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1.
J Toxicol Sci ; 46(9): 425-435, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34470994

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). SARS-CoV-2 enters host cells by binding with the receptor angiotensin-converting enzyme 2 (ACE2). While ACE2 is expressed in multiple cell types, it has been implicated in the clinical progression of COVID-19 as an entry point for SARS-CoV-2 into respiratory cells. Human respiratory cells, such as airway and alveolar epithelial type II (ATII) cells, are considered essential for COVID-19 research; however, primary human respiratory cells are difficult to obtain. In the present study, we generated ATII and club cells from human induced pluripotent stem cells (hiPSCs) for SARS-CoV-2 infection and drug testing. The differentiated cells expressed ATII markers (SFTPB, SFTPC, ABCA3, SLC34A2) or club cell markers (SCGB1A1 and SCGB3A2). Differentiated cells, which express ACE2 and TMPRSS2, were infected with SARS-CoV-2. Remdesivir treatment decreased intracellular SARS-CoV-2 viral replication and, furthermore, treatment with bleomycin showed cytotoxicity in a concentration-dependent manner. These data suggest that hiPSC-derived AT2 and club cells provide a useful in vitro model for drug development.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Células Epiteliais Alveolares/efeitos dos fármacos , Antivirais/farmacologia , Bleomicina/toxicidade , Diferenciação Celular , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , Testes de Toxicidade , Monofosfato de Adenosina/farmacologia , Alanina/farmacologia , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Células Epiteliais Alveolares/virologia , COVID-19/tratamento farmacológico , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Interações Hospedeiro-Patógeno , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Células-Tronco Pluripotentes Induzidas/virologia , Fenótipo , SARS-CoV-2/crescimento & desenvolvimento , SARS-CoV-2/patogenicidade , Replicação Viral/efeitos dos fármacos
2.
J Assoc Physicians India ; 69(8): 11-12, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34472806

RESUMO

BACKGROUND: Despite global efforts, COVID 19 pandemic is still posing a serious challenge with dearth of effective treatment options. Remdesivir has got FDA approval as the first COVID-19 anti-viral agent in adult and paediatric patients (aged ≥12 years and weighing at least 40 kg) requiring hospitalization. OBJECTIVE: The present prospective, observational, cross sectional study was planned to evaluate the impact of early initiation of Remdesivir on clinical outcomes in moderate to severe COVID 19 patients requiring ICU care. Materials and Methods: In this study, 100 consecutive symptomatic RT-PCR positive COVID 19 patients requiring admission to Intensive care unit based on predefined criteria were included for evaluation. All such moderate to severely ill patients were given Remdesivir intravenously as a 200-mg loading dose on day 1, followed by a 100-mg maintenance dose for the next four days along with other standard care. The main outcome measure analysed was the impact of early initiation of Remdesivir on recovery assessed by number of days in hospital, recovery, biochemical improvements and death. Results: Out of total 100 patients, 84 patients recovered with Remdesivir along with supportive treatment and were discharged from the hospital. Mean age of patients at presentation 53.5± 14.8 years with 5:1 male preponderance. Mean duration of hospital stay was 11.6 ± 5.9 days. D-dimer, CRP, Ferritin, IL-6 decreased significantly post treatment with P values <0.05, <0.001, <0.001, <0.01 respectively when compared to values at admission. No significant side effects were seen with remdesivir infusion. CONCLUSION: This real-world experience suggests that in the subset of hospitalized patients with moderate to severe pneumonia, early use of Remdesivir can lead to better clinical outcomes and help in reduction of associated mortality and morbidity of COVID-19.


Assuntos
COVID-19 , Monofosfato de Adenosina/análogos & derivados , Adulto , Idoso , Alanina/análogos & derivados , COVID-19/tratamento farmacológico , Criança , Estudos Transversais , Humanos , Índia , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , SARS-CoV-2 , Resultado do Tratamento
3.
Sci Rep ; 11(1): 17787, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34493774

RESUMO

Despite COVID-19's significant morbidity and mortality, considering cost-effectiveness of pharmacologic treatment strategies for hospitalized patients remains critical to support healthcare resource decisions within budgetary constraints. As such, we calculated the cost-effectiveness of using remdesivir and dexamethasone for moderate to severe COVID-19 respiratory infections using the United States health care system as a representative model. A decision analytic model modelled a base case scenario of a 60-year-old patient admitted to hospital with COVID-19. Patients requiring oxygen were considered moderate severity, and patients with severe COVID-19 required intubation with intensive care. Strategies modelled included giving remdesivir to all patients, remdesivir in only moderate and only severe infections, dexamethasone to all patients, dexamethasone in severe infections, remdesivir in moderate/dexamethasone in severe infections, and best supportive care. Data for the model came from the published literature. The time horizon was 1 year; no discounting was performed due to the short duration. The perspective was of the payer in the United States health care system. Supportive care for moderate/severe COVID-19 cost $11,112.98 with 0.7155 quality adjusted life-year (QALY) obtained. Using dexamethasone for all patients was the most-cost effective with an incremental cost-effectiveness ratio of $980.84/QALY; all remdesivir strategies were more costly and less effective. Probabilistic sensitivity analyses showed dexamethasone for all patients was most cost-effective in 98.3% of scenarios. Dexamethasone for moderate-severe COVID-19 infections was the most cost-effective strategy and would have minimal budget impact. Based on current data, remdesivir is unlikely to be a cost-effective treatment for COVID-19.


