Increased Thromboxane Metabolites Excretion in Liver Cirrhosis

1998 ◽  
Vol 79 (04) ◽  
pp. 747-751 ◽  
Author(s):  
Domenico Ferro ◽  
Stefania Basili ◽  
Luigi Iuliano ◽  
Caterina Camastra ◽  
Carlo Giammarresi ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Urinary Excretion ◽  
Excretion Rate ◽  
Systemic Circulation ◽  
Progressive Increase ◽  
Class A ◽  
Significant Difference ◽  
Cirrhotic Patients ◽  
Class C

SummaryAn augmented systemic production of thromboxane (TX) A2, as assessed by urinary excretion of the thromboxane metabolites, has been described in severe liver cirrhosis. However, the significance of this finding remains unclear since in liver cirrhosis a number of phenomena i.e. altered hepatic TXA2 metabolism, increased intrasplenic platelet destruction, may affect TXA2 entry into systemic circulation as well as its metabolism. In order to further clarify this, we measured both major enzymatic metabolites of TXB2 in the urine of 44 patients affected by liver cirrhosis, subdivided in three classes on the basis of Child-Pugh criteria. Urinary 11-dehydro-TXB2 and 2,3-dinor-TXB2 were assayed with previously validated RIA techniques.The urinary excretion rate of 11-dehydro-TXB2 was significantly (p = 0.0001) increased in the cirrhotic patients (673.5 pg/mg cr, median) in comparison with the controls (275 pg/mg cr, median) but no significant difference could be demonstrated among the excretion rates of the three patient subgroups. The excretion rate of 2,3 dinor-TXB2 was also significantly (p = 0.0001) increased in the patients (824 pg/mg cr, median) in comparison with controls (175 pg/mg cr, median), with a significant (p <0.05) increase from class A (381 pg/mg cr) to class C (1337 pg/mg cr). The sum of the two enzymatic metabolites was significantly (p = 0.0001) increased in the cirrhotic patients in comparison to controls, with a progressive increase from class A (1003 pg/mg cr, median) to class C (2240 pg/mg cr, median). The urinary excretion of 2,3 dinor-TXB2 was significantly (p = 0.008) related to plasma prothrombin fragment 1+2 (F1+2).This study provides further evidence of increased thromboxane biosynthesis in liver cirrhosis. Moreover, we demonstrate intraliver shift of thromboxane metabolic disposition, due to progressive liver decompensation, because only the fraction undergoing β-oxidation to 2,3-dinor-TXB2 was progressively increased with the degree of liver failure. We, also, find a significant correlation between urinary excretion of 2,3-dinor-TXB2 and plasma F1+2, suggesting that clotting activation could partly account for in vivo platelet activation.

Cardiomyopathy in Cirrhotic Patients and Its Relationship with the Severity of Cirrhosis

2021 ◽  
Vol 15 (10) ◽  
pp. 2779-2782
Author(s):  
Saira Khalid ◽  
Nasir Shah ◽  
Yasir Abbas Zaidi ◽  
Muhammad Saleem Hasan ◽  
Saqib Jahangir ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Severe Disease ◽  
P Value ◽  
Cirrhotic Cardiomyopathy ◽  
Male Predominance ◽  
Class A ◽  
Class B ◽  
Cirrhotic Patients ◽  
The Mean ◽  
Class C

