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1.
Effect of Moderate Hepatic Impairment on the Pharmacokinetics of Vadadustat, an Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor.
Chavan, A, Burke, L, Sawant, R, Navarro-Gonzales, P, Vargo, D, Paulson, SK
Clinical pharmacology in drug development. 2021;(8):950-958
Abstract
Vadadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor in development for the treatment of anemia of chronic kidney disease. This phase 1, open-label, parallel-group, single-dose study evaluated the pharmacokinetics of 450-mg vadadustat in adults with moderate hepatic impairment (Child-Pugh class B) vs those with normal hepatic function. Primary end points were area under the plasma concentration-time curve (AUC) from dosing to last concentration and to infinity, as well as maximum concentration (Cmax ); additional pharmacokinetic parameters included time to Cmax (Tmax ) and half-life. Safety and tolerability were also assessed. All enrolled participants (n = 16) completed the study. Demographics were similar in both groups (overall, 100% White; 62.5% female; mean age, 59.2 years). Vadadustat plasma exposure was higher in the moderate hepatic impairment group, whereas maximum concentration was similar between groups. Point estimates of the hepatic impairment : normal geometric mean ratios (90% confidence interval) for AUC from dosing to last concentration, AUC from dosing to infinity, and Cmax were 1.05 (0.82-1.35), 1.06 (0.82-1.36), and 1.02 (0.79-1.32), respectively. Mean elimination half-life was 5.8 and 7.8 hours in the normal and hepatic impairment groups, respectively. Treatment-emergent adverse events were mostly mild in severity, and vadadustat was generally well tolerated. In conclusion, moderate hepatic impairment did not significantly impact vadadustat systemic exposure, and mild hepatic impairment is unlikely to alter vadadustat exposure.
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2.
Non-vitamin K Antagonist Oral Anticoagulants Versus Warfarin in Patients with Atrial Fibrillation and Liver Disease: A Meta-Analysis and Systematic Review.
Fu, Y, Zhu, W, Zhou, Y, Chen, H, Yan, L, He, W
American journal of cardiovascular drugs : drugs, devices, and other interventions. 2020;(2):139-147
Abstract
BACKGROUND The effect of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation (AF) and liver disease remains largely unresolved. Therefore, we performed a meta-analysis to compare the efficacy and safety of NOACs with warfarin in this population. METHODS We systematically searched the Cochrane Library, PubMed, and Embase databases for studies reporting the comparisons of NOACs with warfarin in patients with AF and liver disease. A random-effects model was selected to pool the risk ratios (RRs) and 95% confidence intervals (CIs). RESULTS A total of six studies with 41,954 participants were included in this meta-analysis. In AF patients with liver disease, compared with warfarin use, the use of NOACs was associated with reduced risks of all-cause death (RR 0.78, 95% CI 0.66-0.93), major bleeding (RR 0.68, 95% CI 0.53-0.88), and intracranial hemorrhage (RR 0.49, 95% CI 0.41-0.59), but had comparable risks of stroke or system embolism (RR 0.80, 95% CI 0.57-1.12) and gastrointestinal bleeding (RR 0.90, 95% CI 0.61-1.34). In AF patients with cirrhosis, NOACs significantly reduced the risks of major bleeding (RR 0.53, 95% CI 0.37-0.76), gastrointestinal bleeding (RR 0.57, 95% CI 0.38-0.84), and intracranial hemorrhage (RR 0.55, 95% CI 0.31-0.97) compared with warfarin. CONCLUSIONS Based on current publications, the use of NOACs is at least non-inferior to warfarin in patients with AF and liver disease.
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3.
Contrast-Enhanced Ultrasound for the Characterization of Malignant versus Benign Focal Liver Lesions in a Prospective Multicenter Experience - The SRUMB Study.
