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  1. Article ; Online: Efficacy of aprepitant among patients aged 65 and over receiving moderately to highly emetogenic chemotherapy: a meta-analysis of unpublished data from previously published studies.

    Chapell, Richard / Aapro, Matti S

    Journal of geriatric oncology

    2013  Volume 4, Issue 1, Page(s) 78–83

    Abstract: Background: Various antiemetic agents are commonly administered during and after chemotherapy to prevent nausea and vomiting depending on the emetogenic risk. Data specific for patients older than 65 are rarely discussed and it is often assumed that ... ...

    Abstract Background: Various antiemetic agents are commonly administered during and after chemotherapy to prevent nausea and vomiting depending on the emetogenic risk. Data specific for patients older than 65 are rarely discussed and it is often assumed that such patients have less risk of nausea and vomiting and might not need the same prevention.
    Objective: To determine whether response to antiemetic regimens incorporating aprepitant varies with patient age, we combined previously unpublished subgroup analyses from four previously published studies.
    Methods: Risk ratios were combined using standard meta-analytic techniques to determine whether antiemetic regimens including aprepitant lead to more complete responses to antiemetic therapy than regimens without aprepitant, among patients aged 65 and over.
    Results: Patients aged 65 and over have a significantly greater chance of experiencing a complete response (no vomiting or use of rescue therapy) to antiemetic treatment when aprepitant is included in the antiemetic regimen (Risk Ratio 1.25, 95% Confidence Interval 1.11 to 1.40, p=0.0002) than when it is not. This risk ratio is not significantly different (Q=0.281, p=0.596) from the risk ratio calculated for patients under age 65 (1.30, 95% Confidence Interval 1.19 to 1.42), from the same set of studies.
    Limitations: This meta-analysis combines studies utilizing different antiemetic regimens and different patient populations. Only a single efficacy outcome is included, and safety is not assessed.
    Conclusion: We conclude that for both the under 65years and the age 65 and over populations, antiemetic regimens including aprepitant, along with a 5-HT3 antagonist and a corticosteroid, are more effective in reducing chemotherapy-induced nausea and vomiting than regimens that do not include aprepitant.
    MeSH term(s) Aged ; Antiemetics/therapeutic use ; Antineoplastic Agents/adverse effects ; Double-Blind Method ; Female ; Humans ; Male ; Morpholines/therapeutic use ; Nausea/chemically induced ; Nausea/prevention & control ; Neoplasms/drug therapy ; Randomized Controlled Trials as Topic ; Vomiting/prevention & control
    Chemical Substances Antiemetics ; Antineoplastic Agents ; Morpholines ; aprepitant (1NF15YR6UY)
    Language English
    Publishing date 2013-01
    Publishing country Netherlands
    Document type Journal Article ; Meta-Analysis
    ZDB-ID 2556813-9
    ISSN 1879-4076 ; 1879-4068
    ISSN (online) 1879-4076
    ISSN 1879-4068
    DOI 10.1016/j.jgo.2012.08.008
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Baseline differences in A1C explain apparent differences in efficacy of sitagliptin, rosiglitazone and pioglitazone.

    Chapell, R / Gould, A L / Alexander, C M

    Diabetes, obesity & metabolism

    2009  Volume 11, Issue 11, Page(s) 1009–1016

    Abstract: Aim: Published studies of patients treated with rosiglitazone or pioglitazone have reported greater reductions in HbA1c (A1C) than studies of patients treated with sitagliptin. However, studies of thiazolidinediones tended to enroll patients with higher ...