Study Objectives: To determine the frequency of cirrhotic cardiomyopathy in patients with liver cirrhosis and to compare it across varying grades of cirrhosis on Child Turcotte Pugh classification. Study Design and Settings: It was a descriptive cross-sectional study carried at Department of Medicine, Lahore General Hospital Lahore over 1 year from Jan 2018 to Dec 2018. Patients and Methods: The present research involved 100 male and female patients aged between 16-70 years having liver cirrhosis diagnosed at least 6 months ago. These patients underwent echocardiographic screening of cardiomyopathy which was diagnosed by the presence of diastolic dysfunction (i.e. increased E/A ratio>1). An informed written consent was obtained from every patient. Results of the Study: There was a male predominance (M:F, 1.6:1) among cirrhotic patients with a mean age of 51.9±9.8 years. The mean BMI was 26.5±3.7 Kg/m2 while the mean duration of cirrhosis was 22.0±10.9 months. Majority (49.0%) of the patients belonged to CTP Class C followed by Class-B (39.0%) and Class-A (12.0%). Cirrhotic cardiomyopathy was observed in 41.0% patients with cirrhosis. There was statistically insignificant difference in the observed frequency of cirrhotic cardiomyopathy among various subgroups of cirrhotic patients depending upon patient’s age (p-value=0.928), gender (p-value=0.997), BMI (p-value=0.983) and duration of disease (p-value=0.782). However, it increased considerably with worsening of disease on CTP Classification; Class-A vs. Class-B vs. Class-C (8.3% vs. 35.9% vs. 53.1%; p-value=0.013). Conclusion: Cirrhotic cardiomyopathy was observed in a substantial proportion of cirrhotic patients and was more frequent in patients with more severe disease which warrants routine echocardiographic screening of cirrhotic patients so that timely recognition and anticipated treatment of this complication may improve the case outcome in future medical practice. Keywords: Cirrhosis, Cardiomyopathy, Child Turcotte Pugh Class

scholarly journals Correlation between Hepatic Vein Wave form Changes on Doppler Ultrasound and the Severity of Diseases in Cirrhotic Patients

2021 ◽  
Vol 22 (2) ◽  
pp. 100-106
Author(s):  
Tarana Yasmin ◽  
Sohely Sultana ◽  
Mahmuda Nusrat Ima ◽  
Md Quamrul Islam ◽  
Shyamal Kumar Roy ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Doppler Ultrasound ◽  
Hepatic Vein ◽  
Wave Form ◽  
Venous Blood Flow ◽  
Class A ◽  
Class B ◽  
Pugh Class ◽  
Cirrhotic Patients ◽  
Class C

Background: Cirrhosis is a common problem and is a leading cause of chronic liver disease. Early diagnosis with assessment of severity of diseases may help prevent the associated complications and patients’ sufferings. Now a days Hepatic venous Doppler can be a tool for diagnosis of cirrhosis and to assess correlation between waveform changes and severity of diseases. Objective: The purposes of this study was to determine the significance of hepatic vein waveform changes on doppler ultrasound in cirrhotic patients and to correlate with liver dysfunction. Materials and methods: This study was carried out in the department of Radiology and Imaging of Enam Medical College and Hospital during January 2017 to May 2018. Doppler waveforms were obtained from right hepatic vein in all the cases and classified as triphasic, biphasic and monophasic. Waveform comparisons were made among patients with differing grades of cirrhosis. Child- Pugh class was used to assess severity of cirrhosis. Doppler sonography was done in 80 patients suspecting of having liver cirrhosis. Data on clinical findings, B mode sonographic findings and hepatic vein doppler ultrasound findings were collected and documented in structured forms. Analysis was done using SPSS - 20. Results: Total of 80 patients who met the inclusion criteria are included in the study with mean age of 45.37±7.64 (range 25-75) years. Among these 57 (71%) were males while 23(29%) were females. On the basis of hepatic function 25 (31%) patients presented in Child-Pugh Class A, 31(39%) with Class B and 24(30%) patients had Class C. Hepatic venous waveform was triphasic in 22 (27.5%), biphasic in 28(35%), and monophasic in 30 (37.5%) cases. Our study revealed 88% (21) of Child- Pugh Class C, 23% (7) of Class B and 8% (2) of class A patients had monophasic HV waveform. The hepatic venous waveform progressively changed from triphasic to biphasic to monophasic with advancing grade of cirrhosis. The relationship of these waveforms change had significant relation with hepatic dysfunction (p < 0.022). Conclusion: Hepatic vein wave form changes reflects the change in hepatic circulation associated with progression of liver cirrhosis. It can be used as a new parameter in the assessment of severity of liver cirrhosis. Thus, alteration in hepatic venous blood flow pattern on doppler ultrasound can be a useful noninvasive tool for evaluating diseases severity in patients with cirrhosis. J MEDICINE 2021; 22: 100-106

scholarly journals Correlation of global longitudinal strain with disease severity in liver cirrhosis

