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Nucleotide analog inhibitors, including broad-spectrum remdesivir and favipiravir, have shown promise in in vitro assays and some clinical studies for COVID-19 treatment, this despite an incomplete mechanistic understanding of the viral RNA-dependent RNA polymerase nsp12 drug interactions. Here, we examine the molecular basis of SARS-CoV-2 RNA replication by determining the cryo-EM structures of the stalled pre- and post- translocated polymerase complexes. Compared with the apo complex, the structures show notable structural rearrangements happening to nsp12 and its co-factors nsp7 and nsp8 to accommodate the nucleic acid, whereas there are highly conserved residues in nsp12, positioning the template and primer for an in-line attack on the incoming nucleotide. Furthermore, we investigate the inhibition mechanism of the triphosphate metabolite of remdesivir through structural and kinetic analyses. A transition model from the nsp7-nsp8 hexadecameric primase complex to the nsp12-nsp7-nsp8 polymerase complex is also proposed to provide clues for the understanding of the coronavirus transcription and replication machinery.
Assuntos
Betacoronavirus/química , Betacoronavirus/enzimologia , RNA Polimerase Dependente de RNA/química , Proteínas não Estruturais Virais/química , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/química , Monofosfato de Adenosina/metabolismo , Monofosfato de Adenosina/farmacologia , Alanina/análogos & derivados , Alanina/química , Alanina/metabolismo , Alanina/farmacologia , Antivirais/química , Antivirais/metabolismo , Antivirais/farmacologia , Domínio Catalítico , RNA-Polimerase RNA-Dependente de Coronavírus , Microscopia Crioeletrônica , Modelos Químicos , Modelos Moleculares , RNA Viral/metabolismo , SARS-CoV-2 , Transcrição Gênica , Replicação ViralRESUMO
Remdesivir is a nucleoside analog approved by the US FDA for treatment of COVID-19. Here, we present a 3.9-Å-resolution cryo-EM reconstruction of a remdesivir-stalled RNA-dependent RNA polymerase complex, revealing full incorporation of 3 copies of remdesivir monophosphate (RMP) and a partially incorporated fourth RMP in the active site. The structure reveals that RMP blocks RNA translocation after incorporation of 3 bases following RMP, resulting in delayed chain termination, which can guide the rational design of improved antiviral drugs.
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Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/química , RNA Viral/química , RNA Polimerase Dependente de RNA/química , SARS-CoV-2/fisiologia , Replicação Viral , Monofosfato de Adenosina/química , Monofosfato de Adenosina/uso terapêutico , Alanina/química , Alanina/uso terapêutico , Antivirais/uso terapêutico , Domínio Catalítico , Humanos , Proteínas ViraisRESUMO
The COVID-19 pandemic reminded us of the urgent need for new antivirals to control emerging infectious diseases and potential future pandemics. Immunotherapy has revolutionized oncology and could complement the use of antivirals, but its application to infectious diseases remains largely unexplored. Nucleoside analogs are a class of agents widely used as antiviral and anti-neoplastic drugs. Their antiviral activity is generally based on interference with viral nucleic acid replication or transcription. Based on our previous work and computer modeling, we hypothesize that antiviral adenosine analogs, like remdesivir, have previously unrecognized immunomodulatory properties which contribute to their therapeutic activity. In the case of remdesivir, we here show that these properties are due to its metabolite, GS-441524, acting as an Adenosine A2A Receptor antagonist. Our findings support a new rationale for the design of next-generation antiviral agents with dual - immunomodulatory and intrinsic - antiviral properties. These compounds could represent game-changing therapies to control emerging viral diseases and future pandemics.
