柴琳
中国医学科学院阜外医院
Nifekalant hydrochloride is a class III antiarrhythmic agent which could increase the duration of the action potential and the effective refractory period of ventricular and atrial myocytes by blocking the K+ current. Nifekalant is used to prevent ventricular tachycardia/ventricular fibrillation. QT interval prolongation is the main measurable drug effect. However, due to the complicated dosing plan in clinic, the relationship among dosage, time, drug concentration and efficacy is not fully understood. In this study, a single-center, randomized, blind, dose-ascending, placebo-controlled study was conducted to explore the intrinsic characteristics of nifekalant injection in healthy Chinese volunteers by a population pharmacokinetic (PK)-pharmacodynamic (PD) model approach. 42 subjects were enrolled in this study and received one of three dose plans (loading dose on Day 1 (0.15, 0.3 or 0.5 mg/kg), loading dose followed by maintenance dose (0.2, 0.4 or 0.8 mg/kg/h) on Day 4) or vehicle. Blood samples were drawn for PK evaluation, and ECGs were recorded for QTc calculation at the designed timepoints. No Torsades de Pointes occurred during the study. The popPK model of nifekalant injection could be described by a two-compartment model with first-order elimination. The population mean clearance (CL) was 53.8 L/h. The population mean distribution volume of the central (Vc) and peripheral (Vp) compartments was 8.27 L and 45.6 L, respectively. A nonlinear dose-response (Emax) model well described the pharmacodynamic effect (QTc interval prolongation) of nifekalant. The Emax and EC50 from current study were 101 ms and 342 ng/mL, respectively.
Journal of pharmacokinetics and pharmacodynamics 2024
BACKGROUND:As an acute phase protein, α1-antitrypsin (AAT) has been extensively studied in acute coronary syndrome, but it is unclear whether a relationship exists between AAT and stable angina pectoris (SAP). The purpose of the present study was to investigate the association between AAT plasma levels and SAP.METHODS:Overall, 103 SAP patients diagnosed by coronary angiography and clinical manifestations and 118 control subjects matched for age and gender were enrolled in this case-control study. Plasma levels of AAT, high-sensitivity C-reactive protein (hsCRP), lipid profiles and other clinical parameters were assayed for all participants. The severity of coronary lesions was evaluated based on the Gensini score (GS) assessed by coronary angiography.RESULTS:Positively correlated with the GS (r = 0.564, P < 0.001), the plasma AAT level in the SAP group was significantly higher than that in the control group (142.08 ± 19.61 mg/dl vs. 125.50 ± 19.67 mg/dl, P < 0.001). The plasma AAT level was an independent predictor for both SAP (odds ratio [OR] = 1.037, 95% confidence interval [CI]: 1.020-1.054, P < 0.001) and a high GS (OR = 1.087, 95% CI: 1.051-1.124, P < 0.001) in a multivariate logistic regression model. In the receiver operating characteristic curve analysis, plasma AAT level was found to have a larger area under the curve (AUC) for predicting a high GS (AUC = 0.858, 95% CI: 0.788-0.929, P < 0.001) than that of hsCRP (AUC = 0.665, 95% CI: 0.557-0.773, P = 0.006; Z = 2.9363, P < 0.001), with an optimal cut-off value of 137.85 mg/dl (sensitivity: 94.3%, specificity: 68.2%).CONCLUSIONS:Plasma AAT levels correlate with both the presence and severity of coronary stenosis in patients with SAP, suggesting that it could be a potential predictive marker of severe stenosis in SAP patients.
Chinese medical journal 2015
