Calming the cytokine storm of COVID-19 through inhibition of JAK2/STAT3 signaling

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the unprecedented COVID-19 pandemic, which has infected over 178 million people worldwide. Even with new vaccines, global herd immunity will not be reached soon. New cases and viral variants are being reported at an alarming rate. Effective antiviral treatment is urgently needed. Patients with severe COVID-19 suffer from life-threatening respiratory failure due to acute respiratory distress syndrome in their lungs, a leading cause of COVID-19 mortality. This lung hyper-inflammation is induced by virus-caused massive tissue damage that is associated with uncontrolled cytokine release, known as a cytokine storm, through JAK/STAT signaling pathways. Here, we review the FDA-approved JAK inhibitors that are being clinically evaluated and repurposed for the treatment of patients with severe COVID-19 by calming SARS-CoV-2 infection.     

Application of microfluidic technologies on COVID-19 diagnosis and drug discovery

The ongoing coronavirus disease 2019 (COVID-19) pandemic has boosted the development of antiviral research. Microfluidic technologies offer powerful platforms for diagnosis and drug discovery for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) diagnosis and drug discovery. In this review, we introduce the structure of SARS-CoV-2 and the basic knowledge of microfluidic design. We discuss the application of microfluidic devices in SARS-CoV-2 diagnosis based on detecting viral nucleic acid, antibodies, and antigens. We highlight the contribution of lab-on-a-chip to manufacturing point-of-care equipment of accurate, sensitive, low-cost, and user-friendly virus-detection devices. We then investigate the efforts in organ-on-a-chip and lipid nanoparticles (LNPs) synthesizing chips in antiviral drug screening and mRNA vaccine preparation. Microfluidic technologies contribute to the ongoing SARS-CoV-2 research efforts and provide tools for future viral outbreaks.     

Drug combination therapy for emerging viral diseases

Effective therapeutics to combat emerging viral infections are an unmet need. Historically, treatments for chronic viral infections with single drugs have not been successful, as exemplified by human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections. Combination therapy for these diseases has led to improved clinical outcomes with dramatic reductions in viral load, morbidity, and mortality. Drug combinations can enhance therapeutic efficacy through additive, and ideally synergistic, effects for emerging and re-emerging viruses, such as influenza, severe acute respiratory syndrome-coronavirus (SARS-CoV), Middle East respiratory syndrome (MERS)-CoV, Ebola, Zika, and SARS-coronavirus 2 (CoV-2). Although novel drug development through traditional pipelines remains a priority, in the interim, effective synergistic drug candidates could be rapidly identified by drug-repurposing screens, facilitating accelerated paths to clinical testing and potential emergency use authorizations.     

Current COVID-19 vaccine candidates: Implications in the Saudi population

AimThe purpose of this review is to discuss the current status of local and international efforts undergoing clinical trials aiming at developing a Coronavirus Disease-2019 (COVID-19) vaccine, and to highlight the anticipated challenges of this vaccine globally and in Saudi Arabia.Present FindingsCOVID-19 vaccine development efforts started in early January 2020 when Chinese scientists shared the Coronavirus genomic sequence in public domain. Approximately 321 research groups initiated the search for a vaccine, out of which 41 have reached phase I/II trails and 11 reached phase-III clinical trials, including approved vaccines for early to limited use. Out of these projects are two labs in the Kingdom of Saudi Arabia still in early stages of development of a COVID-19 vaccine. Several vaccine attempts are being tested from traditional, attenuated virus methods, to new nucleic acid-based designs. However, no vaccine has yet completed clinical trials and reached public domain.In spite of the challenges faced during previous vaccine trials, researchers have found that Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19 is structurally similar to the (SARS-CoV-1) and the Middle Eastern Respiratory Syndrome Coronavirus (MERS-CoV), which caused epidemics in 2003 and 2012 respectively. Both SARS strains show identical affinity towards the type-II alveolar pneumocytes angiotensin converting enzyme-2 (ACE-2) receptor binding domains and therefore, similar pathogenicity. The race to develop the vaccine is predominantly for individuals at high risk of developing the infection, i.e. population groups who are most susceptible to experiencing fatal symptoms of the coronavirus. These include patients with comorbidities, above the age of 60 years and people at risk of contracting large viral loads, such as healthcare providers caring for critical admissions in in-patient wards, Intensive Care Units and Emergency Room settings.SummaryMany different vaccine strategies are under development throughout different stages of the research timeline; however, it is estimated that none will show favorable results before end of 2020. For any immunization or interventional prevention/therapy system to reach the public and patients at high risk, it needs to undergo multiple phase trials to ensure safety and effectiveness. In this scoping review we aim to map the literature on COVID-19 vaccines and provide recommendations related to gaps in research, applicability and expected challenges for implementation of nationwide vaccination in Saudi Arabia.     