2021 ◽  
Vol 22 (Supplement_1) ◽  
Author(s):  
Y Dimitroglou ◽  
C Aggeli ◽  
A Alexopoulou ◽  
T Alexopoulos ◽  
D Patsourakos ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Disease Severity ◽  
Longitudinal Strain ◽  
Global Longitudinal Strain ◽  
Left Ventricular ◽  
Class A ◽  
Class B ◽  
Pugh Class ◽  
Cirrhotic Patients ◽  
Class C

Abstract Funding Acknowledgements Type of funding sources: None. Introduction/purpose Cirrhotic cardiomyopathy is characterized by high cardiac output, reduced peripheral resistance and diastolic dysfunction and has been correlated with cirrhosis severity and prognosis. Global longitudinal strain (GLS) is a sensitive marker of cardiac dysfunction which is considered relatively independent of preload and afterload conditions and thus may be of high diagnostic significance in this special population. We sought to investigate alterations of GLS relating to disease severity in cirrhotic patients. Methods Echocardiographic analysis of 51 consecutive cirrhotic patients was performed. Images were acquired and analyzed off-line. GLS was calculated with a semi-automatic way using dedicated software.  Clinical and biochemical examination were used to assess severity of liver disease by calculating Child-Pugh class (class C patients have more severe disease than class B and A patients) and MELD-Na score (increased score as the disease progresses). Results Mean age was 58.4 ± 8.7 years, 38 (74.5%) were males. Among patients, 22 (43.1%) were Child-Pugh class A, 17 (33.3%) Child-Pugh B and 12 (23.5%) Child-Pugh C and mean MELD-Na score was 15.3 ± 7.5. Mean left ventricular end-systolic volume (LVEDV) was 117 ± 29ml, mean stroke volume (SV) 72.5 ± 19.9ml , mean left ventricular ejection fraction (LVEF) 61.0 ± 5.0%, mean systolic blood pressure (SBP) 128 ± 13mmHg, mean ratio of peak transmitral to peak annular (septal) velocity during early diastole (E/e’ ratio) 10.4 ± 4.5, mean left atrial volume index (LAVI) 37.4 ± 11.8 ml/cm2  and mean GLS -21.6 ± 2.6%. GLS of Child-Pugh class A patients (-20.3 ± 2.4) was higher (less negative) than GLS of Child-Pugh class B (-22.2 ± 2.2) and class C (-23.0 ± 2.8) patients. Difference between groups B and C was non-significant (figure). Severity of cirrhosis as determined by higher MELD-Na score correlated with LAVI (r = 0.592, p &lt; 0.001), SV (r = 0.554, p &lt; 0.001), GLS (r=-0.441, p = 0.001) and LVEDV (r = 0.428, p = 0.002). GLS correlated with SV (r=-0.369, p = 0.008) but not with preload (LVEDV), or afterload (SBP). In a linear regression model, GLS was independently associated with Meld-Na score when adjusting for age, SBP, LVEDV and NASH etiology [B=-0.139 (-0.252; -0.025), p = 0.018]. Conclusions GLS is lower (more negative) in patients with liver cirrhosis as disease progresses a relation not affected by preload and afterload conditions. Further research works are required to explain the underlying pathophysiology and to assess prognostic significance of reduced GLS values in patients with advanced cirrhosis. Abstract Figure. GLS stratified by Child-Pugh score

scholarly journals CT hepatic arterial perfusion index does not allow stratification of the degree of esophageal varices and bleeding risk in cirrhotic patients in Child–Pugh classes A and B