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Monofosfato de Adenosina , Adenosina , Alanina , Antivirais , COVID-19 , SARS-CoV-2 , Antivirais/farmacologia , Antivirais/química , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , Adenosina/análogos & derivados , Adenosina/farmacologia , Adenosina/química , Humanos , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Alanina/análogos & derivados , Alanina/farmacologia , Alanina/química , COVID-19/imunologia , COVID-19/virologia , Animais , Agentes de Imunomodulação/farmacologia , Agentes de Imunomodulação/química , Antagonistas do Receptor A2 de Adenosina/farmacologia , Antagonistas do Receptor A2 de Adenosina/química , Antagonistas do Receptor A2 de Adenosina/uso terapêutico , Pandemias , Tratamento Farmacológico da COVID-19 , Chlorocebus aethiops , Replicação Viral/efeitos dos fármacos , Células Vero , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Receptor A2A de Adenosina/metabolismo , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologiaRESUMO
The development of safe and effective broad-spectrum antivirals that target the replication machinery of respiratory viruses is of high priority in pandemic preparedness programs. Here, we studied the mechanism of action of a newly discovered nucleotide analog against diverse RNA-dependent RNA polymerases (RdRps) of prototypic respiratory viruses. GS-646939 is the active 5'-triphosphate metabolite of a 4'-cyano modified C-adenosine analog phosphoramidate prodrug GS-7682. Enzyme kinetics show that the RdRps of human rhinovirus type 16 (HRV-16) and enterovirus 71 incorporate GS-646939 with unprecedented selectivity; GS-646939 is incorporated 20-50-fold more efficiently than its natural ATP counterpart. The RdRp complex of respiratory syncytial virus and human metapneumovirus incorporate GS-646939 and ATP with similar efficiency. In contrast, influenza B RdRp shows a clear preference for ATP and human mitochondrial RNA polymerase does not show significant incorporation of GS-646939. Once incorporated into the nascent RNA strand, GS-646939 acts as a chain terminator although higher NTP concentrations can partially overcome inhibition for some polymerases. Modeling and biochemical data suggest that the 4'-modification inhibits RdRp translocation. Comparative studies with GS-443902, the active triphosphate form of the 1'-cyano modified prodrugs remdesivir and obeldesivir, reveal not only different mechanisms of inhibition, but also differences in the spectrum of inhibition of viral polymerases. In conclusion, 1'-cyano and 4'-cyano modifications of nucleotide analogs provide complementary strategies to target the polymerase of several families of respiratory RNA viruses.
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Subacute sclerosing panencephalitis (SSPE) is a rare but fatal late neurological complication of measles, caused by persistent measles virus (MeV) infection of the central nervous system. There are no drugs approved for the treatment of SSPE. Here, we followed the clinical progression of a 5-year-old SSPE patient after treatment with the nucleoside analog remdesivir, conducted a post-mortem evaluation of the patient's brain, and characterized the MeV detected in the brain. The quality of life of the patient transiently improved after the first two courses of remdesivir, but a third course had no further clinical effect, and the patient eventually succumbed to his condition. Post-mortem evaluation of the brain displayed histopathological changes including loss of neurons and demyelination paired with abundant presence of MeV RNA-positive cells throughout the brain. Next-generation sequencing of RNA isolated from the brain revealed a complete MeV genome with mutations that are typically detected in SSPE, characterized by a hypermutated M gene. Additional mutations were detected in the polymerase (L) gene, which were not associated with resistance to remdesivir. Functional characterization showed that mutations in the F gene led to a hyperfusogenic phenotype predominantly mediated by N465I. Additionally, recombinant wild-type-based MeV with the SSPE-F gene or the F gene with the N465I mutation was no longer lymphotropic but instead efficiently disseminated in neural cultures. Altogether, this case encourages further investigation of remdesivir as a potential treatment of SSPE and highlights the necessity to functionally understand SSPE-causing MeV.IMPORTANCEMeasles virus (MeV) causes acute, systemic disease and remains an important cause of morbidity and mortality in humans. Despite the lack of known entry receptors in the brain, MeV can persistently infect the brain causing the rare but fatal neurological disorder subacute sclerosing panencephalitis (SSPE). SSPE-causing MeVs are characterized by a hypermutated genome and a hyperfusogenic F protein that facilitates the rapid spread of MeV throughout the brain. No treatment against SSPE is available, but the nucleoside analog remdesivir was recently demonstrated to be effective against MeV in vitro. We show that treatment of an SSPE patient with remdesivir led to transient clinical improvement and did not induce viral escape mutants, encouraging the future use of remdesivir in SSPE patients. Functional characterization of the viral proteins sheds light on the shared properties of SSPE-causing MeVs and further contributes to understanding how those viruses cause disease.