Sporea, I, Săndulescu, DL, Şirli, R, Popescu, A, Danilă, M, Spârchez, Z, Mihai, C, Ioanițescu, S, Moga, T, Timar, B, et al
Journal of gastrointestinal and liver diseases : JGLD. 2019;:191-196
Abstract
AIM: This study evaluated the accuracy of contrast-enhanced ultrasound (CEUS) for the differential diagnosis of benign vs. malignant focal liver lesions (FLL) in a real-life, multicenter experience. METHODS This prospective study, including 14 Romanian centers, was performed over a 6 year period (February 2011- April 2017) and included 2062 FLLs assessed by CEUS. Inclusion criteria were: newly diagnosed FLL on B-mode ultrasound, less than three lesions/patient, all FLLs evaluated by CEUS and by a second-line imaging technique (contrast enhanced CT or contrast enhanced MRI) or histology, considered as reference. The trial was registered in clinicaltrials.gov (Identifier NCT01329458). RESULTS From the 2062 FLLs included in the study, 57.2% (1179) were malignant and 42.8% (883) were benign. CEUS had 83.9% sensitivity (Se), 97.8% specificity (Sp), 98.1% positive predictive value (PPV), 82.2% negative predictive value (NPV) and a diagnostic accuracy (Ac) of 89.9% for the positive diagnosis of malignant lesions. For the benign lesions, CEUS had 97.8% Se, 83.9% Sp, 82.2% PPV, 98.1% NPV 89.9% Ac. The diagnostic performance of CEUS for hepatocellular carcinoma was 76.6% Se, 98.4% Sp, and 91.2% Ac; for hemangioma: 89.2% Se, 99% Sp, and 96.9% Ac and for metastases: 90.9% Se, 98.4% Sp, and 96.9% Ac. CONCLUSIONS CEUS proved a high accuracy in differentiating the malignant vs. benign character of a FLL. It can be confidently used as a first line imaging method in daily practice.
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4.
Measurement of the enriched stable isotope 58Fe in iron related disorders- comparison of INAA and MC-ICP-MS.
Yagob, T, van de Wiel, A, Bode, P, Demir, A, van der Wagt, B, Krystek, P, Wolterbeek, B
Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS). 2019;:77-83
Abstract
As a safer alternative for the use of radioactive tracers, the enriched stable 58Fe isotope has been introduced in studies of iron metabolism. In this study this isotope is measured with instrumental neutron activation analysis (INAA) in blood samples of patients with iron related disorders and controls after oral ingestion of a 58Fe containing pharmaceutical. Results were compared with those derived from MC-ICP-MS, applied on the same samples, and analytical and practical aspects of the two techniques were compared. Both techniques showed an increased absorption and incorporation in red blood cells of the 58Fe isotope in iron deficient patients in contrast to the controls. In all individuals results of INAA measurements were in good agreement with those of MC-ICP-MS (|zeta| < 2). Uncertainties in INAA are substantially higher than those achievable by MC-ICP-MS but the INAA technique offers a high specificity and selectivity for iron close to 100%. In contrast to INAA, sample preparation before measurement is very critical in MC-ICP-MS and interferences with 58Ni and 54Cr may hamper the measurement of 58Fe and 54Fe respectively. Since it takes at least five days after irradiation to reduce the activity of interfering radionuclides (mainly 24Na), INAA is a more time consuming procedure; the need of a nuclear reactor facility makes it also less accessible than MC-ICP-MS. Costs are comparable. Both INAA and MC-ICP-MS are able to adequately measure changes in iron isotope composition in blood when an enriched stable iron isotope is applied in clinical research. Although MC-ICP-MS is more sensitive, is faster and has easier access, in INAA preparative steps before measurement are simpler and there are hardly demands on the kind and size of the samples. This may be relevant working with biomaterials in a clinical setting.
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5.
Gastrointestinal side effects in liver transplant recipients taking enteric-coated mycophenolate sodium vs. mycophenolate mofetil.