2021 ◽  
Author(s):  
Felix Peisen ◽  
Kaspar Ekert ◽  
Michael Bitzer ◽  
Hans Bösmüller ◽  
Jan Fritz ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Correlation Coefficient ◽  
Esophageal Varices ◽  
Bleeding Risk ◽  
Perfusion Index ◽  
Arterial Perfusion ◽  
Class A ◽  
Significant Difference ◽  
Pugh Class ◽  
Cirrhotic Patients

Abstract Purpose To evaluate if the hepatic arterial perfusion index (HPI) in liver parenchyma of cirrhotic patients can serve as a surrogate parameter for stratifying the degree of esophageal varices and related bleeding risks. Methods CT image data of sixty-six patients (59 men; mean age 68 years ± 10 years) with liver cirrhosis (Child–Pugh class A (35/66, 53%), B (25/66, 38%), and C (6/66, 9%) who underwent perfusion CT (PCT) for hepatocellular carcinoma (HCC) screening between April 2010 and January 2019 were retrospectively identified. HPI, a parameter calculated by a commercially available CT liver perfusion analysis software that is based on the double maximum slope model, using time attenuation curve to determine perfusion, was correlated with the degree of esophageal varices diagnosed at endoscopy and the number of bleeding events. Results Eta correlation coefficient for HPI/presence of esophageal varices was very weak (0.083). Spearman-Rho for HPI/grading of esophageal varices was very weak (0.037 (p = 0.804)). Kendall-Tau-b for HPI/grading of esophageal varices was very weak (0.027 (p = 0.807)). ANOVA and Bonferroni post-hoc-tests showed no significant difference of HPI between different grades of esophageal varices (F (3, 62) = 1.676, p = 0.186). Eta correlation coefficient for HPI/bleeding event was very weak (0.126). Conclusion The stratification of the degree of esophageal varices and the related bleeding risk by correlation with the HPI as a surrogate parameter for portal venous hypertension was not possible for patients with liver cirrhosis in Child–Pugh class A and B. Graphic abstract

scholarly journals Correlation between Genotypic Diversity, Lipooligosaccharide Gene Locus Class Variation, and Caco-2 Cell Invasion Potential of Campylobacter jejuni Isolates from Chicken Meat and Humans: Contribution to Virulotyping

2009 ◽  
Vol 75 (13) ◽  
pp. 4277-4288 ◽  
Author(s):  
Ihab Habib ◽  
Rogier Louwen ◽  
Mieke Uyttendaele ◽  
Kurt Houf ◽  
Olivier Vandenberg ◽  
...  
Keyword(s):  
Campylobacter Jejuni ◽  
Genotypic Diversity ◽  
Chicken Meat ◽  
Pcr Screening ◽  
Class A ◽  
Invasion Potential ◽  
Cell Surface Carbohydrate ◽  
Significant Difference ◽  
Class B ◽  
Class C

ABSTRACT Significant interest in studying the lipooligosaccharide (LOS) of Campylobacter jejuni has stemmed from its potential role in postinfection paralytic disorders. In this study we present the results of PCR screening of five LOS locus classes (A, B, C, D, and E) for a collection of 116 C. jejuni isolates from chicken meat (n = 76) and sporadic human cases of diarrhea (n = 40). We correlated LOS classes with clonal complexes (CC) assigned by multilocus sequence typing (MLST). Finally, we evaluated the invasion potential of a panel of 52 of these C. jejuni isolates for Caco-2 cells. PCR screening showed that 87.1% (101/116) of isolates could be assigned to LOS class A, B, C, D, or E. Concordance between LOS classes and certain MLST CC was revealed. The majority (85.7% [24/28]) of C. jejuni isolates grouped in CC-21 were shown to express LOS locus class C. The invasion potential of C. jejuni isolates possessing sialylated LOS (n = 29; classes A, B, and C) for Caco-2 cells was significantly higher (P < 0.0001) than that of C. jejuni isolates with nonsialylated LOS (n = 23; classes D and E). There was no significant difference in invasiveness between chicken meat and human isolates. However, C. jejuni isolates assigned to CC-206 (correlated with LOS class B) or CC-21 (correlated with LOS class C) showed statistically significantly higher levels of invasion than isolates from other CC. Correlation between LOS classes and CC was further confirmed by pulsed-field gel electrophoresis. The present study reveals a correlation between genotypic diversity and LOS locus classes of C. jejuni. We showed that simple PCR screening for C. jejuni LOS classes could reliably predict certain MLST CC and add to the interpretation of molecular-typing results. Our study corroborates that sialylation of LOS is advantageous for C. jejuni fitness and virulence in different hosts. The modulation of cell surface carbohydrate structure could enhance the ability of C. jejuni to adapt to or survive in a host.

