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1.
Biomed Chromatogr ; 36(7): e5380, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1772660

ABSTRACT

Remdesivir (RDV), a phosphoramidate prodrug, has broad-spectrum antiviral activity. It is the first antiviral drug approved by the US Food and Drug Administration (FDA) for the treatment of COVID-19. Remdesivir is rapidly metabolized in the body to produce derivatives: alanine metabolite (RM-442) and RDV C-nucleoside (RN). Here, the phosphatase inhibitor PhosSTOP and carboxylesterase inhibitor 5,5'-dithiobis-2-nitrobenzoic acid were used to improve stability of RDV in mouse blood. We developed a rapid and sensitive LC-MS/MS method to simultaneously quantify RDV, RM-442 and RN in mouse blood. Chromatographic separation was achieved by gradient elution on an Acquity HSS T3 column. The run time was 3.2 min. The linearity ranges of the analytes were 0.5-1,000 ng/ml for RDV and 5-10,000 ng/ml for both RM-442 and RN. The method had an acceptable precision (RSD < 8.4% for RDV, RSD < 10.7% for RM-442 and RSD < 7.2% for RN) and accuracy (91.0-106.3% for RDV, 92.5-98.6% for RM-442 and 87.5-98.4% for RN). This method was successfully applied to analyze RDV, RM-442 and RN in the blood of normal and diabetic nephropathy DBA/2 J mice after intravenous injection of RDV at 20 mg/kg. The area under the concentration-time curve of RN between the normal and diabetic nephropathy mice showed a significant difference (P < 0.01).


Subject(s)
COVID-19 , Diabetes Mellitus , Diabetic Nephropathies , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Animals , Antiviral Agents , COVID-19/drug therapy , Chromatography, Liquid/methods , Mice , Mice, Inbred DBA , Nucleosides , Tandem Mass Spectrometry/methods
2.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-314834

ABSTRACT

Background: We describe the development of a dynamic simulation modelling framework to support agile resource planning during the COVID-19 pandemic. The framework takes into consideration the dynamic evolution of the pandemic and the rapidly evolving policies and processes to deal with the ever-changing outbreak scenarios. Methods: A specific use case based on short-term bed resource planning is described within the proposed framework. The simulation model was calibrated against historical data for the Singapore COVID-19 situation. The time period for model calibration was from 1st April till 30th April 2020. The model was used to project for bed resource needs over the period from 1st May 2020 till 31st May 2020. Multivariate sensitivity analysis was also conducted for ICU and general isolation bed demand, length-of-stay (LOS), and age-adjusted conversion rates across different care needs. The unmet needs under various scenarios were also evaluated for planning purposes. Results: : Several variants of the agile resource planning model were developed to adapt to the fast-changing COVID-19 situation in Singapore. The use case demonstrated an agile adaptation of the model to account for previously unexpected scenarios. The rapid evolution of the pandemic locally revealed streams of new infections that arose from two distinct sources. The model projections were calibrated with the latest data for short-term projections. The agility in flexing plans and collaborative management structures to rapidly deploy human and capital resources to surge the level of care during the COVID-19 pandemic have proven utility in guiding the allocation of scarce healthcare resources and helped system resiliency. Conclusions: The rapidly evolving COVID-19 pandemic in Singapore has necessitated the development of an agile and adaptable modelling framework that can be quickly calibrated to changes both from demand and supply. The modelling framework is able to deploy systems modelling concepts in a holistic manner. This facilitates the evaluation of complex cause-and-effect relationships. A robust collaborative framework, coupled with the availability of in-depth domain knowledge and accurate and updated data availability ensures a model is realistic, timely and useful.

3.
Front Pharmacol ; 12: 626510, 2021.
Article in English | MEDLINE | ID: covidwho-1317239

ABSTRACT

Aim: Kidney impairment is observed in patients with COVID-19. The effect of anti-COVID-19 agent remdesivir on kidneys is currently unknown. We aimed to determine the effect of remdesivir on renal fibrosis and its downstream mechanisms. Methods: Remdesivir and its active nucleoside metabolite GS-441524 were used to treat TGF-ß stimulated renal fibroblasts (NRK-49F) and human renal epithelial (HK2) cells. Vehicle or remdesivir were given by intraperitoneal injection or renal injection through the left ureter in unilateral ureteral obstruction (UUO) mice. Serum and kidneys were harvested. The concentrations of remdesivir and GS-441524 were measured using LC-MS/MS. Renal and liver function were assessed. Renal fibrosis was evaluated by Masson's trichrome staining and Western blotting. Results: Remdesivir and GS-441524 inhibited the expression of fibrotic markers (fibronectin and aSMA) in NRK-49F and HK2 cells. Intraperitoneal injection or renal injection of remdesivir attenuated renal fibrosis in UUO kidneys. Renal and liver function were unchanged in remdesivir treated UUO mice. Two remdesivir metabolites were detected after injection. Phosphorylation of Smad3 that was enhanced in cell and animal models for renal fibrosis was attenuated by remdesivir. In addition, the expression of Smad7, an anti-fibrotic factor, was increased after remdesivir treatment in vitro and in vivo. Moreover, knockdown of Smad7 blocked the antifibrotic effect of GS and RDV on renal cells. Conclusion: Remdesivir inhibits renal fibrosis in obstructed kidneys.

