Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 225
Filter
Add filters

Document Type
Year range
1.
JAMA ; 326(17): 1703-1712, 2021 11 02.
Article in English | MEDLINE | ID: covidwho-1525396

ABSTRACT

Importance: Acutely ill inpatients with COVID-19 typically receive antithrombotic therapy, although the risks and benefits of this intervention among outpatients with COVID-19 have not been established. Objective: To assess whether anticoagulant or antiplatelet therapy can safely reduce major adverse cardiopulmonary outcomes among symptomatic but clinically stable outpatients with COVID-19. Design, Setting, and Participants: The ACTIV-4B Outpatient Thrombosis Prevention Trial was designed as a minimal-contact, adaptive, randomized, double-blind, placebo-controlled trial to compare anticoagulant and antiplatelet therapy among 7000 symptomatic but clinically stable outpatients with COVID-19. The trial was conducted at 52 US sites between September 2020 and June 2021; final follow-up was August 5, 2021. Prior to initiating treatment, participants were required to have platelet count greater than 100 000/mm3 and estimated glomerular filtration rate greater than 30 mL/min/1.73 m2. Interventions: Random allocation in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days. Main Outcomes and Measures: The primary end point was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause. The primary analyses for efficacy and bleeding events were limited to participants who took at least 1 dose of trial medication. Results: On June 18, 2021, the trial data and safety monitoring board recommended early termination because of lower than anticipated event rates; at that time, 657 symptomatic outpatients with COVID-19 had been randomized (median age, 54 years [IQR, 46-59]; 59% women). The median times from diagnosis to randomization and from randomization to initiation of study treatment were 7 days and 3 days, respectively. Twenty-two randomized participants (3.3%) were hospitalized for COVID-19 prior to initiating treatment. Among the 558 patients who initiated treatment, the adjudicated primary composite end point occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5-mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group. The risk differences compared with placebo for the primary end point were 0.0% (95% CI not calculable) in the aspirin group, 0.7% (95% CI, -2.1% to 4.1%) in the 2.5-mg apixaban group, and 1.4% (95% CI, -1.5% to 5.0%) in the 5-mg apixaban group. Risk differences compared with placebo for bleeding events were 2.0% (95% CI, -2.7% to 6.8%), 4.5% (95% CI, -0.7% to 10.2%), and 6.9% (95% CI, 1.4% to 12.9%) among participants who initiated therapy in the aspirin, prophylactic apixaban, and therapeutic apixaban groups, respectively, although none were major. Findings inclusive of all randomized patients were similar. Conclusions and Relevance: Among symptomatic clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome. However, the study was terminated after enrollment of 9% of participants because of an event rate lower than anticipated. Trial Registration: ClinicalTrials.gov Identifier: NCT04498273.


Subject(s)
Aspirin/therapeutic use , COVID-19/drug therapy , Factor Xa Inhibitors/therapeutic use , Platelet Aggregation Inhibitors/therapeutic use , Pyrazoles/therapeutic use , Pyridones/therapeutic use , Thrombosis/prevention & control , Adult , Aspirin/adverse effects , COVID-19/complications , Dose-Response Relationship, Drug , Double-Blind Method , Early Termination of Clinical Trials , Factor Xa Inhibitors/administration & dosage , Factor Xa Inhibitors/adverse effects , Female , Hemorrhage/chemically induced , Hospitalization , Humans , Male , Middle Aged , Platelet Aggregation Inhibitors/adverse effects , Pyrazoles/administration & dosage , Pyrazoles/adverse effects , Pyridones/administration & dosage , Pyridones/adverse effects
2.
J Infect Dis ; 224(3): 415-419, 2021 08 02.
Article in English | MEDLINE | ID: covidwho-1526165

ABSTRACT

Mutagenic ribonucleosides can act as broad-based antiviral agents. They are metabolized to the active ribonucleoside triphosphate form and concentrate in genomes of RNA viruses during viral replication. ß-d-N4-hydroxycytidine (NHC, initial metabolite of molnupiravir) is >100-fold more active than ribavirin or favipiravir against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with antiviral activity correlated to the level of mutagenesis in virion RNA. However, NHC also displays host mutational activity in an animal cell culture assay, consistent with RNA and DNA precursors sharing a common intermediate of a ribonucleoside diphosphate. These results indicate highly active mutagenic ribonucleosides may hold risk for the host.


