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1.
Nature ; 603(7899): 25-27, 2022 03.
Article in English | MEDLINE | ID: covidwho-1730273

Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Clinical Trials as Topic , Drug Repositioning , Host-Pathogen Interactions/drug effects , SARS-CoV-2/drug effects , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Administration, Oral , Alanine/administration & dosage , Alanine/analogs & derivatives , Alanine/therapeutic use , Animals , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/therapeutic use , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/administration & dosage , Antibodies, Neutralizing/economics , Antibodies, Neutralizing/therapeutic use , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacology , COVID-19/economics , COVID-19/immunology , COVID-19/mortality , COVID-19/virology , COVID-19 Vaccines , Cytidine/analogs & derivatives , Cytidine/therapeutic use , Depsipeptides/pharmacology , Depsipeptides/therapeutic use , Dexamethasone/administration & dosage , Dexamethasone/therapeutic use , Drug Combinations , Drug Synergism , Esters/pharmacology , Esters/therapeutic use , Guanidines/pharmacology , Guanidines/therapeutic use , Hospitalization , Humans , Hydroxylamines/therapeutic use , Internationality , Lactams/therapeutic use , Leucine/therapeutic use , Mice , National Institutes of Health (U.S.)/organization & administration , Nitriles/therapeutic use , Peptide Elongation Factor 1/antagonists & inhibitors , Peptides, Cyclic/pharmacology , Peptides, Cyclic/therapeutic use , Proline/therapeutic use , Protease Inhibitors/pharmacology , Protease Inhibitors/therapeutic use , RNA-Dependent RNA Polymerase/antagonists & inhibitors
2.
EBioMedicine ; 76: 103856, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1676708

ABSTRACT

BACKGROUND: Many repurposed drugs have progressed rapidly to Phase 2 and 3 trials in COVID19 without characterisation of Pharmacokinetics /Pharmacodynamics including safety data. One such drug is nafamostat mesylate. METHODS: We present the findings of a phase Ib/IIa open label, platform randomised controlled trial of intravenous nafamostat in hospitalised patients with confirmed COVID-19 pneumonitis. Patients were assigned randomly to standard of care (SoC), nafamostat or an alternative therapy. Nafamostat was administered as an intravenous infusion at a dose of 0.2 mg/kg/h for a maximum of seven days. The analysis population included those who received any dose of the trial drug and all patients randomised to SoC. The primary outcomes of our trial were the safety and tolerability of intravenous nafamostat as an add on therapy for patients hospitalised with COVID-19 pneumonitis. FINDINGS: Data is reported from 42 patients, 21 of which were randomly assigned to receive intravenous nafamostat. 86% of nafamostat-treated patients experienced at least one AE compared to 57% of the SoC group. The nafamostat group were significantly more likely to experience at least one AE (posterior mean odds ratio 5.17, 95% credible interval (CI) 1.10 - 26.05) and developed significantly higher plasma creatinine levels (posterior mean difference 10.57 micromol/L, 95% CI 2.43-18.92). An average longer hospital stay was observed in nafamostat patients, alongside a lower rate of oxygen free days (rate ratio 0.55-95% CI 0.31-0.99, respectively). There were no other statistically significant differences in endpoints between nafamostat and SoC. PK data demonstrated that intravenous nafamostat was rapidly broken down to inactive metabolites. We observed no significant anticoagulant effects in thromboelastometry. INTERPRETATION: In hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory, anticoagulant or antiviral activity with intravenous nafamostat, and there were additional adverse events. FUNDING: DEFINE was funded by LifeArc (an independent medical research charity) under the STOPCOVID award to the University of Edinburgh. We also thank the Oxford University COVID-19 Research Response Fund (BRD00230).


