the global outbreak of novel Coronavirus as a public health emergency of international concern. The biological origin of COVID-19 is caused by three primary pathophysiological conditions: immunosuppression, viral infection, and inflammation. In the Philippines, nine alkaloids with potential antiviral and anti-inflammatory effects have been isolated from two plants, Uncaria perrottetii and Uncaria lanosa f. philippinensis. The binding site of A2AR was proven to be pocket 0, which is similar to the literature. Two drug candidates showed the best result for molecular docking: mitraphylline and rauniticine-allo-oxindole A for A2AR and 3CLpro receptors. Mitraphylline candidate showed the lowest free energy scores and RMSD scores. This study is extended to other in silico tests to prove the impact of the alkaloid against COVID-19. © 2022 ACM.

Interactions between COVID-19 and Lung Cancer: Lessons Learned during the Pandemic.

Cancer patients, specifically lung cancer patients, show heightened vulnerability to severe COVID-19 outcomes. The immunological and inflammatory pathophysiological similarities between lung cancer and COVID-19-related ARDS might explain the predisposition of cancer patients to severe COVID-19, while multiple risk factors in lung cancer patients have been associated with worse COVID-19 outcomes, including smoking status, older age, etc. Recent cancer treatments have also been urgently evaluated during the pandemic as potential risk factors for severe COVID-19, with conflicting findings regarding systemic chemotherapy and radiation therapy, while other therapies were not associated with altered outcomes. Given this vulnerability of lung cancer patients for severe COVID-19, the delivery of cancer care was significantly modified during the pandemic to both proceed with cancer care and minimize SARS-CoV-2 infection risk. However, COVID-19-related delays and patients' aversion to clinical settings have led to increased diagnosis of more advanced tumors, with an expected increase in cancer mortality. Waning immunity and vaccine breakthroughs related to novel variants of concern threaten to further impede the delivery of cancer services. Cancer patients have a high risk of severe COVID-19, despite being fully vaccinated. Numerous treatments for early COVID-19 have been developed to prevent disease progression and are crucial for infected cancer patients to minimize severe COVID-19 outcomes and resume cancer care. In this literature review, we will explore the lessons learned during the COVID-19 pandemic to specifically mitigate COVID-19 treatment decisions and the clinical management of lung cancer patients.

[Intrahospital Protocol for the Management of COVID-19 Disease in Adults]. / Protocolo Intra-Hospitalar para Abordagem da Doença COVID-19 no Adulto.

The COVID-19 pandemic is currently responsible for over 526 million infections and over 6.3 million deaths. As a new disease, the number of papers on the subject is extensive, motivating considerable heterogeneity in its approach. Despite some medicines having sound evidence of benefit, new interventions and strategies continue to be proposed, and some still lack scientific evidence, which hinders a uniform and consensual approach. This article aims to standardize healthcare to adult patients with moderate-to-critical COVID-19, from the emergency department to hospitalization, either in a general ward or in level 2 or level 3 intensive care units, based on the best and most updated scientific evidence available. This protocol presents recommendations for the stratification of adult patients with COVID-19 disease, adequate workup at admission and during hospitalization, inpatient treatment criteria, general treatment measures, pharmacological treatment, management of complications such as organizing pneumonia and bacterial superinfection, thromboprophylaxis, special considerations on pregnancy and breastfeeding and possible future therapies.

A pandemia de COVID-19 é, atualmente, responsável por mais de 526 milhões de infeções e mais de 6,3 milhões de mortes. Como nova doença, é extenso o número de publicações sobre o tema, motivando uma considerável heterogeneidade na sua abordagem. Apesar de existirem terapêuticas com benefício comprovado, continuam a ser propostas novas intervenções e estratégias, algumas das quais carecendo ainda de suporte científico, dificultando assim uma abordagem uniforme e consensual. Este documento tem como objetivo uniformizar, baseando-se na melhor e mais atualizada evidência científica disponível, a prestação de cuidados aos doentes adultos com COVID-19 moderada a crítica, desde o serviço de urgência até à hospitalização, quer em enfermarias gerais, quer em enfermarias de cuidados intensivos de nível 2 e 3. Este protocolo apresenta recomendações para a estratificação da doença COVID-19, critérios de hospitalização, meios complementares de diagnóstico adequados à admissão e durante a hospitalização, medidas terapêuticas gerais e terapêutica farmacológica dirigida, gestão de complicações como pneumonia organizativa e sobreinfeção bacteriana, tromboprofilaxia, considerações especiais na gravidez e amamentação, e possíveis opções terapêuticas futuras.

Unraveling the Treatment Effect of Baricitinib on Clinical Progression and Resource Utilization in Hospitalized COVID-19 Patients: Secondary Analysis of the Adaptive COVID-19 Treatment Randomized Trial-2.

Background: The Adaptive COVID Treatment Trial-2 (ACTT-2) found that baricitinib in combination with remdesivir therapy (BCT) sped recovery in hospitalized coronavirus disease 2019 (COVID-19) patients vs remdesivir monotherapy (RMT). We examined how BCT affected progression throughout hospitalization and utilization of intensive respiratory therapies. Methods: We characterized the clinical trajectories of 891 ACTT-2 participants requiring supplemental oxygen or higher levels of respiratory support at enrollment. We estimated the effect of BCT on cumulative incidence of clinical improvement and deterioration using competing risks models. We developed multistate models to estimate the effect of BCT on clinical improvement and deterioration and on utilization of respiratory therapies. Results: BCT resulted in more linear improvement and lower incidence of clinical deterioration compared with RMT (hazard ratio [HR], 0.74; 95% CI, 0.58 to 0.95). The benefit was pronounced among participants enrolled on high-flow oxygen or noninvasive positive-pressure ventilation. In this group, BCT sped clinical improvement (HR, 1.21; 95% CI, 0.99 to 1.51) while slowing clinical deterioration (HR, 0.71; 95% CI, 0.48 to 1.02), which reduced the expected days in ordinal score (OS) 6 per 100 patients by 74 days (95% CI, -8 to 154 days) and the expected days in OS 7 per 100 patients by 161 days (95% CI, 46 to 291 days) compared with RMT. BCT did not benefit participants who were mechanically ventilated at enrollment. Conclusions: Compared with RMT, BCT reduces the clinical burden and utilization of intensive respiratory therapies for patients requiring low-flow oxygen or noninvasive positive-pressure ventilation compared with RMT and may thereby improve care for this patient population.