Subject(s)
Antiviral Agents/pharmacology , Cytidine/analogs & derivatives , Mutagens/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/adverse effects , CHO Cells/drug effects , Cells, Cultured , Cricetulus , Cytidine/adverse effects , Cytidine/pharmacology , Dose-Response Relationship, Drug , Mutagenesis/drug effects , Mutagens/adverse effects , SARS-CoV-2/genetics , Virus Replication/drug effects
3.
Transplantation ; 105(11): e234-e243, 2021 11 01.
Article in English | MEDLINE | ID: covidwho-1494154

ABSTRACT

BACKGROUND: Data about SARS-CoV-2 vaccines efficacy in renal transplant recipients (RTR) are lacking. METHODS: To reveal predictors for humoral response to BNT162b2 vaccine among RTR, patients were divided into positive (N = 42) and negative (N = 78) response groups based on receptor-binding domain (RBD) immunoglobulin G (IgG) ≥1.1 and neutralizing antibodies (NA) ≥16 dilution versus RBD IgG <1.1 or NA <16, respectively. NA were detected using a SARS-CoV-2 pseudo-virus. RESULTS: NA were detected in only 42 of 120 (35%) of RTR versus 197 of 202 (97.5%) immunocompetent controls (P < 0.001). NA geometric mean titers in RTR were significantly lower versus the control group {83.7 (95% confidence interval [CI], 50.5-138.8) versus 482 (95% CI, 411-566), P < 0.001}. In a multivariable analysis, mycophenolic acid (MPA) dose and hemoglobin level were found to be independent predictors for antibody response in RTR. A positive response rate of 27% versus 63% was observed in patients on and off MPA, respectively. An increase in MPA dose by 1 mg/kg weight reduced the odds for a positive response by 17% (odds ratio = 0.83; 95% CI, 0.75-0.92; P < 0.001). Geometric mean titers for RBD IgG were significantly reduced as MPA daily dose increased. Hemoglobin blood level <13 g/dL reduced the antibody response by 63% (P = 0.04). Pain at the injection site after the second vaccine dose was significantly higher in the responders versus nonresponders (20.5% versus 5.5%, P = 0.01). CONCLUSIONS: Only 35% of RTR develop NA to the BNT162b2 mRNA vaccine. MPA is a major suppressor of antibody response in RTR.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/prevention & control , Immunity, Humoral/drug effects , Immunogenicity, Vaccine/drug effects , Kidney Transplantation/adverse effects , Adult , Aged , Aged, 80 and over , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/administration & dosage , Cohort Studies , Dose-Response Relationship, Drug , Female , Graft Rejection/immunology , Graft Rejection/prevention & control , Humans , Immunoglobulin G/blood , Immunoglobulin G/immunology , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/adverse effects , Male , Middle Aged , Mycophenolic Acid/administration & dosage , Mycophenolic Acid/adverse effects , SARS-CoV-2/immunology
4.
Semin Respir Crit Care Med ; 42(5): 672-682, 2021 10.
Article in English | MEDLINE | ID: covidwho-1493295

ABSTRACT

While the use of vitamin C as a therapeutic agent has been investigated since the 1950s, there has been substantial recent interest in the role of vitamin C supplementation in critical illness and particularly, sepsis and septic shock. Humans cannot synthesize vitamin C and rely on exogenous intake to maintain a plasma concentration of approximately 70 to 80 µmol/L. Vitamin C, in healthy humans, is involved with antioxidant function, wound healing, endothelial function, and catecholamine synthesis. Its function in the human body informs the theoretical basis for why vitamin C supplementation may be beneficial in sepsis/septic shock.Critically ill patients can be vitamin C deficient due to low dietary intake, increased metabolic demands, inefficient recycling of vitamin C metabolites, and loss due to renal replacement therapy. Intravenous supplementation is required to achieve supraphysiologic serum levels of vitamin C. While some clinical studies of intravenous vitamin C supplementation in sepsis have shown improvements in secondary outcome measures, none of the randomized clinical trials have shown differences between vitamin C supplementation and standard of care and/or placebo in the primary outcome measures of the trials. There are some ongoing studies of high-dose vitamin C administration in patients with sepsis and coronavirus disease 2019; the majority of evidence so far does not support the routine supplementation of vitamin C in patients with sepsis or septic shock.


Subject(s)
Ascorbic Acid/pharmacology , Ascorbic Acid/therapeutic use , Shock, Septic/drug therapy , Vitamins/pharmacology , Vitamins/therapeutic use , Animals , Antioxidants/pharmacology , Ascorbic Acid/administration & dosage , Ascorbic Acid/adverse effects , Ascorbic Acid Deficiency/physiopathology , Clinical Trials as Topic , Critical Illness , Dose-Response Relationship, Drug , Glucocorticoids/pharmacology , Humans , Inflammation Mediators/metabolism , Vasoconstrictor Agents/pharmacology , Vitamins/administration & dosage , Vitamins/adverse effects
5.
Semin Respir Crit Care Med ; 42(2): 316-326, 2021 04.
Article in English | MEDLINE | ID: covidwho-1493288