    Abstract Aim: Published studies of patients treated with rosiglitazone or pioglitazone have reported greater reductions in HbA1c (A1C) than studies of patients treated with sitagliptin. However, studies of thiazolidinediones tended to enroll patients with higher baseline A1C levels. This meta-analysis investigates the relationship between baseline A1C and perceived efficacy of treatment.
    Methods: This report describes a Bayesian random effects analysis of 23 published studies. We constructed a random effects model including a factor adjusting for between-study differences in baseline A1C levels.
    Results: The random effects model correctly predicts post-treatment A1C levels from baseline A1C within a 95% confidence interval (CI) for each of the 23 studies included in the meta-analysis. After applying the model to adjust for differences in baseline A1C, we found that the difference in efficacy between rosiglitazone and sitagliptin was not significantly different from zero (0.12; 95% CI -0.09 to 0.34). Similarly, no significant differences are observed between the effects of pioglitazone and sitagliptin (0.01; 95% CI -0.21 to 0.22) or between rosiglitazone and pioglitazone (0.11; 95% CI -0.37 to 0.146). When baseline values are omitted from the Bayesian model, the findings suggest that rosiglitazone is superior to pioglitazone or sitagliptin.
    Conclusions: These results illustrate the necessity for careful application of appropriate methodology when comparing results of different studies. When between-study differences in treatment effects are adjusted for baseline differences, then the findings suggest that none of the treatments has an effect that is superior to any of the other treatments.
    MeSH term(s) Bayes Theorem ; Confidence Intervals ; Diabetes Mellitus, Type 2/blood ; Diabetes Mellitus, Type 2/drug therapy ; Glycated Hemoglobin A/metabolism ; Humans ; Hypoglycemic Agents/therapeutic use ; Pyrazines/therapeutic use ; Randomized Controlled Trials as Topic ; Sitagliptin Phosphate ; Thiazolidinediones/therapeutic use ; Treatment Outcome ; Triazoles/therapeutic use
    Chemical Substances Glycated Hemoglobin A ; Hypoglycemic Agents ; Pyrazines ; Thiazolidinediones ; Triazoles ; rosiglitazone (05V02F2KDG) ; Sitagliptin Phosphate (TS63EW8X6F) ; pioglitazone (X4OV71U42S)
    Language English
    Publishing date 2009-11
    Publishing country England
    Document type Journal Article ; Meta-Analysis
    ZDB-ID 1454944-x
    ISSN 1463-1326 ; 1462-8902
    ISSN (online) 1463-1326
    ISSN 1462-8902
    DOI 10.1111/j.1463-1326.2009.01084.x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Book ; Online: 1-2 Timothy and Titus (ESV Edition)

    Hughes, R. Kent / Chapell, Bryan

    To Guard the Deposit

    (Preaching the Word)

    2012  

    Abstract: Offering timely instruction to the local church, Hughes and Chapell teach through three of Paul's ...

    Series title Preaching the Word
    Abstract Offering timely instruction to the local church, Hughes and Chapell teach through three of Paul's pastoral letters. This volume is part of the Preaching the Word series-known for its clear exposition and down-to-earth accessibility
    Language English
    Size Online-Ressource (695 p)
    Publisher Crossway
    Publishing place Wheaton, IL
    Document type Book ; Online
    Note Description based upon print version of record
    ISBN 9781433530531 ; 1433530538
    Database Library catalogue of the German National Library of Science and Technology (TIB), Hannover

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  4. Article: Baseline differences in A1C explain apparent differences in efficacy of sitagliptin, rosiglitazone and pioglitazone

    Chapell, R / Gould, A.L / Alexander, C.M

    Diabetes, obesity & metabolism. 2009 Nov., v. 11, no. 11

    2009  

    Abstract: Published studies of patients treated with rosiglitazone or pioglitazone have reported greater reductions in HbA1c (A1C) than studies of patients treated with sitagliptin. However, studies of thiazolidinediones tended to enroll patients with higher ... ...

    Abstract Published studies of patients treated with rosiglitazone or pioglitazone have reported greater reductions in HbA1c (A1C) than studies of patients treated with sitagliptin. However, studies of thiazolidinediones tended to enroll patients with higher baseline A1C levels. This meta-analysis investigates the relationship between baseline A1C and perceived efficacy of treatment. This report describes a Bayesian random effects analysis of 23 published studies. We constructed a random effects model including a factor adjusting for between-study differences in baseline A1C levels. The random effects model correctly predicts post-treatment A1C levels from baseline A1C within a 95% confidence interval (CI) for each of the 23 studies included in the meta-analysis. After applying the model to adjust for differences in baseline A1C, we found that the difference in efficacy between rosiglitazone and sitagliptin was not significantly different from zero (0.12; 95% CI -0.09 to 0.34). Similarly, no significant differences are observed between the effects of pioglitazone and sitagliptin (0.01; 95% CI -0.21 to 0.22) or between rosiglitazone and pioglitazone (0.11; 95% CI -0.37 to 0.146). When baseline values are omitted from the Bayesian model, the findings suggest that rosiglitazone is superior to pioglitazone or sitagliptin. These results illustrate the necessity for careful application of appropriate methodology when comparing results of different studies. When between-study differences in treatment effects are adjusted for baseline differences, then the findings suggest that none of the treatments has an effect that is superior to any of the other treatments.
    Language English
    Dates of publication 2009-11
    Size p. 1009-1016.
    Publisher Blackwell Publishing Ltd
    Publishing place Oxford, UK
    Document type Article
    ZDB-ID 1454944-x
    ISSN 1463-1326 ; 1462-8902
    ISSN (online) 1463-1326
    ISSN 1462-8902
    DOI 10.1111/j.1463-1326.2009.01084.x
    Database NAL-Catalogue (AGRICOLA)

