BACKGROUND Coronavirus disease 2019(COVID-19)pandemic stimulates research works to find a solution to this crisis from starting 2020 year up to now.With ending of the 2021-year,various advances in pharmacotherapy agai...BACKGROUND Coronavirus disease 2019(COVID-19)pandemic stimulates research works to find a solution to this crisis from starting 2020 year up to now.With ending of the 2021-year,various advances in pharmacotherapy against COVID-19 have emerged.Regarding antiviral therapy,casirivimab and imdevimab antibody combination is a type of new immunotherapy against COVID-19.Standard antiviral therapy against COVID-19 includes Remdesivir and Favipiravir.AIM To evaluate the efficacy of antibodies cocktail(casirivimab and imdevimab)compared to standard antiviral therapy in reducing the need for invasive mechanical ventilation(IMV).METHODS 265 COVID-19 polymerase chain reaction confirmed patients with indication for antiviral therapy were included in this study and were divided into 3 groups(1:2:2):Group A:REGN3048-3051 antibodies cocktail(casirivimab and imdevimab),group B:Remdesivir,group C:Favipiravir.The study design is a single-blind nonrandomized controlled trial Mansoura University Hospital owns the study’s drugs.The duration of the study was about 6 mo after ethical approval.RESULTS Casirivimab and imdevimab achieve less need for O2 therapy and IMV,with less duration of this need than remdesivir and favipiravir.CONCLUSION Group A(casirivimab and imdevimab)achieve better clinical outcomes than groups B(remdesivir)and C(favipiravir)intervention groups.展开更多
BACKGROUND Coronavirus disease 2019(COVID-19)has demonstrated several clinical manifestations which include not only respiratory system issues but also liver,kidney,and other organ injuries.One of these abnormalities ...BACKGROUND Coronavirus disease 2019(COVID-19)has demonstrated several clinical manifestations which include not only respiratory system issues but also liver,kidney,and other organ injuries.One of these abnormalities is coagulopathies,including thrombosis and disseminated intravascular coagulation.Because of this,the administration of low molecular weight heparin is required for patients that need to be hospitalized.In addition,Remdesivir is an antiviral that was used against Middle East Acute Respiratory Syndrome,Ebola,Acute Respiratory Syndrome,and other diseases,showing satisfactory results on recovery.Besides,there is evidence suggesting that this medication can provide a better prognosis for patients with COVID-19.AIM To investigate in silico the interaction between Remdesivir and clotting factors,pursuing a possibility of using it as medicine.METHODS In this in silico study,the 3D structures of angiotensin-converting enzyme 2(ACE2),Factor I(fibrinogen),Factor II(prothrombin),Factor III(thromboplastin),Factor V(proaccelerin),Factor VII(proconvertin),Factor VIII(antihemophilic factor A),Factor IX(antihemophilic factor B),Factor X(Stuart-Prower factor),and Factor XI(precursor of thromboplastin(these structures are technically called receptors)were selected from the Protein Data Bank.The structures of the antivirals Remdesivir and Osetalmivir(these structures are called ligands)were selected from the PubChem database,while the structure of Atazanavir was selected from the ZINC database.The software AutoDock Tools(ADT)was used to prepare the receptors for molecular docking.Ions,peptides,water molecules,and other ones were removed from each ligand,and then,hydrogen atoms were added to the structures.The grid box was delimited and calculated using the same software ADT.A physiological environment with pH 7.4 is needed to make the ligands interact with the receptors,and still the software Marvin sketch®(ChemAxon®)was used to forecast the protonation state.To perform molecular docking,ADT and Vina software was connected.Using PyMol®software and Discovery studio®software from BIOVIA,it was possible to analyze the amino acid residues from receptors that were involved in the interactions with the ligands.Ligand tortions,atoms that participated in the interactions,and the type,strength,and duration of the interactions were also analyzed using those software.RESULTS Molecular docking analysis showed that Remdesivir and ACE2 had an affinity energy of-8.8 kcal/moL,forming a complex with eight hydrogen bonds involving seven atoms of Remdesivir and five amino acid residues of ACE2.Remdesivir and prothrombin had an interaction with six hydrogen bonds involving atoms of the drug and five amino acid residues of the clotting factor.Similar to that,Remdesivir and thromboplastin presented interactions via seven hydrogen bonds involving five atoms of the drug and four residues of the clotting factor.While Remdesivir and Factor V established a complex with seven hydrogen bonds between six antiviral atoms and six amino acid residues from the factor,and Factor VII connected with the drug by four hydrogen bonds,which involved three atoms of the drug and three residues of amino acids of the factor.The complex between Remdesivir and Factor IX formed an interaction via 11 hydrophilic bonds with seven atoms of the drug and seven residues of the clotting factor,plus one electrostatic bond and three hydrophobic interactions.Factor X and Remdesivir had an affinity energy of-9.6 kcal/moL,and the complex presented 10 hydrogen bonds and 14 different hydrophobic interactions which involved nine atoms of the drug and 16 amino acid residues of the clotting factor.The interaction between Remdesivir and Factor XI formed five hydrogen bonds involving five amino acid residues of the clotting factor and five of the antiviral atoms.CONCLUSION Because of the in silico significant affinity,Remdesivir possibly could act in the severe acute respiratory syndrome coronavirus 2 infection blockade by interacting with ACE2 and concomitantly act in the modulation of the coagulation cascade preventing the hypercoagulable state.展开更多
