Anti-Alphaviral Alkaloids: Focus on Some Isoquinolines, Indoles and Quinolizidines.

The discovery and the development of safe and efficient therapeutics against arthritogenic alphaviruses (e.g., chikungunya virus) remain a continuous challenge. Alkaloids are structurally diverse and naturally occurring compounds in plants, with a wide range of biological activities including beneficial effects against prominent pathogenic viruses and inflammation. In this short review, we discuss the effects of some alkaloids of three biologically relevant structural classes (isoquinolines, indoles and quinolizidines). Based on various experimental models (viral infections and chronic diseases), we highlight the immunomodulatory effects of these alkaloids. The data established the capacity of these alkaloids to interfere in host antiviral and inflammatory responses through key components (antiviral interferon response, ROS production, inflammatory signaling pathways and pro- and anti-inflammatory cytokines production) also involved in alphavirus infection and resulting inflammation. Thus, these data may provide a convincing perspective of research for the use of alkaloids as immunomodulators against arthritogenic alphavirus infection and induced inflammation.

Meta-analysis of arbidol versus lopinavir/ritonavir in the treatment of coronavirus disease 2019.

OBJECTIVES: To systematically evaluate the efficacy and safety of arbidol and lopinavir/ritonavir (LPV/r) in the treatment of coronavirus disease 2019 (COVID-19) using a meta-analysis method. METHODS: The China Knowledge Network, VIP database, WanFang database PubMed database, Embase database, and Cochrane Library were searched for a collection of comparative studies on arbidol and lopinavir/ritonavir in the treatment of COVID-19. Meta-analysis was used to evaluate the efficacy and safety of Arbidol and lopinavir/ritonavir in the treatment of COVID-19. RESULTS: The results of the systematic review indicated that Arbidol had a higher positive-to-negative conversion rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acid on Day 7 (p = 0.03), a higher positive-to-negative conversion rate of SARS-CoV-2 nucleic acid on Day 14 (p = 0.006), a higher improvement rate of chest computed tomography on Day 14 (p = 0.02), a lower incidence of adverse reactions (p = 0.002) and lower rate of mortality (p = 0.007). There was no difference in the rate of cough disappearance on Day 14 (p = 0.24) or the rate of severe/critical illness (p = 0.07) between the two groups. CONCLUSIONS: Arbidol may be superior to lopinavir/ritonavir in the treatment of COVID-19. However, due to the small number of included studies and the number of patients, high-quality multicenter large-sample randomized double-blind controlled trials are still needed for verification.

Early experience of nintedanib in COVID-19 ARDS-related pulmonary fibrosis: a case series.

The current COVID-19 pandemic has spread like wildfire worldwide and has affected millions of people. The novel corona virus mainly affects the lungs leading to life threatening disease like acute respiratory distress syndrome (ARDS). The aftermath of the disease in form of pulmonary fibrosis is upcoming cause of further increase in morbidity and mortality. Nintedanib is an oral antifibrotics with proven role in idiopathic pulmonary fibrosis, however its use in COVID-19 related pulmonary fibrosis has not been studied. We report our early experience of use of nintedanib in COVID-19 related pulmonary fibrosis.

Reinforcing the supply chain of umifenovir and other antiviral drugs with retrosynthetic software.

The global disruption caused by the 2020 coronavirus pandemic stressed the supply chain of many products, including pharmaceuticals. Multiple drug repurposing studies for COVID-19 are now underway. If a winning therapeutic emerges, it is unlikely that the existing inventory of the medicine, or even the chemical raw materials needed to synthesize it, will be available in the quantities required. Here, we utilize retrosynthetic software to arrive at alternate chemical supply chains for the antiviral drug umifenovir, as well as eleven other antiviral and anti-inflammatory drugs. We have experimentally validated four routes to umifenovir and one route to bromhexine. In one route to umifenovir the software invokes conversion of six C-H bonds into C-C bonds or functional groups. The strategy we apply of excluding known starting materials from search results can be used to identify distinct starting materials, for instance to relieve stress on existing supply chains.