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  5. Article: Effects of PKC activation and receptor desensitization on neurosteroid modulation of GABA(A) receptors.

    Leidenheimer, N J / Chapell, R

    Brain research. Molecular brain research

    1997  Volume 52, Issue 2, Page(s) 173–181

    Abstract: The effect of calcium-phospholipid-dependent protein kinase (PKC) activation on neurosteroid modulation of the GABA(A) receptor was examined in Xenopus oocytes expressing human recombinant alpha1beta2gamma2L GABA(A) receptors. GABA-gated chloride ... ...

    Abstract The effect of calcium-phospholipid-dependent protein kinase (PKC) activation on neurosteroid modulation of the GABA(A) receptor was examined in Xenopus oocytes expressing human recombinant alpha1beta2gamma2L GABA(A) receptors. GABA-gated chloride currents were measured using the two-electrode voltage-clamp technique. The peak amplitude of GABA-gated chloride currents was reduced by the PKC activator phorbol 12-myristate 13-acetate (PMA), but not by the inactive analog phorbol 12-mono-myristate (PMM). This effect of PMA was inhibited by the protein kinase inhibitor staurosporine. To investigate whether the activation of PKC could alter neurosteroid modulation of the GABA(A) receptor, the effect of PMA was studied on the positive allosteric modulatory steroid 3alpha,21-dihydroxy-5alpha-pregnan-20-one (THDOC) and the negative modulatory neurosteroid pregnenolone sulfate (PS). THDOC potentiation of GABA-gated chloride currents was found to be increased by approximately 120% following PMA treatment, while PS inhibition was not affected. The increase in THDOC potentiation by PMA was blocked by staurosporine. No change in THDOC potentiation was observed following PMM treatment. The enhancement of THDOC potentiation following PMA treatment was not due to a shift in the GABA EC50. In addition to inhibiting the peak amplitude of the GABA response, PMA treatment resulted in non-desensitizing GABA responses. Similarly, GABA responses of receptors which had been desensitized with prolonged GABA application also showed a reduction in peak amplitude and reduced desensitization. THDOC potentiation of desensitized receptors was enhanced approximately 70% with respect to non-desensitized receptors. The present results demonstrate that protein phosphorylation and receptor desensitization alter modulation of the GABA(A) receptor complex by some neurosteroids.
    MeSH term(s) Animals ; Anti-Anxiety Agents/pharmacology ; Chloride Channels/drug effects ; Chloride Channels/physiology ; Desoxycorticosterone/analogs & derivatives ; Desoxycorticosterone/pharmacology ; Enzyme Activation ; Female ; Humans ; Kinetics ; Oocytes/drug effects ; Oocytes/physiology ; Phorbol Esters/pharmacology ; Pregnenolone/pharmacology ; Protein Kinase C/metabolism ; Receptors, GABA-A/biosynthesis ; Receptors, GABA-A/physiology ; Recombinant Proteins/metabolism ; Staurosporine/pharmacology ; Tetradecanoylphorbol Acetate/pharmacology ; Xenopus laevis ; gamma-Aminobutyric Acid/pharmacology
    Chemical Substances Anti-Anxiety Agents ; Chloride Channels ; Phorbol Esters ; Receptors, GABA-A ; Recombinant Proteins ; pregnenolone sulfate (04Y4D91RG0) ; Desoxycorticosterone (40GP35YQ49) ; tetrahydrodeoxycorticosterone (4AB717DP4A) ; gamma-Aminobutyric Acid (56-12-2) ; Pregnenolone (73R90F7MQ8) ; Protein Kinase C (EC 2.7.11.13) ; Staurosporine (H88EPA0A3N) ; Tetradecanoylphorbol Acetate (NI40JAQ945)
    Language English
    Publishing date 1997-12-15
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 632883-0
    ISSN 1872-6941 ; 0169-328X
    ISSN (online) 1872-6941
    ISSN 0169-328X
    DOI 10.1016/s0169-328x(97)00255-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: In vitro binding of synaptic vesicles to the synaptic plasma membrane: lack of effect of beta-bungarotoxin.

