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1.
Clin Infect Dis ; 75(1): e403-e409, 2022 08 24.
Article in English | MEDLINE | ID: covidwho-2188484

ABSTRACT

BACKGROUND: Remdesivir is an antiviral used to treat coronavirus disease 2019 (COVID-19), which improves some clinical outcomes. Dexamethasone has been shown to be effective in reducing mortality. It has been hypothesized that combination of these two drugs can improve mortality. We evaluated the effect of combination on mortality of COVID-19 patients requiring O2 therapy. METHODS: A prospective quasi-experimental study, including two independent, sequential controlled cohorts, one received remdesivir-dexamethasone and the other dexamethasone alone, was designed. All COVID-19 patients requiring supplemental O2 therapy were enrolled consecutively. The sample size to power mortality was a priori calculated. The primary endpoints were 30-day mortality and viral clearance differences. Secondary endpoints were differences in hospitalization times, improvement in respiratory failure (PO2/FiO2) and inflammatory indices (fibrinogen, CRP, neutrophil/lymphocyte ratio, D-Dimer). Kaplan-Meier curves and the log-rank test were used to evaluate significant differences in mortality between groups. RESULTS: In total, 151 COVID-19 patients were enrolled (remdesivir/dexamethasone group, 76, and dexamethasone alone, 75). No differences in demographic, clinical, and laboratory characteristics were observed between the 2 groups at baseline. Faster viral clearance occurred in the remdesivir/dexamethasone group compared to dexamethasone alone (median 6 vs 16 days; P < .001). The 30-day mortality in the remdesivir/dexamethasone group was 1.3%, whereas in dexamethasone alone was 16% (P < .005). In the remdesivir/dexamethasone group compared to dexamethasone alone there was a reduction in hospitalization days (P < .0001) and a faster improvement in both respiratory function and inflammatory markers. CONCLUSIONS: Remdesivir/dexamethasone treatment is associated with significant reduction in mortality, length of hospitalization, and faster SARS-CoV-2 clearance, compared to dexamethasone alone.


Subject(s)
COVID-19 , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents , COVID-19/drug therapy , Dexamethasone/therapeutic use , Humans , Prospective Studies , SARS-CoV-2
2.
Ther Drug Monit ; 42(3): 360-368, 2020 06.
Article in English | MEDLINE | ID: covidwho-2152206

ABSTRACT

BACKGROUND: COVID-19 is a novel infectious disease caused by the severe acute respiratory distress (SARS)-coronavirus-2 (SARS-CoV-2). Several therapeutic options are currently emerging but none with universal consensus or proven efficacy. Solid organ transplant recipients are perceived to be at increased risk of severe COVID-19 because of their immunosuppressed conditions due to chronic use of immunosuppressive drugs (ISDs). It is therefore likely that solid organ transplant recipients will be treated with these experimental antivirals. METHODS: This article is not intended to provide a systematic literature review on investigational treatments tested against COVID-19; rather, the authors aim to provide recommendations for therapeutic drug monitoring of ISDs in transplant recipients infected with SARS-CoV-2 based on a review of existing data in the literature. RESULTS: Management of drug-drug interactions between investigational anti-SARS-CoV-2 drugs and immunosuppressants is a complex task for the clinician. Adequate immunosuppression is necessary to prevent graft rejection while, if critically ill, the patient may benefit from pharmacotherapeutic interventions directed at limiting SARS-CoV-2 viral replication. Maintaining ISD concentrations within the desired therapeutic range requires a highly individualized approach that is complicated by the pandemic context and lack of hindsight. CONCLUSIONS: With this article, the authors inform the clinician about the potential interactions of experimental COVID-19 treatments with ISDs used in transplantation. Recommendations regarding therapeutic drug monitoring and dose adjustments in the context of COVID-19 are provided.