COVID-related fibrosis: insights into potential drug targets.

INTRODUCTION: Lung injury in severe COVID-19 pneumonia can rapidly evolve to established pulmonary fibrosis, with prognostic implications in the acute phase of the disease and long-lasting impact on the quality of life of COVID-19 survivors. This is an emerging medical need, and it has been hypothesized that antifibrotic treatments could have a role in ameliorating the fibrotic process in the lungs of these patients. AREAS COVERED: The safety and efficacy of available antifibrotic drugs (nintedanib and pirfenidone) and novel promising agents are being assessed in several ongoing clinical trials that were performed either in critically ill patients admitted to intensive care, or in discharged patients presenting fibrotic sequalae from COVID-19. Literature search was performed using Medline and Clinicaltrials.org databases (2001-2021). EXPERT OPINION: Despite the strong rationale support the use of antifibrotic therapies in COVID-related fibrosis, there are several uncertainties regarding the timing for their introduction and the real risks/benefits ratio of antifibrotic treatment in the acute and the chronic phases of the disease. The findings of ongoing clinical trials and the long-term observation of longitudinal cohorts will eventually clarify the best management approach for these patients.

Nanoparticle encapsulation of non-genotoxic p53 activator Inauhzin-C for improved therapeutic efficacy.

The tumor suppressor protein p53 remains in a wild type but inactive form in ~50% of all human cancers. Thus, activating it becomes an attractive approach for targeted cancer therapies. In this regard, our lab has previously discovered a small molecule, Inauhzin (INZ), as a potent p53 activator with no genotoxicity. Method: To improve its efficacy and bioavailability, here we employed nanoparticle encapsulation, making INZ-C, an analog of INZ, to nanoparticle-encapsulated INZ-C (n-INZ-C). Results: This approach significantly improved p53 activation and inhibition of lung and colorectal cancer cell growth by n-INZ-C in vitro and in vivo while it displayed a minimal effect on normal human Wi38 and mouse MEF cells. The improved activity was further corroborated with the enhanced cellular uptake observed in cancer cells and minimal cellular uptake observed in normal cells. In vivo pharmacokinetic evaluation of these nanoparticles showed that the nanoparticle encapsulation prolongates the half-life of INZ-C from 2.5 h to 5 h in mice. Conclusions: These results demonstrate that we have established a nanoparticle system that could enhance the bioavailability and efficacy of INZ-C as a potential anti-cancer therapeutic.

SARS-CoV-2 promotes RIPK1 activation to facilitate viral propagation.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the ongoing global pandemic that poses substantial challenges to public health worldwide. A subset of COVID-19 patients experience systemic inflammatory response, known as cytokine storm, which may lead to death. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is an important mediator of inflammation and cell death. Here, we examined the interaction of RIPK1-mediated innate immunity with SARS-CoV-2 infection. We found evidence of RIPK1 activation in human COVID-19 lung pathological samples, and cultured human lung organoids and ACE2 transgenic mice infected by SARS-CoV-2. Inhibition of RIPK1 using multiple small-molecule inhibitors reduced the viral load of SARS-CoV-2 in human lung organoids. Furthermore, therapeutic dosing of the RIPK1 inhibitor Nec-1s reduced mortality and lung viral load, and blocked the CNS manifestation of SARS-CoV-2 in ACE2 transgenic mice. Mechanistically, we found that the RNA-dependent RNA polymerase of SARS-CoV-2, NSP12, a highly conserved central component of coronaviral replication and transcription machinery, promoted the activation of RIPK1. Furthermore, NSP12 323L variant, encoded by the SARS-CoV-2 C14408T variant first detected in Lombardy, Italy, that carries a Pro323Leu amino acid substitution in NSP12, showed increased ability to activate RIPK1. Inhibition of RIPK1 downregulated the transcriptional induction of proinflammatory cytokines and host factors including ACE2 and EGFR that promote viral entry into cells. Our results suggest that SARS-CoV-2 may have an unexpected and unusual ability to hijack the RIPK1-mediated host defense response to promote its own propagation and that inhibition of RIPK1 may provide a therapeutic option for the treatment of COVID-19.