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Benzamidines/therapeutic use , COVID-19/drug therapy , Guanidines/therapeutic use , Administration, Intravenous , Adult , Aged , Aged, 80 and over , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Benzamidines/adverse effects , Benzamidines/pharmacokinetics , Biomarkers/blood , Biomarkers/metabolism , COVID-19/mortality , COVID-19/virology , Drug Administration Schedule , Female , Guanidines/adverse effects , Guanidines/pharmacokinetics , Half-Life , Humans , Immunophenotyping , Kaplan-Meier Estimate , Male , Middle Aged , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Treatment Outcome , Viral Load
3.
J Neuroinflammation ; 19(1): 8, 2022 Jan 06.
Article in English | MEDLINE | ID: covidwho-1613238

ABSTRACT

BACKGROUND: The serine protease inhibitor nafamostat has been proposed as a treatment for COVID-19, by inhibiting TMPRSS2-mediated viral cell entry. Nafamostat has been shown to have other, immunomodulatory effects, which may be beneficial for treatment, however animal models of ssRNA virus infection are lacking. In this study, we examined the potential of the dual TLR7/8 agonist R848 to mimic the host response to an ssRNA virus infection and the associated behavioural response. In addition, we evaluated the anti-inflammatory effects of nafamostat in this model. METHODS: CD-1 mice received an intraperitoneal injection of R848 (200 µg, prepared in DMSO, diluted 1:10 in saline) or diluted DMSO alone, and an intravenous injection of either nafamostat (100 µL, 3 mg/kg in 5% dextrose) or 5% dextrose alone. Sickness behaviour was determined by temperature, food intake, sucrose preference test, open field and forced swim test. Blood and fresh liver, lung and brain were collected 6 h post-challenge to measure markers of peripheral and central inflammation by blood analysis, immunohistochemistry and qPCR. RESULTS: R848 induced a robust inflammatory response, as evidenced by increased expression of TNF, IFN-γ, CXCL1 and CXCL10 in the liver, lung and brain, as well as a sickness behaviour phenotype. Exogenous administration of nafamostat suppressed the hepatic inflammatory response, significantly reducing TNF and IFN-γ expression, but had no effect on lung or brain cytokine production. R848 administration depleted circulating leukocytes, which was restored by nafamostat treatment. CONCLUSIONS: Our data indicate that R848 administration provides a useful model of ssRNA virus infection, which induces inflammation in the periphery and CNS, and virus infection-like illness. In turn, we show that nafamostat has a systemic anti-inflammatory effect in the presence of the TLR7/8 agonist. Therefore, the results indicate that nafamostat has anti-inflammatory actions, beyond its ability to inhibit TMPRSS2, that might potentiate its anti-viral actions in pathologies such as COVID-19.


Subject(s)
Benzamidines , Guanidines , Inflammation/drug therapy , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors , Toll-Like Receptor 7/immunology , Virus Diseases/drug therapy , Animals , Benzamidines/pharmacology , Benzamidines/therapeutic use , COVID-19/complications , COVID-19/drug therapy , Guanidines/pharmacology , Guanidines/therapeutic use , Illness Behavior/drug effects , Imidazoles/administration & dosage , Imidazoles/immunology , Inflammation/metabolism , Inflammation/virology , Male , Mice , Serine Proteinase Inhibitors/pharmacology , Serine Proteinase Inhibitors/therapeutic use , Toll-Like Receptor 7/agonists , Virus Diseases/metabolism , Virus Diseases/virology
4.
J Nippon Med Sch ; 88(6): 533-539, 2021 Dec 29.
Article in English | MEDLINE | ID: covidwho-1613284

ABSTRACT

BACKGROUND: Severe coronavirus disease 2019 (COVID-19) may require continuous administration of analgesics, sedatives, and muscle relaxants. Nafamostat has recently been reported as a therapeutic agent for COVID-19. However, there is a lack of information on the compatibility of nafamostat with the aforementioned drug classes. This study evaluated the physical compatibility of nafamostat with these drug classes. METHODS: Nafamostat was combined with 1-3 target drugs (fentanyl, morphine, midazolam, dexmedetomidine, and rocuronium). Fifteen physical compatibility tests were conducted. Nafamostat was dissolved in 5% glucose solution; the final concentration was 10 mg/mL. All other medications were diluted in 0.9% sodium chloride to obtain clinically relevant concentrations. The power of hydrogen (pH) of all medications was measured during each test. Compatibility tests were conducted with 4 test solutions in which nafamostat and the target drugs were compounded at equal volume ratios (1:1, 1:1:1, or 1:1:1:1). Visual appearance, turbidity, and pH were evaluated immediately after mixing and at 1 and 3 hours. Physical incompatibilities were defined as gross precipitation, cloudiness, appearance of the Tyndall effect, or a turbidity change of ≥0.5 nephelometric turbidity units (NTU) based on nafamostat. RESULTS: The mean pH of nafamostat was 3.13 ± 0.03. The combination of nafamostat, fentanyl, and dexmedetomidine had the highest pH (3.39 ± 0.01; 3 hours after mixing). All drugs were compatible with nafamostat until 3 hours after admixture, with a mean turbidity value of ≤0.03 NTU. CONCLUSIONS: Infusions combining nafamostat with the tested sedatives, analgesics, and muscle relaxants could be safely administered.


