Selective Solid-Liquid Extraction of Lithium Cation Using Tripodal Sulfate-Binding Receptors Driven by Electrostatic Interactions.

Owing to the important role of and increasing demand for lithium resources, lithium extraction is crucial. The use of molecular extractants is a promising strategy for selective lithium recovery, in which the interaction between lithium and the designed extractant can be manipulated at the molecular level. Herein, we demonstrate that anion receptors of tripodal hexaureas can selectively extract Li2SO4 solids into water containing DMSO (0.8% water) compared to other alkali metal sulfates. The hexaurea receptor with terminal hexyl chains displays the best Li+ extraction selectivity at 2-fold over Na+ and 12.5-fold over K+. The driving force underpinning selective lithium extraction is due to the combined interactions of Li+-SO42- electrostatics and the ion-dipole interaction of the lithium-receptor (carbonyl groups and N atoms); the latter was found to be cation size dependent, as supported by computational calculations. This work indicates that anion binding receptors could drive selective cation extraction, thus providing new insights into the design of receptors for ion recognition and separation.

Integrated 3D Open Network of Interconnected Bismuthene Arrays for Energy-Efficient and Electrosynthesis-Assisted Electrocatalytic CO2 Reduction.

Electrocatalytic CO2 reduction reaction (CO2 RR) toward formate production can be operated under mild conditions with high energy conversion efficiency while migrating the greenhouse effect. Herein, an integrated 3D open network of interconnected bismuthene arrays (3D Bi-ene-A/CM) is fabricated via in situ electrochemically topotactic transformation from BiOCOOH nanosheet arrays supported on the copper mesh. The resulted 3D Bi-ene-A/CM consists of 2D atomically thin metallic bismuthene (Bi-ene) in the form of an integrated array superstructure with a 3D interconnected and open network, which harvests the multiple structural advantages of both metallenes and self-supported electrodes for electrocatalysis. Such distinctive superstructure affords the maximized quantity and availability of the active sites with high intrinsic activity and superior charge and mass transfer capability, endowing the catalyst with good CO2 RR performance for stable formate production with high Faradaic efficiency (≈90%) and current density (>300 mA cm-2 ). Theoretical calculation verifies the superior intermediate stabilization of the dominant Bi plane during CO2 RR. Moreover, by further coupling anodic methanol oxidation reaction, an exotic electrolytic system enables highly energy-efficient and value-added pair-electrosynthesis for concurrent formate production at both electrodes, achieving substantially improved electrochemical and economic efficiency and revealing the feasibility for practical implementation.

Curcumin Nicotinate Selectively Induces Cancer Cell Apoptosis and Cycle Arrest through a P53-Mediated Mechanism.

Curcumin is an anticancer agent, but adverse effects and low bioavailability are its main drawbacks, which drives efforts in chemical modifications of curcumin. This study evaluated antiproliferative activity and cancer cell selectivity of a curcumin derivative, curcumin nicotinate (CN), in which two niacin molecules were introduced. Our data showed that CN effectively inhibited proliferation and clonogenic growth of colon (HCT116), breast (MCF-7) and nasopharyngeal (CNE2, 5-8F and 6-10B) cancer cells with IC50 at 27.7 µM, 73.4 µM, 64.7 µM, 46.3 µM, and 31.2 µM, respectively. In cancer cells, CN induced apoptosis and cell cycle arrest at G2/M phase through a p53-mediated mechanism, where p53 was activated, p21 and pro-apoptotic proteins Bid and Bak were upregulated, and PARP was cleaved. In non-transformed human mammary epithelial cells MCF10A, CN at 50 µM had no cytotoxicity and p53 was not activated, but curcumin at 12.5 µM activated p53 and p21 and inhibited MCF10A cell growth. These data suggest that CN inhibits cell growth and proliferation through p53-mediated apoptosis and cell cycle arrest with cancer cell selectivity.

[Inhibition of Yiqi Jiedu formula on proliferation of nasopharyngeal carcinoma cells by MAPK/ERK signaling pathway].