Traditional Chinese Medicine as Potential Therapy for COVID-19.

In December 2019, a novel coronavirus SARS-CoV-2, causing the disease COVID-19, spread from Wuhan throughout China and has infected people over 200 countries. Thus far, more than 3,400,000 cases and 240,000 deaths have occurred worldwide, and the coronavirus pandemic continues to grip the globe. While numbers of cases in China have been steadying, the number of infections outside China is increasing at a worrying pace. We face an urgent need to control the spread of the COVID-19 epidemic, which is currently expanding to a global pandemic. Efforts have focused on testing antiviral drugs and vaccines, but there is currently no treatment specifically approved. Traditional Chinese medicine (TCM) is grounded in empirical observations and the Chinese people use TCM to overcome these sorts of plagues many times in thousands of years of history. Currently, the Chinese National Health Commission recommended a TCM prescription of Qing-Fei-Pai-Du-Tang (QFPDT) in the latest version of the "Diagnosis and Treatment guidelines of COVID-19" which has been reported to provide reliable effects for COVID-19. While doubts about TCM still exist today, this review paper will describe the rationalities that QFPDT is likely to bring a safe and effective treatment of COVID-19.

[A Case Report of Checkpoint Inhibitor Pneumonitis Caused by PD-1
Antibody-Safety and Effectiveness of Pirfenidone].

BACKGROUND: Immune checkpoint inhibitor associated pneumonia (CIP) is a serious side effect of immune checkpoint inhibitors. There is a consensus on the treatment of acute phase of CIP, but the treatment of pulmonary interstitial fibrosis after the acute phase is still a clinical problem to be solved. METHODS: The diagnosis and treatment of a non-small cell lung cancer (NSCLC) patient with immune checkpoint inhibitor associated pneumonia in the Stereotactic Radiotherapy Department of Qingdao Central Hospital were retrospectively analyzed, and literatures were reviewed. RESULTS: A 70-year-old male patient was diagnosed with Poorly differentiated squamous cell carcinoma of left lung with mediastinal lymph node metastasis T3N3M0 stage IIIc, EGFR/ALK/ROS1/RAF negative, PD-L1 (22c3) immunohistochemistry negative. After the progression of first-line chemotherapy, the patient was diagnosed as immune checkpoint inhibitor associated pneumonia grade 3 during second-line monotherapy with Nivolumab. After initial high-dose glucocorticoid pulse therapy, the lung computed tomography (CT) imaging and clinical symptoms of the patients were partially relieved, and then pirfenidone (300 mg tid) was given orally for more than 11 months. During the treatment of pirfenidone, the CT imaging and clinical symptoms of the patients were significantly improved, and there were no other adverse reactions except grade 1 nausea. During this period, chemotherapy and Anlotinib was given concurrently with pirfenidone and showed good safety profile. CONCLUSIONS: This case report is the first report of pirfenidone in the treatment of CIP, which provides a new idea for the clinical practice and research of CIP treatment.

Umifenovir in hospitalized moderate to severe COVID-19 patients: A randomized clinical trial.