COVID-19 is an immune-mediated inflammatory disease caused by SARS-CoV-2 infection,the combination of anti-inflammatory and antiviral therapy is predicted to provide clinical benefits.We recently demonstrated that mas...COVID-19 is an immune-mediated inflammatory disease caused by SARS-CoV-2 infection,the combination of anti-inflammatory and antiviral therapy is predicted to provide clinical benefits.We recently demonstrated that mast cells(MCs)are an essential mediator of SARS-CoV-2-initiated hyperinflammation.We also showed that spike protein-induced MC degranulation initiates alveolar epithelial inflammation for barrier disruption and suggested an off-label use of antihistamines as MC stabilizers to block degranulation and consequently suppress inflammation and prevent lung injury.In this study,we emphasized the essential role of MCs in SARS-CoV-2-induced lung lesions in vivo,and demonstrated the benefits of co-administration of antihistamines and antiviral drug remdesivir in SARS-CoV-2-infected mice.Specifically,SARSCoV-2 spike protein-induced MC degranulation resulted in alveolar-capillary injury,while pretreatment of pulmonary microvascular endothelial cells with antihistamines prevented adhesion junction disruption;predictably,the combination of antiviral drug remdesivir with the antihistamine loratadine,a histamine receptor 1(HR1)antagonist,dampened viral replication and inflammation,thereby greatly reducing lung injury.Our findings emphasize the crucial role of MCs in SARS-CoV-2-induced inflammation and lung injury and provide a feasible combination antiviral and anti-inflammatory therapy for COVID-19 treatment.展开更多
BACKGROUND Since the beginning of corona virus disease 2019(COVID-19)pandemic,there has been a widespread use of remdesivir in adults and children.There is little known information about its outcomes in patients with ...BACKGROUND Since the beginning of corona virus disease 2019(COVID-19)pandemic,there has been a widespread use of remdesivir in adults and children.There is little known information about its outcomes in patients with end stage renal disease who are on dialysis.AIM To assess the clinical outcomes with use of remdesivir in adult patients with end stage kidney failure on hemodialysis.METHODS A retrospective,multicenter study was conducted on patients with end stage renal disease on hemodialysis that were discharged after treatment for COVID-19 between April 1,2020 and December 31,2020.Primary endpoints were oxygen requirements,time to mortality and escalation of care needing mechanical ventilation.RESULTS A total of 45 patients were included in the study.Twenty patients received remdesivir,and 25 patients did not receive remdesivir.Most patients were caucasian,females with diabetes mellitus and hypertension being the commonest comorbidities.There was a trend towards reduced oxygen requirement(beta=-25.93,X^(2)(1)=6.65,P=0.0099,probability of requiring mechanical ventilation(beta=-28.52,X^(2)(1)=22.98,P<0.0001)and mortality(beta=-5.03,X^(2)(1)=7.41,P=0.0065)in patients that received remdesivir compared to the control group.CONCLUSION Larger studies are justified to study the effects of remdesivir in this high-risk population with end stage kidney disease on dialysis.展开更多
Strong infectivity enables coronavirus disease 2019(COVID-19)to rage throughout the world.Moreover,the lack of drugs with definite therapeutic effects further aggravates the spread of the pandemic.Remdesivir is one of...Strong infectivity enables coronavirus disease 2019(COVID-19)to rage throughout the world.Moreover,the lack of drugs with definite therapeutic effects further aggravates the spread of the pandemic.Remdesivir is one of the most promising anti-severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)drugs.However,the limited clinical effects make its therapeutic effect controversial,which may result from the poor accumulation and activation of remdesivir in the lung.Therefore,we developed lyophilized remdesivir liposomes(Rdv-lips)which can be reconstituted as liposomal aerosol for pulmonary delivery to improve the in vivo behavior of existing remdesivir cyclodextrin conclusion compound(Rdv-cyc)injections.Liposome encapsulation endowed remdesivir with much higher solubility and better biocompatibility.The in vitro liposomal aerosol characterization demonstrated that Rdv-lips possessed a mass median aerodynamic diameter of 4.118μm and fine particle fraction(<5μm)higher than 50%,indicating good pulmonary delivery properties.Compared to the Rdv-cyc intravenous injection group,the Rdv-lips inhalation group displayed a nearly 100-fold increase in the remdesivir-active metabolite nucleotide triphosphate(NTP)concentration and better NTP accumulation in the lung than the Rdv-cyc inhalation group.A faster transition from remdesivir to NTP of Rdv-lips(inhalation)could also be observed due to better cell uptake.Compared to other preparations,the superiority of Rdv-lips was further evidenced by the results of an in vivo safety study,with little possibility of inducing inflammation.In conclusion,Rdv-lips for pulmonary delivery will be a potent formulation to improve the in vivo behavior of remdesivir and exert better therapeutic effects in COVID-19 treatment.展开更多
