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1.
Front Med (Lausanne) ; 8: 626633, 2021.
Article in English | MEDLINE | ID: covidwho-1325534

ABSTRACT

Coronavirus disease 2019 (COVID-19) has become a global public health concern. We aimed to study the cytokine profile during the convalescent phase and its association with liver functions. We performed a retrospective study to investigate the longitudinal dynamic serum cytokine, liver function, and metabolomic profiles, as well as their potential correlations, from the viral replication phase to early convalescence. Our results demonstrated that liver injury was common. Liver injury was significantly associated with higher levels of interleukin (IL)-6 and IL-10 (p < 0.05). However, alanine aminotransferase levels decreased during the first week after hospital discharge (p < 0.01). In parallel, T-cell and B-cell immune response-stimulating cytokine IL-4, but not IL-2, was significantly elevated (p < 0.05). Furthermore, interferon-γ (IFN-γ) and tumor necrosis factor-α (TFN-α) levels increased, in contrast to the decrease in IL-6 and IL-10 levels; liver function returned to normal. The metabolomic analysis supported active recovery during early convalescence of COVID-19 patients that had distinct metabolic profiles associated with the hepatic tricarboxylic acid cycle, amino acid metabolism, and lipid metabolism. In addition, we identified a metabolomic association of IL-4 with liver repair. Our findings suggest that discharged patients continue to recover from the physiological effects of COVID-19, and the association of IL-4, IL-6, and IL-10 levels with metabolic changes and liver function repair may have important implications for clinical manifestations and treatment of COVID-19.

2.
Chem Phys ; 542: 111080, 2021 Feb 01.
Article in English | MEDLINE | ID: covidwho-971516

ABSTRACT

Coronavirus disease 2019 (COVID-19) has caused more than 840,000 deaths as of 31 August 2020 in the whole world. The COVID-19 main protease (Mpro) has been validated as an attractive target for drug design. In this work, the binding mechanisms of five protease inhibitors (e.g., danoprevir, darunavir, ASC09, lopinavir and ritonavir) to COVID-19 Mpro were investigated. Based on the docking score, five protease inhibitors structures were selected for further evaluation. It is found that most of the selected drug molecules bind stably to the COVID-19 Mpro from the molecular dynamics simulation. Moreover, the MM/PBSA free energy calculations suggest that lopinavir with positive charge might be most active against COVID-19 Mpro.

3.
Eur J Pharm Sci ; 157: 105631, 2021 Feb 01.
Article in English | MEDLINE | ID: covidwho-893750

ABSTRACT

BACKGROUND: Effective antiviral drugs for COVID-19 are still lacking. This study aims to evaluate the clinical outcomes and plasma concentrations of baloxavir acid and favipiravir in COVID-19 patients. METHODS: Favipiravir and baloxavir acid were evaluated for their antiviral activity against SARS-CoV-2 in vitro before the trial initiation. We conducted an exploratory trial with 3 arms involving hospitalized adult patients with COVID-19. Patients were randomized assigned in a 1:1:1 ratio into baloxavir marboxil group, favipiravir group, and control group. The primary outcome was the percentage of subjects with viral negative by Day 14 and the time from randomization to clinical improvement. Virus load reduction, blood drug concentration and clinical presentation were also observed. The trial was registered with Chinese Clinical Trial Registry (ChiCTR 2000029544). RESULTS: Baloxavir acid showed antiviral activity in vitro with the half-maximal effective concentration (EC50) of 5.48 µM comparable to arbidol and lopinavir, but favipiravir didn't demonstrate significant antiviral activity up to 100 µM. Thirty patients were enrolled. The percentage of patients who turned viral negative after 14-day treatment was 70%, 77%, and 100% in the baloxavir marboxil, favipiravir, and control group respectively, with the medians of time from randomization to clinical improvement was 14, 14 and 15 days, respectively. One reason for the lack of virological effect and clinical benefits may be due to insufficient concentrations of these drugs relative to their antiviral activities. One of the limitations of this study is the time from symptom onset to randomization, especially in the baloxavir marboxil and control groups, which is higher than the favipiravir group. CONCLUSIONS: Our findings could not prove a benefit of addition of either baloxavir marboxil or favipiravir under the trial dosages to the existing standard treatment.


Subject(s)
Amides , COVID-19 , Dibenzothiepins , Morpholines , Pyrazines , Pyridones , Triazines , Amides/administration & dosage , Amides/blood , Amides/pharmacokinetics , Antiviral Agents/administration & dosage , Antiviral Agents/blood , Antiviral Agents/pharmacokinetics , COVID-19/blood , COVID-19/diagnosis , COVID-19/drug therapy , COVID-19/physiopathology , Dibenzothiepins/administration & dosage , Dibenzothiepins/blood , Dibenzothiepins/pharmacokinetics , Drug Monitoring/methods , Female , Humans , Inhibitory Concentration 50 , Male , Middle Aged , Morpholines/administration & dosage , Morpholines/blood , Morpholines/pharmacokinetics , Pyrazines/administration & dosage , Pyrazines/blood , Pyrazines/pharmacokinetics , Pyridones/administration & dosage , Pyridones/blood , Pyridones/pharmacokinetics , SARS-CoV-2/drug effects , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Symptom Assessment , Treatment Outcome , Triazines/administration & dosage , Triazines/blood , Triazines/pharmacokinetics , Viral Load/drug effects
4.
Comput Math Methods Med ; 2020: 1391583, 2020.
Article in English | MEDLINE | ID: covidwho-831314