Subject(s)
Analgesics/therapeutic use , Benzamidines/therapeutic use , COVID-19/drug therapy , Drug Incompatibility , Fentanyl/therapeutic use , Guanidines/therapeutic use , Muscle Relaxants, Central/therapeutic use , Dexmedetomidine/therapeutic use , Humans , Hypnotics and Sedatives , SARS-CoV-2 , Treatment Outcome
5.
Viruses ; 13(9)2021 09 04.
Article in English | MEDLINE | ID: covidwho-1478110

ABSTRACT

SARS-CoV-2 and its vaccine/immune-escaping variants continue to pose a serious threat to public health due to a paucity of effective, rapidly deployable, and widely available treatments. Here, we address these challenges by combining Pegasys (IFNα) and nafamostat to effectively suppress SARS-CoV-2 infection in cell culture and hamsters. Our results indicate that Serpin E1 is an important mediator of the antiviral activity of IFNα and that both Serpin E1 and nafamostat can target the same cellular factor TMPRSS2, which plays a critical role in viral replication. The low doses of the drugs in combination may have several clinical advantages, including fewer adverse events and improved patient outcome. Thus, our study may provide a proactive solution for the ongoing pandemic and potential future coronavirus outbreaks, which is still urgently required in many parts of the world.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Benzamidines/pharmacology , COVID-19/metabolism , COVID-19/virology , Guanidines/pharmacology , Interferon-alpha/pharmacology , SARS-CoV-2/drug effects , Serine Endopeptidases/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Benzamidines/therapeutic use , COVID-19/drug therapy , Cricetinae , Disease Models, Animal , Drug Therapy, Combination , Female , Guanidines/therapeutic use , Host-Pathogen Interactions/drug effects , Humans , Interferon-alpha/therapeutic use , Virus Replication/drug effects
7.
Viruses ; 13(9)2021 09 04.
Article in English | MEDLINE | ID: covidwho-1390793

ABSTRACT

SARS-CoV-2 and its vaccine/immune-escaping variants continue to pose a serious threat to public health due to a paucity of effective, rapidly deployable, and widely available treatments. Here, we address these challenges by combining Pegasys (IFNα) and nafamostat to effectively suppress SARS-CoV-2 infection in cell culture and hamsters. Our results indicate that Serpin E1 is an important mediator of the antiviral activity of IFNα and that both Serpin E1 and nafamostat can target the same cellular factor TMPRSS2, which plays a critical role in viral replication. The low doses of the drugs in combination may have several clinical advantages, including fewer adverse events and improved patient outcome. Thus, our study may provide a proactive solution for the ongoing pandemic and potential future coronavirus outbreaks, which is still urgently required in many parts of the world.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Benzamidines/pharmacology , COVID-19/metabolism , COVID-19/virology , Guanidines/pharmacology , Interferon-alpha/pharmacology , SARS-CoV-2/drug effects , Serine Endopeptidases/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Benzamidines/therapeutic use , COVID-19/drug therapy , Cricetinae , Disease Models, Animal , Drug Therapy, Combination , Female , Guanidines/therapeutic use , Host-Pathogen Interactions/drug effects , Humans , Interferon-alpha/therapeutic use , Virus Replication/drug effects
9.
J Nippon Med Sch ; 88(6): 533-539, 2021 Dec 29.
Article in English | MEDLINE | ID: covidwho-1127748

