Remdesivir: A Review in COVID-19

Drugs, Journal Year: 2023, Volume and Issue: 83(13), P. 1215 - 1237

Published: Aug. 17, 2023

Remdesivir (Veklury®), a nucleotide analogue prodrug with broad-spectrum antiviral activity, is approved for the treatment of coronavirus disease 2019 (COVID-19), illness caused by severe acute respiratory syndrome 2 infection. Unlike some antivirals, remdesivir has low potential drug-drug interactions. In pivotal ACTT-1 trial in hospitalized patients COVID-19, daily intravenous infusions significantly reduced time to recovery relative placebo. Subsequent trials provided additional support efficacy moderate or greater benefit seen minimal oxygen requirements at baseline. Clinical also demonstrated other patient populations, including outpatients high risk progression as well paediatric patients. terms mortality, results were equivocal. However, appeared have small mortality who not already being ventilated was generally tolerated clinical trials, but pharmacovigilance data found an increased hepatic, renal and cardiovascular adverse drug reactions real-world setting. conclusion, represents useful option particularly those require supplemental oxygen. Coronavirus (COVID-19) first reported China quickly spread around world. The symptoms COVID-19 can vary from person person, people having no others becoming very unwell. Most treat their home, may be admitted hospital and/or treated specialized medications such (Veklury®). medicine that reduce amount virus causes COVID-19. It given once day, usually 5–10 days, infusion. been shown improve children adolescents. death are before they start treatment. A 3-day course effective whose age underlying health puts them severely ill. tolerated. Therefore, especially

Language: Английский

---

Discovery of GS-5245 (Obeldesivir), an Oral Prodrug of Nucleoside GS-441524 That Exhibits Antiviral Efficacy in SARS-CoV-2-Infected African Green Monkeys

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(17), P. 11701 - 11717

Published: Aug. 19, 2023

Remdesivir 1 is an phosphoramidate prodrug that releases the monophosphate of nucleoside GS-441524 (2) into lung cells, thereby forming bioactive triphosphate 2-NTP. 2-NTP, analog ATP, inhibits SARS-CoV-2 RNA-dependent RNA polymerase replication and transcription viral RNA. Strong clinical results for have prompted interest in oral approaches to generate Here, we describe discovery a 5′-isobutyryl ester 2 (GS-5245, Obeldesivir, 3) has low cellular cytotoxicity 3–7-fold improved delivery monkeys. Prodrug 3 cleaved presystemically provide high systemic exposures overcome its less efficient metabolism leading strong antiviral efficacy African green monkey infection model. Exposure-based relationships resulted estimated dose 350–400 mg twice daily. Importantly, all variants remain susceptible 2, which supports development as promising COVID-19 treatment.

Language: Английский

---

Remdesivir for the Treatment of COVID-19: A Narrative Review

Infectious Diseases and Therapy, Journal Year: 2024, Volume and Issue: 13(1), P. 1 - 19

Published: Jan. 1, 2024

Despite the wide availability of effective vaccines, COVID-19 continues to be an infectious disease global importance. Remdesivir is a broad-spectrum antiviral and was first US Food Drug Administration-approved treatment for COVID-19. In clinical guidelines, remdesivir currently only recommended use in hospitalized patients with COVID-19, or without supplemental oxygen requirement. It also nonhospitalized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection who are at high risk progression disease. This narrative review explores evidence across various outcomes evolution guidelines through survey over time randomized controlled trials, observational studies, meta-analyses. Remdesivir, compared standard care, appears improve survival variety patient populations spectrum severity SARS-CoV-2 variant periods. recovery, increase rate reduce on readmission rates. More recent large, real-world studies further support early range populations, including those immunocompromising conditions. When people get sick which caused by virus, may needed prevent serious illness. Studies have found that treating can save lives keep from getting sicker. help better faster, need less time, avoid having go back hospital. Newer treated settings, outside research environments, show likely many different groups patients, health conditions weaken their body's ability fight infection. Because this research, recommend should given some hospital stay other reasons but condition puts them

Language: Английский

---

No Remdesivir Resistance Observed in the Phase 3 Severe and Moderate COVID-19 SIMPLE Trials