BACKGROUND Remdesivir is a broad-spectrum antiviral drug having in vitro activity against severe acute respiratory syndrome coronavirus 2 and is currently being used on a compassionate basis outside of clinical trials...BACKGROUND Remdesivir is a broad-spectrum antiviral drug having in vitro activity against severe acute respiratory syndrome coronavirus 2 and is currently being used on a compassionate basis outside of clinical trials.AIM To analyze the efficacy and safety of remdesivir compared with other interventions in coronavirus disease 2019(COVID-19)patients.METHODS We searched online databases to include randomized controlled trials evaluating the efficacy and safety of remdesivir compared with other interventions in COVID-19 patients.We summarized efficacy and safety data as risk ratios(RRs)with 95%confidence interval(CI)and used Mantel-Haenszel fixed or randomeffect models.We estimated the number needed to treat(NNT)to cause one additional outcome.We used the GRADE approach to assess the quality of the evidence for all outcome parameters.RESULTS We included four randomized controlled trials.We observed no significant difference in mortality(RR:0.83;95%CI:0.57–1.20;I2=59%)and rate of ventilation(RR:0.69;95%CI:0.41-1.18;I2=77%)between remdesivir-and placebo-treated patients.Remdesivir showed higher rates of clinical recovery than placebo(RR:1.10;95%CI:1.04–1.16;I2=0%;NNT:14.3).We observed no difference in overall adverse events between remdesivir-and placebo-treated patients(RR:1.05;95%CI:0.86–1.27;I2=77%).We observed less risk of serious adverse events(RR:0.75;95%CI:0.63–0.89;I2=0%)in remdesivir-than placebo-treated patients.The GRADE approach suggested moderate quality of evidence for all efficacy and safety outcomes.CONCLUSION We observed limited clinical benefit of remdesivir over placebo in the treatment of COVID-19.Our findings could be biased because of the small number of trials.展开更多
Infectious pandemics result in hundreds and millions of deaths,notable examples of the Spanish Flu,the Black Death and smallpox.The current pandemic,caused by SARS-CoV-2(severe acute respiratory syndrome coronavirus 2...Infectious pandemics result in hundreds and millions of deaths,notable examples of the Spanish Flu,the Black Death and smallpox.The current pandemic,caused by SARS-CoV-2(severe acute respiratory syndrome coronavirus 2),is unprecedented even in the historical term of pandemics.The unprecedentedness is featured by multiple surges,rapid identification of therapeutic options and accelerated development of vaccines.Remdesivir,originally developed for Ebola viral disease,is the first treatment of COVID-19(Coronavirus disease 2019)approved by the United States Food and Drug Administration.As demonstrated by in vitro and preclinical studies,this therapeutic agent is highly potent with a broad spectrum activity against viruses from as many as seven families even cross species.However,randomized controlled trials have failed to confirm the efficacy and safety.Remdesivir improves some clinical signs but not critical parameters such as mortality.This antiviral agent is an ester/phosphorylation prodrug and excessive hydrolysis which increases cellular toxicity.Remdesivir is given intravenously,leading to concentration spikes and likely increasing the potential of hydrolysis-based toxicity.This review has proposed a conceptual framework for improving its efficacy and minimizing toxicity not only for the COVID-19 pandemic but also for future ones caused by remdesivir-sensitive viruses.展开更多
Background Remdesivir is being studied and used to treat coronavirus disease 2019(COVID-19).This study aimed to systematically identify,critically evaluate,and summarize the findings of the studies on the cost-effecti...Background Remdesivir is being studied and used to treat coronavirus disease 2019(COVID-19).This study aimed to systematically identify,critically evaluate,and summarize the findings of the studies on the cost-effectiveness of remdesivir in the treatment of hospitalized patients with COVID-19.Methods In this systematic review,PubMed,EMBASE,Web of Science,SCOPUS,and the Cochrane Library were searched for studies published between 2019 and 2022.We included all full economic evaluations of remdesivir for the treatment of hospitalized patients with COVID-19.Data were summarized in a structured and narrative manner.Results Out of 616 articles obtained in this literature search,12 studies were included in the final analysis.The mean score of the Quality of Health Economic Studies(QHES)for the studies was 87.66(high quality).All studies were conducted in high-income countries(eight studies in the USA and one study in England),except for three studies from middle-to-high-income countries(China,South Africa,and Turkey).Six studies conducted their economic analysis in terms of a health system perspective;five studies conducted their economic analysis from a payer perspective;three studies from the perspective of a health care provider.The results of five studies showed that remdesivir was cost-effective compared to standard treatment.Furthermore,the therapeutic strategy of combining remdesivir with baricitinib was cost-effective compared to remdesivir alone.Conclusions Based on the results of the present study,remdesivir appears to be cost-effective in comparison with the standard of care in China,Turkey,and South Africa.Studies conducted in the United States show conflicting results,and combining remdesivir with baricitinib is cost-effective compared with remdesivir alone.However,the cost-effectiveness of remdesivir in low-income countries remains unknown.Thus,more studies in different countries are required to determine the cost-effectiveness of this drug.展开更多