A comparison between SARS-CoV-1 and SARS-CoV2: an update on current COVID-19 vaccines

Since the outbreak of the novel coronavirus disease 2019 (COVID-19) in Wuhan, China, many health care systems have been heavily engaged in treating and preventing the disease, and the year 2020 may be called as “historic COVID-19 vaccine breakthrough”. Due to the COVID-19 pandemic, many companies have initiated investigations on developing an efficient and safe vaccine against the virus. From Moderna and Pfizer in the United States to PastocoVac in Pasteur Institute of Iran and the University of Oxford in the United Kingdom, different candidates have been introduced to the market. COVID-19 vaccine research has been facilitated based on genome and structural information, bioinformatics predictions, epitope mapping, and data obtained from the previous developments of severe acute respiratory syndrome coronavirus (SARS-CoV or SARS-CoV-1) and middle east respiratory syndrome coronavirus (MERS-CoV) vaccine candidates. SARS-CoV genome sequence is highly homologous to the one in COVID-19 and both viruses use the same receptor, angiotensin-converting enzyme 2 (ACE2). Moreover, the immune system responds to these viruses, partially in the same way. Considering the on-going COVID-19 pandemic and previous attempts to manufacture SARS-CoV vaccines, this paper is going to discuss clinical cases as well as vaccine challenges, including those related to infrastructures, transportation, possible adverse reactions, utilized delivery systems (e.g., nanotechnology and electroporation) and probable vaccine-induced mutations.Graphical abstract      

Telmisartan as tentative angiotensin receptor blocker therapeutic for COVID-19

In late 2019, a new coronavirus emerged in Wuhan Province, China, causing lung complications similar to those produced by the SARS coronavirus in the 2002–2003 epidemic. This new disease was named COVID-19 and the causative virus SARS-CoV-2. The SARS-CoV-2 virus enters the airway and binds, by means of the S protein on its surface to the membrane protein ACE2 in type 2 alveolar cells. The S protein-ACE2 complex is internalized by endocytosis leading to a partial decrease or total loss of the enzymatic function ACE2 in the alveolar cells and in turn increasing the tissue concentration of pro-inflammatory angiotensin II by decreasing its degradation and reducing the concentration of its physiological antagonist angiotensin 1–7. High levels of angiotensin II on the lung interstitium can promote apoptosis initiating an inflammatory process with release of proinflammatory cytokines, establishing a self-powered cascade, leading eventually to ARDS. Recently, Gurwitz proposed the tentative use of agents such as losartan and telmisartan as alternative options for treating COVID-19 patients prior to development of ARDS. In this commentary article, the authors make the case for the election of telmisartan as such alternative on the basis of its pharmacokinetic and pharmacodynamic properties and present an open-label randomized phase II clinical trial for the evaluation of telmisartan in COVID-19 patients ( NCT04355936 ).     

Self-medication practices during the COVID-19 pandemic among the adult population in Peru: A cross-sectional survey

Self-medication impacts both negatively and positively the health of people, which has become evident during the COVID-19 pandemic. The study aimed to assess the prevalence of self-medicated drugs used for respiratory symptoms, as COVID-19 preventive, for its symptoms or once tested positive. To determine the perception of symptom relief and demographic variables that promote self-medication in Peru. We performed a cross-sectional, analytical, multicenter study in 3792 study respondents on the use, the reason for use, and perception of relief after the use of six drugs during the quarantine period. An online questionnaire was developed, pretested and submitted to the general public. Multivariable logistic regression was used to ascertain factors that influence an individual’s desire to self-medicate, associations were considered significant at p < 0.05 and using region (coast, mountain and jungle) as cluster group. The majority of respondents self-medicated with acetaminophen for respiratory symptoms and mainly because they had a cold or flu. It was observed that all the surveyed drugs (acetaminophen, ibuprofen, azithromycin, penicillin, antiretrovirals and hydroxychloroquine) were consumed for various symptoms including: fever, fatigue, cough, sneezing, muscle pain, nasal congestion, sore throat, headache and breathing difficulty. Over 90% of respondents perceived relief of at least one symptom. Multivariable logistic regression showed that older people have a higher frequency of antiretroviral self-medication, respondents who currently have a job had a higher frequency of penicillin self-medication, and that respondents from the Andes consumed less acetaminophen, while the ones from the rainforest consumed it more. There were significant percentages of self-medication, including drugs without sufficient scientific evidence. Age, region where one lived and job status were variables associated with self-medication frequency. Continuous awareness and sensitization about the risks of self-medication are warranted.     