4.
Respir Res ; 22(1): 188, 2021 Jun 28.
Article in English | MEDLINE | ID: covidwho-1286027

ABSTRACT

Xuan-bai-cheng-qi decoction (XCD), a traditional Chinese medicine (TCM) prescription, has been widely used to treat a variety of respiratory diseases in China, especially to seriously infectious diseases such as acute lung injury (ALI). Due to the complexity of the chemical constituent, however, the underlying pharmacological mechanism of action of XCD is still unclear. To explore its protective mechanism on ALI, firstly, a network pharmacology experiment was conducted to construct a component-target network of XCD, which identified 46 active components and 280 predicted target genes. Then, RNA sequencing (RNA-seq) was used to screen differentially expressed genes (DEGs) between ALI model rats treated with and without XCD and 753 DEGs were found. By overlapping the target genes identified using network pharmacology and DEGs using RNA-seq, and subsequent protein-protein interaction (PPI) network analysis, 6 kernel targets such as vascular epidermal growth factor (VEGF), mammalian target of rapamycin (mTOR), AKT1, hypoxia-inducible factor-1α (HIF-1α), and phosphoinositide 3-kinase (PI3K) and gene of phosphate and tension homology deleted on chromsome ten (PTEN) were screened out to be closely relevant to ALI treatment. Verification experiments in the LPS-induced ALI model rats showed that XCD could alleviate lung tissue pathological injury through attenuating proinflammatory cytokines release such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1ß. Meanwhile, both the mRNA and protein expression levels of PI3K, mTOR, HIF-1α, and VEGF in the lung tissues were down-regulated with XCD treatment. Therefore, the regulations of XCD on PI3K/mTOR/HIF-1α/VEGF signaling pathway was probably a crucial mechanism involved in the protective mechanism of XCD on ALI treatment.


Subject(s)
Acute Lung Injury/genetics , Acute Lung Injury/prevention & control , Drugs, Chinese Herbal/therapeutic use , Lipopolysaccharides/toxicity , Sequence Analysis, RNA/methods , Acute Lung Injury/chemically induced , Animals , Drugs, Chinese Herbal/pharmacology , Male , Rats , Rats, Wistar
5.
ISPRS International Journal of Geo-Information ; 10(6):395, 2021.
Article in English | MDPI | ID: covidwho-1259506

ABSTRACT

At the beginning of 2020, a suddenly appearing novel coronavirus (COVID-19) rapidly spread around the world. The outbreak of the COVID-19 pandemic in China occurred during the Spring Festival when a large number of migrants traveled between cities, which greatly increased the infection risk of COVID-19 across the country. Financially supported by the Wuhan government, and based on cellphone signaling data from Unicom (a mobile phone carrier) and Baidu location-based data, this paper analyzed the effects that city dwellers, non-commuters, commuters, and people seeking medical services had on the transmission risk of COVID-19 in the early days of the pandemic in Wuhan. The paper also evaluated the effects of the city lockdown policy on the spread of the pandemic outside and inside Wuhan. The results show that although the daily business activities in the South China Seafood Wholesale Market and nearby commuters’ travel behaviors concentrated in the Hankou area, a certain proportion of these people were distributed in the Wuchang and Hanyang areas. The areas with relatively high infection risks of COVID-19 were scattered across Wuhan during the early outbreak of the pandemic. The lockdown in Wuhan closed the passageways of external transport at the very beginning, largely decreasing migrant population and effectively preventing the spread of the pandemic to the outside. However, the Wuhan lockdown had little effect on preventing the spread of the pandemic within Wuhan at that time. During this period, a large amount of patients who went to hospitals for medical services were exposed to a high risk of cross-infection without precaution awareness. The pandemic kept dispersing in three towns until the improvement of the capacity of medical treatment, the management of closed communities, the national support to Wuhan, and the implementation of a series of emergency responses at the same time. The findings in this paper reveal the spatiotemporal features of the dispersal of infection risk of COVID-19 and the effects of the prevention and control measures during the early days of the pandemic. The findings were adopted by the Wuhan government to make corresponding policies and could also provide supports to the control of the pandemic in the other regions and countries.