Remdesivir(RDV) is the only US Food and Drug Administration(FDA)-approved drug for treating COVID-19.However,RDV can only be given by intravenous route,and there is a pressing medical need for oral antivirals.Signific...Remdesivir(RDV) is the only US Food and Drug Administration(FDA)-approved drug for treating COVID-19.However,RDV can only be given by intravenous route,and there is a pressing medical need for oral antivirals.Significant evidence suggests that the role of the parent nucleoside GS-441524 in the clinical outcomes of RDV could be largely underestimated.We performed an in vitro and in vivo drug metabolism and pharmacokinetics(DMPK) assessment to examine the potential of RDV,and particularly GS-441524,as oral drugs.In our in vitro assessments,RDV exhibited prohibitively low stability in human liver microsomes(HLMs,t1/2=-1 min),with the primary CYP-mediated metabolism being the mono-oxidation likely on the phosphoramidate moiety.This observation is poorly aligned with any potential oral use of RDV,though in the presence of cobicistat,the microsomal stability was drastically boosted to the level observed without enzyme cofactor NADPH.Conversely,GS-441524 showed excellent metabolic stability in human plasma and HLMs.In further in vivo studies in CD-1 mice,GS-441524 displayed a favorable oral bioavailability of 57%.Importantly,GS-441524 produced adequate drug exposure in the mice plasma and lung,and was effectively converted to the active triphosphate,suggesting that it could be a promising oral antiviral drug for treating COVID-19.展开更多
The coronavirus disease(COVID-19)pandemic has led to a global struggle to cope with the sheer numbers of infected persons,many of whom require intensive care support or eventually succumb to the illness.The outbreak i...The coronavirus disease(COVID-19)pandemic has led to a global struggle to cope with the sheer numbers of infected persons,many of whom require intensive care support or eventually succumb to the illness.The outbreak is managed by a combination of disease containment via public health measures and supportive care for those who are affected.To date,there is no specific anti-COVID-19 treatment.However,the urgency to identify treatments that could turn the tide has led to the emergence of several investigational drugs as potential candidates to improve outcome,especially in the severe to critically ill.While many of these adjunctive drugs are being investigated in clinical trials,professional bodies have attempted to clarify the setting where the use of these drugs may be considered as off-label or compassionate use.This review summarizes the clinical evidence of investigational adjunctive treatments used in COVID-19 patients as well as the recommendations of their use from guidelines issued by international and national organizations in healthcare.展开更多
Global prevalence of coronavirus disease 2019(COVID-19)calls for an urgent development of anti-viral regime.Compared with the development of new drugs,drug repurposing can significantly reduce the cost,time,and safety...Global prevalence of coronavirus disease 2019(COVID-19)calls for an urgent development of anti-viral regime.Compared with the development of new drugs,drug repurposing can significantly reduce the cost,time,and safety risks.Given the fact that coronavirus harnesses spike protein to invade host cells through angiotensinconverting enzyme 2(ACE2),hence we see if any previous anti-virtual compounds can block spike-ACE2 interaction and inhibit the virus entry.The results of molecular docking and molecular dynamic simulations revealed that remdesivir exhibits better than expected anti-viral invasion potential against COVID-19 among the three types of compounds including remdesivir,tenofovir and lopinavir.In addition,a positive correlation between the surface area occupied by remdesivir and anti-viral invasion potential was also found.As such,the structure of remdesivir was modified by linking an N-benzyl substituted diamidine derivative to its hydroxyl group through an ester bond.It was found that this compound has a higher anti-viral invasion potential and greater specificity.展开更多
The start of the global pandemic secondary to the novel SARS-CoV-2 virus was a time of uncertainty and fear as it claimed the lives of many across the world.Since then,there has been a plethora of research designs and...The start of the global pandemic secondary to the novel SARS-CoV-2 virus was a time of uncertainty and fear as it claimed the lives of many across the world.Since then,there has been a plethora of research designs and trials in order to understand what we can do to stop the spread of the disease.Scientists and health care providers have utilized old medications and revamped them for current use such a convalescent plasma and steroids,as well as creating novel therapeutics,some with promising results.In this article,we review the major therapeutic options currently available and look into what the future still holds in order to further our understanding of this mysterious disease.展开更多