Assuntos
COVID-19/tratamento farmacológico , COVID-19/terapia , Custos de Cuidados de Saúde/estatística & dados numéricos , Alocação de Recursos para a Atenção à Saúde/economia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/economia , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/economia , Alanina/uso terapêutico , COVID-19/diagnóstico , COVID-19/economia , COVID-19/mortalidade , COVID-19/virologia , Tomada de Decisão Clínica/métodos , Simulação por Computador , Análise Custo-Benefício , Dexametasona/economia , Dexametasona/uso terapêutico , Alocação de Recursos para a Atenção à Saúde/organização & administração , Humanos , Unidades de Terapia Intensiva/economia , Unidades de Terapia Intensiva/estatística & dados numéricos , Pessoa de Meia-Idade , Oxigênio/administração & dosagem , Oxigênio/economia , Anos de Vida Ajustados por Qualidade de Vida , Respiração Artificial/economia , SARS-CoV-2 , Índice de Gravidade de Doença , Resultado do Tratamento , Estados Unidos/epidemiologia
4.
BMJ Case Rep ; 14(9)2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34479903

RESUMO

Remdesivir is an antiviral used for the treatment of COVID-19 requiring hospitalisation. Information on its cardiovascular safety profile is scarce. We report the case of a 37-year-old man with COVID-19 who developed bradycardia after receiving remdesivir. We recommend a baseline ECG for all patients prior to receiving remdesivir and continuous cardiac monitoring during treatment, especially among those with underlying cardiovascular disease, elderly and using ß-blockers.


Assuntos
Bradicardia , COVID-19 , Monofosfato de Adenosina/análogos & derivados , Adulto , Idoso , Alanina/análogos & derivados , Antivirais/uso terapêutico , Bradicardia/induzido quimicamente , Bradicardia/tratamento farmacológico , COVID-19/tratamento farmacológico , Humanos , Masculino , SARS-CoV-2
5.
Adv Ther ; 38(9): 4935-4948, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34379304

RESUMO

INTRODUCTION: This study aims to evaluate the cost-effectiveness of remdesivir compared to other existing therapies (SoC) in Turkey to treat COVID-19 patients hospitalized with < 94% saturation and low-flow oxygen therapy (LFOT) requirement. METHODS: We compared remdesivir as the treatment for COVID-19 with the treatments in the Turkish treatment guidelines. Analyses were performed using data from 78 hospitalized COVID-19 patients with SpO2 < 94% who received LFOT in a tertiary healthcare facility. COVID-19 episode costs were calculated for 78 patients considering the cost of modeled remdesivir treatment in the same group from the payer's perspective. The incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) was calculated for remdesivir versus the SoC for the population identified. For Turkey, a reimbursement threshold value between USD 8599 (1 × per capita gross domestic product-GDP) and USD 25.797 (3 × GDP) per QALY was used. RESULTS: In the remdesivir arm, the length of hospital stay (LOS) was 3 days shorter than the SOC. The low ventilator requirement in the remdesivir arm was one factor that decreased the QALY disutility value. In patients who were transferred to intensive care unit (ICU) from the ward, the mean LOS was 17.3 days (SD 13.6), and the mean cost of stay was USD 155.3/day (SD 168.0), while in patients who were admitted to ICU at baseline, the mean LOS was 13.1 days (SD 13.7), and the mean cost of stay was USD 207.9/day (SD 133.6). The mean cost of episode per patient was USD 3461.1 (SD 2259.8) in the remdesivir arm and USD 3538.9 (SD 3296.0) in the SOC arm. Incremental QALYs were estimated at 0.174. Remdesivir treatment was determined to be cost saving vs. SoC. CONCLUSIONS: Remdesivir, which results in shorter LOS and lower rates of intubation requirements in ICU patients than existing therapies, is associated with higher QALYs and lower costs, dominating SoC in patients with SpO2 < 94% who require oxygen support.


