ABSTRACT
SARS-CoV-2 has demonstrated extraordinary ability to evade antibody immunity by antigenic drift. Small molecule drugs may provide effective therapy while being part of a solution to circumvent SARS-CoV-2 immune escape. In this study we report an alpha-ketoamide based peptidomimetic inhibitor of SARS-CoV-2 main protease (Mpro), RAY1216. Enzyme inhibition kinetic analysis established that RAY1216 is a slow-tight inhibitor with a Ki of 8.6 nM; RAY1216 has a drug-target residence time of 104 min compared to 9 min of PF-07321332 (nirmatrelvir), the antiviral component in Paxlovid, suggesting that RAY1216 is approximately 12 times slower to dissociate from the protease-inhibitor complex compared to PF-07321332. Crystal structure of SARS-CoV-2 Mpro:RAY1216 complex demonstrates that RAY1216 is covalently attached to the catalytic Cys145 through the alpha-ketoamide warhead; more extensive interactions are identified between bound RAY1216 and Mpro active site compared to PF-07321332, consistent with a more stable acyl-enzyme inhibition complex for RAY1216. In cell culture and human ACE2 transgenic mouse models, RAY1216 demonstrates comparable antiviral activities towards different SARS-CoV-2 virus variants compared to PF-07321332. Improvement in pharmacokinetics has been observed for RAY1216 over PF-07321332 in various animal models, which may allow RAY1216 to be used without ritonavir. RAY1216 is currently undergoing phase III clinical trials (https://clinicaltrials.gov/ct2/show/NCT05620160) to test real-world therapeutic efficacy against COVID-19.
Subject(s)
COVID-19ABSTRACT
Makeshift hospitals have played an important role in responding to the spread of the epidemic caused by the Omicron coronavirus variant, one of the novel coronavirus(SARS-CoV-2) strains with significantly enhanced infectiousness. In order to prevent the patients, healthcare workers and other staff against from infection, Healthcare-associated Infection Management Committee of Chinese Hospital Association organized domestic experts to jointly formulate this consensus according to the comprehensive consideration of national guidelines as well as the actual characteristics and needs of makeshift hospitals. This consensus is mainly applicable for makeshift hospitals where a large number of asymptomatic and mild cases of novel coronavirus disease 2019(COVID-19) are treated. It provides guidance for the managers and staff to implement prevention and control work in line with local conditions in makeshift hospitals based on a perfect organizational structure and efficient working mechanism, the prevention and control work includes training and assessment of infection control knowledge and skills, flowing in and out of the makeshift hospitals for staff and materials, infection monitoring and feedback, implementation of infection prevention and control measures, requirements for infection management in key areas, occupational protection of staff and terminal disinfection, etc. Meanwhile, this consensus particularly emphasizes that the infection prevention and control in makeshift hospitals is a systematic project, which requires not only multi-system and multi-department collaboration, but also uniting in a concrete effort among leaders and staff. In accordance with the national guidelines and evidence-based experiences, it is very important to combine theory with practice for ensuring efficient operation and safety of makeshift hospitals.
ABSTRACT
Objective To explore the effect of Ludangshen Oral Liquid for treatment of convalescent patients with coronavirus disease 2019 (COVID-19) with randomized, double-blind, placebo-controlled multicenter method.Methods200 convalescent COVID-19 patients who had symptoms related to decreased digestive and respiratory function were randomly divided to either receive Ludangshen Oral Liquid or placebo for 2 weeks. The severity of clinical symptoms including fatigue, anorexia, abdominal distension, loose stools, and shortness of breath were assessed by visual analogue scale and observed at before and after treatment. The improvement and resolution rates of clinical symptoms were evaluated. Full analysis set (FAS) and per-protocol set (PPS) were used for statistical analyses. Adverse events were recorded during the study. Results8 patients did not complete the study. After 2 weeks of treatment, both FAS and PPS results showed that patients in Ludangshen group had significantly lower score of fatigue, anorexia, loose stools, and shortness of breath than placebo group (P < 0.05), while there was no significant difference in distention (P > 0.05). The improvement rate of fatigue, anorexia, distension, loose stools and shortness of breath were significantly higher in Ludangshen group (P < 0.05), as well as the resolution rates (P < 0.05) except for shortness of breath (P > 0.05). There were two cases of adverse events, with one nose bleeding in Ludangshen group and one headache in placebo group. ConclusionThe study suggested that two weeks of Ludangshen Oral Liquid treatment may have certain effects for convalescent COVID-19 patients on improving digestive and respiratory symptoms including fatigue, anorexia, loose stools and shortness of breath, which may be one of the choices for management of convalescent COVID-19 patients with digestive and respiratory symptoms.