6.
J Pharm Biomed Anal ; 194: 113806, 2021 Feb 05.
Article in English | MEDLINE | ID: covidwho-1065380

ABSTRACT

Remdesivir is a prodrug of the nucleotide analogue and used for COVID-19 treatment. However, the bioanalysis of the active metabolites remdesivir nucleotide triphosphate (RTP) and its precursor remdesivir nucleotide monophosphate (RMP) is very challenging. Herein, we established a novel method to separate RTP and RMP on a BioBasic AX column and quantified them by high-performance liquid chromatography-tandem mass spectrometry in positive electrospray ionization mode. Stepwise, we optimized chromatographic retention on an anion exchange column, improved stability in matrix through the addition of 5,5'-dithiobis-(2nitrobenzoic acid) and PhosSTOP EASYpack, and increased recovery by dissociation of tight protein binding with 2 % formic acid aqueous solution. The method allowed lower limit of quantification of 20 nM for RMP and 10 nM for RTP. Method validation demonstrated acceptable accuracy (93.6%-103% for RMP, 94.5%-107% for RTP) and precision (RSD < 11.9 % for RMP, RSD < 11.4 % for RTP), suggesting that it was sensitive and robust for simultaneous quantification of RMP and RTP. The method was successfully applied to analyze RMP and RTP in mouse tissues. In general, the developed method is suitable to monitor RMP and RTP, and provides a useful approach for exploring more detailed effects of remdesivir in treating diseases.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Prodrugs/analysis , Prodrugs/metabolism , Tandem Mass Spectrometry/methods , Adenosine Monophosphate/analysis , Adenosine Monophosphate/metabolism , Adenosine Monophosphate/pharmacology , Alanine/analysis , Alanine/metabolism , Alanine/pharmacology , Animals , Antiviral Agents/analysis , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/metabolism , Chromatography, Liquid/methods , Humans , Liver/chemistry , Liver/drug effects , Liver/metabolism , Male , Mice , Prodrugs/pharmacology
7.
SciFinder; 2020.
Preprint | SciFinder | ID: ppcovidwho-5065

ABSTRACT

A review. novel coronavirus pneumonia is a category of "epidemic disease" in TCM. The main causes are two aspects: the sensation of epidemic disease and the deficiency of vital qi. The basic pathogenesis of the disease is to feel epidemic disease, Shangjiao is affected by pathogenic factors, Zhengqi deficiency and Sanjiao transmission. The location of the disease is in the lung, which is related to the spleen, heart, liver and kidney. The pathol. nature involves dampness, toxin, heat, blood stasis, deficiency and closure. The treatment can be based on three jiao syndrome differentiation, combined with Wei Qi Ying Xue syndrome differentiation, six meridians syndrome differentiation and Zang Fu syndrome differentiation. Referring to the novel coronavirus pneumonia diagnosis and treatment plan of the fifth edition of the national health and Health Committee, we should follow the viewpoint of Wu′s theory of "plague" and "expelling evil as the first essential meaning".

8.
Acta Pharmacol Sin ; 42(7): 1195-1200, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-844311

ABSTRACT

Remdesivir (RDV) exerts anti-severe acute respiratory coronavirus 2 activity following metabolic activation in the target tissues. However, the pharmacokinetics and tissue distributions of the parent drug and its active metabolites have been poorly characterized to date. Blood and tissue levels were evaluated in the current study. After intravenous administration of 20 mg/kg RDV in mice, the concentrations of the parent drug, nucleotide monophosphate (RMP) and triphosphate (RTP), as well as nucleoside (RN), in the blood, heart, liver, lung, kidney, testis, and small intestine were quantified. In blood, RDV was rapidly and completely metabolized and was barely detected at 0.5 h, similar to RTP, while its metabolites RMP and RN exhibited higher blood levels with increased residence times. The area under the concentration versus time curve up to the last measured point in time (AUC0-t) values of RMP and RN were 4558 and 136,572 h∙nM, respectively. The maximum plasma concentration (Cmax) values of RMP and RN were 2896 nM and 35,819 nM, respectively. Moreover, RDV presented an extensive distribution, and the lung, liver and kidney showed high levels of the parent drug and metabolites. The metabolic stabilities of RDV and RMP were also evaluated using lung, liver, and kidney microsomes. RDV showed higher clearances in the liver and kidney than in the lung, with intrinsic clearance (CLint) values of 1740, 1253, and 127 mL/(min∙g microsomal protein), respectively.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Nucleosides/metabolism , Nucleotides/metabolism , Polyphosphates/metabolism , Tissue Distribution/physiology , Adenosine Monophosphate/pharmacokinetics , Adenosine Monophosphate/pharmacology , Alanine/pharmacokinetics , Alanine/pharmacology , Animals , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/metabolism , Kidney/metabolism , Liver/metabolism , Lung/metabolism , Male , Mice , SARS-CoV-2/drug effects
9.
Drug Dev Ind Pharm ; 46(8): 1345-1353, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-639745