Subject(s)
Antiviral Agents/adverse effects , Coronavirus Infections/drug therapy , Drug Monitoring , Immunosuppressive Agents/adverse effects , Pneumonia, Viral/drug therapy , Transplant Recipients , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antibodies, Monoclonal, Humanized , Antiviral Agents/therapeutic use , Betacoronavirus , COVID-19 , Drug Interactions , Glucocorticoids , Humans , Hydroxychloroquine , Immunosuppressive Agents/therapeutic use , Pandemics , Protease Inhibitors , SARS-CoV-2
3.
Lancet ; 399(10339): 1941-1953, 2022 05 21.
Article in English | MEDLINE | ID: covidwho-2159958

ABSTRACT

BACKGROUND: The Solidarity trial among COVID-19 inpatients has previously reported interim mortality analyses for four repurposed antiviral drugs. Lopinavir, hydroxychloroquine, and interferon (IFN)-ß1a were discontinued for futility but randomisation to remdesivir continued. Here, we report the final results of Solidarity and meta-analyses of mortality in all relevant trials to date. METHODS: Solidarity enrolled consenting adults (aged ≥18 years) recently hospitalised with, in the view of their doctor, definite COVID-19 and no contraindication to any of the study drugs, regardless of any other patient characteristics. Participants were randomly allocated, in equal proportions between the locally available options, to receive whichever of the four study drugs (lopinavir, hydroxychloroquine, IFN-ß1a, or remdesivir) were locally available at that time or no study drug (controls). All patients also received the local standard of care. No placebos were given. The protocol-specified primary endpoint was in-hospital mortality, subdivided by disease severity. Secondary endpoints were progression to ventilation if not already ventilated, and time-to-discharge from hospital. Final log-rank and Kaplan-Meier analyses are presented for remdesivir, and are appended for all four study drugs. Meta-analyses give weighted averages of the mortality findings in this and all other randomised trials of these drugs among hospital inpatients. Solidarity is registered with ISRCTN, ISRCTN83971151, and ClinicalTrials.gov, NCT04315948. FINDINGS: Between March 22, 2020, and Jan 29, 2021, 14 304 potentially eligible patients were recruited from 454 hospitals in 35 countries in all six WHO regions. After the exclusion of 83 (0·6%) patients with a refuted COVID-19 diagnosis or encrypted consent not entered into the database, Solidarity enrolled 14 221 patients, including 8275 randomly allocated (1:1) either to remdesivir (ten daily infusions, unless discharged earlier) or to its control (allocated no study drug although remdesivir was locally available). Compliance was high in both groups. Overall, 602 (14·5%) of 4146 patients assigned to remdesivir died versus 643 (15·6%) of 4129 assigned to control (mortality rate ratio [RR] 0·91 [95% CI 0·82-1·02], p=0·12). Of those already ventilated, 151 (42·1%) of 359 assigned to remdesivir died versus 134 (38·6%) of 347 assigned to control (RR 1·13 [0·89-1·42], p=0·32). Of those not ventilated but on oxygen, 14·6% assigned to remdesivir died versus 16·3% assigned to control (RR 0·87 [0·76-0·99], p=0·03). Of 1730 not on oxygen initially, 2·9% assigned to remdesivir died versus 3·8% assigned to control (RR 0·76 [0·46-1·28], p=0·30). Combining all those not ventilated initially, 11·9% assigned to remdesivir died versus 13·5% assigned to control (RR 0·86 [0·76-0·98], p=0·02) and 14·1% versus 15·7% progressed to ventilation (RR 0·88 [0·77-1·00], p=0·04). The non-prespecified composite outcome of death or progression to ventilation occurred in 19·6% assigned to remdesivir versus 22·5% assigned to control (RR 0·84 [0·75-0·93], p=0·001). Allocation to daily remdesivir infusions (vs open-label control) delayed discharge by about 1 day during the 10-day treatment period. A meta-analysis of mortality in all randomised trials of remdesivir versus no remdesivir yielded similar findings. INTERPRETATION: Remdesivir has no significant effect on patients with COVID-19 who are already being ventilated. Among other hospitalised patients, it has a small effect against death or progression to ventilation (or both). FUNDING: WHO.