Assuntos
Monofosfato de Adenosina , Alanina , Vírus do Sarampo , Sarampo , Panencefalite Esclerosante Subaguda , Proteínas Virais , Pré-Escolar , Humanos , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/administração & dosagem , Alanina/análogos & derivados , Alanina/uso terapêutico , Autopsia , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/virologia , Progressão da Doença , Evolução Fatal , Genoma Viral/genética , Sequenciamento de Nucleotídeos em Larga Escala , Sarampo/complicações , Sarampo/tratamento farmacológico , Sarampo/virologia , Vírus do Sarampo/efeitos dos fármacos , Vírus do Sarampo/genética , Vírus do Sarampo/metabolismo , Proteínas Mutantes/análise , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Qualidade de Vida , RNA Viral/análise , RNA Viral/genética , Panencefalite Esclerosante Subaguda/tratamento farmacológico , Panencefalite Esclerosante Subaguda/etiologia , Panencefalite Esclerosante Subaguda/virologia , Proteínas Virais/análise , Proteínas Virais/genética , Proteínas Virais/metabolismoRESUMO
BACKGROUND: Although antivirals remain important for the treatment COVID-19, methods to assess treatment efficacy are lacking. Here, we investigated the impact of remdesivir on viral dynamics and their contribution to understanding antiviral efficacy in the multicenter ACTT-1 clinical trial that randomized patients to remdesivir or placebo. METHODS: Longitudinal specimens collected during hospitalization from a substudy of 642 COVID-19 patients were measured for viral RNA (upper respiratory tract and plasma), viral nucleocapsid antigen (serum), and host immunologic markers. Associations with clinical outcomes and response to therapy were assessed. RESULTS: Higher baseline plasma viral loads were associated with poorer clinical outcomes, and decreases in viral RNA and antigen in blood but not the upper respiratory tract correlated with enhanced benefit from remdesivir. The treatment effect of remdesivir was most pronounced in patients with elevated baseline nucleocapsid antigen levels: the recovery rate ratio was 1.95 (95%CI 1.40-2.71) for levels >245â pg/ml vs 1.04 (95%CI 0.76-1.42) for levels < 245â pg/ml. Remdesivir also accelerated the rate of viral RNA and antigen clearance in blood, and patients whose blood levels decreased were more likely to recover and survive. CONCLUSIONS: Reductions in SARS-CoV-2 RNA and antigen levels in blood correlated with clinical benefit from antiviral therapy.
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BACKGROUND: Pregnant people with COVID-19 experience higher risk for severe disease and adverse pregnancy outcomes, but no pharmacokinetic (PK) data exist to support dosing of COVID-19 therapeutics during pregnancy. We report PK and safety data for intravenous remdesivir in pregnancy. METHODS: IMPAACT 2032 was a phase IV prospective, open-label, non-randomized opportunistic study of hospitalized pregnant and non-pregnant women receiving intravenous remdesivir as part of clinical care. Intensive PK sampling was performed on infusion days 3, 4, or 5 with collection of plasma and peripheral blood mononuclear cells (PBMCs). Safety data were recorded from first infusion through 4 weeks post-last infusion and at delivery. Geometric mean ratios (GMR) (90% confidence intervals [CI]) of PK parameters between pregnant and non-pregnant women were calculated. RESULTS: Fifty-three participants initiated remdesivir (25 pregnant; median (IQR) gestational age 27.6 (24.9, 31.0) weeks). Plasma exposures of remdesivir, its two major metabolites (GS-704277 and GS-441524), and the free remdesivir fraction were similar between pregnant and non-pregnant participants. Concentrations of the active triphosphate (GS-443902) in PBMCs increased 2.04-fold (90% CI 1.35, 3.03) with each additional infusion in non-pregnant versus pregnant participants. Three adverse events in non-pregnant participants were related to treatment (one Grade 3; two Grade 2 resulting in treatment discontinuation). There were no treatment-related adverse pregnancy outcomes or congenital anomalies detected. CONCLUSIONS: Plasma remdesivir PK parameters were comparable between pregnant and non-pregnant women, and no safety concerns were identified based on our limited data. These findings suggest no dose adjustments are indicated for intravenous remdesivir during pregnancy.
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BACKGROUND: We aimed to evaluate the cardiac adverse events (AEs) in hospitalized patients with coronavirus disease 2019 (COVID-19) who received remdesivir plus standard of care (SoC) compared with SoC alone (control), as an association was noted in some cohort studies and disproportionality analyses of safety databases. METHODS: This post hoc safety analysis is based on data from the multicenter, randomized, open-label, controlled DisCoVeRy trial in hospitalized patients with COVID-19. Any first AE that occurred between randomization and day 29 in the modified intention-to-treat (mITT) population randomized to either remdesivir or control group was considered. Analysis was performed using Kaplan-Meier survival curves, and Kaplan-Meier estimates were calculated for event rates. RESULTS: Cardiac AEs were reported in 46 (11.2%) of 410 and 48 (11.3%) of 423 patients in the mITT population (n = 833) enrolled in the remdesivir and control groups, respectively. The difference between both groups was not significant (hazard ratio [HR], 1.0; 95% confidence interval [CI], .7-1.5; P = .98), even when serious and nonserious cardiac AEs were evaluated separately. The majority of reports in both groups were of arrhythmic nature (remdesivir, 84.8%; control, 83.3%) and were associated with a favorable outcome. There was no significant difference between the two groups in the occurrence of cardiac AE subclasses, including arrhythmic events (HR, 1.1; 95% CI, .7-1.7; P = .68). CONCLUSIONS: Remdesivir treatment was not associated with an increased risk of cardiac AEs compared with control in patients hospitalized with moderate or severe COVID-19. These results are consistent with other randomized, controlled trials and meta-analyses. Clinical Trials Registration. NCT04315948; EudraCT 2020-000936-23.