ABSTRACT

Venous thromboembolism, occlusion of dialysis catheters, circuit thrombosis in extracorporeal membrane oxygenation (ECMO) devices, acute limb ischemia, and isolated strokes, all in the face of prophylactic and even therapeutic anticoagulation, are features of novel coronavirus disease 2019 (COVID-19) coagulopathy. It seems well established at this time that a COVID-19 patient deemed sick enough to be hospitalized, should receive at least prophylactic dose anticoagulation. However, should some hospitalized patients have dosage escalation to intermediate dose? Should some be considered for full-dose anticoagulation without a measurable thromboembolic event and how should that anticoagulation be monitored? Should patients receive postdischarge anticoagulation and with what medication and for how long? What thrombotic issues are related to the various medications being used to treat this coagulopathy? Is antiphospholipid antibody part of this syndrome? What is the significance of isolated ischemic stroke and limb ischemia in this disorder and how does this interface with the rest of the clinical and laboratory features of this disorder? The aims of this article are to explore these questions and interpret the available data based on the current evidence.


Subject(s)
Anticoagulants/administration & dosage , COVID-19/drug therapy , Thrombophilia/drug therapy , Thrombosis/prevention & control , Venous Thromboembolism/prevention & control , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/therapeutic use , Ambulatory Care , Antibodies, Antiphospholipid/immunology , Antibodies, Monoclonal, Humanized/therapeutic use , Antirheumatic Agents/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/blood , COVID-19/complications , COVID-19/immunology , COVID-19/therapy , Dose-Response Relationship, Drug , Drug Combinations , Duration of Therapy , Glucocorticoids/therapeutic use , Hospitalization , Humans , Hydroxychloroquine/therapeutic use , Immunization, Passive , Lopinavir/therapeutic use , Ritonavir/therapeutic use , SARS-CoV-2 , Thrombolytic Therapy , Thrombophilia/blood , Thrombophilia/etiology , Thrombosis/drug therapy , Thrombosis/immunology , Venous Thromboembolism/drug therapy , Venous Thromboembolism/immunology
7.
PLoS One ; 16(3): e0247782, 2021.
Article in English | MEDLINE | ID: covidwho-1456064

ABSTRACT

OBJECTIVE: To evaluate the effect of aspirin dose on the incidence of all gestational age preeclampsia and preterm preeclampsia. DATA SOURCES: Electronic databases (Cochrane, PubMed, Scopus, ClinicalTrials.gov and the Web of Science) were searched for articles published between January 1985 and March 2019 with no language restrictions. METHODS: We followed the PRIMSA guidelines and utilized Covidence software. Articles were screened by 2 independent reviewers, with discrepancies settled by an independent 3rd party. Study selection criteria were randomized trials comparing aspirin for prevention of all gestational age and preterm preeclampsia to placebo or no antiplatelet treatment in women aged 15-55 years with moderate or high-risk factors according to the list of risk factors from American College of Obstetricians and Gynecologists and United States Preventive Services Task Force guidelines. The quality of trials was assessed using the Cochrane risk of bias tool. The data were pooled using a random-effects meta-analysis comparing aspirin at doses of <81, 81, 100, and 150 mg. Pre-specified outcomes were all gestational age and preterm preeclampsia. RESULTS: Of 1,609 articles screened, 23 randomized trials, which included 32,370 women, fulfilled the inclusion criteria. In preterm preeclampsia, women assigned at random to 150 mg experienced a significant 62% reduction in risk of preterm preeclampsia (RR = 0.38; 95% CI: 0.20-0.72; P = 0.011). Aspirin doses <150 mg produced no significant reductions. The number needed to treat with 150 mg of aspirin was 39 (95% CI: 23-100). There was a maximum 30% reduction in risk of all gestational age preeclampsia at all aspirin doses. CONCLUSIONS: In this meta-analysis, based on indirect comparisons, aspirin at a dose greater than the current, recommended 81 mg was associated with the highest reduction in preterm preeclampsia. Our meta-analysis is limited due to the deficiency of homogeneous high evidence data available in the literature to date; however, it may be prudent for clinicians to consider that the optimal aspirin dose may be higher than the current guidelines advise. Future research to compare the efficacy aspirin doses greater than 81 mg is recommended. STUDY REGISTRATION: PROSPERO, CRD42019127951 (University of York, UK; http://www.crd.york.ac.uk/PROSPERO/).