ABSTRACT

BACKGROUND: Severe coronavirus disease 2019 (COVID-19) may require continuous administration of analgesics, sedatives, and muscle relaxants. Nafamostat has recently been reported as a therapeutic agent for COVID-19. However, there is a lack of information on the compatibility of nafamostat with the aforementioned drug classes. This study evaluated the physical compatibility of nafamostat with these drug classes. METHODS: Nafamostat was combined with 1-3 target drugs (fentanyl, morphine, midazolam, dexmedetomidine, and rocuronium). Fifteen physical compatibility tests were conducted. Nafamostat was dissolved in 5% glucose solution; the final concentration was 10 mg/mL. All other medications were diluted in 0.9% sodium chloride to obtain clinically relevant concentrations. The power of hydrogen (pH) of all medications was measured during each test. Compatibility tests were conducted with 4 test solutions in which nafamostat and the target drugs were compounded at equal volume ratios (1:1, 1:1:1, or 1:1:1:1). Visual appearance, turbidity, and pH were evaluated immediately after mixing and at 1 and 3 hours. Physical incompatibilities were defined as gross precipitation, cloudiness, appearance of the Tyndall effect, or a turbidity change of ≥0.5 nephelometric turbidity units (NTU) based on nafamostat. RESULTS: The mean pH of nafamostat was 3.13 ± 0.03. The combination of nafamostat, fentanyl, and dexmedetomidine had the highest pH (3.39 ± 0.01; 3 hours after mixing). All drugs were compatible with nafamostat until 3 hours after admixture, with a mean turbidity value of ≤0.03 NTU. CONCLUSIONS: Infusions combining nafamostat with the tested sedatives, analgesics, and muscle relaxants could be safely administered.


Subject(s)
Analgesics/therapeutic use , Benzamidines/therapeutic use , COVID-19/drug therapy , Drug Incompatibility , Fentanyl/therapeutic use , Guanidines/therapeutic use , Muscle Relaxants, Central/therapeutic use , Dexmedetomidine/therapeutic use , Humans , Hypnotics and Sedatives , SARS-CoV-2 , Treatment Outcome
10.
Int J Mol Sci ; 22(6)2021 Mar 10.
Article in English | MEDLINE | ID: covidwho-1125145

ABSTRACT

In order to treat Coronavirus Disease 2019 (COVID-19), we predicted and implemented a drug delivery system (DDS) that can provide stable drug delivery through a computational approach including a clustering algorithm and the Schrödinger software. Six carrier candidates were derived by the proposed method that could find molecules meeting the predefined conditions using the molecular structure and its functional group positional information. Then, just one compound named glycyrrhizin was selected as a candidate for drug delivery through the Schrödinger software. Using glycyrrhizin, nafamostat mesilate (NM), which is known for its efficacy, was converted into micelle nanoparticles (NPs) to improve drug stability and to effectively treat COVID-19. The spherical particle morphology was confirmed by transmission electron microscopy (TEM), and the particle size and stability of 300-400 nm were evaluated by measuring DLSand the zeta potential. The loading of NM was confirmed to be more than 90% efficient using the UV spectrum.


Subject(s)
COVID-19/drug therapy , Computational Biology/methods , Drug Delivery Systems/methods , A549 Cells , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/therapeutic use , Benzamidines/chemistry , Benzamidines/therapeutic use , Cell Survival/drug effects , Cluster Analysis , Computer Simulation , Databases, Pharmaceutical , Drug Carriers/chemistry , Drug Repositioning , Drug Stability , Glycyrrhizic Acid/chemistry , Glycyrrhizic Acid/therapeutic use , Guanidines/chemistry , Guanidines/therapeutic use , Humans , Hydrophobic and Hydrophilic Interactions , Micelles , Microscopy, Electron, Transmission , Molecular Structure , Nanoparticles/chemistry , Particle Size
11.
Int J Hematol ; 113(1): 45-57, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1064611