    Chapell, R / Rosenberg, P

    Toxicon : official journal of the International Society on Toxinology

    1996  Volume 34, Issue 3, Page(s) 339–349

    Abstract: To help characterize the mechanisms of neurotransmitter release, and the role of the specific neurotoxin beta-bungarotoxin in inhibiting release, the interaction of synaptic vesicles with the synaptic plasma membrane was investigated using two in vitro ... ...

    Abstract To help characterize the mechanisms of neurotransmitter release, and the role of the specific neurotoxin beta-bungarotoxin in inhibiting release, the interaction of synaptic vesicles with the synaptic plasma membrane was investigated using two in vitro systems. Binding of radiolabeled synaptic vesicles to immobilized synaptic plasma membrane was specific, protein-dependent, and modulated by phosphorylation of membrane proteins. Stimulation of phosphorylation by phorbol ester increased binding, and reduction of phosphorylation by alkaline phosphatase or staurosporine reduced binding. beta-Bungarotoxin did not alter basal binding of synaptic vesicles to synaptic plasma membrane, nor did it affect the increase in binding induced by phorbol esters. Under conditions which stimulate acetylcholine release from synaptosomes, both phorbol ester and 4-aminopyridine caused an increase in attachment of the synaptic vesicle marker protein synaptophysin to the synaptic plasma membrane. beta-Bungarotoxin did not alter the change in localization of synaptophysin induced by either drug, under conditions in which it inhibits ACh release induced by 4-aminopyridine. It is concluded that beta-bungarotoxin inhibition probably does not occur at the level of the interaction of the synaptic vesicle and the synaptic plasma membrane, but occurs at an earlier stage in the neurotransmission process.
    MeSH term(s) 4-Aminopyridine/toxicity ; Acetylcholine/metabolism ; Acetylcholinesterase/metabolism ; Alkaline Phosphatase/pharmacology ; Animals ; Binding, Competitive ; Bungarotoxins/toxicity ; Carcinogens/toxicity ; Cell Membrane/drug effects ; Cell Membrane/metabolism ; Cerebral Cortex/drug effects ; Cerebral Cortex/metabolism ; Enzyme-Linked Immunosorbent Assay ; In Vitro Techniques ; Membrane Proteins/drug effects ; Membrane Proteins/metabolism ; Phosphorylation ; Swine ; Synaptic Transmission/drug effects ; Synaptic Vesicles/drug effects ; Synaptic Vesicles/metabolism ; Synaptophysin/metabolism ; Synaptosomes/metabolism ; Tetradecanoylphorbol Acetate/toxicity
    Chemical Substances Bungarotoxins ; Carcinogens ; Membrane Proteins ; Synaptophysin ; 4-Aminopyridine (BH3B64OKL9) ; Acetylcholinesterase (EC 3.1.1.7) ; Alkaline Phosphatase (EC 3.1.3.1) ; Acetylcholine (N9YNS0M02X) ; Tetradecanoylphorbol Acetate (NI40JAQ945)
    Language English
    Publishing date 1996-03
    Publishing country England
    Document type Journal Article ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 204479-1
    ISSN 1879-3150 ; 0041-0101
    ISSN (online) 1879-3150
    ISSN 0041-0101
    DOI 10.1016/0041-0101(95)00144-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: Poor outcome for neural surgery (epineurotomy or neurolysis) for carpal tunnel syndrome compared with carpal tunnel release alone: a meta-analysis of global outcomes.

    Chapell, Richard / Coates, Vivian / Turkelson, Charles

    Plastic and reconstructive surgery

    2003  Volume 112, Issue 4, Page(s) 983–90; discussion 991–2

    Abstract: A meta-analysis was performed on the results of eight studies that compared the global outcomes of patients who received carpal tunnel release with the global outcomes of patients who received carpal tunnel release and neurolysis or epineurotomy. The ... ...