INTRODUCTION: The effectiveness of umifenovir against COVID-19 is controversial; therefore, clinical trials are crucial to evaluate its efficacy. METHODS: The study was conducted as a single-center, randomized, open-label clinical trial. Eligible moderate-severe hospitalized patients with confirmed SARS-Cov-2 infection were randomly segregated into intervention and control groups. The intervention group were treated with lopinavir/ritonavir (400 mg/100 mg bid for 10-14 days) + hydroxychloroquine (400 mg single dose) + interferon-ß1a (Subcutaneous injections of 44 µg (12,000 IU) on days 1, 3, 5) + umifenovir (200 mg trice daily for 10 days), and the control group received lopinavir/ritonavir (same dose) + hydroxychloroquine (same dose) + interferon-ß1a (same dose). RESULTS: Of 1180 patients with positive RT-PCRs and positive chest CT scans, 101 patients were finally included in the trial; 50 were assigned to receive IFNß1a + hydroxychloroquine + lopinavir/ritonavir group and 51 were managed to treat with IFNß1a + hydroxychloroquine + lopinavir/ritonavir + umifenovir. Since all patients received the intended treatment as scheduled, the analysis just included as the ITT population. Time to clinical improvement (TTCI) did not hold a statistically significant difference between intervention and control groups (median, 9 days for intervention group versus 7 days for the control group; P: 0.22). Besides, Hazard Ratio for TTCI in the Cox regression model was 0.75 (95% CI: 0.45-1.23, P:0.25) which also confirmed that there was no statistically significant difference between the treatment group and the control group. The mortality was not statistically significant between the two groups (38% in controls vs 33.3% treatment group). CONCLUSIONS: Our findings shed new lights on the facts that additional umifenovir has not been found to be effective in shortening the duration of SARS-CoV-2 in severe patients and improving the prognosis in non-ICU patients and mortality. TRIAL REGISTRATION: The trial was confirmed by the Ethics in Medical Research Committee of the Shahid Beheshti University of Medical Sciences. signed informed consents were obtained from all the participants or their legally authorized representatives. This trial has been registered as ClinicalTrials.gov, NCT04350684.

Antibody Responses and the Effects of Clinical Drugs in COVID-19 Patients.

The coronavirus disease 2019 (COVID-19) emerged around December 2019 and have become a global epidemic disease currently. Specific antibodies against SAS-COV-2 could be detected in COVID-19 patients' serum or plasma, but the clinical values of these antibodies as well as the effects of clinical drugs on humoral responses have not been fully demonstrated. In this study, 112 plasma samples were collected from 36 patients diagnosed with laboratory-confirmed COVID-19 in the Fifth Affiliated Hospital of Sun Yat-sen University. The IgG and IgM antibodies against receptor binding domain (RBD) and spike protein subunit 1 (S1) of SAS-COV-2 were detected by ELISA. We found that COVID-19 patients generated specific antibodies against SARS-CoV-2 after infection, and the levels of anti-RBD IgG within 2 to 3 weeks from onset were negatively associated with the time of positive-to-negative conversion of SARS-CoV-2 nucleic acid. Patients with severe symptoms had higher levels of anti-RBD IgG in 2 to 3 weeks from onset. The use of chloroquine did not significantly influence the patients' antibody titer but reduced C-reaction protein (CRP) level. Using anti-viral drugs (lopinavir/ritonavir or arbidol) reduced antibody titer and peripheral lymphocyte count. While glucocorticoid therapy developed lower levels of peripheral lymphocyte count and higher levels of CRP, lactate dehydrogenase (LDH), α-Hydroxybutyrate dehydrogenase(α-HBDH), total bilirubin (TBIL), direct bilirubin (DBIL). From these results, we suggested that the anti-RBD IgG may provide an early protection of host humoral responses against SAS-COV-2 infection within 2 to 3 weeks from onset, and clinical treatment with different drugs displayed distinct roles in humoral and inflammatory responses.

Clinical efficacy of antiviral agents against coronavirus disease 2019: A systematic review of randomized controlled trials.