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Aspirin/administration & dosage , Pre-Eclampsia/epidemiology , Pre-Eclampsia/prevention & control , Adolescent , Adult , Dose-Response Relationship, Drug , Female , Humans , Incidence , Middle Aged , Pregnancy , Risk Factors , Young Adult
8.
Sci Rep ; 11(1): 19728, 2021 10 05.
Article in English | MEDLINE | ID: covidwho-1454814

ABSTRACT

Life-threatening COVID-19 is associated with strong inflammation, where an IL-6-driven cytokine storm appears to be a cornerstone for enhanced pathology. Nonetheless, the specific inhibition of such pathway has shown mixed outcomes. This could be due to variations in the dose of tocilizumab used, the stage in which the drug is administered or the severity of disease presentation. Thus, we performed a retrospective multicentric study in 140 patients with moderate to critical COVID-19, 79 of which received tocilizumab in variable standard doses (< 400 mg, 400-800 mg or > 800 mg), either at the viral (1-7 days post-symptom onset), early inflammatory (8-15) or late inflammatory (16 or more) stages, and compared it with standard treated patients. Mortality, reduced respiratory support requirements and pathology markers were measured. Tocilizumab significantly reduced the respiratory support requirements (OR 2.71, CI 1.37-4.85 at 95%) and inflammatory markers (OR 4.82, CI 1.4-15.8) of all patients, but mortality was only reduced (4.1% vs 25.7%, p = 0.03) when the drug was administered at the early inflammatory stage and in doses ranging 400-800 mg in severely-ill patients. Despite the apparent inability of Tocilizumab to prevent the progression of COVID-19 into a critical presentation, severely-ill patients may be benefited by its use in the early inflammatory stage and moderate doses.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/drug therapy , C-Reactive Protein/analysis , COVID-19/mortality , COVID-19/pathology , Dose-Response Relationship, Drug , Fibrin Fibrinogen Degradation Products/analysis , Humans , Odds Ratio , Retrospective Studies , SARS-CoV-2/isolation & purification , Severity of Illness Index , Survival Analysis , Survival Rate
9.
Jpn J Infect Dis ; 74(5): 421-423, 2021 Sep 22.
Article in English | MEDLINE | ID: covidwho-1436359

ABSTRACT

Green tea extracts effectively inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro in a dose-dependent manner. Ten-fold serially diluted solutions of catechin mixture reagent from green tea were mixed with the viral culture fluid at a volume ratio of 9:1, respectively, and incubated at room temperature for 5 min. The solution of 10 mg/mL catechin reagent reduced the viral titer by 4.2 log and 1.0 mg/mL solution by one log. Pre-infection treatment of cells with the reagent alone did not affect viral growth. In addition, cells treated with only the reagent were assayed for host cell viability using the WST-8 system, and almost no host cell damage by the treatment was observed. These findings suggested that the direct treatment of virus with the reagent before inoculation decreased the viral activity and that catechins might have the potential to suppress SARSCoV-2 infection.


Subject(s)
Antiviral Agents/pharmacology , Catechin/pharmacology , SARS-CoV-2/drug effects , Tea/chemistry , Animals , COVID-19/virology , Cell Survival/drug effects , Chlorocebus aethiops , Dose-Response Relationship, Drug , Humans , Vero Cells , Viral Load/drug effects
10.
Viruses ; 13(8)2021 08 12.
Article in English | MEDLINE | ID: covidwho-1436097

ABSTRACT

Type III interferons (lambda IFNs) are a quite new, small family of three closely related cytokines with interferon-like activity. Attention to IFN-λ is mainly focused on direct antiviral activity in which, as with IFN-α, viral genome replication is inhibited without the participation of immune system cells. The heterodimeric receptor for lambda interferons is exposed mainly on epithelial cells, which limits its possible action on other cells, thus reducing the likelihood of developing undesirable side effects compared to type I IFN. In this study, we examined the antiviral potential of exogenous human IFN-λ1 in cellular models of viral infection. To study the protective effects of IFN-λ1, three administration schemes were used: 'preventive' (pretreatment); 'preventive/therapeutic' (pre/post); and 'therapeutic' (post). Three IFN-λ1 concentrations (from 10 to 500 ng/mL) were used. We have shown that human IFN-λ1 restricts SARS-CoV-2 replication in Vero cells with all three treatment schemes. In addition, we have shown a decrease in the viral loads of CHIKV and IVA with the 'preventive' and 'preventive/therapeutic' regimes. No significant antiviral effect of IFN-λ1 against AdV was detected. Our study highlights the potential for using IFN-λ as a broad-spectrum therapeutic agent against respiratory RNA viruses.


Subject(s)
Adenoviruses, Human/drug effects , Chikungunya virus/drug effects , Influenza A virus/drug effects , Interferons/pharmacology , SARS-CoV-2/drug effects , A549 Cells , Adenoviruses, Human/physiology , Animals , Chikungunya virus/physiology , Chlorocebus aethiops , Dose-Response Relationship, Drug , Gene Expression Regulation , Humans , Influenza A virus/physiology , Interferons/therapeutic use , Interleukins , RNA Virus Infections/drug therapy , RNA Virus Infections/prevention & control , Recombinant Proteins/pharmacology , SARS-CoV-2/physiology , Vero Cells , Viral Load/drug effects , Virus Replication/drug effects
11.
Aging (Albany NY) ; 13(17): 20906-20914, 2021 09 09.
Article in English | MEDLINE | ID: covidwho-1404174