Functional significance of exaggerated renal thromboxane A2 synthesis induced by cyclosporin A

1986 ◽  
Vol 251 (4) ◽  
pp. F581-F587 ◽  
Author(s):  
N. Perico ◽  
A. Benigni ◽  
C. Zoja ◽  
F. Delaini ◽  
G. Remuzzi
Keyword(s):  
Urinary Excretion ◽  
Cyclosporin A ◽  
Chronic Treatment ◽  
Excretion Rate ◽  
Thromboxane A2 ◽  
Significant Negative Correlation ◽  
Progressive Increase ◽  
Urinary Excretion Rate ◽  
Acid Clearance ◽  
Selective Increase

Animals and humans undergoing a chronic treatment with cyclosporin A (CyA) show a reduction in glomerular filtration rate (GFR). The cause of this abnormality has not been established. Since CyA interferes with arachidonic acid (AA) metabolism in various cells, we wished to determine whether alterations in renal AA metabolites contribute to deteriorating renal function in rats on CyA. We show that chronic CyA treatment induces a progressive increase in the renal synthesis of thromboxane (TX) A2. This is a selective abnormality in that CyA does not influence the renal synthesis of prostaglandin E2 (PGE2) and prostacyclin (PGI2). A significant negative correlation has been found between TXB2 urinary excretion rate and inulin clearance. No correlation has been observed between TXB2 excretion and p-aminohippuric acid clearance. The withdrawal of CyA is followed by a normalization of both TXB2 urinary excretion rate and GFR. The administration of a selective TXA2 inhibitor, UK-38,485, resulted in a significant reduction in urinary excretion of TXB2 accompanied by a significant increase in GFR. We conclude that chronic treatment with CyA in rats is associated with a selective increase in renal TXA2 synthesis and suggest that this abnormality may play a role in the reduction of GFR.

scholarly journals Liver Retraction Using n-Butyl-2-Cyanoacrylate (NBCA) Glue during Laparoscopic Splenectomy and Azygoportal Disconnection in Cirrhotic Patients

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Du Kong ◽  
Wei Wang ◽  
Gang Du ◽  
Binyao Shi ◽  
Zhengchen Jiang ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Portal Hypertension ◽  
Liver Function ◽  
Blood Loss ◽  
Laparoscopic Splenectomy ◽  
Postoperative Bleeding ◽  
Gastroesophageal Varices ◽  
Liver Retraction ◽  
Significant Difference ◽  
Cirrhotic Patients

Background. Although liver retraction using n-butyl-2-cyanoacrylate (NBCA) glue has been applied to laparoscopic upper abdominal surgery in noncirrhotic patients, there is still no consensus on its safety and feasibility for cirrhotic patients. In this study, we aimed to investigate the safety and effectiveness of liver retraction using NBCA glue during laparoscopic splenectomy and azygoportal disconnection (LSD) for gastroesophageal varices and hypersplenism secondary to liver cirrhosis and portal hypertension. Methods. Thirty-nine gastroesophageal varices and hypersplenism secondary to liver cirrhosis and portal hypertension patients were included in our study. We performed LSD in the presence of NBCA glue (n = 22, NBCA group) and absence of NBCA glue (n = 17, n-NBCA group), respectively. The operation time, blood loss, postoperative hospitalization, and liver function were compared between the two groups. Results. There was no mortality during the operation. One patient in non-NBCA group received open surgery due to parenchyma hemorrhage. Postoperative pleural effusion occurred in 2 cases of the NBCA group and 1 of the non-NBCA group. One showed left subphrenic abscess in the non-NBCA group. No postoperative bleeding occurred after 9-30 months of follow-up. The time of operation in NBCA group was significantly shorter than those in n-NBCA group (198.86±17.86 versus 217.81±20.25min, P<0.01). Blood loss in NBCA group was significantly lower than non-NBCA group (159.09±56.98 versus 212.50±88.51 ml, P<0.05). The levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were increased on day 1 after LSD and decreased to normal level on day 7 after LSD in both groups. There was no significant difference in postoperative hospitalization and liver function between the two groups. Conclusion. Liver retraction using NBCA glue during LSD for gastroesophageal varices and hypersplenism secondary to liver cirrhosis and portal hypertension is safe, effective, and feasible.

