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CSL112 (Apolipoprotein A-I [Human]) Strongly Enhances Plasma Apoa-I and Cholesterol Efflux Capacity in Post-Acute Myocardial Infarction Patients: A PK/PD Substudy of the AEGIS-I Trial.
Gibson, CM, Kazmi, SHA, Korjian, S, Chi, G, Phillips, AT, Montazerin, SM, Duffy, D, Zheng, B, Heise, M, Liss, C, et al
Journal of cardiovascular pharmacology and therapeutics. 2022;:10742484221121507
Abstract
INTRODUCTION Cholesterol efflux capacity (CEC) is impaired following acute myocardial infarction (AMI). CSL112 is an intravenous preparation of human plasma-derived apoA-I formulated with phosphatidylcholine (PC). CSL112 is intended to improve CEC and thereby prevent early recurrent cardiovascular events following AMI. AEGIS-I (ApoA-I Event Reducing in Ischemic Syndromes I) was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging phase 2b study, designed to evaluate the hepatic and renal safety of CSL112. Here, we report an analysis of a pharmacokinetic (PK) and pharmacodynamic (PD) substudy of AEGIS-I. METHODS AMI patients were stratified by renal function and randomized 3:3:2 to 4, weekly, 2-hour infusions of low- and high-dose (2 g and 6 g) CSL112, or placebo. PK/PD assessments included plasma concentrations of apoA-I and PC, and measures of total and ABCA1-dependent CEC, as well as lipids/lipoproteins including high density lipoprotein cholesterol (HDL-C), non-HDL-C, low density lipoprotein cholesterol (LDL-C), ApoB, and triglycerides. Inflammatory and cardio-metabolic biomarkers were also evaluated. RESULTS The substudy included 63 subjects from AEGIS-I. CSL112 infusions resulted in rapid, dose-dependent increases in baseline corrected apoA-I and PC, which peaked at the end of the infusion (Tmax ≈ 2 hours). Similarly, there was a dose-dependent elevation in both total CEC and ABCA1-mediated CEC. Mild renal impairment did not affect the PK or PD of CSL112. CSL112 administration was also associated with an increase in plasma levels of HDL-C but not non-HDL-C, LDL-C, apoB, or triglycerides. No dose-effects on inflammatory or cardio-metabolic biomarkers were observed. CONCLUSION Among patients with AMI, impaired CEC was rapidly elevated by CSL112 infusions in a dose-dependent fashion, along with an increase in apoA-I plasma concentrations. Findings from the current sub-study of the AEGIS-I support a potential atheroprotective benefit of CSL112 for AMI patients.
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Effect of CSL112 (apolipoprotein A-I [human]) on cholesterol efflux capacity in Japanese subjects: Findings from a phase I study and a cross-study comparison.
Zheng, B, Goto, S, Clementi, R, Feaster, J, Duffy, D, Dalitz, P, Airey, J, Korjian, S, Tortorici, MA, Roberts, J, et al
Clinical and translational science. 2022;(10):2331-2341
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Abstract
CSL112 (apolipoprotein A-I [apoA-I, human]) is a novel drug in development to reduce the risk of recurrent cardiovascular events following acute myocardial infarction by increasing cholesterol efflux capacity (CEC). This phase I study aimed to compare the pharmacokinetics (PKs), pharmacodynamics (PDs), and safety of CSL112 in Japanese and White subjects. A total of 34 Japanese subjects were randomized to receive a single infusion of CSL112 (2, 4, or 6 g) or placebo and 18 White subjects were randomized to receive a single dose of 6 g CSL112 or placebo, followed by PK/PD assessment and adverse events monitoring. In addition, PK/PD parameters were compared across the CSL112 clinical development program. Plasma exposure of apoA-I increased in a dose-dependent but nonlinear manner in Japanese subjects receiving a single dose of CSL112. Mean baseline-corrected area under the curve from 0 to 72 h (AUC0-72 ) increased from 840 to 6490 mg h/dl, in the 2 and 6 g cohorts, respectively, followed by dose-dependent increase of CEC. The plasma PK profile of apoA-I and increases in total and ATP binding cassette transporter A1 dependent CEC were comparable in Japanese and White subjects. The geometric mean ratio (Japanese:White) for plasma apoA-I AUC0-72 and maximum plasma concentration (Cmax ) was 1.08 and 0.945, respectively. Cross-study comparison analysis demonstrated similar CSL112 exposure and CEC enhancement in Japanese and non-Japanese subjects (including patients with cardiovascular disease) and further confirmed consistent PKs/PDs of CSL112. This study suggests CSL112 acutely enhances CEC and is well-tolerated with no differences between Japanese and White subjects.