文摘BACKGROUND Coronavirus disease 2019(COVID-19)pandemic stimulates research works to find a solution to this crisis from starting 2020 year up to now.With ending of the 2021-year,various advances in pharmacotherapy against COVID-19 have emerged.Regarding antiviral therapy,casirivimab and imdevimab antibody combination is a type of new immunotherapy against COVID-19.Standard antiviral therapy against COVID-19 includes Remdesivir and Favipiravir.AIM To evaluate the efficacy of antibodies cocktail(casirivimab and imdevimab)compared to standard antiviral therapy in reducing the need for invasive mechanical ventilation(IMV).METHODS 265 COVID-19 polymerase chain reaction confirmed patients with indication for antiviral therapy were included in this study and were divided into 3 groups(1:2:2):Group A:REGN3048-3051 antibodies cocktail(casirivimab and imdevimab),group B:Remdesivir,group C:Favipiravir.The study design is a single-blind nonrandomized controlled trial Mansoura University Hospital owns the study’s drugs.The duration of the study was about 6 mo after ethical approval.RESULTS Casirivimab and imdevimab achieve less need for O2 therapy and IMV,with less duration of this need than remdesivir and favipiravir.CONCLUSION Group A(casirivimab and imdevimab)achieve better clinical outcomes than groups B(remdesivir)and C(favipiravir)intervention groups.
文摘BACKGROUND Coronavirus disease 2019(COVID-19)has demonstrated several clinical manifestations which include not only respiratory system issues but also liver,kidney,and other organ injuries.One of these abnormalities is coagulopathies,including thrombosis and disseminated intravascular coagulation.Because of this,the administration of low molecular weight heparin is required for patients that need to be hospitalized.In addition,Remdesivir is an antiviral that was used against Middle East Acute Respiratory Syndrome,Ebola,Acute Respiratory Syndrome,and other diseases,showing satisfactory results on recovery.Besides,there is evidence suggesting that this medication can provide a better prognosis for patients with COVID-19.AIM To investigate in silico the interaction between Remdesivir and clotting factors,pursuing a possibility of using it as medicine.METHODS In this in silico study,the 3D structures of angiotensin-converting enzyme 2(ACE2),Factor I(fibrinogen),Factor II(prothrombin),Factor III(thromboplastin),Factor V(proaccelerin),Factor VII(proconvertin),Factor VIII(antihemophilic factor A),Factor IX(antihemophilic factor B),Factor X(Stuart-Prower factor),and Factor XI(precursor of thromboplastin(these structures are technically called receptors)were selected from the Protein Data Bank.The structures of the antivirals Remdesivir and Osetalmivir(these structures are called ligands)were selected from the PubChem database,while the structure of Atazanavir was selected from the ZINC database.The software AutoDock Tools(ADT)was used to prepare the receptors for molecular docking.Ions,peptides,water molecules,and other ones were removed from each ligand,and then,hydrogen atoms were added to the structures.The grid box was delimited and calculated using the same software ADT.A physiological environment with pH 7.4 is needed to make the ligands interact with the receptors,and still the software Marvin sketch®(ChemAxon®)was used to forecast the protonation state.To perform molecular docking,ADT and Vina software was connected.Using PyMol®software and Discovery studio®software from BIOVIA,it was possible to analyze the amino acid residues from receptors that were involved in the interactions with the ligands.Ligand tortions,atoms that participated in the interactions,and the type,strength,and duration of the interactions were also analyzed using those software.RESULTS Molecular docking analysis showed that Remdesivir and ACE2 had an affinity energy of-8.8 kcal/moL,forming a complex with eight hydrogen bonds involving seven atoms of Remdesivir and five amino acid residues of ACE2.Remdesivir and prothrombin had an interaction with six hydrogen bonds involving atoms of the drug and five amino acid residues of the clotting factor.Similar to that,Remdesivir and thromboplastin presented interactions via seven hydrogen bonds involving five atoms of the drug and four residues of the clotting factor.While Remdesivir and Factor V established a complex with seven hydrogen bonds between six antiviral atoms and six amino acid residues from the factor,and Factor VII connected with the drug by four hydrogen bonds,which involved three atoms of the drug and three residues of amino acids of the factor.The complex between Remdesivir and Factor IX formed an interaction via 11 hydrophilic bonds with seven atoms of the drug and seven residues of the clotting factor,plus one electrostatic bond and three hydrophobic interactions.Factor X and Remdesivir had an affinity energy of-9.6 kcal/moL,and the complex presented 10 hydrogen bonds and 14 different hydrophobic interactions which involved nine atoms of the drug and 16 amino acid residues of the clotting factor.The interaction between Remdesivir and Factor XI formed five hydrogen bonds involving five amino acid residues of the clotting factor and five of the antiviral atoms.CONCLUSION Because of the in silico significant affinity,Remdesivir possibly could act in the severe acute respiratory syndrome coronavirus 2 infection blockade by interacting with ACE2 and concomitantly act in the modulation of the coagulation cascade preventing the hypercoagulable state.