Despite aggressive efforts on containment measures for the coronavirus disease 2019 (COVID-19) pandemic around the world, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is continuously spreading. Therefore, there is an urgent need for an effective antiviral agent. To date, considerable research has been conducted to develop different approaches to COVID-19 therapy. In addition to early observational studies, which could be limited by study design, small sample size, non-randomized design, or different timings of treatment, an increasing number of randomized controlled trials (RCTs) investigating the clinical efficacy and safety of antiviral agents are being carried out. This study reviews the updated findings of RCTs regarding the clinical efficacy of eight antiviral agents against COVID-19, including remdesivir, lopinavir/ritonavir, favipiravir, sofosbuvir/daclatasvir, sofosbuvir/ledipasvir, baloxavir, umifenovir, darunavir/cobicistat, and their combinations. Treatment with remdesivir could accelerate clinical improvement; however, it lacked additional survival benefits. Moreover, 5-day regimen of remdesivir might show adequate effectiveness in patients with mild to moderate COVID-19. Favipiravir was only marginally effective regarding clinical improvement and virological assessment based on the results of small RCTs. The present evidence suggests that sofosbuvir/daclatasvir may improve survival and clinical outcomes in patients with COVID-19. However, the sample sizes for analysis were relatively small, and all studies were exclusively conducted in Iran. Further larger RCTs in other countries are warranted to support these findings. In contrast, the present findings of limited RCTs did not indicate the use of lopinavir/ritonavir, sofosbuvir/ledipasvir, baloxavir, umifenovir, and darunavir/cobicistat in the treatment of patients hospitalized for COVID-19.

Treatment strategies of hospitalized patients with coronavirus disease-19.

With the outbreak of coronavirus disease-19 (COVID-19), Changsha faced an increasing burden of treating the Wuhan migrants and their infected patients. This study is a retrospective, single-center case series of the 238 consecutive hospitalized patients with confirmed COVID-19 at the First Hospital of Changsha city, China, from 01/21 to 02/14, 2020; the final date of follow-up was 02/27, 2020. Of 238 patients 43.7% visited Wuhan, 58.4% got in touch with Wuhan people, and 47.5% had contacted with diagnosed patients. 37.8% patients had family members infected. 190 cases had mild / general disease, and 48 cases had severe / critical disease. Compared to mild or general patients, more severe or critical patients visited Wuhan (59.6% vs 40.2%; P=0.02) and contacted with Wuhan people (74.5% vs 55.0%; P=0.02). All patients received antiviral treatment, including Lopinavir / Ritonavir (29.3%), Interferon (14.6%) and their combination (40.6%), Arbidol (6.7%), Xuebijing (7.1%) and Chloroquine phosphate (1.3%). Severe and critical patients received glucocorticoid, Gamma-globulin and oxygen inhalation. Some received mechanic ventilation support. As of 02/27, 161 patients discharged. The median length of hospital stay was 13 days. The 10-, 14-, 20- and 28-day discharge rate was 19.1%, 42.8%, 65.0% and 76.4%, respectively. No hospital-related transmission was observed.

Efficacy and safety of umifenovir for coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis.

We conducted this systemic review and meta-analysis in an attempt to evaluate the efficacy and safety of umifenovir in coronavirus disease 2019 (COVID-19). We searched PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure, and medRxiv database. We included both retrospective and prospective studies. The mean difference (MD) and risk ratio (RR) with 95% confidence intervals (CI) were applied to assess the effectiveness of umifenovir for COVID-19. A total of 12 studies with 1052 patients were included in our final studies. Compared with control group, umifenovir was associated with higher negative rate of PCR on day 14 (RR:1.27; 95% CI: 1.04 to 1.55). However, umifenovir is not related to nucleus acid negative conversion time (MD: 0.09; 95% CI: -1.48 to 1.65), negative rate on day 7 (RR:1.09; 95% CI: 0.91 to 1.31), incidence of composite endpoint (RR:1.20; 95% CI: 0.61 to 2.37), rate of fever alleviation on day 7 (RR:1.00; 95% CI: 0.91 to 1.10), rate of cough alleviation on day 7 (RR:1.00; 95% CI: 0.85 to 1.18), or hospital length of stay (MD: 1.34; 95% CI: -2.08 to 4.76). Additionally, umifenovir was safe in COVID-19 patients (RR for incidence of adverse events: 1.29; 95% CI: 0.57 to 2.92). The results of sensitivity analysis and subgroup analysis were similar to pooled results. There is no evidence to support the use of umifenovir for improving patient-important outcomes in patients with COVID-19.

Discharge may not be the end of treatment: Pay attention to pulmonary fibrosis caused by severe COVID-19.