To study the effect of aqueous extracts of Yiqi Jiedu formula (YQ) on the proliferation of CNE2 cells in human nasopharyngeal carcinoma, and investigate its mechanism to provide a new theoretical basis for the clinical application of YQ. CNE2 cells were treated with different concentrations (0.125, 0.25, 0.5, 0.25 g·L⁻¹) of YQ, positive control medicine (cisplatin 4.0 mg·L⁻¹), inhibitor PD98059 (50 µmol·L⁻¹), activator isoproterenol hydrochloride (20 µmol·L⁻¹), activator isoproterenol hydrochloride (ISO)+YQ 0.5 g·L⁻¹. Then cell labeling by using real-time analyzer (RTCA) and CCK 8 method were used to detect cell proliferation activity, and the half inhibitory concentration (IC50) was calculated. The cell cycle distribution was detected by fluorescence double dye flow cytometry PI staining, and Western blot method was used to detect the expression levels of related protein and MAPK/ERK signaling pathway. The results of RTCA and CCK-8 test showed that as compared with the control group, YQ group could effectively inhibit the proliferation of CNE2 cells (P<0.01), with a dose and time dependence, and 48 h IC50 value was 0.5 g·L⁻¹. The results of cell cycle showed that after 48 h of water extract treatment, the cell cycle was significantly changed, the proportion of G0/G1 was reduced, the ratio of G2/M increased, and the cell cycle was in G2/M period (P<0.01). Western blot results showed that after 48 h treatment with different concentrations of aqueous extract, cell cycle-related proteins cyclinD1, cyclinD3 and CDK2 expression levels were down-regulated; MAPK/ERK signaling pathway related protein p-c-Raf, p-MEK, p-ERK1/2 expression level significantly lower as compared with the control group (P<0.05). After adding activator and inhibitor in MAPK/ERK signaling pathway on this basis, the results showed that after adding activator ISO, cell proliferation was significantly higher than that in the Control group; the cycle related proteins cyclinD1, cyclinD3, and CDK2 expression levels were increased; at the same time, key protein p-c-Raf, p-MEK, p-ERK1/2 expression levels in the signal pathways were relatively increased. While after the addition of inhibitor PD98059, the cell proliferation was significantly lower than that in the Control group, and the expression level of corresponding protein was decreased, which was significantly different from the Control group (P<0.05). So YQ could block cell cycle and inhibit the proliferation of CNE2 cells mainly by reducing the expression of MAPK/ERK signaling pathway key protein p-c-Raf, p-MEK and p-ERK1/2.

Population pharmacokinetics of moxifloxacin and its concentration-QT interval relationship modeling in Chinese healthy volunteers.

Moxifloxacin (MX) is an 8-methoxyquinolone antimicrobial drug, which is often used as a positive control in thorough QT (TQT) studies. In the present study we established the population pharmacokinetics model of MX and the relationship of MX concentrations with the QT and various corrected QT (QTc) intervals, and compared the results with other ethnicities. The MX data used for modeling were obtained from a published TQT interval prolongation study of antofloxacin with MX as the positive control. In this four-period crossover study, 24 adult Chinese healthy volunteers received either 200 or 400 mg of oral antofloxacin once daily, 400 mg of MX, or a placebo. Population concentration-effect models were used to investigate the relationship between MX concentrations and QT interval prolongation, baseline-adjusted QTc (ΔQTc), or ΔQTc adjusted with time-matched placebo corrections (ΔΔQTc). The influencing factors of MX PK and the concentration-QTc relationship were determined through covariate screening. Simulation studies were conducted in R2.30 by using the final model with the estimated population mean and intra-individual and inter-individual variability. The estimated pharmacokinetic parameters and the estimated slope of the MX concentration-QT/ΔQTc/ΔΔQTc relationship were described using models and were compared to results for other ethnicities from the literature. We showed that the population pharmacokinetic parameter estimates for total plasma clearance (CL/F), the volume of distribution of central compartment (Vc/F), the distributional clearance in plasma (Q), the volume of distribution of peripheral compartment (Vp/F), and the absorption rate constant (Ka) were 8.22 L/h, 104 L, 3.98 L/h, 37.7 L, and 1.81 1/h, respectively. There was no significant covariate included in the final model. QT interval prolongation of MX estimates ranging from 9.77 to 12.91 ms at the mean average maximum concentration of MX (4.36 µg/mL) and a mean slope ranging from 2.33 to 2.96 ms per µg/mL. In conclusion, no ethnic differences were observed for the MX pharmacokinetic parameters and QT interval prolongation.