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Pharmacometric analyses to characterize the effect of CSL112 on apolipoprotein A-I and cholesterol efflux capacity in acute myocardial infarction patients.
Zheng, B, Duffy, D, Tricoci, P, Kastrissios, H, Pfister, M, Wright, SD, Gille, A, Tortorici, MA
British journal of clinical pharmacology. 2021;(6):2558-2571
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Abstract
AIMS: To characterize relationships between apolipoprotein A-I (apoA-I) exposure and cholesterol efflux capacity (CEC) and covariate effects following CSL112 (apoA-I [human]) administration in an integrated population including acute myocardial infarction (AMI) patients. METHODS A pharmacometric analysis utilized data from seven clinical trials, including patients with AMI, subjects with renal impairment and healthy subjects. A population pharmacokinetic (PK) analysis was performed to relate CSL112 doses to changes in apoA-I plasma concentrations. Covariate analysis was conducted to identify sources of variability in apoA-I exposure. Exposure-response modeling was conducted to describe the relationship between apoA-I exposure and total or ATP binding cassette transporter A1-(ABCA1)-dependent CEC and to identify clinical predictors of CEC. RESULTS A two-compartment model described apoA-I PK. ApoA-I clearance was slightly lower in subjects with AMI, whereas baseline apoA-I was marginally higher in female and Japanese subjects. Covariate effects on apoA-I exposure were in the order of 10% and thus not clinically relevant. The relationships between apoA-I exposure and CECs were described by nonlinear models. Simulations showed CEC elevation resulting from apoA-I exposure increment was comparable in AMI and non-AMI subjects; no covariate had clinically meaningful effects on CEC. Simulations also demonstrated that CEC in patients with AMI post 6 g CSL112 dosing was substantially elevated compared to placebo and lower dose levels. CONCLUSIONS The model-based exposure-response analysis demonstrated, irrespective of body weight, sex and race, that fixed 6 g CSL112 dosing causes a desired CEC elevation, which may benefit AMI patients by potentially reducing early recurrent cardiovascular event risk.
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Lenvatinib versus sorafenib for unresectable hepatocellular carcinoma: a cost-effectiveness analysis.
Cai, H, Zhang, L, Li, N, Zheng, B, Liu, M
Journal of comparative effectiveness research. 2020;(8):553-562
Abstract
Aim: To investigate the cost-effectiveness of lenvatinib and sorafenib in the treatment of patients with nonresected hepatocellular carcinoma in China. Materials & methods: Markov model was used to simulate the direct medical cost and quality-adjusted life years (QALY) of patients with hepatocellular carcinoma. Clinical data were derived from the Phase 3 randomized clinical trial in a Chinese population. Results: Sorafenib treatment resulted in 1.794 QALYs at a cost of $43,780.73. Lenvatinib treatment resulted in 2.916 QALYs for patients weighing <60 and ≥60 kg at a cost of $57,049.43 and $75,900.36, The incremental cost-effectiveness ratio to the sorafenib treatment group was $11,825.94/QALY and $28,627.12/QALY, respectively. Conclusion: According to WHO's triple GDP per capita, the use of lenvatinib by providing drugs is a cost-effective strategy.
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Whole-genome sequencing revealed an interstitial deletion encompassing OCRL and SMARCA1 gene in a patient with Lowe syndrome.