基金supported by the National Natural Science Foundation of China(82172242,81873965)State Key Laboratory of Respiratory Disease,Guangzhou,China(SKLRD-OP-202207)+2 种基金National Key R&D Program of China(2020YFC0842000)Natural Science Foundation of Guangdong(2022A1515012053)Key Project from the Chinese Academy of Sciences(QYZDB-SSWSMC059)。
文摘COVID-19 is an immune-mediated inflammatory disease caused by SARS-CoV-2 infection,the combination of anti-inflammatory and antiviral therapy is predicted to provide clinical benefits.We recently demonstrated that mast cells(MCs)are an essential mediator of SARS-CoV-2-initiated hyperinflammation.We also showed that spike protein-induced MC degranulation initiates alveolar epithelial inflammation for barrier disruption and suggested an off-label use of antihistamines as MC stabilizers to block degranulation and consequently suppress inflammation and prevent lung injury.In this study,we emphasized the essential role of MCs in SARS-CoV-2-induced lung lesions in vivo,and demonstrated the benefits of co-administration of antihistamines and antiviral drug remdesivir in SARS-CoV-2-infected mice.Specifically,SARSCoV-2 spike protein-induced MC degranulation resulted in alveolar-capillary injury,while pretreatment of pulmonary microvascular endothelial cells with antihistamines prevented adhesion junction disruption;predictably,the combination of antiviral drug remdesivir with the antihistamine loratadine,a histamine receptor 1(HR1)antagonist,dampened viral replication and inflammation,thereby greatly reducing lung injury.Our findings emphasize the crucial role of MCs in SARS-CoV-2-induced inflammation and lung injury and provide a feasible combination antiviral and anti-inflammatory therapy for COVID-19 treatment.
文摘BACKGROUND Since the beginning of corona virus disease 2019(COVID-19)pandemic,there has been a widespread use of remdesivir in adults and children.There is little known information about its outcomes in patients with end stage renal disease who are on dialysis.AIM To assess the clinical outcomes with use of remdesivir in adult patients with end stage kidney failure on hemodialysis.METHODS A retrospective,multicenter study was conducted on patients with end stage renal disease on hemodialysis that were discharged after treatment for COVID-19 between April 1,2020 and December 31,2020.Primary endpoints were oxygen requirements,time to mortality and escalation of care needing mechanical ventilation.RESULTS A total of 45 patients were included in the study.Twenty patients received remdesivir,and 25 patients did not receive remdesivir.Most patients were caucasian,females with diabetes mellitus and hypertension being the commonest comorbidities.There was a trend towards reduced oxygen requirement(beta=-25.93,X^(2)(1)=6.65,P=0.0099,probability of requiring mechanical ventilation(beta=-28.52,X^(2)(1)=22.98,P<0.0001)and mortality(beta=-5.03,X^(2)(1)=7.41,P=0.0065)in patients that received remdesivir compared to the control group.CONCLUSION Larger studies are justified to study the effects of remdesivir in this high-risk population with end stage kidney disease on dialysis.
基金supported by National Natural Science Foundation(81871477,81603051,and 81673377)Natural Science Foundation of Jiangsu Province(BK20160760 and BK20170748)+2 种基金The Anti-COVID-19 Emergency Research Project of China Pharmaceutical University(2632020ZX007)The Creation of Major New Drugs National Major Projects(2017ZX09101001-004)Fundamental Research Funds for the Central Universities(2016ZPY015,2632017PY18).