ABSTRACT

The pathology of coronavirus disease 2019 (COVID-19) is exacerbated by the progression of thrombosis, and disseminated intravascular coagulation (DIC), and cytokine storms. The most frequently reported coagulation/fibrinolytic abnormality in COVID-19 is the increase in D-dimer, and its relationship with prognosis has been discussed. However, limits exist to the utility of evaluation by D-dimer alone. In addition, since the coagulation/fibrinolytic condition sometimes fluctuates within a short period of time, regular examinations in recognition of the significance of the examination are desirable. The pathophysiology of disseminated intravascular coagulation (DIC) associated with COVID-19 is very different from that of septic DIC, and both thrombotic and hemorrhagic pathologies should be noted. COVID-19 thrombosis includes macro- and microthrombosis, with diagnosis of the latter depending on markers of coagulation and fibrinolysis. Treatment of COVID-19 is classified into antiviral treatment, cytokine storm treatment, and thrombosis treatment. Rather than providing uniform treatment, the treatment method most suitable for the severity and stage should be selected. Combination therapy with heparin and nafamostat is expected to develop in the future. Fibrinolytic therapy and adsorption therapy require further study.


Subject(s)
Blood Coagulation Disorders/etiology , COVID-19/blood , Pandemics , SARS-CoV-2 , Adult , Anticoagulants/therapeutic use , Benzamidines , Blood Coagulation Disorders/physiopathology , Blood Coagulation Tests , COVID-19/complications , COVID-19/drug therapy , COVID-19/mortality , COVID-19/therapy , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , Disseminated Intravascular Coagulation/etiology , Disseminated Intravascular Coagulation/physiopathology , Female , Fibrin Fibrinogen Degradation Products/analysis , Fibrinolysis , Guanidines/pharmacology , Guanidines/therapeutic use , Humans , Lymphopenia/etiology , Male , Middle Aged , Prognosis , Pulmonary Circulation , SARS-CoV-2/drug effects , Survivors , Thrombocytopenia/etiology , Thrombophilia/drug therapy , Thrombophilia/etiology , Thrombophilia/physiopathology
12.
Appl Biochem Biotechnol ; 193(6): 1909-1923, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1053100

ABSTRACT

The unprecedented coronavirus SARS-CoV-2 outbreak at Wuhan, China, caused acute respiratory infection to humans. There is no precise vaccine/therapeutic agents available to combat the COVID-19 disease. Some repurposed drugs are saving the life of diseased, but the complete cure is relatively less. Several drug targets have been reported to inhibit the SARS-CoV-2 virus infection, in that TMPRSS2 (transmembrane protease serine 2) is one of the potential targets; inhibiting this protease stops the virus entry into the host human cell. Camostat mesylate, nafamostat, and leupeptin are the drugs, in which the first two drugs are being used for COVID-19 and leupeptin also tested. To consider these drugs as the repurposed drug for COVID-19, it is essential to understand their binding affinity and stability with TMPRSS2. In the present study, we performed the molecular docking and molecular dynamics (MD) simulation of these molecules with the TMPRSS2. The docking study reveals that leupeptin molecule strongly binds with TMPRSS2 protein than the other two drug molecules. The RMSD and RMSF values of MD simulation confirm that leupeptin and the amino acids of TMPRSS2 are very stable than the other two molecules. Furthermore, leupeptin forms interactions with the key amino acids of TMPRSS2 and the same have been maintained during the MD simulations. This structural and dynamical information is useful to evaluate these drugs to be used as repurposed drugs, however, the strong binding profile of leupeptin with TMPRSS2, suggests, it may be considered as a repurposed drug for COVID-19 disease after clinical trial.


Subject(s)
Antiviral Agents/pharmacology , Benzamidines/therapeutic use , COVID-19/drug therapy , Drug Repositioning , Esters/therapeutic use , Guanidines/therapeutic use , Leupeptins/metabolism , Molecular Docking Simulation , Molecular Dynamics Simulation , Serine Endopeptidases/metabolism , Antiviral Agents/therapeutic use , Benzamidines/pharmacology , COVID-19/virology , Esters/pharmacology , Guanidines/pharmacology , Humans , Protein Binding , SARS-CoV-2/drug effects
13.
Basic Clin Pharmacol Toxicol ; 128(2): 204-212, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-919229