Since December 2019, coronavirus disease (COVID-19) has rapidly swept the world. So far, more than 30 million people have been infected and nearly one million have died. Although the world is still in the stage of COVID-19 pandemic, the treatment of new cases and critically ill patients is the focus of the current work. However, COVID-19 patients lead to pulmonary fibrosis, such a serious threat to the prognosis of complications were also worthy of our attention. First of all, we proposed the possible mechanism of pulmonary fibrosis caused by SARS-CoV-2, based on the published data of COVID-19 ((i) Direct evidence: pulmonary fibrosis was found in autopsy and pulmonary puncture pathology. (ii) Indirect evidence: increased levels of fibrosis-related cytokines[transforming growth factor [TGF]- ß, tumor necrosis factor [TNF]- α, interleukin [IL]-6, etc] in peripheral blood of severe patients.) What is more, we summarized the role of three fibrosis-related signaling pathways (TGF- ß signal pathway, WNT signal pathway and YAP/TAZ signal pathway) in pulmonary fibrosis. Finally, we suggested the therapeutic value of two drugs (pirfenidone and nintedanib) for idiopathic pulmonary fibrosis in COVID-19-induced pulmonary fibrosis.

Association between detectable SARS-COV-2 RNA in anal swabs and disease severity in patients with coronavirus disease 2019.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was found in the intestines and feces, but its clinical significance is not completely clear. We aim to characterize the longitudinal test results of SARS-CoV-2 RNA in anal swabs and to explore the association with disease severity. METHODS: We included laboratory-confirmed coronavirus disease 2019 (COVID-19) patients, who were hospitalized in Guangzhou Eighth People's Hospital and excluded those who had not received anal swabs for SARS-COV-2 RNA testing. Epidemiological, clinical, and laboratory data were obtained. Throat swabs and anal swabs were collected periodically for SARS-COV-2 RNA detection. RESULTS: Two hundred and seventeen eligible patients (median aged 50 years, 50.2% were females) were analyzed. 21.2% (46/217) of the patients were detected with SARS-CoV-2 RNA in anal swabs. The duration of viral RNA was longer, but the viral load was lower in anal swabs than throat swabs in the early stage of the disease. During a median follow-up of 20 days, 30 (13.8%) patients were admitted to the intensive care unit (ICU) for high-flow nasal cannula or higher-level oxygen support measures to correct hypoxemia. Detectable viral RNA in anal swabs (adjusted hazard ratio [aHR], 2.50; 95% confidence interval [CI], 1.20-5.24), increased C-reactive protein (aHR, 3.14; 95% CI, 1.35-7.32) and lymphocytopenia (aHR, 3.12; 95% CI, 1.46-6.67) were independently associated with ICU admission. The cumulative incidence of ICU admission was higher among patients with detectable viral RNA in anal swabs (26.3% vs 10.7%, P = .006). CONCLUSION: Detectable SARS-CoV-2 RNA in the digestive tract was a potential warning indicator of severe disease.

Comparison of the antiviral effect of Arbidol and Chloroquine in treating COVID-19.

BACKGROUND: The novel coronavirus disease 2019 (COVID-19) was broken out in December 2019 and soon became a global health emergency. Effective treatment for COVID-19 is urgently needed. In the present study, we aimed to evaluate the antiviral effect of Arbidol vs. Chloroquine in treating COVID-19. METHODS: We retrospectively analyzed 62 patients with COVID-19 diagnosed according to the guidelines for diagnosis and treatment of COVID-19 in China. They were divided into two groups depending on the antiviral drugs that they received. Participants in the Arbidol group (n=42) received 0.2 g Arbidol, tid for 10 days,and those in Chloroquine group (n=20) received 500 mg Chloroquine, bid for 10 days. The coronavirus negative conversion time and the length of hospital stay were analyzed and compared between the two groups. RESULTS: There was no significant difference in demographic and clinical characteristics between the two groups. After antiviral treatment, the nasopharyngeal specimen negative conversion time of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the length of hospital stay in the Arbidol group were significantly shorter than those in the Chloroquine group (18.50 vs. 25.05 days, P=0.001; 23.52 vs. 28.75 days, P=0.001). Adverse events observed during the antiviral treatment period were comparable between the two groups. Overall, 3 (7.14%) participants in the Arbidol group and 4 (20.0%) in the Chloroquine group experienced adverse events during antiviral treatment. CONCLUSIONS: These results suggest that Arbidol is advantageous over Chloroquine in terms of the SARS-CoV-2 negative conversion and the length of hospital stay in treating COVID-19 patients.