Subject(s)
Antiviral Agents , COVID-19 , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Adult , Alanine/analogs & derivatives , Alanine/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Humans , Hydroxychloroquine/therapeutic use , Interferon beta-1a/therapeutic use , Lopinavir/therapeutic use , Oxygen/administration & dosage , Randomized Controlled Trials as Topic , Treatment Outcome , World Health Organization
4.
Int J Environ Res Public Health ; 19(14)2022 07 21.
Article in English | MEDLINE | ID: covidwho-1958591

ABSTRACT

In response to global efforts to control and exterminate infectious diseases, this study aims to provide insight into the productivity of remdesivir research and highlight future directions. To achieve this, there is a need to summarize and curate evidence from the literature. As a result, this study carried out comprehensive scientific research to detect trends in published articles related to remdesivir using a bibliometric analysis. Keywords associated with remdesivir were used to access pertinent published articles using the Scopus database. A total of 5321 research documents were retrieved, primarily as novel research articles (n = 2440; 46%). The number of publications increased exponentially from 2020 up to the present. The papers published by the top 12 institutions focusing on remdesivir accounted for 25.69% of the overall number of articles. The USA ranked as the most productive country, with 906 documents (37.1%), equivalent to one-third of the global publications in this field. The most productive institution was Icahn School of Medicine, Mount Sinai, in the USA (103 publications). The New England Journal of Medicine was the most cited, with an h-index of 13. The publication of research on remdesivir has gained momentum in the past year. The importance of remdesivir suggests that it needs continued research to help global health organizations detect areas requiring instant action to implement suitable measures. Furthermore, this study offers evolving hotspots and valuable insights into the scientific advances in this field and provides scaling-up analysis and evidence diffusion on remdesivir.


Subject(s)
Adenosine Monophosphate , Alanine , Bibliometrics , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Databases, Factual , Efficiency , Global Health , Publications/trends
6.
Infect Dis Clin North Am ; 36(1): 1-14, 2022 03.
Article in English | MEDLINE | ID: covidwho-2130977

ABSTRACT

Although COVID-19 has impacted many children, severe disease is rare and most recover with supportive care. Manifestations are diverse and often nonrespiratory. Adolescents/children with medical comorbidities are at risk for severe respiratory compromise. The most serious manifestation in previously healthy children is a delayed multisystem inflammatory syndrome with cardiac compromise in severe cases. Anti-SARS-CoV-2 monoclonal antibodies are available for adolescents at risk of progression and not hospitalized. Therapeutic options for severe respiratory disease with hypoxia include remdesivir and glucocorticoids. Therapies for multisystem inflammatory syndrome in children include intravenous immunoglobulin and glucocorticoids. Refractory cases may benefit from additional immunomodulators.


Subject(s)
COVID-19 , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Adolescent , Alanine/analogs & derivatives , Alanine/therapeutic use , COVID-19/complications , COVID-19/epidemiology , COVID-19/therapy , Child , Glucocorticoids/therapeutic use , Hospitalization , Humans , Immunoglobulins, Intravenous/therapeutic use , Systemic Inflammatory Response Syndrome
7.
Ann Intern Med ; 175(10): JC115, 2022 10.
Article in English | MEDLINE | ID: covidwho-2110760

ABSTRACT

SOURCE CITATION: Wolfe CR, Tomashek KM, Patterson TF, et al. Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial. Lancet Respir Med. 2022;10:888-99. 35617986.


Subject(s)
COVID-19 , Adenosine Monophosphate/analogs & derivatives , Adult , Alanine/analogs & derivatives , Azetidines , COVID-19/drug therapy , Dexamethasone/therapeutic use , Double-Blind Method , Humans , Purines , Pyrazoles , Sulfonamides
9.
CMAJ Open ; 10(3): E807-E817, 2022.
Article in English | MEDLINE | ID: covidwho-2090865