ABSTRACT

BACKGROUND: Cardiac injury is common and associated with poor clinical outcomes in COVID-19. Data are lacking whether high-dose intravenous vitamin C (HIVC) could help to ameliorate myocardial injury in the pandemic. METHODS: The retrospective cohort study included consecutive severe and critically ill COVID-19 patients with cardiac injury receiving symptomatic supportive treatments alone or together with HIVC. Troponin I and inflammatory markers were collected at admission and day 21 during hospitalization from the electronic medical records. RESULTS: The patients (n = 113) were categorized into the ameliorated cardiac injury (ACI) group (n = 70) and the non-ameliorated cardiac injury (NACI) group (n = 43). Overall, fifty-one (45.1%) patients were administered with HIVC, the percentages of patients with HIVC were higher in the ACI group than those in the NACI group. Logistic regression analysis revealed that HIVC was independently associated with the improvement of myocardial injury. Further analysis showed that inflammatory markers levels significantly decreased at day 21 during hospitalization in patients with HIVC therapy compared to those administered with symptomatic supportive treatments alone. Meanwhile, similar results were also observed regarding changes in inflammatory markers levels from baseline to day 21 during hospitalization in the patients treated with HIVC. CONCLUSIONS: HIVC can ameliorate cardiac injury through alleviating hyperinflammation in severe and critically ill patients with COVID-19.


Subject(s)
Ascorbic Acid/therapeutic use , COVID-19/drug therapy , COVID-19/epidemiology , Heart Injuries/drug therapy , Pandemics , Aged , Biomarkers/blood , COVID-19/blood , Dose-Response Relationship, Drug , Female , Hospitalization , Humans , Inflammation/pathology , Inflammation Mediators/blood , Male , Middle Aged , Retrospective Studies , Troponin I/metabolism
13.
Med Clin (Barc) ; 156(5): 221-228, 2021 03 12.
Article in English, Spanish | MEDLINE | ID: covidwho-1386235

ABSTRACT

INTRODUCTION: Several studies have reported the beneficial effect of glucocorticoids in the treatment of cytokine storm that occurs in patients with severe COVID-19. Various glucocorticoids regimens have been proposed. METHODS: Retrospective observational study that includes patients with severe SARS-CoV-2 pneumonia and compares admission to an Intensive Care Unit (ICU) or death during hospitalization in three groups of patients: no glucocorticoids treatment, use of glucocorticoids doses equivalent to less than 250mg of prednisone daily and use of equivalent doses greater than or equal to 250mg of prednisone daily. Multivariate analysis was performed using logistic regression, using the propensity index as a covariant. RESULTS: Of the 259 patients enrolled in the study, 67 (25.9%) had an unfavorable evolution, dying or requiring ICU admission. Comparative analyzes between different glucocorticoids treatments and the association with ICU admission or death were: glucocorticoids treatment (any dose) versus no glucocorticoids treatment (OR: 0.71 [0.30-1.66]), treatment with glucocorticoids (≥250mg prednisone daily) versus no glucocorticoids treatment (OR: 0.35 [0.11-1.08]) and glucocorticoids treatment (≥250mg prednisone daily) versus patients with glucocorticoids doses <250mg prednisone daily or without glucocorticoids treatment (OR: 0.30 [0.10-0.88]). CONCLUSION: The results of this study show that patients with severe SARS-CoV-2 pneumonia treated with glucocorticoids pulses with equivalent doses of prednisone greater than or equal to 250mg have a more favorable evolution (less mortality and less admission to ICU).


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/drug therapy , Glucocorticoids/therapeutic use , Adolescent , Adult , Aged , COVID-19/complications , COVID-19/mortality , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Hospitalization , Humans , Logistic Models , Male , Middle Aged , Retrospective Studies , Severity of Illness Index , Treatment Outcome , Young Adult
14.
N Engl J Med ; 385(9): 803-814, 2021 08 26.
Article in English | MEDLINE | ID: covidwho-1373469