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Monofosfato de Adenosina , Alanina , Antivirais , Tratamento Farmacológico da COVID-19 , COVID-19 , Hospitalização , SARS-CoV-2 , Humanos , Alanina/análogos & derivados , Alanina/uso terapêutico , Alanina/efeitos adversos , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Monofosfato de Adenosina/efeitos adversos , Masculino , Feminino , Antivirais/uso terapêutico , Antivirais/efeitos adversos , Pessoa de Meia-Idade , Idoso , Hospitalização/estatística & dados numéricos , Cardiopatias/induzido quimicamente , AdultoRESUMO
Data regarding coronavirus disease 2019 (COVID-19) outcomes in solid organ transplant recipients (SOTr) across severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) waves, including the impact of different measures, are lacking. This cohort study, conducted from March 2020 to May 2023 in Toronto, Canada, aimed to analyze COVID-19 outcomes in 1975 SOTr across various SARS-CoV-2 waves and assess the impact of preventive and treatment measures. The primary outcome was severe COVID-19, defined as requiring supplemental oxygen, with secondary outcomes including hospitalization, length of stay, intensive care unit (ICU) admission, and 30-day and 1-year all-cause mortality. SARS-CoV-2 waves were categorized as Wildtype/Alpha/Delta (318 cases, 16.1%), Omicron BA.1 (268, 26.2%), Omicron BA.2 (268, 13.6%), Omicron BA.5 (561, 28.4%), Omicron BQ.1.1 (188, 9.5%), and Omicron XBB.1.5 (123, 6.2%). Severe COVID-19 rate was highest during the Wildtype/Alpha/Delta wave (44.6%), and lower in Omicron waves (5.7%-16.1%). Lung transplantation was associated with severe COVID-19 (OR: 4.62, 95% CI: 2.71-7.89), along with rituximab treatment (OR: 4.24, 95% CI: 1.04-17.3), long-term corticosteroid use (OR: 3.11, 95% CI: 1.46-6.62), older age (OR: 1.51, 95% CI: 1.30-1.76), chronic lung disease (OR: 2.11, 95% CI: 1.36-3.30), chronic kidney disease (OR: 2.18, 95% CI: 1.17-4.07), and diabetes (OR: 1.97, 95% CI: 1.37-2.83). Early treatment and ≥3 vaccine doses were associated with reduced severity (OR: 0.29, 95% CI: 0.19-0.46, and 0.35, 95% CI: 0.21-0.60, respectively). Tixagevimab/cilgavimab and bivalent boosters did not show a significant impact. The study concludes that COVID-19 severity decreased across different variants in SOTr. Lung transplantation was associated with worse outcomes and may benefit more from preventive and early therapeutic interventions.
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COVID-19 , Transplante de Órgãos , SARS-CoV-2 , Transplantados , Humanos , COVID-19/epidemiologia , Transplante de Órgãos/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , Transplantados/estatística & dados numéricos , Adulto , Idoso , Hospitalização/estatística & dados numéricos , Estudos Longitudinais , Unidades de Terapia Intensiva , Canadá/epidemiologiaRESUMO
Viral RNA-dependent RNA polymerase (RdRp), a highly conserved molecule in RNA viruses, has recently emerged as a promising drug target for broad-acting inhibitors. Through a Vero E6-based anti-cytopathic effect assay, we found that BPR3P0128, which incorporates a quinoline core similar to hydroxychloroquine, outperformed the adenosine analog remdesivir in inhibiting RdRp activity (EC50 = 0.66 µM and 3 µM, respectively). BPR3P0128 demonstrated broad-spectrum activity against various severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern. When introduced after viral adsorption, BPR3P0128 significantly decreased SARS-CoV-2 replication; however, it did not affect the early entry stage, as evidenced by a time-of-drug-addition assay. This suggests that BPR3P0128's primary action takes place during viral replication. We also found that BPR3P0128 effectively reduced the expression of proinflammatory cytokines in human lung epithelial Calu-3 cells infected with SARS-CoV-2. Molecular docking analysis showed that BPR3P0128 targets the RdRp channel, inhibiting substrate entry, which implies it operates differently-but complementary-with remdesivir. Utilizing an optimized cell-based minigenome RdRp reporter assay, we confirmed that BPR3P0128 exhibited potent inhibitory activity. However, an enzyme-based RdRp assay employing purified recombinant nsp12/nsp7/nsp8 failed to corroborate this inhibitory activity. This suggests that BPR3P0128 may inhibit activity by targeting host-related RdRp-associated factors. Moreover, we discovered that a combination of BPR3P0128 and remdesivir had a synergistic effect-a result likely due to both drugs interacting with separate domains of the RdRp. This novel synergy between the two drugs reinforces the potential clinical value of the BPR3P0128-remdesivir combination in combating various SARS-CoV-2 variants of concern.