ABSTRACT

The coronavirus responsible for COVID-19, SARS-CoV-2, utilizes a viral membrane spike protein for host cell entry. For the virus to engage in host membrane fusion, SARS-CoV-2 utilizes the human transmembrane surface protease, TMPRSS2, to cleave and activate the spike protein. Camostat mesylate, an orally available well-known serine protease inhibitor, is a potent inhibitor of TMPRSS2 and has been hypothesized as a potential antiviral drug against COVID-19. In vitro human cell and animal studies have shown that camostat mesylate inhibits virus-cell membrane fusion and hence viral replication. In mice, camostat mesylate treatment during acute infection with influenza, also dependent on TMPRSS2, leads to a reduced viral load. The decreased viral load may be associated with an improved patient outcome. Because camostat mesylate is administered as an oral drug, it may be used in outpatients as well as inpatients at all disease stages of SARS-CoV-2 infection if it is shown to be an effective antiviral agent. Clinical trials are currently ongoing to test whether this well-known drug could be repurposed and utilized to combat the current pandemic. In the following, we will review current knowledge on camostat mesylate mode of action, potential benefits as an antiviral agent and ongoing clinical trials.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Esters/therapeutic use , Guanidines/therapeutic use , Serine Proteinase Inhibitors/therapeutic use , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Drug Repositioning , Esters/administration & dosage , Esters/adverse effects , Guanidines/administration & dosage , Guanidines/adverse effects , Humans , Mice , Patient Safety , Serine Endopeptidases/drug effects , Serine Proteinase Inhibitors/administration & dosage , Serine Proteinase Inhibitors/adverse effects
14.
Int J Hematol ; 113(1): 45-57, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-915246

ABSTRACT

The pathology of coronavirus disease 2019 (COVID-19) is exacerbated by the progression of thrombosis, and disseminated intravascular coagulation (DIC), and cytokine storms. The most frequently reported coagulation/fibrinolytic abnormality in COVID-19 is the increase in D-dimer, and its relationship with prognosis has been discussed. However, limits exist to the utility of evaluation by D-dimer alone. In addition, since the coagulation/fibrinolytic condition sometimes fluctuates within a short period of time, regular examinations in recognition of the significance of the examination are desirable. The pathophysiology of disseminated intravascular coagulation (DIC) associated with COVID-19 is very different from that of septic DIC, and both thrombotic and hemorrhagic pathologies should be noted. COVID-19 thrombosis includes macro- and microthrombosis, with diagnosis of the latter depending on markers of coagulation and fibrinolysis. Treatment of COVID-19 is classified into antiviral treatment, cytokine storm treatment, and thrombosis treatment. Rather than providing uniform treatment, the treatment method most suitable for the severity and stage should be selected. Combination therapy with heparin and nafamostat is expected to develop in the future. Fibrinolytic therapy and adsorption therapy require further study.


Subject(s)
Blood Coagulation Disorders/etiology , COVID-19/blood , Pandemics , SARS-CoV-2 , Adult , Anticoagulants/therapeutic use , Benzamidines , Blood Coagulation Disorders/physiopathology , Blood Coagulation Tests , COVID-19/complications , COVID-19/drug therapy , COVID-19/mortality , COVID-19/therapy , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , Disseminated Intravascular Coagulation/etiology , Disseminated Intravascular Coagulation/physiopathology , Female , Fibrin Fibrinogen Degradation Products/analysis , Fibrinolysis , Guanidines/pharmacology , Guanidines/therapeutic use , Humans , Lymphopenia/etiology , Male , Middle Aged , Prognosis , Pulmonary Circulation , SARS-CoV-2/drug effects , Survivors , Thrombocytopenia/etiology , Thrombophilia/drug therapy , Thrombophilia/etiology , Thrombophilia/physiopathology
15.
EMBO Mol Med ; 13(1): e13105, 2021 01 11.
Article in English | MEDLINE | ID: covidwho-814824