ABSTRACT

BACKGROUND: Additional interventions are needed to reduce the morbidity and mortality caused by malaria. METHODS: We conducted a two-part, phase 1 clinical trial to assess the safety and pharmacokinetics of CIS43LS, an antimalarial monoclonal antibody with an extended half-life, and its efficacy against infection with Plasmodium falciparum. Part A of the trial assessed the safety, initial side-effect profile, and pharmacokinetics of CIS43LS in healthy adults who had never had malaria. Participants received CIS43LS subcutaneously or intravenously at one of three escalating dose levels. A subgroup of participants from Part A continued to Part B, and some received a second CIS43LS infusion. Additional participants were enrolled in Part B and received CIS43LS intravenously. To assess the protective efficacy of CIS43LS, some participants underwent controlled human malaria infection in which they were exposed to mosquitoes carrying P. falciparum sporozoites 4 to 36 weeks after administration of CIS43LS. RESULTS: A total of 25 participants received CIS43LS at a dose of 5 mg per kilogram of body weight, 20 mg per kilogram, or 40 mg per kilogram, and 4 of the 25 participants received a second dose (20 mg per kilogram regardless of initial dose). No safety concerns were identified. We observed dose-dependent increases in CIS43LS serum concentrations, with a half-life of 56 days. None of the 9 participants who received CIS43LS, as compared with 5 of 6 control participants who did not receive CIS43LS, had parasitemia according to polymerase-chain-reaction testing through 21 days after controlled human malaria infection. Two participants who received 40 mg per kilogram of CIS43LS and underwent controlled human malaria infection approximately 36 weeks later had no parasitemia, with serum concentrations of CIS43LS of 46 and 57 µg per milliliter at the time of controlled human malaria infection. CONCLUSIONS: Among adults who had never had malaria infection or vaccination, administration of the long-acting monoclonal antibody CIS43LS prevented malaria after controlled infection. (Funded by the National Institute of Allergy and Infectious Diseases; VRC 612 ClinicalTrials.gov number, NCT04206332.).


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antimalarials/therapeutic use , Malaria, Falciparum/prevention & control , Adult , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/pharmacokinetics , Antibodies, Protozoan/blood , Antimalarials/administration & dosage , Antimalarials/adverse effects , Antimalarials/pharmacokinetics , Dose-Response Relationship, Drug , Healthy Volunteers , Humans , Infusions, Intravenous/adverse effects , Injections, Subcutaneous/adverse effects , Middle Aged , Plasmodium falciparum/immunology , Plasmodium falciparum/isolation & purification
15.
Proc Natl Acad Sci U S A ; 118(36)2021 09 07.
Article in English | MEDLINE | ID: covidwho-1370748

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed more than 4 million humans globally, but there is no bona fide Food and Drug Administration-approved drug-like molecule to impede the COVID-19 pandemic. The sluggish pace of traditional therapeutic discovery is poorly suited to producing targeted treatments against rapidly evolving viruses. Here, we used an affinity-based screen of 4 billion DNA-encoded molecules en masse to identify a potent class of virus-specific inhibitors of the SARS-CoV-2 main protease (Mpro) without extensive and time-consuming medicinal chemistry. CDD-1714, the initial three-building-block screening hit (molecular weight [MW] = 542.5 g/mol), was a potent inhibitor (inhibition constant [K i] = 20 nM). CDD-1713, a smaller two-building-block analog (MW = 353.3 g/mol) of CDD-1714, is a reversible covalent inhibitor of Mpro (K i = 45 nM) that binds in the protease pocket, has specificity over human proteases, and shows in vitro efficacy in a SARS-CoV-2 infectivity model. Subsequently, key regions of CDD-1713 that were necessary for inhibitory activity were identified and a potent (K i = 37 nM), smaller (MW = 323.4 g/mol), and metabolically more stable analog (CDD-1976) was generated. Thus, screening of DNA-encoded chemical libraries can accelerate the discovery of efficacious drug-like inhibitors of emerging viral disease targets.


Subject(s)
Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/genetics , Drug Discovery/methods , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , Animals , COVID-19/drug therapy , COVID-19/virology , Cells, Cultured , Coronavirus 3C Proteases/metabolism , Dose-Response Relationship, Drug , Enzyme Activation , Genetic Engineering , Humans , Models, Molecular , Molecular Conformation , Molecular Structure , SARS-CoV-2/metabolism , Structure-Activity Relationship , Virus Replication
16.
Proc Natl Acad Sci U S A ; 118(36)2021 09 07.
Article in English | MEDLINE | ID: covidwho-1366851

ABSTRACT

The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the associated disease COVID-19, requires therapeutic interventions that can be rapidly identified and translated to clinical care. Traditional drug discovery methods have a >90% failure rate and can take 10 to 15 y from target identification to clinical use. In contrast, drug repurposing can significantly accelerate translation. We developed a quantitative high-throughput screen to identify efficacious agents against SARS-CoV-2. From a library of 1,425 US Food and Drug Administration (FDA)-approved compounds and clinical candidates, we identified 17 hits that inhibited SARS-CoV-2 infection and analyzed their antiviral activity across multiple cell lines, including lymph node carcinoma of the prostate (LNCaP) cells and a physiologically relevant model of alveolar epithelial type 2 cells (iAEC2s). Additionally, we found that inhibitors of the Ras/Raf/MEK/ERK signaling pathway exacerbate SARS-CoV-2 infection in vitro. Notably, we discovered that lactoferrin, a glycoprotein found in secretory fluids including mammalian milk, inhibits SARS-CoV-2 infection in the nanomolar range in all cell models with multiple modes of action, including blockage of virus attachment to cellular heparan sulfate and enhancement of interferon responses. Given its safety profile, lactoferrin is a readily translatable therapeutic option for the management of COVID-19.