Subject(s)
COVID-19ABSTRACT
Background: A methodical comparison of confirmed and suspected COVID-19 patients has not been previously reported. Therefore, we thoroughly analyzed the demographic and clinical characteristics between these groups to identify mortality risk factors.Methods: A retrospective cohort of 1,276 hospitalized COVID-19 pneumonia patients at Tongren Hospital (Wuhan, China; January 27 to March 3, 2020) was studied. Cox regression analyses were performed to evaluate multiple mortality risk factors. Results: Both cohorts of confirmed (n=797) and suspected (n=479) patients exhibited typical demographic, clinical, and radiological characteristics. Treatment methods were consistent and both groups shared similarities in many demographic and clinical characteristics: age (≥65, 45.9% vs 41.8%, P=0.378) and lung disease (12.5% vs 14.6%, P=0.293). However, confirmed patients exhibited more severe disease manifestations than those in suspected patients: a higher incidence of fever (65.4% vs 58.0%, P<0.01), lower lymphocyte count (1.12×109/L vs 1.22×109/L, P=0.022), higher C-reactive protein (CRP) (11.60 mg/L vs 7.61mg/L, P=0.021), and more severe radiographic manifestations (lung infection incidence, 3.8% vs 3.0%, P=0.014; ground-glass opacity lesion incidence, 2.3% vs 2.0%, P=0.033). The dynamic profiles of lymphocytes, monocytes, D-dimer, and CRP, clearly delineated confirmed patients from suspected patients exhibiting critical illness. Cox regression analysis demonstrated that lung disease (adjusted hazard ratio 8.972, 95% CI: 3.782-21.283), cardiovascular disease (3.083, 1.347-7.059), neutrophil count (1.189, 1.081-1.307), age (1.068, 1.027-1.110), and ground-glass opacity lesions (1.039, 95% 1.013-1.065), were the main risk factors for mortality in confirmed patients; lung disease (14.725, 2.187-99.147), age (1.076, 1.004-1.153), and CRP level (1.012, 95% CI 1.004-1.020) were the primary factors in suspected patients.Conclusions: Suspected patients with serious illness should seek medical attention to reduce mortality. Multiple factors must be assessed to determine the mortality risk and the appropriate treatment.
Subject(s)
Lung Diseases , Cardiovascular Diseases , Fever , Pneumonia , COVID-19 , Corneal OpacityABSTRACT
Preliminary results from the RECOVERY trial indicated that dexamethasone usage markedly reduced death rate in COVID-19 patients receiving invasive mechanical ventilation. However, the overall reduction for the entire patient cohort in that trial was much more modest, indicating highly variable effects of corticosteroid usage among COVID-19 patients. While steroid treatment is known to have both clinical efficacy and detrimental adverse-effects, defining a clinic parameter that could guide the beneficial corticosteroid usage for treating COVID-19 remains an elusive, urgent, and critical unmet need in COVID-19 therapy. Here, we undertook a multicentered retrospective study on a cohort of 12,862 confirmed COVID-19 cases from 21 hospitals in Hubei Province, China, including 3,254 received corticosteroid treatment and 9,608 received usual care without corticosteroid. We uncovered that the clinical benefits of corticosteroid use were closely associated with the neutrophil-to-lymphocyte ratio (NLR) measured at admission. Among participants with NLR > 6.12 at admission, corticosteroid treatment was significantly associated with a lower risk of 60-day all-cause mortality of COVID-19 based on both Cox model with time-varying exposure and Marginal Structural Model. However, in patients with NLR ≤ 6.12 at admission, corticosteroid treatment was no longer associated with reduced risk of all-cause death, but rather with increased risks of severe adverse effects, particularly in hyperglycemia and infection. In diabetic patients with COVID-19, corticosteroid treatment was associated with increased glycemia, but not with a higher risk of 60-day mortality. Therefore, our study has uncovered NLR as a clinical indicator to stratify COVID-19 patients in their response to corticosteroid therapy. This finding may assist clinical evaluation and future randomized controlled trials to establish proper guidelines for corticosteroid therapy in COVID-19 patients.