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Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , COVID-19 , Pirazóis , Quinolinas , Humanos , SARS-CoV-2/metabolismo , RNA Polimerase Dependente de RNA/metabolismo , Simulação de Acoplamento Molecular , Tratamento Farmacológico da COVID-19 , Antivirais/químicaRESUMO
Severe acute respiratory syndrome 2 (SARS-CoV-2) caused the emergence of the COVID-19 pandemic all over the world. Several studies have suggested that antiviral drugs such as favipiravir (FAV), remdesivir (RDV), and lopinavir (LPV) may potentially prevent the spread of the virus in the host cells and person-to-person transmission. Simultaneously with the widespread use of these drugs, their stability and action mechanism studies have also attracted the attention of many researchers. This review focuses on the action mechanism, metabolites and degradation products of these antiviral drugs (FAV, RDV and LPV) and demonstrates various methods for their quantification and discrimination in the different biological samples. Herein, the instrumental methods for analysis of the main form of drugs or their metabolite and degradation products are classified into two types: optical and chromatography methods which the last one in combination with various detectors provides a powerful method for routine and stability analyses. Some representative studies are reported in this review and the details of them are carefully explained. It is hoped that this review will be a good guideline study and provide a better understanding of these drugs from the aspects investigated in this study.
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Monofosfato de Adenosina , Monofosfato de Adenosina/análogos & derivados , Alanina , Alanina/análogos & derivados , Amidas , Antivirais , Tratamento Farmacológico da COVID-19 , Lopinavir , Pirazinas , Pirazinas/metabolismo , Amidas/metabolismo , Amidas/química , Antivirais/farmacologia , Monofosfato de Adenosina/metabolismo , Humanos , Alanina/metabolismo , Lopinavir/uso terapêutico , Lopinavir/metabolismo , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/metabolismo , AnimaisRESUMO
Remdesivir (RDV) emerged as an effective drug against the SARS-CoV-2 virus pandemic. One of the crucial steps in the mechanism of action of RDV is its incorporation into the growing RNA strand. RDV, an adenosine analogue, forms Watson-Crick (WC) type hydrogen bonds with uridine in the complementary strand and the strength of this interaction will control efficacy of RDV. While there is a plethora of structural and energetic information available about WC H-bonds in natural base pairs, the interaction of RDV with uridine has not been studied yet at the atomic level. In this article, we aim to bridge this gap, to understand RDV and its hydrogen bonding interactions, by employing density functional theory (DFT) at the M06-2X/cc-pVDZ level. The interaction energy, QTAIM analysis, NBO and SAPT2 are performed for RDV, adenosine, and their complex with uridine to gain insights into the nature of hydrogen bonding. The computations show that RDV has similar geometry, energetic, molecular orbitals, and aromaticity as adenosine, suggesting that RDV is an effective adenosine analogue. The important geometrical parameters, such as bond distances and red-shift in the stretching vibrational modes of adenosine, RDV and uridine identify two WC-type H-bonds. The relative strength of these two H-bonds is computed using QTAIM parameters and the computed hydrogen bond energy. Finally, the SAPT2 study is performed at the minima and at non-equilibrium base pair distances to understand the dominant intermolecular physical force. This study, based on a thorough analysis of a variety of computations, suggests that both adenosine and RDV have similar structure, energetic, and hydrogen bonding behaviour.
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Adenosina , Alanina/análogos & derivados , Teoria Quântica , Ligação de Hidrogênio , Uridina , Monofosfato de Adenosina/farmacologiaRESUMO
PURPOSE: Preliminary evidence suggests a potential effect of antiviral medication used during the acute COVID-19 phase for preventing long-COVID. This review investigates if having received pharmacological treatment during acute SARS-CoV-2 infection may reduce the risk of long-COVID. METHODS: MEDLINE, CINAHL, PubMed, EMBASE, Web of Science databases, as well as medRxiv/bioRxiv preprint servers were searched up to July 15th, 2023. Articles comparing the presence of long-COVID symptoms between individuals who received or not a specific medication, particularly antivirals, during the acute phase of SARS-CoV-2 infection were included. Methodological quality was assessed using the Newcastle-Ottawa Scale or Cochrane's Risk of Bias (Rob) tool. RESULTS: From 517 studies identified, 6 peer-reviewed studies and one preprint met all inclusion criteria. The sample included 2683 (n = 4) hospitalized COVID-19 survivors and 307,409 (n = 3) non-hospitalized patients. The methodological quality was high in 71% of studies (n = 5/7). Two studies investigating the effects of Nirmaltrevir/Ritonavir and three studies the effect of Remdesivir reported conflicting results on effectiveness for preventing long-COVID. Three studies investigating the effects of other medication such as Dexamethasone (n = 2) or Metformin (n = 1) found positive results of these medications for preventing long-COVID. CONCLUSION: Available evidence about the effect of medication treatment with antivirals during acute COVID-19 and reduced risk of developing long-COVID is conflicting. Heterogeneous evidence suggests that Remdesivir or Nirmaltrevir/Ritonavir could have a potential protective effect for long-COVID. A limited number of studies demonstrated a potential benefit of other medications such as Dexamethasone or Metformin, but more studies are needed.
