BACKGROUND Hepatic steatosis is a common form of cystic fibrosis associated liver disease(CFLD)seen in an estimated 15%-60%of patients with cystic fibrosis(CF).The pathophysiology and health implications of hepatic st...BACKGROUND Hepatic steatosis is a common form of cystic fibrosis associated liver disease(CFLD)seen in an estimated 15%-60%of patients with cystic fibrosis(CF).The pathophysiology and health implications of hepatic steatosis in cystic fibrosis remain largely unknown.In the general population,hepatic steatosis is strongly associated with insulin resistance and type 2 diabetes.Cystic fibrosis related diabetes(CFRD)impacts 40%-50%of CF adults and is characterized by both insulin insufficiency and insulin resistance.We hypothesized that patients with CFRD would have higher levels of hepatic steatosis than cystic fibrosis patients without diabetes.AIM To determine whether CFRD is associated with hepatic steatosis and to explore the impact of lumacaftor/ivacaftor therapy on hepatic steatosis in CF.METHODS Thirty patients with CF were recruited from a tertiary care medical center for this cross-sectional study.Only pancreatic insufficient patients with CFRD or normal glucose tolerance(NGT)were included.Patients with established CFLD,end stage lung disease,or persistently elevated liver enzymes were excluded.Mean magnetic resonance imaging(MRI)proton density fat fraction(PDFF)was obtained for all participants.Clinical characteristics[age,sex,body mass index,percent predicted forced expiratory volume at 1 s(FEV1),lumacaftor/ivacaftor use]and blood chemistries were assessed for possible association with hepatic steatosis.Hepatic steatosis was defined as a mean MRI PDFF>5%.Patients were grouped by diabetes status(CFRD,NGT)and cystic fibrosis transmembrane conductance regulator(CFTR)modulator use(lumacaftor/ivacaftor,no lumacaftor/ivacaftor)to determine between group differences.Continuous variables were analyzed with a Wilcoxon rank sum test and discrete variables with a Chi square test or Fisher’s exact test.RESULTS Twenty subjects were included in the final analysis.The median age was 22.3 years(11.3-39.0)and median FEV1 was 77%(33%-105%).Twelve subjects had CFRD and 8 had NGT.Nine subjects were receiving lumacaftor/ivacaftor.The median PDFF was 3.0%(0.0%-21.0%).Six subjects(30%)had hepatic steatosis defined as PDFF>5%.Hepatic fat fraction was significantly lower in patients receiving lumacaftor/ivacaftor(median,range)(2.0%,0.0%-6.4%)than in patients not receiving lumacaftor/ivacaftor(4.1%,2.7-21.0%),P=0.002.Though patients with CFRD had lower PDFF(2.2%,0.0%-14.5%)than patients with NGT(4.9%,2.4-21.0%)this did not reach statistical significance,P=0.06.No other clinical characteristic was strongly associated with hepatic steatosis.CONCLUSION Use of the CFTR modulator lumacaftor/ivacaftor was associated with significantly lower hepatic steatosis.No association between CFRD and hepatic steatosis was found in this cohort.展开更多
Inhaled antibiotics such as colistin and ciprofloxacin are increasingly used to treat bacterial lung infections in cystic fibrosis patients.In this study,we established and validated a new HPLC-MS/MS method that could...Inhaled antibiotics such as colistin and ciprofloxacin are increasingly used to treat bacterial lung infections in cystic fibrosis patients.In this study,we established and validated a new HPLC-MS/MS method that could simultaneously detect drug concentrations of ciprofloxacin,colistin and ivacaftor in rat plasma,human epithelial cell lysate,cell culture medium,and drug transport media.An aliquot of200 μL drug-containing rat plasma or cell culture medium was treated with 600 μL of extraction solution(acetonitrile containing 0.1% formic acid and 0.2% trifluoroacetic acid(TFA)).The addition of 0.2% TFA helped to break the drug-protein bonds.Moreover,the addition of 0.1% formic acid to the transport medium and cell lysate samples could significantly improve the response and reproducibility.After vortexing and centrifuging,the sample components were analyzed by HPLC-MS/MS.The multiple reaction monitoring mode was used to detect the following transitions:585.5-101.1(colistin A),578.5-101.1(colistin B),393.2-337.2(ivacaftor),332.2-314.2(ciprofloxacin),602.3-101.1(polymyxin B1 as internal standard(IS)) and 595.4-101.1(polymyxin B2 as IS).The running time of a single sample was only 6 min,making this a time-efficient method.Linear correlations were found for colistin A at 0.029-5.82 μg/m L,colistin B at 0.016-3.14 μg/m L,ivacaftor at 0.05-10.0 μg/m L,and ciprofloxacin at 0.043-8.58 μg/m L.Accuracy,precision,and stability of the method were within the acceptable range.This method would be highly useful for research on cytotoxicity,animal pharmacokinetics,and in vitro drug delivery.展开更多