ABSTRACT

BACKGROUND: The role of remdesivir in the treatment of hospitalized patients with COVID-19 remains ill-defined. We conducted a cost-effectiveness analysis alongside the Canadian Treatments for COVID-19 (CATCO) open-label, randomized clinical trial evaluating remdesivir. METHODS: Patients with COVID-19 in Canadian hospitals from Aug. 14, 2020, to Apr. 1, 2021, were randomly assigned to receive remdesivir plus usual care versus usual care alone. Taking a public health care payer's perspective, we collected in-hospital outcomes and health care resource utilization alongside estimated unit costs in 2020 Canadian dollars over a time horizon from randomization to hospital discharge or death. Data from 1281 adults admitted to 52 hospitals in 6 Canadian provinces were analyzed. RESULTS: The total mean cost per patient was $37 918 (standard deviation [SD] $42 413; 95% confidence interval [CI] $34 617 to $41 220) for patients randomly assigned to the remdesivir group and $38 026 (SD $46 021; 95% CI $34 480 to $41 573) for patients receiving usual care (incremental cost -$108 [95% CI -$4953 to $4737], p > 0.9). The difference in proportions of in-hospital deaths between remdesivir and usual care groups was -3.9% (18.7% v. 22.6%, 95% CI -8.3% to 1.0%, p = 0.09). The difference in proportions of incident invasive mechanical ventilation events between groups was -7.0% (8.0% v. 15.0%, 95% CI -10.6% to -3.4%, p = 0.006), whereas the difference in proportions of total mechanical ventilation events between groups was -5.7% (16.4% v. 22.1%, 95% CI -10.0% to -1.4%, p = 0.01). Remdesivir was the dominant intervention (but only marginally less costly, with mildly lower mortality) with an incalculable incremental cost effectiveness ratio; we report results of incremental costs and incremental effects separately. For willingness-to-pay thresholds of $0, $20 000, $50 000 and $100 000 per death averted, a strategy using remdesivir was cost-effective in 60%, 67%, 74% and 79% of simulations, respectively. The remdesivir costs were the fifth highest cost driver, offset by shorter lengths of stay and less mechanical ventilation. INTERPRETATION: From a health care payer perspective, treating patients hospitalized with COVID-19 with remdesivir and usual care appears to be preferrable to treating with usual care alone, albeit with marginal incremental cost and small clinical effects. The added cost of remdesivir was offset by shorter lengths of stay in the intensive care unit and less need for ventilation. STUDY REGISTRATION: ClinicalTrials. gov, no. NCT04330690.


Subject(s)
COVID-19 , Adenosine Monophosphate/analogs & derivatives , Adult , Alanine/analogs & derivatives , COVID-19/drug therapy , Canada , Cost-Benefit Analysis , Humans
12.
Yakugaku Zasshi ; 142(10): 1125-1127, 2022.
Article in Japanese | MEDLINE | ID: covidwho-2054202

ABSTRACT

A 55-year-old man with hypertrophic cardiomyopathy and a pacemaker was admitted with coronavirus disease 2019 (COVID-19). Before admission, the patient's medications included amiodarone, diltiazem, bisoprolol, atorvastatin, etizolam, and warfarin (WF). After admission, dexamethasone (DXM) and remdesivir (RDV) were initiated for treating COVID-19. The international normalized ratio (INR) on admission was 1.8, which increased to 3.4 on day 5 and to 6.9 on day 10 after admission. Although there have been reports that RDV may occasionally prolong prothrombin time and that the degree of prolongation is often less severe, the mechanism of action has not been elucidated till date. There are reports of prolonged INR when WF is co-administered with RDV and DXM, suggesting that drug interactions may be a potential cause for the prolongation. A similar drug interaction may have potentially occurred in the case reported here. In addition, this case used amiodarone (AMD), and it has been reported that the RDV concentration increases when used in combination with AMD. Further investigations are needed to elucidate the cause of INR prolongation. Thus, close monitoring of the patient is recommended when RDV is co-administered with high-risk agents to avoid unnecessary side effects.