文摘Strong infectivity enables coronavirus disease 2019(COVID-19)to rage throughout the world.Moreover,the lack of drugs with definite therapeutic effects further aggravates the spread of the pandemic.Remdesivir is one of the most promising anti-severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)drugs.However,the limited clinical effects make its therapeutic effect controversial,which may result from the poor accumulation and activation of remdesivir in the lung.Therefore,we developed lyophilized remdesivir liposomes(Rdv-lips)which can be reconstituted as liposomal aerosol for pulmonary delivery to improve the in vivo behavior of existing remdesivir cyclodextrin conclusion compound(Rdv-cyc)injections.Liposome encapsulation endowed remdesivir with much higher solubility and better biocompatibility.The in vitro liposomal aerosol characterization demonstrated that Rdv-lips possessed a mass median aerodynamic diameter of 4.118μm and fine particle fraction(<5μm)higher than 50%,indicating good pulmonary delivery properties.Compared to the Rdv-cyc intravenous injection group,the Rdv-lips inhalation group displayed a nearly 100-fold increase in the remdesivir-active metabolite nucleotide triphosphate(NTP)concentration and better NTP accumulation in the lung than the Rdv-cyc inhalation group.A faster transition from remdesivir to NTP of Rdv-lips(inhalation)could also be observed due to better cell uptake.Compared to other preparations,the superiority of Rdv-lips was further evidenced by the results of an in vivo safety study,with little possibility of inducing inflammation.In conclusion,Rdv-lips for pulmonary delivery will be a potent formulation to improve the in vivo behavior of remdesivir and exert better therapeutic effects in COVID-19 treatment.
文摘BACKGROUND Remdesivir is a broad-spectrum antiviral drug having in vitro activity against severe acute respiratory syndrome coronavirus 2 and is currently being used on a compassionate basis outside of clinical trials.AIM To analyze the efficacy and safety of remdesivir compared with other interventions in coronavirus disease 2019(COVID-19)patients.METHODS We searched online databases to include randomized controlled trials evaluating the efficacy and safety of remdesivir compared with other interventions in COVID-19 patients.We summarized efficacy and safety data as risk ratios(RRs)with 95%confidence interval(CI)and used Mantel-Haenszel fixed or randomeffect models.We estimated the number needed to treat(NNT)to cause one additional outcome.We used the GRADE approach to assess the quality of the evidence for all outcome parameters.RESULTS We included four randomized controlled trials.We observed no significant difference in mortality(RR:0.83;95%CI:0.57–1.20;I2=59%)and rate of ventilation(RR:0.69;95%CI:0.41-1.18;I2=77%)between remdesivir-and placebo-treated patients.Remdesivir showed higher rates of clinical recovery than placebo(RR:1.10;95%CI:1.04–1.16;I2=0%;NNT:14.3).We observed no difference in overall adverse events between remdesivir-and placebo-treated patients(RR:1.05;95%CI:0.86–1.27;I2=77%).We observed less risk of serious adverse events(RR:0.75;95%CI:0.63–0.89;I2=0%)in remdesivir-than placebo-treated patients.The GRADE approach suggested moderate quality of evidence for all efficacy and safety outcomes.CONCLUSION We observed limited clinical benefit of remdesivir over placebo in the treatment of COVID-19.Our findings could be biased because of the small number of trials.
基金supported by National Institutes of Health Grants R01 EB018748,R21 Al153031University of Cincinnati Cancer Center(Yan,B).
文摘Infectious pandemics result in hundreds and millions of deaths,notable examples of the Spanish Flu,the Black Death and smallpox.The current pandemic,caused by SARS-CoV-2(severe acute respiratory syndrome coronavirus 2),is unprecedented even in the historical term of pandemics.The unprecedentedness is featured by multiple surges,rapid identification of therapeutic options and accelerated development of vaccines.Remdesivir,originally developed for Ebola viral disease,is the first treatment of COVID-19(Coronavirus disease 2019)approved by the United States Food and Drug Administration.As demonstrated by in vitro and preclinical studies,this therapeutic agent is highly potent with a broad spectrum activity against viruses from as many as seven families even cross species.However,randomized controlled trials have failed to confirm the efficacy and safety.Remdesivir improves some clinical signs but not critical parameters such as mortality.This antiviral agent is an ester/phosphorylation prodrug and excessive hydrolysis which increases cellular toxicity.Remdesivir is given intravenously,leading to concentration spikes and likely increasing the potential of hydrolysis-based toxicity.This review has proposed a conceptual framework for improving its efficacy and minimizing toxicity not only for the COVID-19 pandemic but also for future ones caused by remdesivir-sensitive viruses.