Assuntos
COVID-19 , Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , COVID-19/tratamento farmacológico , Análise Custo-Benefício , Humanos , Oxigênio , SARS-CoV-2 , Turquia
6.
Drug Saf ; 44(9): 987-998, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34374967

RESUMO

INTRODUCTION: The safety profile of remdesivir, conditionally approved for COVID-19, was limited at its 2020 introduction. Adverse drug reactions (ADRs) for medicines are collected in VigiBase, the WHO Global Database of Individual Case Safety Reports (ICSRs). OBJECTIVE: This study aimed to provide a descriptive analysis of COVID-19 ICSR data focusing on remdesivir, including a disproportionality analysis (DA) of ADRs. METHODS: A dedicated algorithm enabled retrieval of all COVID-19 treatment-specific ICSRs. A severity algorithm based on co-reported medicines and symptoms enabled selection of tocilizumab with its well established safety profile as comparator for remdesivir. Descriptive statistics were used for general ICSR demographics for all COVID-19-specific medicines, remdesivir and tocilizumab individually and furthermore to present treatment patterns of medicines co-reported with remdesivir. A COVID-19 indication-focused DA was deployed to minimize confounding from underlying polysymptomatic disease. RESULTS: 14,574 COVID-19-related ICSRs were entered into VigiBase during 2020. Remdesivir was the most common medicine reported. Of 4944 remdesivir ICSRs, where tocilizumab was not co-reported, 93% described remdesivir as the sole suspect medicine. Sixty percent of ICSRs concerned males, median age was 63 years and the majority originated from the Americas (72%). In 1089 (21%) of remdesivir ICSRs, data indicated severe/critical disease. Co-reported medicines peaked during the first 3 days of remdesivir treatment. The DA for the established tocilizumab and the new remdesivir were mainly in line with the safety profiles for both medicines but suggested new safety concerns. The most reported ADRs for remdesivir represented liver dysfunction, kidney injury, death and bradycardia. CONCLUSION: Global COVID-19-related ADR reporting proved useful in providing information on ADRs as well as on treatment patterns in this patient group. Indication-focused disproportionality analysis, together with the use of a comparator with a known safety profile, proved effective in identifying known safety information and suggested new safety concerns for remdesivir.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Alanina/análogos & derivados , Antivirais/efeitos adversos , COVID-19/tratamento farmacológico , Monofosfato de Adenosina/efeitos adversos , Monofosfato de Adenosina/uso terapêutico , Adolescente , Adulto , Fatores Etários , Idoso , Alanina/efeitos adversos , Alanina/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Antivirais/uso terapêutico , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , SARS-CoV-2 , Índice de Gravidade de Doença , Fatores Sexuais , Fatores Socioeconômicos , Organização Mundial da Saúde , Adulto Jovem
7.
Curr Opin Crit Care ; 27(5): 487-492, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34353998

RESUMO

PURPOSE OF REVIEW: COVID-19 represents an unprecedented public health crisis caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The antiviral remdesivir is one component of treating COVID-19. Unfortunately, the trials evaluating remdesivir have reported mixed results, leading to uncertainty on when to use remdesivir. This review discusses the trials evaluating the efficacy of remdesivir for COVID-19 and other supporting data to help inform the role of remdesivir in patients with COVID-19. RECENT FINDINGS: Since the start of the pandemic, there have been four randomized trials of remdesivir in treating patients hospitalized with COVID-19. More recently, extensive observational studies have provided supportive data. SUMMARY: The majority of trials evaluating remdesivir suggest that remdesivir is effective in the treatment of patients hospitalized with COVID-19. Although there may be a benefit in some subgroups more than others, there is insufficient data to make definitive statements about benefits or lack of benefits in particular groups. Remdesivir has demonstrated clinical benefits such as decreased time in the hospital, lower progression to mechanical ventilation, and decreased utilization of other hospital resources; it is unclear if it reduces mortality, but one randomized controlled trial suggested possible survival benefits. Based on the data available, remdesivir has been approved (or authorized for early use) in 48 countries.


Assuntos
COVID-19 , Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Humanos , SARS-CoV-2
8.
Viruses ; 13(8)2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34452451

RESUMO

SARS-CoV-2 has caused an extensive pandemic of COVID-19 all around the world. Key viral enzymes are suitable molecular targets for the development of new antivirals against SARS-CoV-2 which could represent potential treatments of the corresponding disease. With respect to its essential role in the replication of viral RNA, RNA-dependent RNA polymerase (RdRp) is one of the prime targets. HeE1-2Tyr and related derivatives were originally discovered as inhibitors of the RdRp of flaviviruses. Here, we present that these pyridobenzothiazole derivatives also significantly inhibit SARS-CoV-2 RdRp, as demonstrated using both polymerase- and cell-based antiviral assays.