AI-based language models powering drug discovery and development

The discovery and development of new medicines is expensive, time-consuming, and often inefficient, with many failures along the way. Powered by artificial intelligence (AI), language models (LMs) have changed the landscape of natural language processing (NLP), offering possibilities to transform treatment development more effectively. Here, we summarize advances in AI-powered LMs and their potential to aid drug discovery and development. We highlight opportunities for AI-powered LMs in target identification, clinical design, regulatory decision-making, and pharmacovigilance. We specifically emphasize the potential role of AI-powered LMs for developing new treatments for Coronavirus 2019 (COVID-19) strategies, including drug repurposing, which can be extrapolated to other infectious diseases that have the potential to cause pandemics. Finally, we set out the remaining challenges and propose possible solutions for improvement.     

新型冠状病毒肺炎病毒性脓毒症治疗策略研究进展

新型冠状病毒肺炎（COVID-19）已造成全球疫情并仍在持续蔓延。大量COVID-19重症或危重症患者的临床表现符合脓毒症和脓毒症休克的诊断标准,研究其发病机制和治疗策略对COVID-19的防控有重要意义。对COVID-19病毒性脓毒症的临床特征和治疗进展做一综述。     

Early clinical trial data and real-world assessment of COVID-19 vaccines: Insights from the Society of Infectious Diseases Pharmacists

As of August 2021, there were three COVID-19 vaccines available in the United States for the prevention of coronavirus 2019 (COVID-19). The purpose of this narrative review is to examine the early experience from the Emergency Use Authorization (EUA) of BNT162b2 (Pfizer, Inc./BioNTech), mRNA-1273 (Moderna, Inc.), and Ad26.COV2.S (Johnson and Johnson/Janssen Global Services, LLC) through July 2021. The EUA data from the clinical trials have largely been corroborated by real-world effectiveness investigations post-authorization. These studies indicate that immunity is obtained within 2 weeks post-vaccination and may endure for 6 months. The immunity conferred by the vaccines may also be effective against SARS-CoV-2 variants of concern. Additionally, populations not included in the emergency use authorization studies may also benefit from vaccination. This look back at the initial clinical experience can be used by the global community to inform and develop COVID-19 vaccine programs.     

Potential therapeutic effects of dipyridamole in the severely ill patients with COVID-19

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause acute respiratory distress syndrome, hypercoagulability, hypertension, and multiorgan dysfunction. Effective antivirals with safe clinical profile are urgently needed to improve the overall prognosis. In an analysis of a randomly collected cohort of 124 patients with COVID-19, we found that hypercoagulability as indicated by elevated concentrations of D-dimers was associated with disease severity. By virtual screening of a U.S. FDA approved drug library, we identified an anticoagulation agent dipyridamole (DIP) in silico, which suppressed SARS-CoV-2 replication in vitro. In a proof-of-concept trial involving 31 patients with COVID-19, DIP supplementation was associated with significantly decreased concentrations of D-dimers (P < 0.05), increased lymphocyte and platelet recovery in the circulation, and markedly improved clinical outcomes in comparison to the control patients. In particular, all 8 of the DIP-treated severely ill patients showed remarkable improvement: 7 patients (87.5%) achieved clinical cure and were discharged from the hospitals while the remaining 1 patient (12.5%) was in clinical remission.     

Coagulopathy,Venous Thromboembolism,and Anticoagulation in Patients with COVID-19

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a worldwide pandemic, and patients with the infection are referred to as having COVID-19. Although COVID-19 is commonly considered a respiratory disease, there is clearly a thrombotic potential that was not expected. The pathophysiology of the disease and subsequent coagulopathy produce an inflammatory, hypercoagulable, and hypofibrinolytic state. Several observational studies have demonstrated surprisingly high rates of venous thromboembolism (VTE) in both general ward and intensive care patients with COVID-19. Many of these observational studies demonstrate high rates of VTE despite patients being on standard, or even higher intensity, pharmacologic VTE prophylaxis. Fibrinolytic therapy has also been used in patients with acute respiratory distress syndrome. Unfortunately, high quality randomized controlled trials are lacking. A literature search was performed to provide the most up-to-date information on the pathophysiology, coagulopathy, risk of VTE, and prevention and treatment of VTE in patients with COVID-19. These topics are reviewed in detail, along with practical issues of anticoagulant selection and duration. Although many international organizations have produced guidelines or consensus statements, they do not all cover the same issues regarding anticoagulant therapy for patients with COVID-19, and they do not all agree. These statements and the most recent literature are combined into a list of clinical considerations that clinicians can use for the prevention and treatment of VTE in patients with COVID-19.     