Viruses, Journal Year: 2024, Volume and Issue: 16(4), P. 546 - 546

Published: March 31, 2024

Remdesivir (RDV) is a broad-spectrum nucleotide analog prodrug approved for the treatment of COVID-19 in hospitalized and non-hospitalized patients with clinical benefit demonstrated multiple Phase 3 trials. Here we present SARS-CoV-2 resistance analyses from SIMPLE studies evaluating RDV participants severe or moderate disease. The enrolled radiologic evidence pneumonia room-air oxygen saturation ≤94% >94%, respectively. Virology sample collection was optional study protocols. Sequencing related viral load data were obtained retrospectively at subset sites local sequencing capabilities (10 183 sites) timepoints detectable load. Among both baseline post-baseline treated RDV, emergent Nsp12 substitutions observed 4 19 (21%) none 2 study. following 5 emerged: T76I, A526V, A554V, E665K, C697F. C697F had an EC50 fold change ≤1.5 relative to wildtype reference using subgenomic replicon system, indicating no significant susceptibility RDV. phenotyping E665K could not be determined due lack replication. These reveal relevant emergence further confirm established efficacy profile high barrier patients.

Language: Английский

---

Remdesivir is Associated with Reduced Mortality in Patients Hospitalized for COVID-19 Not Requiring Supplemental Oxygen

Open Forum Infectious Diseases, Journal Year: 2024, Volume and Issue: 11(6)

Published: April 16, 2024

Abstract Background Remdesivir has demonstrated benefit in some hospitalized patients with coronavirus disease 2019 (COVID-19) on supplemental oxygen and nonhospitalized breathing room air. The durability of this across time periods different circulating severe acute respiratory syndrome 2 variants concern (VOC) is unknown. This comparative effectiveness study for COVID-19 not receiving at admission compared those starting remdesivir treatment the first days no during their hospitalization VOC periods. Method Using a large, multicenter US hospital database, in-hospital mortality rates were among but requiring between December 2020 April 2022. Patients matched 1:1 to hospitalization, using propensity score matching. Cox proportional hazards models used assess 14- 28-day or discharge hospice. Results Among 121 336 eligible patients, 58 188 remdesivir-treated 17 574 unique remdesivir. Overall, 5.4% 7.3% non-remdesivir group died within 14 days, 8.0% 9.8%, respectively, 28 days. was associated statistically significant reduction rate (14-day adjusted hazard ratios [95% confidence interval], 0.75 [0.68–0.83] 0.83 [0.76–0.90], respectively). endured Conclusions initiation significantly reduced rate. These findings highlight potential survival when clinicians initiated dominant variant eras evolving pandemic.

Language: Английский

---

BioMapAI: Artificial Intelligence Multi-Omics Modeling of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 28, 2024

Chronic diseases like ME/CFS and long COVID exhibit high heterogeneity with multifactorial etiology progression, complicating diagnosis treatment. To address this, we developed BioMapAI, an explainable Deep Learning framework using the richest longitudinal multi-'omics dataset for to date. This includes gut metagenomics, plasma metabolome, immune profiling, blood labs, clinical symptoms. By connecting asymptom matrix, BioMapAI identified both disease- symptom-specific biomarkers, reconstructed symptoms, achieved state-of-the-art precision in disease classification. We also created first connectivity map of these 'omics healthy states revealed how microbiome-immune-metabolome crosstalk shifted from ME/CFS. Thus, proposed several innovative mechanistic hypotheses ME/CFS: Disrupted microbial functions - SCFA (butyrate), BCAA (amino acid), tryptophan, benzoate lost connection lipids bile acids, activated inflammatory mucosal cells (MAIT, γδT cells) INFγ GzA secretion. These abnormal dynamics are linked key including gastrointestinal issues, fatigue, sleep problems.