ABSTRACT

The ongoing SARS-CoV-2 pandemic stresses the need for effective antiviral drugs that can quickly be applied in order to reduce morbidity, mortality, and ideally viral transmission. By repurposing of broadly active antiviral drugs and compounds that are known to inhibit viral replication of related viruses, several advances could be made in the development of treatment strategies against COVID-19. The nucleoside analog remdesivir, which is known for its potent in vitro activity against Ebolavirus and other RNA viruses, was recently shown to reduce the time to recovery in patients with severe COVID-19. It is to date the only approved antiviral for treating COVID-19. Here, we provide a mechanism and evidence-based comparative review of remdesivir and other repurposed drugs with proven in vitro activity against SARS-CoV-2.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Drug Repositioning , SARS-CoV-2/drug effects , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Alanine/pharmacology , Alanine/therapeutic use , Amides/pharmacology , Amides/therapeutic use , Antiviral Agents/pharmacology , Benzamidines , Drug Repositioning/methods , Esters/pharmacology , Esters/therapeutic use , Guanidines/pharmacology , Guanidines/therapeutic use , Guanine/pharmacology , Guanine/therapeutic use , Humans , Indoles/pharmacology , Indoles/therapeutic use , Lopinavir/pharmacology , Lopinavir/therapeutic use , Protease Inhibitors/pharmacology , Protease Inhibitors/therapeutic use , Pyrazines/pharmacology , Pyrazines/therapeutic use , Ribavirin/pharmacology , Ribavirin/therapeutic use , Ritonavir/pharmacology , Ritonavir/therapeutic use , SARS-CoV-2/physiology , Virus Internalization/drug effects , Virus Replication/drug effects
16.
J Thromb Thrombolysis ; 51(3): 649-656, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-754362

ABSTRACT

Critical illnesses associated with coronavirus disease 2019 (COVID-19) are attributable to a hypercoagulable status. There is limited knowledge regarding the dynamic changes in coagulation factors among COVID-19 patients on nafamostat mesylate, a potential therapeutic anticoagulant for COVID-19. First, we retrospectively conducted a cluster analysis based on clinical characteristics on admission to identify latent subgroups among fifteen patients with COVID-19 on nafamostat mesylate at the University of Tokyo Hospital, Japan, between April 6 and May 31, 2020. Next, we delineated the characteristics of all patients as well as COVID-19-patient subgroups and compared dynamic changes in coagulation factors among each subgroup. The subsequent dynamic changes in fibrinogen and D-dimer levels were presented graphically. All COVID-19 patients were classified into three subgroups: clusters A, B, and C, representing low, intermediate, and high risk of poor outcomes, respectively. All patients were alive 30 days from symptom onset. No patient in cluster A required mechanical ventilation; however, all patients in cluster C required mechanical ventilation, and half of them were treated with venovenous extracorporeal membrane oxygenation. All patients in cluster A maintained low D-dimer levels, but some critical patients in clusters B and C showed dynamic changes in fibrinogen and D-dimer levels. Although the potential of nafamostat mesylate needs to be evaluated in randomized clinical trials, admission characteristics of patients with COVID-19 could predict subsequent coagulopathy.


Subject(s)
Anticoagulants/therapeutic use , Benzamidines/therapeutic use , COVID-19/drug therapy , Fibrin Fibrinogen Degradation Products/metabolism , Fibrinogen/metabolism , Guanidines/therapeutic use , Aged , Anticoagulants/pharmacology , Benzamidines/pharmacology , COVID-19/blood , COVID-19/classification , Female , Fibrinogen/drug effects , Guanidines/pharmacology , Humans , Male , Middle Aged , Retrospective Studies
17.
Clin Rheumatol ; 39(11): 3171-3175, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-730357