基金Supported by a grant from the University Hospitals Fellowship Research Award Program(FRAP)
文摘BACKGROUND Hepatic steatosis is a common form of cystic fibrosis associated liver disease(CFLD)seen in an estimated 15%-60%of patients with cystic fibrosis(CF).The pathophysiology and health implications of hepatic steatosis in cystic fibrosis remain largely unknown.In the general population,hepatic steatosis is strongly associated with insulin resistance and type 2 diabetes.Cystic fibrosis related diabetes(CFRD)impacts 40%-50%of CF adults and is characterized by both insulin insufficiency and insulin resistance.We hypothesized that patients with CFRD would have higher levels of hepatic steatosis than cystic fibrosis patients without diabetes.AIM To determine whether CFRD is associated with hepatic steatosis and to explore the impact of lumacaftor/ivacaftor therapy on hepatic steatosis in CF.METHODS Thirty patients with CF were recruited from a tertiary care medical center for this cross-sectional study.Only pancreatic insufficient patients with CFRD or normal glucose tolerance(NGT)were included.Patients with established CFLD,end stage lung disease,or persistently elevated liver enzymes were excluded.Mean magnetic resonance imaging(MRI)proton density fat fraction(PDFF)was obtained for all participants.Clinical characteristics[age,sex,body mass index,percent predicted forced expiratory volume at 1 s(FEV1),lumacaftor/ivacaftor use]and blood chemistries were assessed for possible association with hepatic steatosis.Hepatic steatosis was defined as a mean MRI PDFF>5%.Patients were grouped by diabetes status(CFRD,NGT)and cystic fibrosis transmembrane conductance regulator(CFTR)modulator use(lumacaftor/ivacaftor,no lumacaftor/ivacaftor)to determine between group differences.Continuous variables were analyzed with a Wilcoxon rank sum test and discrete variables with a Chi square test or Fisher’s exact test.RESULTS Twenty subjects were included in the final analysis.The median age was 22.3 years(11.3-39.0)and median FEV1 was 77%(33%-105%).Twelve subjects had CFRD and 8 had NGT.Nine subjects were receiving lumacaftor/ivacaftor.The median PDFF was 3.0%(0.0%-21.0%).Six subjects(30%)had hepatic steatosis defined as PDFF>5%.Hepatic fat fraction was significantly lower in patients receiving lumacaftor/ivacaftor(median,range)(2.0%,0.0%-6.4%)than in patients not receiving lumacaftor/ivacaftor(4.1%,2.7-21.0%),P=0.002.Though patients with CFRD had lower PDFF(2.2%,0.0%-14.5%)than patients with NGT(4.9%,2.4-21.0%)this did not reach statistical significance,P=0.06.No other clinical characteristic was strongly associated with hepatic steatosis.CONCLUSION Use of the CFTR modulator lumacaftor/ivacaftor was associated with significantly lower hepatic steatosis.No association between CFRD and hepatic steatosis was found in this cohort.
基金supported by the National Institute of Health’s National Institute of Allergy and Infectious Diseases under Award Nos. R01AI146160 and R01AI132681。
文摘Inhaled antibiotics such as colistin and ciprofloxacin are increasingly used to treat bacterial lung infections in cystic fibrosis patients.In this study,we established and validated a new HPLC-MS/MS method that could simultaneously detect drug concentrations of ciprofloxacin,colistin and ivacaftor in rat plasma,human epithelial cell lysate,cell culture medium,and drug transport media.An aliquot of200 μL drug-containing rat plasma or cell culture medium was treated with 600 μL of extraction solution(acetonitrile containing 0.1% formic acid and 0.2% trifluoroacetic acid(TFA)).The addition of 0.2% TFA helped to break the drug-protein bonds.Moreover,the addition of 0.1% formic acid to the transport medium and cell lysate samples could significantly improve the response and reproducibility.After vortexing and centrifuging,the sample components were analyzed by HPLC-MS/MS.The multiple reaction monitoring mode was used to detect the following transitions:585.5-101.1(colistin A),578.5-101.1(colistin B),393.2-337.2(ivacaftor),332.2-314.2(ciprofloxacin),602.3-101.1(polymyxin B1 as internal standard(IS)) and 595.4-101.1(polymyxin B2 as IS).The running time of a single sample was only 6 min,making this a time-efficient method.Linear correlations were found for colistin A at 0.029-5.82 μg/m L,colistin B at 0.016-3.14 μg/m L,ivacaftor at 0.05-10.0 μg/m L,and ciprofloxacin at 0.043-8.58 μg/m L.Accuracy,precision,and stability of the method were within the acceptable range.This method would be highly useful for research on cytotoxicity,animal pharmacokinetics,and in vitro drug delivery.