ABSTRACT

PURPOSE: We aimed to analyze and evaluate the safety signals of ribavirin-interferon combination through data mining of the US Food and Drug Administration Adverse Event Reporting System (FAERS), so as to provide reference for the rationale use of these agents in the management of relevant toxicities emerging in patients with novel coronavirus pneumonia (COVID-19). METHODS: Reports to the FAERS from 1 January 2004 to 8 March 2020 were analyzed. The proportion of report ratio (PRR), reporting odds ratio (ROR), and Bayesian confidence interval progressive neural network (BCPNN) method were used to detect the safety signals. RESULTS: A total of 55 safety signals were detected from the top 250 adverse event reactions in 2200 reports, but 19 signals were not included in the drug labels. All the detected adverse event reactions were associated with 13 System Organ Classes (SOC), such as gastrointestinal, blood and lymph, hepatobiliary, endocrine, and various nervous systems. The most frequent adverse events were analyzed, and the results showed that females were more likely to suffer from anemia, vomiting, neutropenia, diarrhea, and insomnia. CONCLUSION: The ADE (adverse drug event) signal detection based on FAERS is helpful to clarify the potential adverse events related to ribavirin-interferon combination for novel coronavirus therapy; clinicians should pay attention to the adverse reactions of gastrointestinal and blood systems, closely monitor the fluctuations of the platelet count, and carry out necessary mental health interventions to avoid serious adverse events.


Subject(s)
Coronavirus Infections/drug therapy , Interferons/adverse effects , Pneumonia, Viral/drug therapy , Ribavirin/adverse effects , Adolescent , Adult , Adverse Drug Reaction Reporting Systems , Aged , Algorithms , Bayes Theorem , COVID-19 , Data Mining , Drug Administration Schedule , Drug Therapy, Combination/adverse effects , Female , Humans , Interferons/administration & dosage , Male , Middle Aged , Neural Networks, Computer , Odds Ratio , Pandemics , Patient Safety , Ribavirin/administration & dosage , Young Adult
5.
Chin. Pharm. J. (China) ; 9(55): 685-691, 20200508.
Article in Chinese | WHO COVID, ELSEVIER | ID: covidwho-703885

ABSTRACT

OBJECTIVE: To analyze and evaluate the safety signals of chloroquine in the patients, and to provide a valuable reference for rational use in clinic. METHODS: Both the reporting odds ratio (ROR) method and Bayesian confidence propagation neural network (BCPNN) were applied to analyze safety signals of chloroquine based upon the adverse drug events (ADEs) data ranging from 2004 to 2020 as reported in the Adverse Event Reporting System (FAERS) database of the Food and Drug Administration (FDA), and to systematically assesse the safety signals of chloroquine phosphate on various organs systems. RESULTS: Among the 2 063 reports of ADEs studied, 557 reports were considered to be mainly caused by chloroquine. The results demonstrated that the high-risk ADEs signals of chloroquine involved various systems, such as atrioventricular block complete (ROR=2.90, IC-2SD=1.64), ventricular fibrillation (ROR=3.40, IC-2SD=1.27), blindness (ROR=27.51, IC-2SD=0.55), cardiogenic shock (ROR=6.86, IC-2SD=0.54), vomiting (ROR=1.70, IC-2SD=1.83). Moreover, some rare ADEs with high-risk signals showed a correlation with chloroquine, including hypokalaemia (ROR=4.18,IC-2SD=1.51), renal failure acute (ROR=3.08, IC-2SD=0.30), methaemoglobinaemia (ROR=4.37, IC-2SD=0.03), and pyrexia (ROR=1.80, IC-2SD=1.84), which were consistent with literature reports. However, these ADEs were not listed in instruction and worth much attention in clinic. Moreover, basic diseases of patients and drug incompatibility need much attention to prevent the occurrence and exacerbation of chloroquine-related adverse reactions. CONCLUSION: A comprehensive analysis of the ADEs signals of chloroquine could shed some light on understanding of its safety characteristics and would provide valuable information for rational use of chloroquine in clinic, especially in treatment of COVID-19.

6.
Chin. Pharm. J. (China) ; 9(55): 665-670, 20200508.
Article in Chinese | WHO COVID, ELSEVIER | ID: covidwho-703882

ABSTRACT

SARS-CoV-2, which is similar to SARS-CoV, can bind to human cell surface receptor ACE2 through its S-protein, sequentially infecting human cells such as respiratory epithelial cells or corneal and conjunctival tissues, thereby invading the human body. Recent studies have shown that organs with high expression levels of ACE2 protein, such as kidneys and lungs, are more vulnerable to virus damage. Therefore, lots of efforts have been devoted to the development of drugs targeting the combination of SARS-CoV-2 and ACE2. This paper reviewed the most recently published literatures that related to ACE2 and coronavirus infection, with an emphasis on ACE2, especially its distribution in vivo and organ damages of the patients with SARS-CoV-2 infection, as well as recent progress of drug development targeting the binding process of SARS-CoV-2 and ACE2. This paper aimed to shed some light on clinically fight against SARS-CoV-2 infection.

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