Language: Английский

---

Discovery of GS-5245 (Obeldesivir), an Oral Prodrug of Nucleoside GS-441524 that Exhibits Antiviral Efficacy in SARS-CoV-2 Infected African Green Monkeys

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: April 28, 2023

Abstract Remdesivir 1 is an amidate prodrug that releases the monophosphate of nucleoside GS-441524 ( 2 ) into lung cells thereby forming bioactive triphosphate 2-NTP . , analog ATP, inhibits SARS-CoV-2 RNA-dependent RNA polymerase replication and transcription viral RNA. Strong clinical results for have prompted interest in oral approaches to generate Here we describe discovery a 5’-isobutyryl ester GS-5245, Obeldesivir, 3 has low cellular cytotoxicity three seven-fold improved delivery monkeys. Prodrug cleaved pre-systemically provide high systemic exposures overcome its less efficient metabolism leading strong antiviral efficacy African green monkey infection model. Exposure-based relationships resulted estimated dose 350-400 mg twice-daily. Importantly, all variants remain susceptible which supports development as promising COVID-19 treatment.

Language: Английский

---

Oral and intravenous 1'-cyano-substituted adenosine-like antivirals for early COVID-19

The Lancet Infectious Diseases, Journal Year: 2023, Volume and Issue: 24(2), P. 108 - 110

Published: Nov. 22, 2023

Language: Английский

---

Changes in Lymphocyte Subpopulations after Remdesivir Therapy for COVID-19: A Brief Report

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(19), P. 14973 - 14973

Published: Oct. 7, 2023

Remdesivir (RDV) has demonstrated clinical benefit in hospitalized COronaVIrus Disease (COVID)-19 patients. The objective of this brief report was to assess a possible correlation between RDV therapy and the variation lymphocyte subpopulations. We retrospectively studied 43 COVID-19 patients: 30 men 13 women (mean age 69.3 ± 15 years); 9/43 had received therapy. Six patients no need for oxygen (severity group 0); 22 were on treatment with fraction inspired (FiO2) ≤ 50% (group 1); 7 not-invasive ventilation 2); 3 invasive mechanical 3); 5 died 4). Cytofluorimetric assessment subpopulations showed substantial changes after therapy: B lymphocytes plasmablasts significantly increased (p = 0.002 p 0.08, respectively). Cytotoxic T robust reduction 0.008). No observed CD4+-T cells natural killers (NKs). There significant regulatory (Tregs) 0.02) increase circulating monocytes 0.03). Stratifying by disease severity, therapy, severity 0-2 higher monocyte counts lower memory effector cytotoxic cell counts. Instead, 3-4 plasmablast differences cells, Tregs, NKs observed. Our analyzed who did not receive those treatment. Despite small sample size, due retrospective nature report, reported could lead speculation role both immune responses against virus downregulation cytokine storm more severe disease.

Language: Английский

---

The effects of remdesivir on long-term symptoms in patients hospitalised for COVID-19: a pre-specified exploratory analysis

Communications Medicine, Journal Year: 2024, Volume and Issue: 4(1)

Published: Nov. 12, 2024

There is an unmet need for treatment of long-term symptoms following COVID-19. Remdesivir currently the only antiviral approved by European Medicines Agency hospitalised patients. Here, we report on effect remdesivir in addition to standard care and quality life patients with COVID-19 as part open-label randomised NOR-Solidarity trial (NCT04321616). A total 185 were included main trial, which 118 (60%) either (n = 42; 36%) or a post-hoc defined control group composed who received alone hydroxychloroquine 76; 64%). Participants given surveys fill out gauge their self-reported health over time (the COPD assessment test, EQ-5D-5L RAND SF-36). Here show that after three months, treated do not significant improvements stated compared those not. are fatigue [mean 2.6 (standard deviation 1.5) v 2.1 (1.6), 95% confidence interval(CI) −1.17 0.15, p 0.129], shortness breath [3.0 (1.7) (1.8), CI −1.53 0.16, 0.110] coughing [1.8 (1.6) 1.2 (1.5), −1.3 0.33, 0.237] 3 months randomisation assessed via Assessment Test. Our findings indicate during hospitalisation does provide any clinically relevant benefit. medicine used treat people It has been found help get better faster, but did know whether it also relieved them such persistent coughing, fatigue, breath. To research this, randomly assigned top normal care, without (a drug later have no COVID-19). We then participant's months. results there probably benefit using symptom relief. Patrick-Brown et al secondary study adjunct Nor-Solidarity evaluated versus While appears be safe use these patients, appear clinical its terms long-COVID symptoms.

Language: Английский

---