    Abstract A meta-analysis was performed on the results of eight studies that compared the global outcomes of patients who received carpal tunnel release with the global outcomes of patients who received carpal tunnel release and neurolysis or epineurotomy. The meta-analysis suggests that patients who received such neural surgery tended to have poorer global outcomes than those who did not (odds ratio, 0.54; 95 percent confidence interval, 0.32 to 0.90). The data are homogenous, and linear-regression analysis indicates that patient attrition did not influence the outcome of the meta-analysis. The results of this meta-analysis indicate that neural surgery is potentially harmful for most patients with carpal tunnel syndrome. The possibility remains that neural surgery may be helpful in special cases, such as in the presence of marked scarring or neural adhesion, but no available evidence specifically documents the benefits and harms of surgery among such patients.
    MeSH term(s) Carpal Tunnel Syndrome/surgery ; Humans ; Neurosurgical Procedures/methods ; Treatment Outcome
    Language English
    Publishing date 2003-09-15
    Publishing country United States
    Document type Comparative Study ; Journal Article ; Meta-Analysis
    ZDB-ID 208012-6
    ISSN 1529-4242 ; 0032-1052 ; 0096-8501
    ISSN (online) 1529-4242
    ISSN 0032-1052 ; 0096-8501
    DOI 10.1097/01.PRS.0000076222.77125.1F
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Application of human factors analysis and classification system model to event analysis in radiation oncology.

    Mosaly, Prithima R / Mazur, Lukasz / Miller, Seth / Eblan, Michael / Falchook, Aaron / Goldin, Gregg / Burkhart, Kathy / LaChapell, Dana / Adams, Robert / Chera, Bishamjith / Marks, Lawrence B

    Practical radiation oncology

    2015  Volume 5, Issue 2, Page(s) 113–119

    Abstract: Purpose: To assess the applicability of the human factors analysis and classification system (HFACS) model for analyzing events in a radiation oncology environment by comparing the HFACS analysis results between novices and experts.: Methods and ... ...

    Abstract Purpose: To assess the applicability of the human factors analysis and classification system (HFACS) model for analyzing events in a radiation oncology environment by comparing the HFACS analysis results between novices and experts.
    Methods and materials: Four novices (resident physicians, 2-4 postgraduate years) volunteered to participate and were asked to independently perform the HFACS analysis on the selected 30 events. The events were divided into the following 2 sets: (1) the description of events was given in detail (eg, the conditions under which the events occurred including information about root causes of error); (2) the description of events was given without detailed information. Each novice's categorization of events into 4 main and 12 sublevels were compared with expert categorization ("gold standard") and used for statistical analysis. Analysis of variance was performed to test the difference in mean agreement with the expert-defined gold standard between the novices across the 4 main levels; and across the 12 sublevels independently.
    Results: There were no significant differences in mean agreement with the expert-defined gold standard among the 4 novices (novice versus novice; P > .05) across the 4 main and 12 sublevels, respectively. There was a significant difference in mean agreement with the expert-defined gold standard among the 4 main levels and 12 sublevels (P < .05) across the 4 novices. For the 4 main levels, there was a significant difference in agreement with the expert-defined gold standard for events with detailed information versus events without detailed information provided across the 4 novices. The additional information did not improve mean agreement on the 12 sublevels.
    Conclusions: Novices learned to use the HFACS model for higher level analysis (4 main levels) with 1 hour training. Regardless of the amount of detail provided in the event description, the study results indicate a need of formal training for novices to better understand the definition and their interpretation at the 12 sublevel analyses.
    MeSH term(s) Factor Analysis, Statistical ; Humans ; Radiation Oncology/methods ; Radiation Oncology/standards
    Language English
    Publishing date 2015-03
    Publishing country United States
    Document type Journal Article
    ISSN 1879-8519
    ISSN (online) 1879-8519
    DOI 10.1016/j.prro.2014.05.010
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 and multiple endemic, epidemic and bat coronavirus

    Sheahan, Timothy P. / Sims, Amy C. / Zhou, Shuntai / Graham, Rachel L. / Hill, Collin S. / Leist, Sarah R. / Schäfer, Alexandra / Dinnon, Kenneth H. / Montgomery, Stephanie A. / Agostini, Maria L. / Pruijssers, Andrea J. / Chapell, James D. / Brown, Ariane J. / Bluemling, Gregory R. / Natchus, Michael G. / Saindane, Manohar / Kolykhalov, Alexander A. / Painter, George / Harcourt, Jennifer /
    Tamin, Azaibi / Thornburg, Natalie J. / Swanstrom, Ronald / Denison, Mark R. / Baric, Ralph S.

    bioRxiv

    Abstract: Coronaviruses (CoVs) traffic frequently between species resulting in novel disease outbreaks, most recently exemplified by the newly emerged SARS-CoV-2. Herein, we show that the ribonucleoside analog β-D-N4-hydroxycytidine (NHC, EIDD-1931) has broad ... ...