ABSTRACT

We treated two patients with severe respiratory failure due to coronavirus disease 2019 (COVID-19). Case 1 was a 73-year-old woman, and Case 2 was a 65-year-old-man. Neither of them had a history of autoimmune disease. Chest computed tomography scans before the antiviral therapy showed bilateral multiple patchy ground-glass opacities (GGO) consistent with COVID-19 pneumonia. The GGO regressed over the course of the antiviral treatment; however, new non-segmental patchy consolidations emerged, which resembled those of interstitial lung disease (ILD), specifically collagen vascular disease-associated ILD. We tested the patients' sera for autoantibodies and discovered that both patients had high anti-SSA/Ro antibody titers. In Case 1, the patient recovered with antiviral therapy alone. However, in Case 2, the patient did not improve with antiviral therapy alone but responded well to corticosteroid therapy (methylprednisolone) and made a full recovery. The relationship between some immunological responses and COVID-19 pneumonia exacerbation has been discussed previously; our discovery of the elevation of anti-SSA/Ro antibodies suggests a contribution from autoimmunity functions of the immune system. Although it is unclear whether the elevation of anti-SSA/Ro antibodies was a cause or an outcome of aggravated COVID-19 pneumonia, we hypothesize that both patients developed aggravated the COVID-19 pneumonia due to an autoimmune response. In COVID-19 lung injury, there may be a presence of autoimmunity factors in addition to the known effects of cytokine storms. In patients with COVID-19, a high level of anti-SSA/Ro52 antibodies may be a surrogate marker of pneumonia severity and poor prognosis.


Subject(s)
Antibodies, Antinuclear/immunology , Coronavirus Infections/immunology , Lung Diseases, Interstitial/immunology , Pneumonia, Viral/immunology , Respiratory Insufficiency/immunology , Aged , Amides/therapeutic use , Antiviral Agents/therapeutic use , Benzamidines , Betacoronavirus , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/diagnostic imaging , Coronavirus Infections/drug therapy , Female , Glucocorticoids/therapeutic use , Guanidines/therapeutic use , Humans , Hydroxychloroquine/therapeutic use , Lung Diseases, Interstitial/diagnostic imaging , Lung Diseases, Interstitial/drug therapy , Lung Diseases, Interstitial/etiology , Male , Methylprednisolone/therapeutic use , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/diagnostic imaging , Pneumonia, Viral/drug therapy , Pregnenediones/therapeutic use , Pyrazines/therapeutic use , Recovery of Function , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/immunology , Respiratory Insufficiency/etiology , SARS-CoV-2 , Severity of Illness Index , Tomography, X-Ray Computed
19.
Am J Trop Med Hyg ; 102(6): 1210-1213, 2020 06.
Article in English | MEDLINE | ID: covidwho-596941

ABSTRACT

Novel coronavirus disease (COVID-19) caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has become a public health emergency of international concern. This was first noted in Wuhan, Hubei Province, China, and since then has become widespread globally. We report a 71-year-old woman with documented viral shedding (based on reverse transcription-polymerase chain reaction (RT-PCR) testing) of SARS-CoV-2 for 60 days from the onset of symptoms (55 days from her first positive test and 36 days after complete resolution of symptoms). This is to our knowledge the longest duration of viral shedding reported to date. This case demonstrates that viral shedding after COVID-19 diagnosis can be prolonged.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/diagnostic imaging , Lung/diagnostic imaging , Pneumonia, Viral/diagnostic imaging , Virus Shedding , Acids, Carbocyclic , Aged , Betacoronavirus/drug effects , Betacoronavirus/isolation & purification , COVID-19 , China , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Coronavirus Infections/therapy , Cyclopentanes/therapeutic use , Extracorporeal Membrane Oxygenation , Female , Guanidines/therapeutic use , Humans , Indoles/therapeutic use , Lung/drug effects , Lung/pathology , Lung/virology , Moxifloxacin/therapeutic use , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Pneumonia, Viral/therapy , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2 , Time Factors , Tomography, X-Ray Computed , Treatment Outcome
20.
Int J Infect Dis ; 96: 500-502, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-378227

ABSTRACT

No effective treatment for COVID-19 has been well established yet. Nafamostat, known as anticoagulant, has potential anti-inflammatory and anti-viral activities against COVID-19. We report three cases of COVID-19 pneumonia who progressed while using antiviral drugs and needed supplementary oxygen therapy, improved after treatment with nafamostat. These preliminary findings show the possibility that Nafamostat can be considered to be used in elderly patients with COVID-19 pneumonia who need oxygen therapy. The effectiveness of nafamostat should be evaluated in further studies.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections/therapy , Guanidines/therapeutic use , Oxygen/therapeutic use , Pneumonia, Viral/therapy , Aged , Benzamidines , COVID-19 , Humans , Male , Pandemics , SARS-CoV-2 , Treatment Outcome
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