Pharmacological interventions for COVID-19: a systematic review of observational studies and clinical trials.

Introduction: Currently, there is no approved therapeutic entity for coronavirus disease 2019 (COVID-19) and clinicians are primarily relying on drug repurposing. However, findings across studies are widely disparate, making it difficult to draw firm conclusions. Since clinicians need accurate evidence to treat COVID-19, this manuscript systematically analyzed the published and ongoing studies evaluating the pharmacological interventions for COVID-19.Areas Covered: A systematic search of observational studies and Clinical Trials on the treatment and prevention of COVID-19 was performed by using various databases from inception to 2 December 2020.Expert Opinion: A total of 460 studies met the inclusion criteria. Of these, 37 were research studies, 386 were ongoing trials, and 37 were completed trials. Anti-virals, steroids, anti-malarial, plasma exchange, and monoclonal antibodies were the most common treatment modalities used alone or in combination in these studies. However, tocilizumab, plasma exchange, and steroids have shown significant improvements in patient's clinical and radiological status. Tocilizumab reported minimum hospital stay of 2 days along with maximum recovery and patient's stability rate. Existing literature demonstrate promising results of tocilizumab, plasma exchange, and steroids among COVID-19 patients. Nevertheless, these studies are accompanied by several methodological disparities which should be considered while interpreting the results.

[Effect of anticoagulant therapy on the course of COVID-19 in comorbid patients].

INTRODUCTION: Analysis of the pathogenesis of coronavirus infection caused SARS-CoV-2 indicates a significant impact of hemorheological disorders on its course and outcomes. It is known that chronic cardiovascular diseases are associated with the risk of severe course and lethal outcomes both in COVID-19 and other infectious diseases. Therefore, in each case it is necessary to study the interaction and mutual influence of different components of the treatment program prescribed to such patients.The purpose of this work was to evaluate the effect of coagulation activity on the course of a novel coronavirus infection (COVID-19) and to justify the management of comorbid patients having been received novel oral anticoagulants (NOACs) in previously selected doses according to indications in concomitant somatic diseases. MATERIAL AND METHODS: Total 76 cases of confirmed coronavirus infection in patients who had been received initial therapy on an outpatient basis were analyzed. 26 patients who received NOACs (rivaroxaban, apixaban, dabigatran) made up the main group and 50 - the comparison (control) group in which patients had not been administered any drugs that affect blood clotting until the episode of COVID-19. All patients have been prescribed therapy following the Provisional guidelines «Prevention, diagnosis and treatment of coronavirus infection (COVID-19)¼ (https://static-0.minzdrav.gov.ru/system/attachments/attaches/). RESULTS AND DISCUSSION: The number of hospitalizations was significantly fewer in the group of patients who had been received NOACs (19 vs. 66% in the control group). No deaths or cases of severe respiratory and/or renal failure were observed in the main group, while adverse outcomes were noted in 14% of patients who had not been administered these drugs. CONCLUSION: Taking NOACs reduces the probability of severe course and adverse outcomes in the development of coronavirus infection caused by SARS-CoV-2, which indicates a significant contribution of coagulation mechanisms to the pathogenesis in COVID-19. There were no indications for drug replacement and correction of anticoagulant therapy regimens in patients who received adequate therapy with oral anticoagulants for treating a non-severe form of coronavirus infection in ambulatory patient settings.