Managing COVID-19 in Renal Transplant Recipients: A Review of Recent Literature and Case Supporting Corticosteroid-sparing Immunosuppression

Novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome virus (SARS-CoV-2) has become a global health care crisis. The Centers for Disease Control and Prevention (CDC) lists immunocompromised patients, including those requiring immunosuppression following renal transplantation, as high risk for severe disease from SARS-CoV-2. Treatment for other viral infections in renal transplant recipients often includes a reduction in immunosuppression; however, no current guidelines are available recommending the optimal approach to managing immunosuppression in the patients who are infected with SARS-CoV-2. It is currently advised to avoid corticosteroids in the treatment of SARS-CoV-2 outside of critically ill patients. Recently published cases describing inpatient care of COVID-19 in renal transplant recipients differ widely in disease severity, time from transplantation, baseline immunosuppressive therapy, and the modifications made to immunosuppression during COVID-19 treatment. This review summarizes and compares inpatient immunosuppressant management strategies of recently published reports in the renal transplant population infected with SARS-CoV-2 and discusses the limitations of corticosteroids in managing immunosuppression in this patient population.     

Potential adjuvants for the development of a SARS-CoV-2 vaccine based on experimental results from similar coronaviruses

The extensive efforts around the globe are being made to develop a suitable vaccine against COVID-19 (Coronavirus Disease-19) caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2). An effective vaccine should be able to induce high titers of neutralizing antibodies to prevent the virus from attaching to the host cell receptors. However, to elicit the protective levels of antibodies, a vaccine may require multiple doses or assistance from other immunostimulatory molecules. Further, the vaccine should be able to induce protective levels of antibodies rapidly with the least amount of antigen used. This decreases the cost of a vaccine and makes it affordable. As the pandemic has hit most countries across the globe, there will be an overwhelming demand for the vaccine in a quick time. Incorporating a suitable adjuvant in a SARS-CoV-2 vaccine may address these requirements. This review paper will discuss the experimental results of the adjuvanted vaccine studies with similar coronaviruses (CoVs) which might be useful to select an appropriate adjuvant for a vaccine against rapidly emerging SARS-CoV-2. We also discuss the current progress in the development of adjuvanted vaccines against the disease.     

对本院新型冠状病毒肺炎药物治疗问题的探讨

目的:对本院新型冠状病毒(COVID-9)的药物治疗情况进行分析和探讨,旨在提高该病药物治疗方案的合理性、有效性及安全性。方法:回顾收集1566例COVID-19出院患者的病历资料,统计患者的基本信息、住院情况和治疗用药情况。针对抗病毒药、抗菌药、糖皮质激素、调节免疫药和护肝药的使用特点和存在的问题,进行研析。结果:抗病毒药以阿比多尔、奥司他韦、更昔洛韦应用最为广泛;抗感染药主要莫西沙星和头孢哌酮钠舒巴坦钠;糖皮质激素主要应用甲泼尼龙;免疫调节药主要使用人免疫球蛋白和胸腺肽α1;护肝药主要使用甘草酸二铵和还原性谷胱甘肽等。存在用药问题主要为遴选治疗药不适宜;用药疗程过长;无指征使用和用法用量不适宜等。结论:抗病毒药物治疗问题为奥司他韦和更昔洛韦的遴选不适宜;阿比多尔的用药疗程过长;不推荐3个以上抗病毒药同时使用;利巴韦林应限制使用。抗感染药无指征用药和联合用药的情况较为普遍;关注抗感染药与其他药物之间的相互作用。糖皮质激素主要问题是无指征使用和疗程过长。免疫调节药使用较为合理,需注意普通轻型患者的不合理联合用药。护肝应避免预防性使用多烯磷脂酰胆碱。针对存在的问题应重视临床合理用药。     

Structure genomics of SARS-CoV-2 and its Omicron variant: drug design templates for COVID-19

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has brought an unprecedented public health crisis and persistently threatens to humanity. With tireless efforts from scientists around the world, understanding of the biology of coronavirus has been greatly enhanced over the past 2 years. Structural biology has demonstrated its powerful impact on uncovering structures and functions for the vast majority of SARS-CoV-2 proteins and guided the development of drugs and vaccines against COVID-19. In this review, we summarize current progress in the structural biology of SARS-CoV-2 and discuss important biological issues that remain to be addressed. We present the examples of structure-based design of Pfizer’s novel anti-SARS-CoV-2 drug PF-07321332 (Paxlovid), Merck’s nucleotide inhibitor molnupiravir (Lagevrio), and VV116, an oral drug candidate for COVID-19. These examples highlight the importance of structure in drug discovery to combat COVID-19. We also discussed the recent variants of Omicron and its implication in immunity escape from existing vaccines and antibody therapies.     

中和抗体在新型冠状病毒肺炎治疗中的重要意义:进展与展望

SARS-CoV-2感染是对全世界人类生命和健康的一大严重威胁,新型冠状病毒肺炎是由SARS-CoV-2感染引起的全球流行病.SARS-CoV-2病毒具有高度的传染性、诡异性和多变性.因此,新型冠状病毒肺炎的治疗是紧迫且有针对性的.然而,疫苗和目前使用的药物一般不具有上述特点.虽然新型冠状病毒肺炎的恢复期血浆在危重患者...