文摘Background Remdesivir is being studied and used to treat coronavirus disease 2019(COVID-19).This study aimed to systematically identify,critically evaluate,and summarize the findings of the studies on the cost-effectiveness of remdesivir in the treatment of hospitalized patients with COVID-19.Methods In this systematic review,PubMed,EMBASE,Web of Science,SCOPUS,and the Cochrane Library were searched for studies published between 2019 and 2022.We included all full economic evaluations of remdesivir for the treatment of hospitalized patients with COVID-19.Data were summarized in a structured and narrative manner.Results Out of 616 articles obtained in this literature search,12 studies were included in the final analysis.The mean score of the Quality of Health Economic Studies(QHES)for the studies was 87.66(high quality).All studies were conducted in high-income countries(eight studies in the USA and one study in England),except for three studies from middle-to-high-income countries(China,South Africa,and Turkey).Six studies conducted their economic analysis in terms of a health system perspective;five studies conducted their economic analysis from a payer perspective;three studies from the perspective of a health care provider.The results of five studies showed that remdesivir was cost-effective compared to standard treatment.Furthermore,the therapeutic strategy of combining remdesivir with baricitinib was cost-effective compared to remdesivir alone.Conclusions Based on the results of the present study,remdesivir appears to be cost-effective in comparison with the standard of care in China,Turkey,and South Africa.Studies conducted in the United States show conflicting results,and combining remdesivir with baricitinib is cost-effective compared with remdesivir alone.However,the cost-effectiveness of remdesivir in low-income countries remains unknown.Thus,more studies in different countries are required to determine the cost-effectiveness of this drug.
基金the Center for Drug Design, College of Pharmacy, University of Minnesota, USA, for supporting this research。
文摘Remdesivir(RDV) is the only US Food and Drug Administration(FDA)-approved drug for treating COVID-19.However,RDV can only be given by intravenous route,and there is a pressing medical need for oral antivirals.Significant evidence suggests that the role of the parent nucleoside GS-441524 in the clinical outcomes of RDV could be largely underestimated.We performed an in vitro and in vivo drug metabolism and pharmacokinetics(DMPK) assessment to examine the potential of RDV,and particularly GS-441524,as oral drugs.In our in vitro assessments,RDV exhibited prohibitively low stability in human liver microsomes(HLMs,t1/2=-1 min),with the primary CYP-mediated metabolism being the mono-oxidation likely on the phosphoramidate moiety.This observation is poorly aligned with any potential oral use of RDV,though in the presence of cobicistat,the microsomal stability was drastically boosted to the level observed without enzyme cofactor NADPH.Conversely,GS-441524 showed excellent metabolic stability in human plasma and HLMs.In further in vivo studies in CD-1 mice,GS-441524 displayed a favorable oral bioavailability of 57%.Importantly,GS-441524 produced adequate drug exposure in the mice plasma and lung,and was effectively converted to the active triphosphate,suggesting that it could be a promising oral antiviral drug for treating COVID-19.
文摘The coronavirus disease(COVID-19)pandemic has led to a global struggle to cope with the sheer numbers of infected persons,many of whom require intensive care support or eventually succumb to the illness.The outbreak is managed by a combination of disease containment via public health measures and supportive care for those who are affected.To date,there is no specific anti-COVID-19 treatment.However,the urgency to identify treatments that could turn the tide has led to the emergence of several investigational drugs as potential candidates to improve outcome,especially in the severe to critically ill.While many of these adjunctive drugs are being investigated in clinical trials,professional bodies have attempted to clarify the setting where the use of these drugs may be considered as off-label or compassionate use.This review summarizes the clinical evidence of investigational adjunctive treatments used in COVID-19 patients as well as the recommendations of their use from guidelines issued by international and national organizations in healthcare.
文摘Global prevalence of coronavirus disease 2019(COVID-19)calls for an urgent development of anti-viral regime.Compared with the development of new drugs,drug repurposing can significantly reduce the cost,time,and safety risks.Given the fact that coronavirus harnesses spike protein to invade host cells through angiotensinconverting enzyme 2(ACE2),hence we see if any previous anti-virtual compounds can block spike-ACE2 interaction and inhibit the virus entry.The results of molecular docking and molecular dynamic simulations revealed that remdesivir exhibits better than expected anti-viral invasion potential against COVID-19 among the three types of compounds including remdesivir,tenofovir and lopinavir.In addition,a positive correlation between the surface area occupied by remdesivir and anti-viral invasion potential was also found.As such,the structure of remdesivir was modified by linking an N-benzyl substituted diamidine derivative to its hydroxyl group through an ester bond.It was found that this compound has a higher anti-viral invasion potential and greater specificity.
文摘The start of the global pandemic secondary to the novel SARS-CoV-2 virus was a time of uncertainty and fear as it claimed the lives of many across the world.Since then,there has been a plethora of research designs and trials in order to understand what we can do to stop the spread of the disease.Scientists and health care providers have utilized old medications and revamped them for current use such a convalescent plasma and steroids,as well as creating novel therapeutics,some with promising results.In this article,we review the major therapeutic options currently available and look into what the future still holds in order to further our understanding of this mysterious disease.