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COVID-19 , Metformina , Humanos , Síndrome de COVID-19 Pós-Aguda , Ritonavir , SARS-CoV-2 , Antivirais/uso terapêutico , Dexametasona/uso terapêuticoRESUMO
BACKGROUND: The health crisis due to Covid-19 led to the search for therapeutics that could improve the evolution of the disease. Remdesivir, an antiviral that interferes with viral replication, was one of the first to be used for the treatment of this pathology. OBJECTIVE: To determine clinical course and mortality of patients with severe SARS-CoV-2 pneumonia treated with remdesivir, in comparison of those who didn't receive the medication. PATIENTS AND METHODS: Retrospective cohort study, with medical records review of COVID-19 patients, between August 2020 and August 2021. The subjects were divided into two groups, those who received remdesivir before or after admission to intensive care and those who didn't. The primary outcome variable was mortality in intensive care. RESULTS: Of 214 subjects included, 109 (50,9%) received remdesivir. The median of days for the drug administration was 8 (2-20), IQR: 3. The bivariate analysis prove that the use of remdesivir was related with lower risk of develop Acute Respiratory Distress Syndrome (ARDS) (p = 0,019; OR: 0,521) and lower requirement of mechanical ventilation (p = 0,006; OR:0,450). Additionally, patients treated with remdesivir develop less kidney injury (p = 0,009; OR: 0,441). There was a total of 82 deaths, 29 (26,6%) in the remdesivir group and 53 (50,5%) in the control group [p < 0,001; OR: 0,356 (0,201-0,630)]. All the risk factors associated with mortality in the bivariate analysis were entered into the multivariate analysis by logistic regression, the use of remdesivir remained associated as an independent protective factor to mortality (p = 0.034; OR: 0.429). CONCLUSION: Critically ill patients with SARS-CoV-2 pneumonia treated with remdesivir had a lower risk of death and need for mechanical ventilation and develop less ARDS as compared to the control group. No differences were found in the presentation of adverse effects.
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COVID-19 , Síndrome do Desconforto Respiratório , Adulto , Humanos , SARS-CoV-2 , Estado Terminal , Paraguai , Estudos Retrospectivos , Resultado do Tratamento , Tratamento Farmacológico da COVID-19 , Unidades de Terapia Intensiva , Síndrome do Desconforto Respiratório/tratamento farmacológico , Antivirais/uso terapêuticoRESUMO
BACKGROUNDS: Remdesivir (RDV) is an antiviral agent approved for the treatment of coronavirus disease 2019 (COVID-19); however, is not recommended for patients with renal impairment. Due to limitations associated with prospective clinical trials, real-world data on the safety and efficacy of RDV in patients with renal impairment are necessary. METHODS: Propensity score-matched (PSM) retrospective analysis was conducted between March 2020 and September 2022 in COVID-19 patients with an eGFR < 30 mL/min in four Korean hospitals. The RDV treatment group was matched to the untreated control group. The safety and clinical outcomes in patients who received RDV were analyzed. RESULTS: A total of 564 patients were enrolled; 229 patients received RDV either for treatment or prophylaxis. On day 5, no difference in nephrotoxicity was observed between the two groups, and liver enzyme levels were within the normal range. In multivariate analysis for new dialysis, RDV treatment was not a risk factor for new dialysis. Among the 564 patients, 417 were indicated for a 5-day course of RDV treatment and 211 patients were treated with RDV. After PSM, no differences in the clinical outcomes were observed between the two groups. CONCLUSION: RDV use in COVID-19 patients with renal impairment did not result in significant nephrotoxicity or hepatotoxicity.