Lopez-Solis, R, DeVera, M, Steel, J, Fedorek, S, Sturdevant, M, Hughes, C, Humar, A
Clinical transplantation. 2014;(7):783-8
Abstract
In the setting of liver transplantation, mycophenolate mofetil (MMF) may be used as an adjuvant therapy for immunosuppression to prevent graft rejection; however, its use may be limited due to severe gastrointestinal (GI) side effects. In contrast, enteric-coated mycophenolate sodium (EC-MPS) may be associated with less severe side effects and hence better tolerability. We compared the side effects of EC-MPS to MMF in liver transplant patients in a de novo study (Study I-randomized, prospective, double-blinded) and a conversion study (Study II). In both studies, the severity of GI symptoms was assessed at various time points using the Gastrointestinal Symptoms Rating Scale (GSRS) survey, a validated survey of GI symptoms (abdominal pain, reflux, indigestion, diarrhea, and constipation). In Study I, the symptoms of 30 recipients receiving EC-MPS (n = 15) were compared to 15 recipients receiving MMF. A multivariate analysis of variance (MANOVA) of the total GSRS scores and symptom syndrome subscores revealed no significant difference (p > 0.05) between the two medications over time. A conversion study (Study II) with 29 participants, however, showed that over time, all GI symptoms improved significantly (p < 0.001) when the patients were treated with EC-MPS instead of MMF.
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6.
Body size indexes for optimizing iodine dose for aortic and hepatic enhancement at multidetector CT: comparison of total body weight, lean body weight, and blood volume.
Kondo, H, Kanematsu, M, Goshima, S, Tomita, Y, Kim, MJ, Moriyama, N, Onozuka, M, Shiratori, Y, Bae, KT
Radiology. 2010;(1):163-9
Abstract
PURPOSE To evaluate and compare total body weight (TBW), lean body weight (LBW), and estimated blood volume (BV) for the adjustment of the iodine dose required for contrast material-enhanced multidetector computed tomography (CT) of the aorta and liver. MATERIALS AND METHODS Institutional review committee approval and written informed consent were obtained. One hundred twenty patients (54 men, 66 women; mean age, 64.1 years; range, 19-88 years) who underwent multidetector CT of the upper abdomen were randomized into three groups of 40 patients each: (a) TBW group (0.6 g of iodine per kilogram of TBW), (b) LBW group (0.821 g of iodine per kilogram of LBW), and (c) BV group (men, 8.6 g of iodine per liter of BV; women, 9.9 g of iodine per liter of BV). Change in CT number between unenhanced and contrast-enhanced images per gram of iodine and maximum hepatic enhancement (MHE) adjusted for iodine dose were examined for correlation with TBW, LBW, and BV by using linear regression analysis. RESULTS In the portal venous phase, correlation coefficients for the correlation of change in CT number per gram of iodine with TBW for the aorta and liver were -0.71 and -0.79, respectively, in the TBW group; -0.80 and -0.86, respectively, in the LBW group; and -0.68 and -0.66, respectively, in the BV group. In the liver, they were marginally higher in the LBW group than in the BV group (P = .03). Adjusted MHE remained constant at 77.9 HU +/- 10.2 (standard deviation) in the LBW group with respect to TBW, but it increased in the TBW (r = 0.80, P < .001) and BV (r = 0.70, P < .001) groups as TBW increased. CONCLUSION When LBW, rather than TBW or BV, is used, the iodine dose required to achieve consistent hepatic enhancement may be estimated more precisely and with reduced patient-to-patient variability.
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7.
Detection and characterization of focal liver lesions: a Japanese phase III, multicenter comparison between gadoxetic acid disodium-enhanced magnetic resonance imaging and contrast-enhanced computed tomography predominantly in patients with hepatocellular carcinoma and chronic liver disease.