Subject(s)
Amiodarone , COVID-19 , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Amiodarone/adverse effects , Anticoagulants/pharmacology , Atorvastatin , Bisoprolol , COVID-19/drug therapy , Dexamethasone/adverse effects , Diltiazem , Drug Interactions , Humans , International Normalized Ratio , Male , Middle Aged , Warfarin/pharmacology
13.
J Cardiovasc Pharmacol ; 80(4): 616-622, 2022 10 01.
Article in English | MEDLINE | ID: covidwho-2051608

ABSTRACT

ABSTRACT: Bradycardia and QTc interval prolongation on the ECG have been reported with remdesivir (Veklury), an antiviral drug recently approved for treating severely ill patients with COVID-19. The objective was to evaluate the effects of remdesivir on cardiac electrophysiology ex vivo and in vivo. Ex vivo: Langendorff retroperfusion experiments were performed on isolated hearts from male Hartley guinea pigs (n = 23, total) exposed to either remdesivir 3, 10, or 30 µmol/L to assess drug-induced prolongation of the monophasic action potential duration measured at 90% repolarization (MAPD 90 ). In vivo: ECG recordings using wireless cardiac telemetry were performed in guinea pigs (n = 6) treated with daily i.p. doses of remdesivir 5 mg/kg on day 1 and 2.5 mg/kg on days 2-10. Ex vivo remdesivir (3, 10, and 30 µmol/L) had no statistically significant effect on MAPD 90 , while pacing the hearts at basic stimulation cycle lengths of 200 or 250 milliseconds, or when the hearts were not paced and beating at their intrinsic heart rate. In a second set of similar ex vivo experiments, remdesivir 10 µmol/L did not potentiate the MAPD 90 -prolonging effects of dofetilide 20 nmol/L (n = 4) hearts. In vivo remdesivir caused small but statistically significant prolongations of the RR and QTc F intervals at day 1 (5 mg/kg) and at day 10 (2.5 mg/kg). No ventricular arrhythmias were ever observed under the effect of remdesivir. Remdesivir causes bradycardia, and mild QTc prolongation, which nonetheless, could be of clinical relevance in many hospitalized patients with COVID-19 concomitantly treated with multiple drugs.


Subject(s)
COVID-19 , Long QT Syndrome , Action Potentials , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Animals , Antiviral Agents/adverse effects , Bradycardia/chemically induced , COVID-19/drug therapy , Electrocardiography , Guinea Pigs , Long QT Syndrome/chemically induced , Male
14.
Int J Mol Sci ; 23(19)2022 Sep 20.
Article in English | MEDLINE | ID: covidwho-2043767

ABSTRACT

The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified as the pathogenic cause of coronavirus disease 2019 (COVID-19). The RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 is a potential target for the treatment of COVID-19. An RdRp complex:dsRNA structure suitable for docking simulations was prepared using a cryo-electron microscopy (cryo-EM) structure (PDB ID: 7AAP; resolution, 2.60 Å) that was reported recently. Structural refinement was performed using energy calculations. Structure-based virtual screening was performed using the ChEMBL database. Through 1,838,257 screenings, 249 drugs (37 approved, 93 clinical, and 119 preclinical drugs) were predicted to exhibit a high binding affinity for the RdRp complex:dsRNA. Nine nucleoside triphosphate analogs with anti-viral activity were included among these hit drugs, and among them, remdesivir-ribonucleoside triphosphate and favipiravir-ribonucleoside triphosphate adopted a similar docking mode as that observed in the cryo-EM structure. Additional docking simulations for the predicted compounds with high binding affinity for the RdRp complex:dsRNA suggested that 184 bioactive compounds could be anti-SARS-CoV-2 drug candidates. The hit bioactive compounds mainly consisted of a typical noncovalent major groove binder for dsRNA. Three-layer ONIOM (MP2/6-31G:AM1:AMBER) geometry optimization calculations and frequency analyses (MP2/6-31G:AMBER) were performed to estimate the binding free energy of a representative bioactive compound obtained from the docking simulation, and the fragment molecular orbital calculation at the MP2/6-31G level of theory was subsequently performed for analyzing the detailed interactions. The procedure used in this study represents a possible strategy for discovering anti-SARS-CoV-2 drugs from drug libraries that could significantly shorten the clinical development period for drug repositioning.