Zheng, B, Chen, Q, Wang, C, Zhou, W, Chen, Y, Ding, G, Jia, Z, Zhang, A, Huang, S
Molecular genetics & genomic medicine. 2019;(9):e876
Abstract
BACKGROUND Lowe syndrome is a rare X-linked syndrome that is characterized by involvement of the eyes, central nervous system, and kidneys. The aim of the present study was to determine the molecular basis of four patients with congenital cataract, infantile congenital hypotonia, and proximal renal tubular defect. METHODS Four children who met the clinical manifestations of Lowe syndrome were enrolled in this study. Patients' clinical information on eyes, central nervous system, kidneys, and family histories, etc., were reviewed and analyzed. After obtaining informed consent, we performed a mutation analysis of OCRL gene using direct sequencing. Because of failure of PCR amplification, low coverage shortread whole genome sequencing (CNVseq) analysis was performed on one proband. Real-time PCR was subsequently performed to confirm the CNV that was detected from the CNVseq results. RESULTS We identified three OCRL allelic variants, including two novel missense mutations (c.1423C>T/p.Pro475Ser, c.1502T>G/p.Ile501Ser) and one recurrent nonsense mutation (c.2464C>T/p.Arg822Ter). Various bioinformatic tools revealed scores associated with potential pathogenic effects for the two missense variants, and protein alignments revealed that both variants affected an amino acid highly conserved among species. Since deletion of the entire gene was suspected in a patient, CNVseq was used, identifying an interstitial deletion to approximately 190 kb, encompassing OCRL, and SMARCA1 gene. Moreover, the hemizygous CNV was confirmed by qPCR. Reviewing another case reported in the literature, we found that the deletion of OCRL and nearby genes may contribute to a more severe phenotype and premature death. CONCLUSIONS This is the first report of an interstitial deletion encompassing OCRL and SMARCA1 gene in Lowe syndrome. Our results expand the spectrum of mutations of the OCRL gene in Chinese population. Moreover, whole-genome sequencing presents a comprehensive and reliable approach for detecting genomic copy number variation in patients or carriers in the family with rare inherited disorders.
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Thrombus aspiration plus intra-infarct-related artery administration of tirofiban improves myocardial perfusion during primary angioplasty for acute myocardial infarction.
Yan, HB, Li, SY, Song, L, Wang, J, Wu, Z, Chi, YP, Zheng, B, Zhao, HJ, Li, QX, Zhang, XJ, et al
Chinese medical journal. 2010;(7):877-83
Abstract
BACKGROUND We developed a new combined strategy of thrombus aspiration plus intra-infarct-related artery (IRA) bolus administration of tirofiban via the aspiration catheter in patients with ST-segment elevation myocardial infarction (STEMI). This strategy can reduce the distal embolism and achieve highly localized concentrations of tirofiban, which can improve myocardial reperfusion without increasing the risk of bleeding. The aim of this study was to investigate whether this combined strategy is superior to thrombus aspiration alone in improving myocardial perfusion in patients with STEMI undergoing primary angioplasty. METHODS This single center study included 108 matched control patients with STEMI, angioplasty after thrombus aspiration, and 108 study patients with STEMI plus intra-IRA administration of 500 microg of tirofiban. Both groups had subsequent 12-hour intravenous infusion of 0.1 microg x kg(-1) x min(-1) of tirofiban after angioplasty. The primary end points were Thrombolysis in Myocardial Infarction (TIMI) flow immediately after angioplasty, ST-segment elevation resolution (STR) (> 70%) at 90 minutes after angioplasty, and the peak of creatine kinase-MB (CK-MB) and troponin I (TnI). The secondary end points were the left ventricular ejection fraction (LVEF) in the hospital and at nine months follow-up, cardiac death, target vessel revascularization (TVR), re-infarction and the combination of these three as major adverse cardiac events (MACE) within nine months and any bleeding events. RESULTS Baseline characteristics of the two groups were well-balanced. The TIMI 3 flow showed a better tendency in the intra-IRA group than in the aspiration alone group (97.22% vs. 87.04%, chi(2) = 7.863, P = 0.049). The peak of CK-MB (83.9 (68.9 - 310.5) U/L vs. 126.1 (74.7 - 356.7) U/L, P = 0.034) and TnI (42.7 (14.7 - 113.9) ng/ml vs. 72.5 (59.8 - 135.3) ng/ml, P = 0.029) were lower in the intra-IRA group than in the aspiration alone group. LVEF in the hospital favored the intra-IRA group, (45.7 +/- 8.3)% to (42.9 +/- 12.1)%, t = 1.98, P = 0.049. There was a tendency towards a lower MACE at 9-month follow-up in the intra-IRA group although it did not reach statistical difference (Log-rank chi(2) = 2.865, P = 0.09). There was no statistical difference in any bleeding events between the two groups. CONCLUSIONS Thrombus aspiration plus intra-IRA bolus administration of tirofiban combined with angioplasty may be related with improved myocardium perfusion, saved more myocardium, and resulted in a better clinical prognosis.
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Electrolyte intake and nonpharmacologic blood pressure control.