Assuntos
Antivirais/farmacologia , Benzotiazóis/farmacologia , RNA-Polimerase RNA-Dependente de Coronavírus/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , SARS-CoV-2/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Alanina/análogos & derivados , Alanina/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , SARS-CoV-2/enzimologia , SARS-CoV-2/fisiologia
9.
Nutrients ; 13(8)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34445055

RESUMO

BACKGROUND: We previously reported that severe COVID-19 patients had higher chances of survival and a reduced risk of developing respiratory failure when administered with the probiotic formulation SLAB51. This study aimed to investigate further bacteriotherapy mechanisms and how early they are activated. METHODS: We performed an analysis on the blood oxygenation parameters collected in sixty-nine severe COVID-19 patients requiring non-invasive oxygen therapy and presenting a CT lung involvement ≥50%. Twenty-nine patients received low-molecular-weight heparin, azithromycin and Remdesivir. In addition, forty subjects received SLAB51. Blood gas analyses were performed before the beginning of treatments and at 24 h. RESULTS: The patients receiving only standard therapy needed significantly increased oxygen amounts during the 24 h observation period. Furthermore, they presented lower blood levels of pO2, O2Hb and SaO2 than the group also supplemented with oral bacteriotherapy. In vitro data suggest that SLAB51 can reduce nitric oxide synthesis in intestinal cells. CONCLUSIONS: SARS-CoV-2 infected patients may present lesions in the lungs compromising their gas exchange capability. The functionality of the organs essential for these patients' survival depends mainly on the levels of pO2, O2Hb and SaO2. SLAB51 contains enzymes that could reduce oxygen consumption in the intestine, making it available for the other organs.


Assuntos
COVID-19/terapia , Oxigênio/uso terapêutico , Probióticos/uso terapêutico , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Idoso , Alanina/análogos & derivados , Alanina/uso terapêutico , Antivirais/uso terapêutico , Azitromicina/uso terapêutico , Gasometria , Linhagem Celular , Feminino , Heparina , Humanos , Hipóxia , Itália , Pulmão , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
10.
Int J Mol Sci ; 22(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34445605

RESUMO

Coronavirus disease (COVID-19) is a contagious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This case report presents a patient who had difficulty eradicating the corona virus due to being treated with Rituximab, which depletes B lymphocyte cells and therefore disables the production of neutralizing antibodies. The combined use of external anti-viral agents like convalescent plasma, IVIG and Remdesivir successfully helped the patient's immune system to eradicate the virus without B-cell population recovery. In vitro studies showed that convalescent plasma is the main agent that helped in eradicating the virus.


Assuntos
Anticorpos Antivirais/imunologia , Linfócitos B/imunologia , COVID-19/tratamento farmacológico , COVID-19/imunologia , COVID-19/terapia , SARS-CoV-2/imunologia , Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Animais , Anticorpos Neutralizantes/uso terapêutico , Antivirais/uso terapêutico , COVID-19/diagnóstico por imagem , Chlorocebus aethiops , Humanos , Imunização Passiva , Hospedeiro Imunocomprometido , Rituximab/uso terapêutico , Linfócitos T/imunologia , Células Vero
11.
Beijing Da Xue Xue Bao Yi Xue Ban ; 53(4): 716-720, 2021 Aug 18.
Artigo em Chinês | MEDLINE | ID: mdl-34393234

RESUMO

OBJECTIVE: To investigate the role of rebamipide in the treatment of acute gout arthritis rats induced by monosodium urate (MSU) crystal. METHODS: Forty-two male rats were randomly divided into three groups (n=14). Group A was treated with oral rebamipide, group B with oral colchicine, and group C with oral placebo. The rats were monitored for the induction of arthritis with clinical manifestations and pathological changes, and the levels of interleukin (IL)-1ß、IL-6、IL-10, and tumor necrosis factor (TNF)-α in serum were measured. RESULTS: In group C, the clinical score and swelling index reached the maximum in 24 h, and then gradually decreased to 72 h. After 24 h of model induced, the clinical scores in group C were significantly higher than those in group A and group B [2 (1-3) vs. 0 (0-1) vs. 1 (0-2), P < 0.01], the swelling indexes in group C were significantly higher than those in group A and group B [0.36 (0.16-0.52) vs. 0.11 (0-0.20) vs. 0.12 (0-0.16), P < 0.01]. Histologically, after 24 h of model induced, there was a large number of neutrophil infiltration in the synovium of group C [scale score: 4 (2-4)], and there was no significant inflammatory cell infiltration in group A [1 (0-2)] and group B [1 (0-2)], the difference was statistically significant (P < 0.001). After 24 h of model induced, the levels of IL-1ß, IL-6, IL-10, and TNF-α in serum of group C were significantly higher than those in group A and B [IL-1ß: (41.86±5.72) vs. (27.35±7.47) vs. (27.76±5.28) ng/L, IL-6: (1 575.55±167.11) vs. (963.53±90.22) vs. (964.08±99.31) ng/L, IL-10: (37.96±3.76) vs. (21.68±4.83) vs. (16.20±2.49) ng/L, TNF-α: (21.32±1.34) vs. (15.82±2.54) vs. (17.35±7.47) µg/L, P < 0.001]. CONCLUSION: Rebamipide has a protective effect on acute gout arthritis rats induced by MUS crystals.