    Abstract Coronaviruses (CoVs) traffic frequently between species resulting in novel disease outbreaks, most recently exemplified by the newly emerged SARS-CoV-2. Herein, we show that the ribonucleoside analog β-D-N4-hydroxycytidine (NHC, EIDD-1931) has broad spectrum antiviral activity against SARS-CoV 2, MERS-CoV, SARS-CoV, and related zoonotic group 2b or 2c Bat-CoVs, as well as increased potency against a coronavirus bearing resistance mutations to another nucleoside analog inhibitor. In mice infected with SARS-CoV or MERS-CoV, both prophylactic and therapeutic administration of EIDD-2801, an orally bioavailable NHC-prodrug (b-D-N4-hydroxycytidine-5’-isopropyl ester), improved pulmonary function, and reduced virus titer and body weight loss. Decreased MERS-CoV yields in vitro and in vivo were associated with increased transition mutation frequency in viral but not host cell RNA, supporting a mechanism of lethal mutagenesis. The potency of NHC/EIDD-2801 against multiple coronaviruses, its therapeutic efficacy, and oral bioavailability in vivo, all highlight its potential utility as an effective antiviral against SARS-CoV-2 and other future zoonotic coronaviruses.
    Keywords covid19
    Publisher BioRxiv; WHO
    Document type Article ; Online
    DOI 10.1101/2020.03.19.997890
    Database COVID19

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  10. Article ; Online: An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 and multiple endemic, epidemic and bat coronavirus

    Sheahan, Timothy P. / Sims, Amy C. / Zhou, Shuntai / Graham, Rachel L. / Hill, Collin S. / Leist, Sarah R. / Schäfer, Alexandra / Dinnon, Kenneth H. / Montgomery, Stephanie A. / Agostini, Maria L. / Pruijssers, Andrea J. / Chapell, James D. / Brown, Ariane J. / Bluemling, Gregory R. / Natchus, Michael G. / Saindane, Manohar / Kolykhalov, Alexander A. / Painter, George / Harcourt, Jennifer /
    Tamin, Azaibi / Thornburg, Natalie J. / Swanstrom, Ronald / Denison, Mark R. / Baric, Ralph S.

    bioRxiv

    Abstract: Coronaviruses (CoVs) traffic frequently between species resulting in novel disease outbreaks, most recently exemplified by the newly emerged SARS-CoV-2. Herein, we show that the ribonucleoside analog Beta-D-N4-hydroxycytidine (NHC, EIDD-1931) has broad ... ...

    Abstract Coronaviruses (CoVs) traffic frequently between species resulting in novel disease outbreaks, most recently exemplified by the newly emerged SARS-CoV-2. Herein, we show that the ribonucleoside analog Beta-D-N4-hydroxycytidine (NHC, EIDD-1931) has broad spectrum antiviral activity against SARS-CoV 2, MERS-CoV, SARS-CoV, and related zoonotic group 2b or 2c Bat-CoVs, as well as increased potency against a coronavirus bearing resistance mutations to another nucleoside analog inhibitor. In mice infected with SARS-CoV or MERS-CoV, both prophylactic and therapeutic administration of EIDD-2801, an orally bioavailable NHC-prodrug (Beta-D-N4-hydroxycytidine-5[9]-isopropyl ester), improved pulmonary function, and reduced virus titer and body weight loss. Decreased MERS-CoV yields in vitro and in vivo were associated with increased transition mutation frequency in viral but not host cell RNA, supporting a mechanism of lethal mutagenesis. The potency of NHC/EIDD-2801 against multiple coronaviruses, its therapeutic efficacy, and oral bioavailability in vivo, all highlight its potential utility as an effective antiviral against SARS-CoV-2 and other future zoonotic coronaviruses.
    Keywords covid19
    Language English
    Publishing date 2020-03-20
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2020.03.19.997890
    Database COVID19

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