Subject(s)
COVID-19 , Ribonucleosides , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Amides , Antiviral Agents/chemistry , COVID-19/drug therapy , Cryoelectron Microscopy , Humans , Molecular Docking Simulation , Nucleosides , Polyphosphates , Pyrazines , RNA, Viral , RNA-Dependent RNA Polymerase , Reproduction , Ribonucleosides/pharmacology , SARS-CoV-2
15.
Medicine (Baltimore) ; 101(38): e30474, 2022 Sep 23.
Article in English | MEDLINE | ID: covidwho-2042654

ABSTRACT

Although some studies have reported prognostic factors for coronavirus disease 2019 (COVID-19), they were conducted before standard treatment with remdesivir and dexamethasone was implemented. This retrospective, observational study was conducted to evaluate various prognostic factors in patients with COVID-19 pneumonia receiving standard treatment with remdesivir and dexamethasone. Of 99 patients with COVID-19 pneumonia, 68 (68.7%) died within 30 days of hospitalization. The mean age was 71.3 years. Remdesivir and dexamethasone were administered to 80 (80.8%) and 84 (84.8%) patients, respectively. Early antibiotic treatment was administered to 70 patients (70.7%) within 5 days of hospitalization. Dexamethasone (79.4% vs 96.8%, P = .033) was more frequently administered in the survived group, whereas early antibiotics (60.3% vs 93.5%, P = .001) were less frequently administered. In the multivariate analysis, a high National Early Warning Score (NEWS; odds ratio [OR] 1.272), high Charlson Comorbidity Index (CCI; OR 1.441), and dyspnea (OR 4.033) were independent risk factors for 30-day mortality. There was no significant difference in age, sex, and vaccination doses between the survived and fatal groups. Lymphopenia, monocytopenia and high levels of C-reactive protein (CRP)/lactate dehydrogenase (LDH) reflected poor prognosis. NEWS, CCI, and dyspnea were predictors of 30-day mortality in patients with COVID-19 pneumonia. Early antibiotic use did not lower the 30-day mortality risk.


Subject(s)
COVID-19 , Pneumonia , Adenosine Monophosphate/analogs & derivatives , Aged , Alanine/analogs & derivatives , Anti-Bacterial Agents/therapeutic use , C-Reactive Protein/metabolism , COVID-19/drug therapy , Dexamethasone/therapeutic use , Dyspnea , Humans , Lactate Dehydrogenases , Prognosis , Retrospective Studies , SARS-CoV-2
16.
J Glob Health ; 12: 05031, 2022 Aug 31.
Article in English | MEDLINE | ID: covidwho-2025296

ABSTRACT

Background: Treatment of the coronavirus disease (COVID-19) is still challenging due to the lack of evidence-based treatment protocols and continuously changing epidemiological situations and vaccinations. Remdesivir (RDV) is among the few antiviral medications with confirmed efficacy for specific patient groups. However, real-world data on long-term outcomes for a short treatment course are scarce. Methods: This retrospective observational cohort study included real-life data collected during the second and third wave of the COVID-19 pandemic in Hungary (September 1, 2020-April 30, 2021) from inpatients at a University Center (n = 947). Participants consisted of two propensity score-matched cohorts (370/370 cases): Group RDV including patients receiving RDV and supplementary oxygen and Group standard of care (SOC) as control. The primary outcome was the effect of 5-day RDV treatment on 30- and 60-day all-cause mortality. Multivariate analyses were performed to assess the effect of RDV by different covariates. Results: Group RDV included significantly more patients from the alpha variant wave, with greater frequency of comorbidities diabetes and anemia, and larger degree of parenchymal involvement. All-cause mortality at 30- and 60-day were significantly lower in Group RDV compared to Group SOC. Significant risk reduction of 60-day all-cause mortality was observed for RDV treatment in men and patients with COPD or multiple comorbidities. Conclusions: Hospitalized COVID-19 patients with 5-day RDV treatment had significantly lower 30- and 60-day all-cause mortality, despite their more severe clinical condition. Men and patients with multiple comorbidities, including COPD, profited the most from RDV treatment in the long term. Due to the ongoing COVID-19 pandemic, effective treatment regimens are needed for hospitalized patients.