ABSTRACT

PURPOSE: Huashi Baidu formula (HSBDF) was developed to treat the patients with severe COVID-19 in China. The purpose of this study was to explore its active compounds and demonstrate its mechanisms against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through network pharmacology and molecular docking. METHODS: All the components of HSBDF were retrieved from the pharmacology database of TCM system. The genes corresponding to the targets were retrieved using UniProt and GeneCards database. The herb-compound-target network was constructed by Cytoscape. The target protein-protein interaction network was built using STRING database. The core targets of HSBDF were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The main active compounds of HSBDF were docked with SARS-CoV-2 and angiotensin converting enzyme II (ACE2). RESULTS: Compound-target network mainly contained 178 compounds and 272 corresponding targets. Key targets contained MAPK3, MAPK8, TP53, CASP3, IL6, TNF, MAPK1, CCL2, PTGS2, etc. There were 522 GO items in GO enrichment analysis (p < .05) and 168 signaling pathways (p < .05) in KEGG, mainly including TNF signaling pathway, PI3K-Akt signaling pathway, NOD-like receptor signaling pathway, MAPK signaling pathway, and HIF-1 signaling pathway. The results of molecular docking showed that baicalein and quercetin were the top two compounds of HSBDF, which had high affinity with ACE2. CONCLUSION: Baicalein and quercetin in HSBDF may regulate multiple signaling pathways through ACE2, which might play a therapeutic role on COVID-19.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Molecular Docking Simulation/methods , Pharmacology, Clinical/methods , Pneumonia, Viral/drug therapy , Angiotensin-Converting Enzyme 2 , Betacoronavirus/chemistry , Betacoronavirus/genetics , COVID-19 , China , Databases, Factual , Gene Ontology , Gene Targeting , Genes, Viral/drug effects , Genes, Viral/genetics , Humans , Medicine, Chinese Traditional , Pandemics , Peptidyl-Dipeptidase A/drug effects , Peptidyl-Dipeptidase A/genetics , SARS-CoV-2 , Signal Transduction/drug effects , Signal Transduction/genetics
10.
J Clin Virol ; 127: 104353, 2020 06.
Article in English | MEDLINE | ID: covidwho-65320

ABSTRACT

BACKGROUND: The outbreak of a new coronavirus, first reported in Wuhan, China, is spreading around the world. Information on the characteristics of children with Coronavirus Disease 2019 (COVID-19) is limited. METHODS: In this retrospective study, we recruited 10 children infected with SARS-COV-2 from January 27 to March 10, 2020, in Changsha, China. We report the epidemiological, clinical, laboratory, and high-resolution CT findings for these children. Qualitative descriptive analysis was used to describe the key results. RESULTS: Ten children were included. Three were male and seven were female. Three were from Wuhan, Hubei Province, and seven were from Changsha. All had a history of close contact with adults with COVID-19 before the onset of disease. Clinical manifestations included fever in four cases, respiratory symptoms in three cases, febrile convulsions in one case, vomiting in one case, abdominal pain in one case, and asymptomatic infection in two cases. All the children tested positive for nucleic acid in throat swabs at admission. Stool swabs of three cases were positive for nucleic acid after several days of fever. In nine children, blood routine results were normal, whereas in one case the white blood cell count was elevated. In four cases, CT findings of the lungs showed light ground-glass opacities, one case showed changes similar to bronchopneumonia, and the remaining cases were normal. All were treated with symptomatic support without complications. CONCLUSION: Our findings indicate that intrafamily transmission may be the main form of transmission of COVID-19 in children, and persistent intestinal excretion of virus is another characteristic among children. The results of stool swab tests should be considered for discharge and release from isolation.


Subject(s)
Coronavirus Infections/diagnosis , Feces/virology , Lung/virology , Pneumonia, Viral/diagnosis , Abdominal Pain/epidemiology , Abdominal Pain/etiology , Asymptomatic Infections/epidemiology , Betacoronavirus , COVID-19 , Child , Child, Preschool , China/epidemiology , Coronavirus Infections/pathology , Coronavirus Infections/transmission , Female , Fever/virology , Humans , Infant , Lung/diagnostic imaging , Male , Pandemics , Pneumonia, Viral/pathology , Pneumonia, Viral/transmission , Qualitative Research , Retrospective Studies , SARS-CoV-2 , Tomography, X-Ray Computed
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