Ichikawa, T, Saito, K, Yoshioka, N, Tanimoto, A, Gokan, T, Takehara, Y, Kamura, T, Gabata, T, Murakami, T, Ito, K, et al
Investigative radiology. 2010;(3):133-41
Abstract
OBJECTIVES To prospectively evaluate the safety and efficacy of combined unenhanced and gadoxetic acid disodium (Gd-EOB-DTPA)-enhanced magnetic resonance (MR) imaging compared with unenhanced MR imaging and triphasic contrast-enhanced spiral computed tomography (CT) for the detection and characterization of focal liver lesions. MATERIALS AND METHODS The study was reviewed and approved by the institutional review board at each of the 15 centers involved in the study, and informed written consent was given by all patients. In total, 178 patients with suspected focal hepatic lesions (based, in most patients, on CT, tumor marker and ultrasound examinations) underwent combined MR imaging with a single, rapid injection of Gd-EOB-DTPA 0.025 mmol/kg, including T1-weighted dynamic and delayed MR images 20 to 40 minutes postinjection. Triphasic contrast-enhanced CT, the comparator examination, was performed within 4 weeks of MR imaging. Standard of references (SOR) were resection histopathology and intraoperative ultrasonography, or combined CT during arterial portography and CT hepatic arteriography; in cases where, although the major lesions were treated, some lesion(s) were not treated, follow-up superparamagnetic iron oxide-enhanced MR imaging was additionally performed. All images were assessed for differences in lesion detection and characterization (specific lesion type) by on-site readers and 3, blinded (off-site) reviewers. All adverse events (AEs) occurring within 72 hours after Gd-EOB-DTPA administration were reported. RESULTS Overall, 9.6% of patients who received Gd-EOB-DTPA reported 21 drug-related AEs. A total of 151 patients were included in the efficacy analysis. Combined MR imaging showed statistically higher sensitivity in lesion detection (67.5%-79.5%) than unenhanced MR imaging (46.5%-59.1%; P < 0.05 for all). Combined MR imaging also showed higher sensitivity in lesion detection than CT (61.1%-73.0%), with the results being statistically significant (P < 0.05) for on-site readers and 2 of 3 blinded readers. Higher sensitivity in lesion detection with combined MR imaging compared with CT was also clearly demonstrated in the following subgroups: lesions with a diameter CONCLUSION In this study, hepatocyte-specific Gd-EOB-DTPA was shown to be safe and to improve the detection and characterization of focal hepatic lesions compared with unenhanced MR imaging. When compared with spiral CT, Gd-EOB-DTPA enhanced MRI seems to be beneficial especially for the detection for smaller lesions or hepatocellular carcinoma underlying cirrhotic liver.
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8.
A pharmacokinetics evaluation of a new, low-volume, oral sulfate colon cleansing preparation in patients with renal or hepatic impairment and healthy volunteers.
Pelham, RW, Alcorn, H, Cleveland, Mv
Journal of clinical pharmacology. 2010;(3):350-4
Abstract
The pharmacokinetics (PK) of an oral sulfate solution (OSS) for bowel cleansing preparation was studied. OSS (30 g of sulfate) was split between 2 doses, 12 hours apart. Safety measures included electrocardiography, vital signs, adverse events, hematology, blood chemistry, and urinalysis. Six adult patients with moderate renal disease (MRD), 6 with mild-moderate hepatic disease (M/MHD), and 6 normal healthy volunteers (NHVs) completed the study. Adverse events were mild to moderate in severity and were mainly limited to headache and expected gastrointestinal symptoms. Serum sulfate levels were highly variable at all times, even after adjusting for baseline. Sulfate was higher in MRD in comparison to the other groups. The C(max) and AUC were higher in the patients, but no statistically significant differences emerged. Sulfate levels returned to predose values within 54 hours after dosing. No electrolyte disturbances occurred. Urinary sulfate excretion was approximately 20% of the dose. OSS was well tolerated. The types and severity of adverse events were similar to those seen in large phase III trials. While patients with MRD had elevated sulfate, the levels were less than those in renal failure and did not alter biochemical parameters that are associated with hypersulfatemia.