Subject(s)
COVID-19 , Coronavirus Infections , Coronavirus , Pulmonary Disease, Chronic Obstructive , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Betacoronavirus , COVID-19/drug therapy , Coronavirus Infections/drug therapy , Humans , Male , Pandemics , Retrospective Studies , SARS-CoV-2
17.
J Med Chem ; 65(18): 12044-12054, 2022 09 22.
Article in English | MEDLINE | ID: covidwho-2016519

ABSTRACT

COVID-19 patients with severe symptoms still lack antiviral treatment options. Although remdesivir is the only FDA-approved drug for those patients, its efficacy is limited by premature hydrolysis to nucleoside (NUC), low accumulation in the disease-targeted tissue (lungs), and low antiviral potency. In this study, we synthesized a new series of remdesivir analogues by modifying the ProTide moiety. In comparison with remdesivir, the lead compound MMT5-14 showed 2- to 7-fold higher antiviral activity in four variants of SARS-CoV-2. By reducing premature hydrolysis in hamsters, MMT5-14 increased the prodrug concentration by 200- to 300-fold in the plasma and lungs but also enhanced lung accumulation of the active metabolite triphosphate nucleosides (NTP) by 5-fold. Compared to remdesivir, MMT5-14 also increased the intracellular uptake and activation in lung epithelial cells by 4- to 25-fold. These data suggest that MMT5-14 could be a potential antiviral drug to treat COVID-19 patients with severe symptoms.


Subject(s)
COVID-19 , Prodrugs , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Alanine/pharmacology , Alanine/therapeutic use , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Humans , Lung , Nucleosides , Prodrugs/pharmacology , Prodrugs/therapeutic use , SARS-CoV-2
18.
J Appl Toxicol ; 42(10): 1688-1700, 2022 10.
Article in English | MEDLINE | ID: covidwho-2013548

ABSTRACT

The antiviral drug remdesivir has been used to treat the growing number of coronavirus disease 2019 (COVID-19) patients. However, the drug is mainly excreted through urine and feces and introduced into the environment to affect non-target organisms, including fish, which has raised concerns about potential ecotoxicological effects on aquatic organisms. Moreover, studies on the ecological impacts of remdesivir on aquatic environments have not been reported. Here, we aimed to explore the toxicological impacts of microinjection of remdesivir on zebrafish early embryonic development and larvae and the associated mechanism. We found that 100 µM remdesivir delayed epiboly and impaired convergent movement of embryos during gastrulation, and dose-dependent increases in mortality and malformation were observed in remdesivir-treated embryos. Moreover, 10-100 µM remdesivir decreased blood flow and swimming velocity and altered the behavior of larvae. In terms of molecular mechanisms, 80 differentially expressed genes (DEGs) were identified by transcriptome analysis in the remdesivir-treated group. Some of these DEGs, such as manf, kif3a, hnf1ba, rgn, prkcz, egr1, fosab, nr4a1, and ptgs2b, were mainly involved in early embryonic development, neuronal developmental disorders, vascular disease and the blood flow pathway. These data reveal that remdesivir can impair early embryonic development, blood flow and behavior of zebrafish embryos/larvae, probably due to alterations at the transcriptome level. This study suggests that it is important to avoid the discharge of remdesivir to aquatic ecosystems and provides a theoretical foundation to hinder remdesivir-induced ecotoxicity to aquatic environments.


Subject(s)
COVID-19 , Water Pollutants, Chemical , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Animals , COVID-19/drug therapy , Ecosystem , Embryo, Nonmammalian , Hepatocyte Nuclear Factor 1-beta/metabolism , Hepatocyte Nuclear Factor 1-beta/pharmacology , Larva , Water Pollutants, Chemical/metabolism , Water Pollutants, Chemical/toxicity , Zebrafish , Zebrafish Proteins/metabolism
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