Assuntos
Artrite Gotosa , Quinolonas , Alanina/análogos & derivados , Animais , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/tratamento farmacológico , Interleucina-1beta , Masculino , Ratos , Ácido Úrico
12.
Cochrane Database Syst Rev ; 8: CD014962, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34350582

RESUMO

BACKGROUND: Remdesivir is an antiviral medicine with properties to inhibit viral replication of SARS-CoV-2. Positive results from early studies attracted media attention and led to emergency use authorisation of remdesivir in COVID-19.  A thorough understanding of the current evidence regarding the effects of remdesivir as a treatment for SARS-CoV-2 infection based on randomised controlled trials (RCTs) is required. OBJECTIVES: To assess the effects of remdesivir compared to placebo or standard care alone on clinical outcomes in hospitalised patients with SARS-CoV-2 infection, and to maintain the currency of the evidence using a living systematic review approach. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register (which comprises the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and medRxiv) as well as Web of Science (Science Citation Index Expanded and Emerging Sources Citation Index) and WHO COVID-19 Global literature on coronavirus disease to identify completed and ongoing studies without language restrictions. We conducted the searches on 16 April 2021. SELECTION CRITERIA: We followed standard Cochrane methodology. We included RCTs evaluating remdesivir for the treatment of SARS-CoV-2 infection in hospitalised adults compared to placebo or standard care alone irrespective of disease severity, gender, ethnicity, or setting.  We excluded studies that evaluated remdesivir for the treatment of other coronavirus diseases. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess risk of bias in included studies, we used the Cochrane RoB 2 tool for RCTs. We rated the certainty of evidence using the GRADE approach for outcomes that were reported according to our prioritised categories: all-cause mortality at up to day 28, duration to liberation from invasive mechanical ventilation, duration to liberation from supplemental oxygen, new need for mechanical ventilation (high-flow oxygen or non-invasive or invasive mechanical ventilation), new need for invasive mechanical ventilation, new need for non-invasive mechanical ventilation or high-flow oxygen, new need for oxygen by mask or nasal prongs, quality of life, adverse events (any grade), and serious adverse events. MAIN RESULTS: We included five RCTs with 7452 participants diagnosed with SARS-CoV-2 infection and a mean age of 59 years, of whom 3886 participants were randomised to receive remdesivir. Most participants required low-flow oxygen (n=4409) or mechanical ventilation (n=1025) at baseline. We identified two ongoing studies, one was suspended due to a lack of COVID-19 patients to recruit. Risk of bias was considered to be of some concerns or high risk for clinical status and safety outcomes because participants who had died did not contribute information to these outcomes. Without adjustment, this leads to an uncertain amount of missing values and the potential for bias due to missing data. Effects of remdesivir in hospitalised individuals  Remdesivir probably makes little or no difference to all-cause mortality at up to day 28 (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.81 to 1.06; risk difference (RD) 8 fewer per 1000, 95% CI 21 fewer to 7 more; 4 studies, 7142 participants; moderate-certainty evidence). Considering the initial severity of condition, only one study showed a beneficial effect of remdesivir in patients who received low-flow oxygen at baseline (RR 0.32, 95% CI 0.15 to 0.66, 435 participants), but conflicting results exists from another study, and we were unable to validly assess this observations due to limited availability of comparable data. Remdesivir may have little or no effect on the duration to liberation from invasive mechanical ventilation (2 studies, 1298 participants, data not pooled, low-certainty evidence). We are uncertain whether remdesivir increases or decreases the chance of clinical improvement in terms of duration to liberation from supplemental oxygen at up to day 28 (3 studies, 1691 participants, data not pooled, very low-certainty evidence).   We are very uncertain whether remdesivir decreases or increases the risk of clinical worsening in terms of new need for mechanical ventilation at up to day 28 (high-flow oxygen or non-invasive ventilation or invasive mechanical ventilation) (RR 0.78, 95% CI 0.48 to 1.24; RD 29 fewer per 1000, 95% CI 68 fewer to 32 more; 3 studies, 6696 participants; very low-certainty evidence); new need for non-invasive mechanical ventilation or high-flow oxygen (RR 0.70, 95% CI 0.51 to 0.98; RD 72 fewer per 1000, 95% CI 118 fewer to 5 fewer; 1 study, 573 participants; very low-certainty evidence); and new need for oxygen by mask or nasal prongs (RR 0.81, 95% CI 0.54 to 1.22; RD 84 fewer per 1000, 95% CI 204 fewer to 98 more; 1 study, 138 participants; very low-certainty evidence). The evidence suggests that remdesivir may decrease the risk of clinical worsening in terms of new need for invasive mechanical ventilation (67 fewer participants amongst 1000 participants; RR 0.56, 95% CI 0.41 to 0.77; 2 studies, 1159 participants; low-certainty evidence).  None of the included studies reported quality of life. Remdesivir probably decreases the serious adverse events rate at up to 28 days (RR 0.75, 95% CI 0.63 to 0.90; RD 63 fewer per 1000, 95% CI 94 fewer to 25 fewer; 3 studies, 1674 participants; moderate-certainty evidence). We are very uncertain whether remdesivir increases or decreases adverse events rate (any grade) (RR 1.05, 95% CI 0.86 to 1.27; RD 29 more per 1000, 95% CI 82 fewer to 158 more; 3 studies, 1674 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: Based on the currently available evidence, we are moderately certain that remdesivir probably has little or no effect on all-cause mortality at up to day 28 in hospitalised adults with SARS-CoV-2 infection. We are uncertain about the effects of remdesivir on clinical improvement and worsening. There were insufficient data available to validly examine the effect of remdesivir on mortality in subgroups depending on the extent of respiratory support at baseline.  Future studies should provide additional data on efficacy and safety of remdesivir for defined core outcomes in COVID-19 research, especially for different population subgroups. This could allow us to draw more reliable conclusions on the potential benefits and harms of remdesivir in future updates of this review. Due to the living approach of this work, we will update the review periodically.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Monofosfato de Adenosina/uso terapêutico , Alanina/uso terapêutico , Viés , COVID-19/mortalidade , Causas de Morte , Intervalos de Confiança , Progressão da Doença , Humanos , Pessoa de Meia-Idade , Oxigênio/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Respiração Artificial , SARS-CoV-2 , Desmame do Respirador
13.
Life Sci Alliance ; 4(10)2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34344719