Espeland, MA, Kumanyika, S, Yunis, C, Zheng, B, Brown, WM, Jackson, S, Wilson, AC, Bahnson, J
Annals of epidemiology. 2002;(8):587-95
Abstract
PURPOSE To characterize relationships between sodium and potassium intakes and blood pressure control. METHODS We analyzed repeated 24-hour diet recalls and 24-hour urine assays from 873 elderly participants with established hypertension in a 3-year clinical trial of lifestyle interventions. Pooled estimates of electrolyte intakes were developed using hierarchical measurement error models and related to nonpharmacologic blood pressure control. RESULTS Relative decreases in sodium and increases in potassium intakes each had graded relationships with better blood pressure control. After adjustment for measurement error, a 100 mmol/24-hour decrease in sodium intake was associated with an odds ratio of 2.93 [95% confidence interval: 1.83, 4.64] for maintaining nonpharmacologic blood pressure control throughout follow-up. A 50 mmol/24-hour increase in potassium intake was associated with an odds ratio of 2.00 [1.12, 3.55]. These relationships were independent of each other and of baseline levels of intakes. Blood pressure control was most strongly associated with sodium intake for participants with lower systolic blood pressures and longer duration of hypertension, and with potassium for those with elevated diastolic blood pressures. CONCLUSIONS Sodium and potassium intakes exert independent graded influences on nonpharmacologic blood pressure control. Correlated measurement error may spuriously introduce a dependency among these relationships.
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A randomized, controlled clinical trial on meropenem versus imipenem/cilastatin for the treatment of bacterial infections.
Hou, F, Li, J, Wu, G, Zheng, B, Chen, Y, Gu, J, Wang, H, Huo, L, Xue, X, Jia, C, et al
Chinese medical journal. 2002;(12):1849-54
Abstract
OBJECTIVE To evaluate the efficacy and safety of meropenem in Chinese patients, we conducted a study for the treatment of patients with lower respiratory tract infections, urinary tract infections and other infections. METHODS A total of 182 hospitalized patients were enrolled in the study. 90 patients received 500 mg meropenem every 12 hours (or 1 g every 12 hours if necessary) and 92 patients received imipenem/cilastatin 500 mg/500 mg every 12 hours (or 1 g every 12 hours if necessary) by intravenous infusion. The duration of treatment was 7 - 14 days for both groups. RESULTS Seventy of 90 cases receiving meropenem and 70 of 92 cases receiving imipenem/cilastatin were assessable for clinical efficacy. The overall efficacy rates were 90% for the meropenem group and 87% for the imipenem/cilastatin group, and the bacterial eradication rates were 86% in both groups. 93 (76%) of 123 strains isolated from patients produced beta-lactamases. Adverse drug reactions were evaluated in 72 cases in the meropenem group and 70 cases in the imipenem/cilastatin group. The adverse drug reaction rates were 9.7% and 8.6%, respectively. The results showed that there were no statistical differences between these two groups (P > 0.05). CONCLUSION Meropenem is effective and safe for the treatment of bacterial infections caused mainly by beta-lactamase-producing strains.
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Lifestyle interventions influence relative errors in self-reported diet intake of sodium and potassium.
Espeland, MA, Kumanyika, S, Wilson, AC, Wilcox, S, Chao, D, Bahnson, J, Reboussin, DM, Easter, L, Zheng, B
Annals of epidemiology. 2001;(2):85-93
Abstract
PURPOSE To characterize the distribution of errors in self-reported sodium and potassium dietary intakes relative to more objective urine measures among participants receiving lifestyle interventions. METHODS We analyzed longitudinal data from 900 individuals with hypertension who had been enrolled in a randomized controlled clinical trial to establish whether usual care or three lifestyle interventions (weight loss, sodium reduction, and combined weight loss and sodium reduction) could effectively substitute for phamacotherapy. Repeated standardized 24-hour diet recalls and 24-hour urine collections were collected over up to three years of follow-up to estimate sodium and potassium intakes. By contrasting self-reported and urine-based sodium and potassium data collected before and during interventions, we examined the relative impact of intervention assignment on estimated intakes, repeatability, and multivariate measurement error. RESULTS Relative to urine-based measures, mean self-reported sodium intakes were biased about 10% lower among participants assigned to combined weight loss and sodium reduction, but were unaffected by the other interventions. The repeatability of self-report measures increased slightly with time, particularly among participants assigned to sodium interventions. Errors in self-reported sodium and potassium intakes were correlated before the start of the intervention, but became uncorrelated among individuals assigned to sodium restriction interventions. CONCLUSIONS Lifestyle interventions may influence not only diet intake, but also the measurement of diet intake.