Subject(s)
Antiviral Agents/pharmacology , Immunologic Factors/pharmacology , Lactoferrin/pharmacology , SARS-CoV-2/drug effects , Virus Internalization/drug effects , Virus Replication/drug effects , Animals , COVID-19/drug therapy , COVID-19/immunology , COVID-19/prevention & control , COVID-19/virology , Caco-2 Cells , Cell Line, Tumor , Chlorocebus aethiops , Dose-Response Relationship, Drug , Drug Discovery , Drug Repositioning/methods , Epithelial Cells , Heparitin Sulfate/antagonists & inhibitors , Heparitin Sulfate/immunology , Heparitin Sulfate/metabolism , Hepatocytes , High-Throughput Screening Assays , Humans , SARS-CoV-2/growth & development , SARS-CoV-2/pathogenicity , Vero Cells
17.
N Engl J Med ; 385(8): 695-706, 2021 08 19.
Article in English | MEDLINE | ID: covidwho-1364626

ABSTRACT

BACKGROUND: Atogepant is an oral, small-molecule, calcitonin gene-related peptide receptor antagonist that is being investigated for the preventive treatment of migraine. METHODS: In a phase 3, double-blind trial, we randomly assigned adults with 4 to 14 migraine days per month in a 1:1:1:1 ratio to receive a once-daily dose of oral atogepant (10 mg, 30 mg, or 60 mg) or placebo for 12 weeks. The primary end point was the change from baseline in the mean number of migraine days per month across the 12 weeks. Secondary end points included headache days per month, a reduction from baseline of at least 50% in the 3-month average of migraine days per month, quality of life, and scores on the Activity Impairment in Migraine-Diary (AIM-D). RESULTS: A total of 2270 participants were screened, 910 were enrolled, and 873 were included in the efficacy analysis; 214 were assigned to the 10-mg atogepant group, 223 to the 30-mg atogepant group, 222 to the 60-mg atogepant group, and 214 to the placebo group. The mean number of migraine days per month at baseline ranged from 7.5 to 7.9 in the four groups. The changes from baseline across 12 weeks were -3.7 days with 10-mg atogepant, -3.9 days with 30-mg atogepant, -4.2 days with 60-mg atogepant, and -2.5 days with placebo. The mean differences from placebo in the change from baseline were -1.2 days with 10-mg atogepant (95% confidence interval [CI], -1.8 to -0.6), -1.4 days with 30-mg atogepant (95% CI, -1.9 to -0.8), and -1.7 days with 60-mg atogepant (95% CI, -2.3 to -1.2) (P<0.001 for all comparisons with placebo). Results for the secondary end points favored atogepant over placebo with the exceptions of the AIM-D Performance of Daily Activities score and the AIM-D Physical Impairment score for the 10-mg dose. The most common adverse events were constipation (6.9 to 7.7% across atogepant doses) and nausea (4.4 to 6.1% across atogepant doses). Serious adverse events included one case each of asthma and optic neuritis in the 10-mg atogepant group. CONCLUSIONS: Oral atogepant once daily was effective in reducing the number of migraine days and headache days over a period of 12 weeks. Adverse events included constipation and nausea. Longer and larger trials are needed to determine the effect and safety of atogepant for migraine prevention. (Funded by Allergan; ADVANCE ClinicalTrials.gov number, NCT03777059.).


Subject(s)
Calcitonin Gene-Related Peptide Receptor Antagonists/administration & dosage , Migraine Disorders/prevention & control , Adolescent , Adult , Aged , Calcitonin Gene-Related Peptide Receptor Antagonists/adverse effects , Calcitonin Gene-Related Peptide Receptor Antagonists/therapeutic use , Constipation/chemically induced , Dose-Response Relationship, Drug , Double-Blind Method , Female , Humans , Intention to Treat Analysis , Male , Middle Aged , Nausea/chemically induced , Young Adult
18.
Sci Rep ; 11(1): 16629, 2021 08 17.
Article in English | MEDLINE | ID: covidwho-1361646

ABSTRACT

Since understanding molecular mechanisms of SARS-CoV-2 infection is extremely important for developing effective therapies against COVID-19, we focused on the internalization mechanism of SARS-CoV-2 via ACE2. Although cigarette smoke is generally believed to be harmful to the pathogenesis of COVID-19, cigarette smoke extract (CSE) treatments were surprisingly found to suppress the expression of ACE2 in HepG2 cells. We thus tried to clarify the mechanism of CSE effects on expression of ACE2 in mammalian cells. Because RNA-seq analysis suggested that suppressive effects on ACE2 might be inversely correlated with induction of the genes regulated by aryl hydrocarbon receptor (AHR), the AHR agonists 6-formylindolo(3,2-b)carbazole (FICZ) and omeprazole (OMP) were tested to assess whether those treatments affected ACE2 expression. Both FICZ and OMP clearly suppressed ACE2 expression in a dose-dependent manner along with inducing CYP1A1. Knock-down experiments indicated a reduction of ACE2 by FICZ treatment in an AHR-dependent manner. Finally, treatments of AHR agonists inhibited SARS-CoV-2 infection into Vero E6 cells as determined with immunoblotting analyses detecting SARS-CoV-2 specific nucleocapsid protein. We here demonstrate that treatment with AHR agonists, including FICZ, and OMP, decreases expression of ACE2 via AHR activation, resulting in suppression of SARS-CoV-2 infection in mammalian cells.


Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Basic Helix-Loop-Helix Transcription Factors/agonists , COVID-19/drug therapy , Carbazoles/pharmacology , Omeprazole/pharmacology , Receptors, Aryl Hydrocarbon/agonists , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , Basic Helix-Loop-Helix Transcription Factors/metabolism , COVID-19/virology , Carbazoles/therapeutic use , Chlorocebus aethiops , Cytochrome P-450 CYP1A1/metabolism , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Gene Expression Regulation/drug effects , Gene Knockdown Techniques , Hep G2 Cells , Humans , Omeprazole/therapeutic use , RNA-Seq , Receptors, Aryl Hydrocarbon/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , Signal Transduction/drug effects , Vero Cells , Virus Internalization/drug effects
19.
J Clin Lab Anal ; 35(9): e23937, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1358069

ABSTRACT

OBJECTIVE: To deal with COVID-19, various countries have made many efforts, including the research and development of vaccines. The purpose of this manuscript was to summarize the development, application, and problems of COVID-19 vaccines. METHODS: This article reviewed the existing literature to see the development of the COVID-19 vaccine. RESULTS: We found that different types of vaccines had their own advantages and disadvantages. At the same time, the side effects of the vaccine, the dose of vaccination, the evaluation of the efficacy, and the application of the vaccine were all things worth studying. CONCLUSION: The successful development of the COVID-19 vaccine concerns almost all countries and people in the world. We must do an excellent job of researching the immunogenicity and immune reactivity of the vaccines. We hope this review can help colleagues at home and abroad.


Subject(s)
COVID-19 Vaccines , COVID-19/prevention & control , SARS-CoV-2/immunology , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/classification , Dose-Response Relationship, Drug , Drug Development/methods , Humans
20.
Pharmacol Res ; 172: 105820, 2021 10.
Article in English | MEDLINE | ID: covidwho-1356396

ABSTRACT

Coronavirus Disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which enter the host cells through the interaction between its receptor binding domain (RBD) of spike glycoprotein with angiotensin-converting enzyme 2 (ACE2) receptor on the plasma membrane of host cell. Neutralizing antibodies and peptide binders of RBD can block viral infection, however, the concern of accessibility and affordability of viral infection inhibitors has been raised. Here, we report the identification of natural compounds as potential SARS-CoV-2 entry inhibitors using the molecular docking-based virtual screening coupled with bilayer interferometry (BLI). From a library of 1871 natural compounds, epigallocatechin gallate (EGCG), 20(R)-ginsenoside Rg3 (RRg3), 20(S)-ginsenoside Rg3 (SRg3), isobavachalcone (Ibvc), isochlorogenic A (IscA) and bakuchiol (Bkc) effectively inhibited pseudovirus entry at concentrations up to 100 µM. Among these compounds, four compounds, EGCG, Ibvc, salvianolic acid A (SalA), and isoliensinine (Isl), were effective in inhibiting SARS-CoV-2-induced cytopathic effect and plaque formation in Vero E6 cells. The EGCG was further validated with no observable animal toxicity and certain antiviral effect against SARS-CoV-2 pseudovirus mutants (D614G, N501Y, N439K & Y453F). Interestingly, EGCG, Bkc and Ibvc bind to ACE2 receptor in BLI assay, suggesting a dual binding to RBD and ACE2. Current findings shed some insight into identifications and validations of SARS-CoV-2 entry inhibitors from natural compounds.


Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Antiviral Agents/chemistry , Biological Products/chemistry , COVID-19/drug therapy , Enzyme Inhibitors/chemistry , SARS-CoV-2/enzymology , Spike Glycoprotein, Coronavirus/metabolism , Animals , Antiviral Agents/pharmacology , Binding, Competitive , Biological Products/pharmacology , Catechin/analogs & derivatives , Catechin/pharmacology , Cell Membrane/metabolism , Cell Membrane/ultrastructure , Chalcones/pharmacology , Chlorogenic Acid/analogs & derivatives , Chlorogenic Acid/pharmacology , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Enzyme Inhibitors/pharmacology , Ginsenosides/pharmacology , Humans , Interferometry , Mice, Inbred C57BL , Molecular Dynamics Simulation , Phenols/pharmacology , Protein Binding
SELECTION OF CITATIONS
SEARCH DETAIL
...