[Exploration of visual check approaches in clinical data management].

Due to a great amount of data in clinical trials, the data cleansing needs to adopt a variety of measures, including the latest developed visual check approach. According to the different types of clinical data and the different stages in the course of clinical data management, this study reviews 8 types of visual graphics that show the relevance and trend among the data. The series of graphics can rapidly detect abnormal data, monitor clinical research in real-time, make the data management process much easier and improve the clinical trial efficiency and data quality.

[Comparison of paper and electronic data management in clinical trials].

Electronic case report forms (eCRFs) instead of the traditional paper case report forms (pCRFs) are increasingly used by investigators and sponsors of clinical research. We include a total of 14 phase III studies (8 pCRF, 6 eCRF) to compare paper and electronic data documentation both quantitatively and qualitatively in clinical studies. The result suggests that adaptions of electronic data capture (EDC) in clinical trials have the advantages in optimization of data capture process, improvement of data quality and earlier clinical decision compared to paper-based methods. Furthermore, the successful implementation of EDC requires accouplements with corresponding data management processes and reallocation of resources.

[Quality control of clinical data management based on EDC].

With the wide application of electronic data management (EDC), the data management is shifting to a new mode. In order to recognize the advantages of EDC, we choose 20 representative registered clinical trials, which involve 5 404 subjects and 321 sites. We found that EDC has many beneficial impacts on the course of clinical trial data management, including the process of data collection, data cleaning, data quality control and clinical trial decision-making. The result also provides a reference for the adoption of EDC in clinical trials.

Apoptotic death of cancer stem cells for cancer therapy.

Cancer stem cells (CSCs) play crucial roles in tumor progression, chemo- and radiotherapy resistance, and recurrence. Recent studies on CSCs have advanced understanding of molecular oncology and development of novel therapeutic strategies. This review article updates the hypothesis and paradigm of CSCs with a focus on major signaling pathways and effectors that regulate CSC apoptosis. Selective CSC apoptotic inducers are introduced and their therapeutic potentials are discussed. These include synthetic and natural compounds, antibodies and recombinant proteins, and oligonucleotides.

A cyclic fluctuation model for 24-h ambulatory blood pressure monitoring in Chinese patients with mild to moderate hypertension.

AIM: The conventional method for analyzing 24-h ambulatory blood pressure monitoring (24-h ABPM) is insufficient to deal with the large amount of data collected. The aim of this study was to develop a novel cyclic fluctuation model for 24-h ABPM in Chinese patients with mild to moderate hypertension. METHODS: The data were obtained from 4 independent antihypertensive drug clinical trials in Chinese patients with mild to moderate hypertension. The measurements of 24-h ABPM at the end of the placebo run-in period in study 1 were used to develop the cyclic fluctuation model. After evaluated, the structural model was used to analyze the measurements in the other 3 studies. Models were fitted using NONMEM software. RESULTS: The cyclic fluctuation model, which consisted of 2 cosine functions with fixed-effect parameters for rhythm-adjusted 24-h mean blood pressure, amplitude and phase shift, successfully described the blood pressure measurements of study 1. Model robustness was validated by the bootstrap method. The measurements in the other 3 studies were well described by the same structural model. Moreover, the parameters from all the 4 studies were very similar. Visual predictive checks demonstrated that the cyclic fluctuation model could predict the blood pressure fluctuations in the 4 studies. CONCLUSION: The cyclic fluctuation model for 24-h ABPM deepens our understanding of blood pressure variability, which will be beneficial for drug development and individual therapy in hypertensive patients.