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9.
In vivo and in vitro nuclear magnetic resonance spectroscopy as a tool for investigating hepatobiliary disease: a review of H and P MRS applications.
Khan, SA, Cox, IJ, Hamilton, G, Thomas, HC, Taylor-Robinson, SD
Liver international : official journal of the International Association for the Study of the Liver. 2005;(2):273-81
Abstract
Nuclear magnetic resonance (NMR) spectroscopy is a non-invasive technique, which allows the study of cellular biochemistry and metabolism. It is a diverse research tool, widely used by biochemists to investigate pathophysiological processes in vitro and, more recently, by physicians to determine disease abnormalities in vivo. This article reviews the basics of the NMR phenomenon and summarises previous research on the hepatobiliary system using both laboratory-based and clinical methodologies. The role of proton and phosphorus-31 ((31)P) NMR spectroscopy in the study of malignant and non-malignant liver disease and studies of bile composition are discussed. In vivo techniques (magnetic resonance spectroscopy, MRS) can be performed as an adjunct to standard MR examination of the liver. Although still primarily a research tool, the in vivo technique provides non-invasive biochemical information on disease severity and holds promise in its use to gauge response to treatment regimens.
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10.
Optimizing scan delays of fixed duration contrast injection in contrast-enhanced biphasic multidetector-row CT for the liver and the detection of hypervascular hepatocellular carcinoma.
Kanematsu, M, Goshima, S, Kondo, H, Nishibori, H, Kato, H, Yokoyama, R, Miyoshi, T, Hoshi, H, Onozuka, M, Moriyama, N
Journal of computer assisted tomography. 2005;(2):195-201
Abstract
OBJECTIVE To determine the optimal scan delay required for fixed duration contrast injection in contrast-enhanced biphasic multidetector-row CT for the liver and the detection of hypervascular hepatocellular carcinoma (HCC). METHODS CT images (2.5-mm collimation, 5-mm thickness with no intersectional gap) were obtained after an intravenous bolus injection of 2 mL/kg of nonionic iodine contrast material (300 mg I/mL) for a fixed 30-second injection in 206 patients, who were prospectively randomized into four groups, for which scans were initiated at -5, 15, and 35 seconds; at 0, 20, and 40 seconds; at 5, 25, and 45 seconds; or at 10, 30, and 50 seconds for the first (acquisition time: 4.3 seconds), second (4.3 seconds), and third (9.1 seconds) phases, respectively, after the completion of contrast injection. Mean CT values (HU) of the abdominal aorta, spleen, main portal veins, liver parenchyma, and hepatic veins were measured. Increases in CT values between pre- and post-contrast CTs (DeltaHU) for the organs, and spleen-to-liver and HCC-to-liver contrast differences (deltaHU) were assessed. RESULTS Abdominal aorta reached 273-301 DeltaHU at -5 to 10 seconds with a peak (301 DeltaHU) at 5 seconds. Spleen peaked (115 DeltaHU) at 10 seconds. Liver parenchyma were enhanced weakly (11-34 DeltaHU) at -5 to 10 seconds, exceeded 50 DeltaHU at 20 seconds, peaked (61 DeltaHU) at 30 seconds, and then plateaued (54-58 DeltaHU) at 35-50 seconds. Hepatic veins were enhanced weakly (14-37 DeltaHU) at -5 to 10 seconds, and reached 67 DeltaHU at 15 seconds. Spleen-to-liver (65-69 deltaHU) and HCC-to-liver (31-34 deltaHU) contrast differences were highest at 5-10 seconds. Qualitative results corresponded well with quantitative results. CONCLUSIONS For the detection of hypervascular HCCs, the optimal scan delay after a 30-second contrast injection of the hepatic arterial phase, was found to range from 5 to 10 seconds, and that of the portal venous phase was 35 seconds or somewhat longer.