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COVID-19 , Insuficiência Renal , Humanos , Tratamento Farmacológico da COVID-19 , Pontuação de Propensão , Estudos Prospectivos , Estudos Retrospectivos , Insuficiência Renal/complicações , Antivirais/efeitos adversosRESUMO
BACKGROUND: A trial performed among unvaccinated, high-risk outpatients with COVID-19 during the delta period showed remdesivir reduced hospitalization. We used our real-world data platform to determine the effectiveness of remdesivir on reducing 28-day hospitalization among outpatients with mild-moderate COVID-19 during an Omicron period including BQ.1/BQ.1.1/XBB.1.5. METHODS: We did a propensity-matched, retrospective cohort study of non-hospitalized adults with SARS-CoV-2 infection between April 7, 2022, and February 7, 2023. Electronic healthcare record data from a large health system in Colorado were linked to statewide vaccination and mortality data. We included patients with a positive SARS-CoV-2 test or outpatient remdesivir administration. Exclusion criteria were other SARS-CoV-2 treatments or positive SARS-CoV-2 test more than seven days before remdesivir. The primary outcome was all-cause hospitalization up to day 28. Secondary outcomes included 28-day COVID-related hospitalization and 28-day all-cause mortality. RESULTS: Among 29,270 patients with SARS-CoV-2 infection, 1,252 remdesivir-treated patients were matched to 2,499 untreated patients. Remdesivir was associated with lower 28-day all-cause hospitalization (1.3% vs. 3.3%, adjusted hazard ratio (aHR) 0.39 [95% CI 0.23-0.67], p < 0.001) than no treatment. All-cause mortality at 28 days was numerically lower among remdesivir-treated patients (0.1% vs. 0.4%; aOR 0.32 [95% CI 0.03-1.40]). Similar benefit of RDV treatment on 28-day all-cause hospitalization was observed across Omicron periods, aOR (95% CI): BA.2/BA2.12.1 (0.77[0.19-2.41]), BA.4/5 (0.50[95% CI 0.50-1.01]), BQ.1/BQ.1.1/XBB.1.5 (0.21[95% CI 0.08-0.57]. CONCLUSION: Among outpatients with SARS-CoV-2 during recent Omicron surges, remdesivir was associated with lower hospitalization than no treatment, supporting current National Institutes of Health Guidelines.
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Monofosfato de Adenosina , Alanina , Antivirais , Tratamento Farmacológico da COVID-19 , COVID-19 , Hospitalização , Pacientes Ambulatoriais , SARS-CoV-2 , Humanos , Alanina/análogos & derivados , Alanina/uso terapêutico , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Antivirais/uso terapêutico , COVID-19/mortalidade , Hospitalização/estatística & dados numéricos , SARS-CoV-2/efeitos dos fármacos , Idoso , Pacientes Ambulatoriais/estatística & dados numéricos , Adulto , Colorado , Resultado do TratamentoRESUMO
BACKGROUND AND METHODS: Heart transplant recipients (HTr) have a higher probability of suffer from severe coronavirus disease-2019 (COVID-19) in comparison to general population, but their risk has changed over the course of the pandemic in relation to various factors. We conducted a prospective study including all HTr at risk of COVID-19 in a tertiary center between February 2020 and October 2022. The aim was to analyze how the prognosis (incidence of pneumonia and mortality) of COVID-19 in HTr has evolved over time, contextualizing variants, vaccination, and other treatments. RESULTS: Of 308 HTr included, 124 got the infection (39.2%). COVID and non-COVID HTr had similar baseline characteristics. COVID-19 patients with pneumonia had a poorer prognosis than those with less severe presentations, with a higher rate of hospitalization (93.3 vs. 14.1%, p < .001) and death (41.0 vs. 1.2%, p < .001). Multivariate analysis identified age ≥60 years (odds ratio [OR] 3.65, 95% confidence interval [CI] 1.16-11.49, p = .027), and chronic kidney disease ≥3a (OR 4.95, 95% CI 1.39-17.54, p = .014) as predictors of pneumonia. Two-dose vaccination (OR 0.20, CI 95% 0.05-0.72, p = .02) and early remdesivir administration (OR 0.17, CI 0.03-0.90, p = .037) were protective factors. Over the course of the pandemic considering three periods in the follow-up (prevaccination February-December 2020, postvaccination January-December 2021, and post early remdesivir indication January-October 2022), we observed a reduction in pneumonia incidence from 62% to 19% (p < .001); and mortality (from 23% to 4%, p < .001). CONCLUSIONS: The prognosis of COVID-19 in HTr has improved over time, likely due to vaccination and early administration of remdesivir.