Circulating miR-21, miR-210 and miR-146a as potential biomarkers to differentiate acute tubular necrosis from hepatorenal syndrome in patients with liver cirrhosis: a pilot study

2018 ◽  
Vol 56 (5) ◽  
pp. 739-747 ◽  
Author(s):  
Mona Mohamed Watany ◽  
Rasha Youssef Hagag ◽  
Hanaa Ibrahim Okda
Keyword(s):  
Liver Cirrhosis ◽  
Acute Tubular Necrosis ◽  
Hepatorenal Syndrome ◽  
Case Control Study ◽  
Kidney Injury ◽  
Tubular Necrosis ◽  
Specificity And Sensitivity ◽  
Significant Difference ◽  
Cirrhotic Patients ◽  
Control Study

AbstractBackground:Acute kidney injury (AKI) in cirrhotic patients may be functional (hepatorenal syndrome [HRS]) or structural (acute tubular necrosis [ATN]). The differentiation between these two conditions remains challenging; no definite biomarker with a clear cutoff value had been declared. miRNAs seem to be attractive innovative biomarkers to identify the nature of kidney injury in cirrhotic patients. This study aimed to investigate the possibility of using miR-21, miR-210 and miR-146a as differentiating markers between HRS and ATN.Methods:This pilot case control study included 50 patients with liver cirrhosis; 25 with HRS and another 25 with ATN beside 30 healthy controls. Real-time qPCR was used to measure the circulating miRNA tested.Results:Higher levels of miR-21 were observed in both ATN and HRS vs. controls with statistically significant difference between ATN and HRS. The means were 9.466±3.21 in ATN, 2.670±1.387 in HRS and 1.090±0.586 in controls. miR-146a and miR-210 were both significantly lower in ATN and HRS compared to controls with statistically significant differences between ATN and HRS. The means of miR-210 were 1.020±0.643, 1.640±0.605 and 3.0±0.532 in ATN, HRS and controls, respectively. The means of miR-146a were 2.543±1.929, 4.98±1.353 and 6.553±0.426 in ATN, HRS and controls, respectively. ROC analyses proved that the three studied mi-RNAs can be used as differentiating biomarkers between ATN and HRS with the best performance observed with mi-21 achieving specificity and sensitivity equal 96%.Conclusions:miR-21, miR-210 and miR-146a may be candidate differentiating markers between HRS and ATN in cirrhotic patients.

scholarly journals Expression of LAIR-1 (CD305) on Human Blood Monocytes as a Marker of Hepatic Cirrhosis Progression

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
María Martínez-Esparza ◽  
Antonio José Ruiz-Alcaraz ◽  
Violeta Carmona-Martínez ◽  
María Dolores Fernández-Fernández ◽  
Gonzalo Antón ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Cell Surface ◽  
Human Blood ◽  
Total Content ◽  
Cell Surface Expression ◽  
Human Macrophage ◽  
Blood Monocytes ◽  
Cirrhotic Patients