RESUMO

The duration of viral shedding is determined by a balance between de novo infection and removal of infected cells. That is, if infection is completely blocked with antiviral drugs (100% inhibition), the duration of viral shedding is minimal and is determined by the length of virus production. However, some mathematical models predict that if infected individuals are treated with antiviral drugs with efficacy below 100%, viral shedding may last longer than without treatment because further de novo infections are driven by entry of the virus into partially protected, uninfected cells at a slower rate. Using a simple mathematical model, we quantified SARS-CoV-2 infection dynamics in non-human primates and characterized the kinetics of viral shedding. We counterintuitively found that treatments initiated early, such as 0.5 d after virus inoculation, with intermediate to relatively high efficacy (30-70% inhibition of virus replication) yield a prolonged duration of viral shedding (by about 6.0 d) compared with no treatment.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , COVID-19/virologia , Eliminação de Partículas Virais/efeitos dos fármacos , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Alanina/análogos & derivados , Alanina/farmacologia , Animais , Pulmão/virologia , Macaca mulatta , Modelos Teóricos , Nariz/virologia , Faringe/virologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia , Fatores de Tempo , Carga Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
14.
Eur Rev Med Pharmacol Sci ; 25(14): 4854-4867, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34337735

RESUMO

OBJECTIVE: The purpose of this narrative review is to discuss the available information regarding the currently utilized COVID-19 therapies (and the evidence level supporting them) and opioids for chronic pain with a focus on warnings of potential interactions between these two therapeutic approaches. MATERIALS AND METHODS: Papers were retrieved from a PubMed search, using different combinations of keywords [e.g., pain treatment AND COVID-19 AND drug-drug interaction (DDI)], without limitations in terms of publication date and language. RESULTS: Remdesivir is an inhibitor of CYP3A4 and may increase the plasma concentration of CYP3A4 substrates (e.g., fentanyl). Dexamethasone is an inducer of CYP3A4 and glycoprotein P, thus coadministration with drugs metabolized by this isoform will lead to their increased clearance. Dexamethasone may cause hypokalemia, thus potentiating the risk of ventricular arrhythmias if it is given with opioids able to prolong the QT interval, such as oxycodone and methadone. Finally, the existing differences among opioids with regard to their impact on immune responses should also be taken into account with only tapentadol and hydromorphone appearing neutral on both cytokine production and immune parameters. CONCLUSIONS: Clinicians should keep in mind the frequent DDIs with drugs extensively metabolized by the CYP450 system and prefer opioids undergoing a limited hepatic metabolism. Identification and management of DDIs and dissemination of the related knowledge should be a major goal in the delivery of chronic care to ensure optimized patient outcomes and facilitate updating recommendations for COVID-19 therapy in frail populations, namely comorbid, poly-medicated patients or individuals suffering from substance use disorder.