Assuntos
COVID-19 , Transplante de Coração , Humanos , Pessoa de Meia-Idade , COVID-19/epidemiologia , COVID-19/prevenção & controle , Pandemias , SARS-CoV-2 , Estudos Prospectivos , Transplante de Coração/efeitos adversos , TransplantadosRESUMO
Remdesivir and acetyl salicylic acid are often co-administered medications in the treatment of COVID-19, specifically targeting the viral infection and thromboembolism associated with the condition. Hence, it is essential to establish a technique that enables the concurrent quantification of these pharmaceutical compounds in plasma while also keeping environmentally friendly methods. Accordingly, the aim of this work is to simultaneously determine remdesivir and acetyl salicylic acid through a bioanalytical validated synchronous spectrofluorimetric method with applying principles of green chemistry. Since, the two drugs showed severe overlap after excitation at 242.0 nm, 284.0 nm for remdesivir and acetyl salicylic acid, respectively. The overlap was effectively overcome by using synchronous mode with a wavelength difference (Δλ) of 160.0 nm for remdesivir and 100.0 nm for acetyl salicylic acid. Different parameters have been optimized such as Δλ, solvent, pH and surfactant. A linear calibration was obtained over the concentration range 0.01-4.00 µg/mL for remdesivir and 0.01-3.00 µg/mL for acetyl salicylic acid and the method was precise and accurate. The method was successfully used for the investigation of pharmaceutical formulation and the quantification of the maximum plasma concentration (Cmax) of the two drugs. The method has been evaluated as an excellent green analytical method based on three greenness assessment tools.
RESUMO
Despite 3.5 years of the SARS-CoV-2 pandemic, we still lack effective drugs against COVID-19. The first and most widely used drug, remdesivir, has not yet been shown to be effective in adults. Even less is known about its effectiveness in children. Therefore, the aim of this retrospective study was to evaluate the safety and efficacy of remdesivir in pediatric patients with COVID-19 hospitalized in one medical center. The medical records of 328 children with COVID-19 were analyzed. Analysis was performed on the subgroups of children treated and not treated with remdesivir. Clinical data on general health, course of COVID-19 and treatment received were analyzed. Remdesivir was administered to 64 children, 16 to treat severe or critical illness and 48 because of the presence of risk factors to prevent progression to severe COVID-19. In children with severe COVID-19, remdesivir did not reduce the mortality rate. However, in patients with milder disease and risk factors, the drug significantly reduced the risk of progression to severe disease. Among adverse events, only mild aminotransferase elevations were observed in 4 patients, but none of these required discontinuation of treatment. CONCLUSIONS: Remdesivir is a safe treatment option for children with COVID-19. However, the efficacy of this therapy is still uncertain. It appears that in children with asymptomatic to moderate COVID-19 and risk factors for severe disease, remdesivir could be an effective method of prophylaxis. However, its efficacy in controlling severe disease is questionable and requires further study. WHAT IS KNOWN: ⢠There are still no effective drugs to combat COVID-19, and the efficacy of the widely used remdesivir in adults is controversial. ⢠All recommendations and guidelines on the use of remdesivir in the pediatric population are based mainly on clinical trials in adults. WHAT IS NEW: ⢠Remdesivir is a safe treatment for COVID-19 in the pediatric population. ⢠In children with asymptomatic to moderate COVID-19 and risk factors for severe disease, remdesivir could be an effective drug to prevent disease progression. However, its efficacy in treating severe disease in children needs further exploration.
Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , COVID-19 , Adulto , Humanos , Criança , SARS-CoV-2 , Estudos Retrospectivos , Estudos de Coortes , Tratamento Farmacológico da COVID-19 , Antivirais/efeitos adversosRESUMO
Remdesivir plays a key role in the treatment of coronavirus disease in 2019 (COVID-19). Haemodialysis is sometimes required for hospitalised patients with COVID-19, and patients undergoing haemodialysis are at an increased risk of severe COVID-19. In the present study, we report the serum concentrations of GS-441524, the active metabolite of remdesivir, in four patients undergoing continuous renal replacement therapy (CRRT). Patient 1, a male aged 70s, received a loading dose of 200 mg remdesivir on day 1, followed by 100 mg remdesivir from day 2, according to the package insert as in non-haemodialysis patients. The mean trough serum concentration of GS-441524 was 783.5 ng/mL, which was approximately 7-fold higher than the mean for patients with an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min. Patients 2-4 received a loading dose of 200 mg remdesivir on day 1, followed by 100 mg once every 2 days from day 2. The mean trough serum concentrations of GS-441524 were 302.2 ng/mL, 585.8 ng/mL and 677.3 ng/mL, respectively. These were 3 to 6-fold higher than the mean for patients with eGFR ≥60 mL/min. The target doses for patients 1, 2, 3, and 4 receiving CRRT were 13.6 mL/kg/h, 6.0-12.5 mL/kg/h, 20.1 mL/kg/h, and 15.1 mL/kg/h, respectively, using a polysulphone membrane. The package insert dose of remdesivir is an overdose for CRRT patients with a target dose of 10-20 mL/kg/h. In low-intensity CRRT, as in Japan, it may be necessary to extend the interval between the doses of remdesivir.