Background and Aim. The presumed role of the inhibitory receptor LAIR-1 (CD305) in the inflammatory response suggests that it might contribute to the pathophysiology of chronic inflammatory diseases such as liver cirrhosis. We studied the LAIR-1 expression on liver macrophages and blood monocytes related to the progression of liver cirrhosis. Methods. The expression of LAIR-1 was analyzed by immunohistochemistry, flow cytometry, and Western blot. Results. We found a decreased number of macrophages expressing LAIR-1 in cirrhotic liver that could be due to a high presence of collagen, ligand of LAIR-1, in the fibrotic tissue which could downregulate its expression or interfere with the immunostaining. The expression of LAIR-1 decreased after cell differentiation, and the total content, but not the cell surface expression, increased after activation in the HL-60 human macrophage in vitro model. Blood monocytes exhibited higher LAIR-1 expression levels in cirrhotic patients, which were evident even in early clinical stages in all monocyte subsets, and greater in the “intermediate” inflammatory monocyte subpopulation. The in vitro activation of human blood monocytes did not increase its expression on the cell surface suggesting that the in vivo increase of LAIR-1 must be the result of a specific combination of stimuli present in cirrhotic patients. This represents an exclusive feature of liver cirrhosis, since blood monocytes from other chronic inflammatory pathologies showed similar or lower LAIR-1 levels compared with those of healthy controls. Conclusions. These results may indicate that monocyte LAIR-1 expression is a new biomarker to early detect liver damage caused by chronic inflammation in liver cirrhosis.

scholarly journals Microbiological characterization of VNRX-5236: a broad spectrum β-lactamase inhibitor for rescue of the orally bioavailable cephalosporin ceftibuten as a carbapenem-sparing agent against strains of Enterobacterales expressing extended spectrum β-lactamases and serine carbapenemases.

2021 ◽  
Author(s):  
Cassandra L. Chatwin ◽  
Jodie C. Hamrick ◽  
Robert E. L. Trout ◽  
Cullen L. Myers ◽  
Susan M. Cusick ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Clinical Isolates ◽  
Class A ◽  
Extended Spectrum ◽  
Oral Agents ◽  
Class C ◽  
Orally Bioavailable ◽  
Lactamase Inhibitor

There is an urgent need for oral agents to combat resistant gram-negative pathogens. Here we describe the characterization of VNRX-5236, a broad-spectrum boronic acid β-lactamase inhibitor (BLI) and its orally bioavailable etzadroxil prodrug, VNRX-7145. VNRX-7145 is being developed in combination with ceftibuten, an oral cephalosporin, to combat strains of Enterobacterales expressing extended spectrum β-lactamases (ESBLs) and serine carbapenemases. VNRX-5236 is a reversible covalent inhibitor of serine β-lactamases, with inactivation efficiencies on the order of 104 M−1. sec−1, and prolonged active site residence times (t1/2, 5 to 46 min). The spectrum of inhibition includes Ambler class A ESBLs, class C cephalosporinases, and class A and D carbapenemases (KPC and OXA-48, respectively). Rescue of ceftibuten by VNRX-5236 (fixed at 4 μg/mL) in isogenic strains of E. coli expressing class A, C or D β-lactamases demonstrated an expanded spectrum of activity relative to oral comparators including investigational penems, sulopenem and tebipenem. VNRX-5236 rescued ceftibuten activity in clinical isolates of Enterobacterales expressing ESBLs (MIC90 = 0.25 μg/mL), KPCs (MIC90 = 1 μg/mL), class C cephalosporinases (MIC90 = 1 μg/mL) and OXA-48-type carbapenemases (MIC90 = 1 μg/mL). Frequency of resistance studies demonstrated a low propensity for recovery of resistant variants at 4× the MIC of the ceftibuten/VNRX-5236 combination. In vivo, whereas ceftibuten alone was ineffective (ED50, >128 mg/kg), ceftibuten/VNRX-7145 administered orally protected mice from lethal septicemia caused by K. pneumoniae producing KPC carbapenemase (ED50, 12.9 mg/kg). The data demonstrate potent, broad-spectrum rescue of ceftibuten activity by VNRX-5236 in clinical isolates of cephalosporin-resistant and carbapenem-resistant Enterobacterales.

Sign in / Sign up

Export Citation Format

Share Document