Assuntos
Analgésicos Opioides/uso terapêutico , COVID-19/tratamento farmacológico , Dor Crônica/tratamento farmacológico , SARS-CoV-2 , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , Dexametasona/uso terapêutico , Interações Medicamentosas , Humanos
15.
Front Cell Infect Microbiol ; 11: 700502, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34395311

RESUMO

The recent COVID-19 pandemic has highlighted the urgency to develop effective antiviral therapies against the disease. Murine hepatitis virus (MHV) is a coronavirus that infects mice and shares some sequence identity to SARS-CoV-2. Both viruses belong to the Betacoronavirus genus, and MHV thus serves as a useful and safe surrogate model for SARS-CoV-2 infections. Clinical trials have indicated that remdesivir is a potentially promising antiviral drug against COVID-19. Using an in vitro model of MHV infection of RAW264.7 macrophages, the safety and efficacy of monotherapy of remdesivir, chloroquine, ivermectin, and doxycycline were investigated. Of the four drugs tested, remdesivir monotherapy exerted the strongest inhibition of live virus and viral RNA replication of about 2-log10 and 1-log10, respectively (at 6 µM). Ivermectin treatment showed the highest selectivity index. Combination drug therapy was also evaluated using remdesivir (6 µM) together with chloroquine (15 µM), ivermectin (2 µM) or doxycycline (15 µM) - above their IC50 values and at high macrophage cell viability of over 95%. The combination of remdesivir and ivermectin exhibited highly potent synergism by achieving significant reductions of about 7-log10 of live virus and 2.5-log10 of viral RNA in infected macrophages. This combination also resulted in the lowest cytokine levels of IL-6, TNF-α, and leukemia inhibitory factor. The next best synergistic combination was remdesivir with doxycycline, which decreased levels of live virus by ~3-log10 and viral RNA by ~1.5-log10. These results warrant further studies to explore the mechanisms of action of the combination therapy, as well as future in vivo experiments and clinical trials for the treatment of SARS-CoV-2 infection.


Assuntos
COVID-19 , Infecções por Coronavirus , Vírus da Hepatite Murina , Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Infecções por Coronavirus/tratamento farmacológico , Humanos , Ivermectina/farmacologia , Camundongos , Pandemias , SARS-CoV-2
16.
Viruses ; 13(7)2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34372575

RESUMO

GS-441524 is an adenosine analog and the parent nucleoside of the prodrug remdesivir, which has received emergency approval for treatment of COVID-19. Recently, GS-441524 has been proposed to be effective in the treatment of COVID-19, perhaps even being superior to remdesivir for treatment of this disease. Evaluation of the clinical effectiveness of GS-441524 requires understanding of its uptake and intracellular conversion to GS-441524 triphosphate, the active antiviral substance. We here discuss the potential impact of these pharmacokinetic steps of GS-441524 on the formation of its active antiviral substance and effectiveness for treatment of COVID-19. Available protein expression data suggest that several adenosine transporters are expressed at only low levels in the epithelial cells lining the alveoli in the lungs, i.e., the alveolar cells or pneumocytes from healthy lungs. This may limit uptake of GS-441524. Importantly, cellular uptake of GS-441524 may be reduced during hypoxia and inflammation due to decreased expression of adenosine transporters. Similarly, hypoxia and inflammation may lead to reduced expression of adenosine kinase, which is believed to convert GS-441524 to GS-441524 monophosphate, the perceived rate-limiting step in the intracellular formation of GS-441524 triphosphate. Moreover, increases in extracellular and intracellular levels of adenosine, which may occur during critical illnesses, has the potential to competitively decrease cellular uptake and phosphorylation of GS-441524. Taken together, tissue hypoxia and severe inflammation in COVID-19 may lead to reduced uptake and phosphorylation of GS-441524 with lowered therapeutic effectiveness as a potential outcome. Hypoxia may be particularly critical to the ability of GS-441524 to eliminate SARS-CoV-2 from tissues with low basal expression of adenosine transporters, such as alveolar cells. This knowledge may also be relevant to treatments with other antiviral adenosine analogs and anticancer adenosine analogs as well.


Assuntos
Adenosina/análogos & derivados , Antivirais/farmacologia , COVID-19/tratamento farmacológico , SARS-CoV-2/efeitos dos fármacos , Adenosina/farmacocinética , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Alanina/análogos & derivados , Alanina/farmacologia , Animais , Humanos , Fosforilação , Pró-Fármacos
17.
J Assoc Physicians India ; 69(7): 14-19, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34431263

RESUMO

Introduction: Remdesivir and Tocilizumab are two experimental drugs used in severely ill COVID-19 patients. Various clinical trials studying these drugs are giving conflicting results. Our aim is to study these two drugs and share the experience in our setting. Methods: Our Study is a retrospective analysis of Clinico-laboratory details and outcome of three groups of patients who were given either (i) Remdesivir or (ii) Tocilizumab or (iii)both Remdesivir and Tocilizumab . We compared the outcome of these patients with other patients who did not receive either of these drugs, when it was not available or not introduced as experimental drugs earlier in treatment guidelines. Results: Out of a total of 521 patients, in the above three groups who received either or both Remdesivir or Tocilizumab, 334 survived. Out of 214 patients who did not receive any of the two drugs only 74 survived. The outcome was better individually for all the three groups of patients receiving either or both of the drugs as compared to neither of the drugs.(p <0.01) Conclusion: Remdesivir and Tocilizumab were useful drugs in treatment of severely ill covid -19 patients as compared with the patients who did not receive any of the above drugs.


Assuntos
COVID-19 , Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Anticorpos Monoclonais Humanizados , COVID-19/tratamento farmacológico , Humanos , Estudos Retrospectivos , SARS-CoV-2
18.
Int J Mol Sci ; 22(13)2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34206780

RESUMO

Vascular calcification (VC) is a risk factor for cardiovascular events and mortality in chronic kidney disease (CKD). Several components influence the occurrence of VC, among which inflammation. A novel uremic toxin, lanthionine, was shown to increase intracellular calcium in endothelial cells and may have a role in VC. A group of CKD patients was selected and divided into patients with a glomerular filtration rate (GFR) of <45 mL/min/1.73 m2 and ≥45 mL/min/1.73 m2. Total Calcium Score (TCS), based on the Agatston score, was assessed as circulating lanthionine and a panel of different cytokines. A hemodialysis patient group was also considered. Lanthionine was elevated in CKD patients, and levels increased significantly in hemodialysis patients with respect to the two CKD groups; in addition, lanthionine increased along with the increase in TCS, starting from one up to three. Interleukin IL-6, IL-8, and Eotaxin were significantly increased in patients with GFR < 45 mL/min/1.73 m2 with respect to those with GFR ≥ 45 mL/min/1.73 m2. IL-1b, IL-7, IL-8, IL-12, Eotaxin, and VEGF increased in calcified patients with respect to the non-calcified. IL-8 and Eotaxin were elevated both in the low GFR group and in the calcified group. We propose that lanthionine, but also IL-8 and Eotaxin, in particular, are a key feature of VC of CKD, with possible marker significance.


Assuntos
Alanina/análogos & derivados , Citocinas/sangue , Insuficiência Renal Crônica/metabolismo , Sulfetos/sangue , Calcificação Vascular/metabolismo , Adulto , Alanina/sangue , Biomarcadores/sangue , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/complicações , Calcificação Vascular/sangue , Calcificação Vascular/etiologia
20.
Fish Shellfish Immunol ; 116: 140-149, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34256134

RESUMO

Most antibiotics, insecticides, and other chemicals used in agricultural and fishery production tend to persist in the environment. Fenvalerate, sulfide gatifloxacin, and ridomil are widely used in aquaculture as antibacterial, antifungal, and antiparasitic drugs; however, their toxicity mechanism remains unclear. Thus, we herein analyzed the effects of these three drugs on the hepatopancreas of Procambarus clarkii at the transcriptome level. Twelve normalized cDNA libraries were constructed using RNA extracted from P. clarkii after treatment with fenvalerate, sulfide gatifloxacin, or ridomil and from an untreated control group, followed by Kyoto Encyclopedia of Genes and Genomes pathway analysis. In the control vs fenvalerate and control vs sulfide gatifloxacin groups, 14 and seven pathways were significantly enriched, respectively. Further, the effects of fenvalerate and sulfide gatifloxacin were similar on the hepatopancreas of P. clarkii. We also found that the expression level of genes encoding senescence marker protein-30 and arylsulfatase A was downregulated in the sulfide gatifloxacin group, indicating that sulfide gatifloxacin accelerated the apoptosis of hepatopancreatocytes. The expression level of major facilitator superfamily domain containing 10 was downregulated, implying that it interferes with the ability of the hepatopancreas to metabolize drugs. Interestingly, we found that Niemann pick type C1 and glucosylceramidase-ß potentially interact with each other, consequently decreasing the antioxidant capacity of P. clarkii hepatopancreas. In the fenvalerate group, the downregulation of the expression level of xanthine dehydrogenase indicated that fenvalerate affected the immune system of P. clarkii; moreover, the upregulation of the expression level of pancreatitis-associated protein-2 and cathepsin C indicated that fenvalerate caused possible inflammatory pathological injury to P. clarkii hepatopancreas. In the ridomil group, no pathway was significantly enriched. In total, 21 genes showed significant differences in all three groups. To conclude, although there appears to be some overlap in the toxicity mechanisms of fenvalerate, sulfide gatifloxacin, and ridomil, further studies are warranted.


Assuntos
Alanina/análogos & derivados , Antibacterianos/toxicidade , Astacoidea/efeitos dos fármacos , Fungicidas Industriais/toxicidade , Gatifloxacina/toxicidade , Inseticidas/toxicidade , Nitrilas/toxicidade , Piretrinas/toxicidade , Poluentes Químicos da Água/toxicidade , Alanina/toxicidade , Animais , Astacoidea/genética , Perfilação da Expressão Gênica , Hepatopâncreas/efeitos dos fármacos , Hepatopâncreas/metabolismo , Transcriptoma/efeitos dos fármacos
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