Limited sampling strategy models for estimating the AUC of gliclazide in Chinese healthy volunteers.

The aim of this work is to reduce the cost of required sampling for the estimation of the area under the gliclazide plasma concentration versus time curve within 60 h (AUC0-60t ). The limited sampling strategy (LSS) models were established and validated by the multiple regression model within 4 or fewer gliclazide concentration values. Absolute prediction error (APE), root of mean square error (RMSE) and visual prediction check were used as criterion. The results of Jack-Knife validation showed that 10 (25.0 %) of the 40 LSS based on the regression analysis were not within an APE of 15 % using one concentration-time point. 90.2, 91.5 and 92.4 % of the 40 LSS models were capable of prediction using 2, 3 and 4 points, respectively. Limited sampling strategies were developed and validated for estimating AUC0-60t of gliclazide. This study indicates that the implementation of an 80 mg dosage regimen enabled accurate predictions of AUC0-60t by the LSS model. This study shows that 12, 6, 4, 2 h after administration are the key sampling times. The combination of (12, 2 h), (12, 8, 2 h) or (12, 8, 4, 2 h) can be chosen as sampling hours for predicting AUC0-60t in practical application according to requirement.

[Treating influenza patients of wind-heat affecting Fei syndrome by jinhua qinggan granule: a double-blinded randomized control trial].

OBJECTIVE: To assess the effect and safety of Jinhua Qinggan Granule (JHG) in treating influenza patients of wind-heat affecting Fei syndrome (WHAFS). METHODS: Totally 136 influenza patients of WHAFS were randomized by stratification into 3 groups, the high dose JHG group (44 cases, 10 g each time), the low dose JHG group (45 cases, 5 g JHG + 5 g placebo each time), and the placebo control group (47 cases, 10 g placebo each time). All medication was administered three times daily for 5 days. The fever disappearance time, the fever disappearance rate, efficacy of TCM syndrome, the disappearance rate of main symptoms and physical signs of flu, the negative rate of virus nucleic acid in the pharyngeal secretion, and safety indicators were assessed. RESULTS: The median fever disappearance time was 32.8 h (95% CI: 22.5-41.0 h) in the high dose JHG group, 26.0 h (95% CI: 14.5-36.5 h) in the low dose JHG group, 39.5 h (95% CI: 29.0-46.0 h) in the placebo control group. There was statistical difference in the median fever disappearance time between the low dose JHG group and the placebo control group (P = 0.011). Three days after treatment, the markedly effective rate of TCM symptoms in the low dose JHG group was 66.7%, higher than that of the placebo control group (38.3%), and its effective rate was superior to that of the high dose JHG group (P = 0.043). Five days after treatment, the recovery rate of the low dose JHG group (42.2%) was higher than that of the high dose JHG group (25.0%, P = 0.026) and that of the placebo control group (14.9%, P = 0.002). The markedly effective rate of the low dose JHG group (86.7%) was higher than that of the placebo control group (55.3%, P = 0.001). Similar effects were obtained in the low dose JHG group and the high dose JHG group, but slightly poor in partial indicators of the high dose JHG group. There was no statistical difference in adverse reaction among these three groups (P > 0.05). CONCLUSIONS: JHG was effective and safe in treating influenza patients of WHAFS. Routinely low dose was the optimal dosage of JHG.

Anti-Nasopharyngeal carcinoma mechanism of sanguinarine based on network pharmacology and molecular docking.

BACKGROUND: The purpose of this study was to investigate the mechanism of sanguinarine (SAN) against nasopharyngeal carcinoma (NPC) by means of network pharmacology, molecular docking technique, and experimental verification. METHODS: The SAN action targets were predicted using the Swiss Target Prediction database, the related NPC targets were determined using the GEO database, and the intersection of drug and disease pathway targets were considered to be the potential targets of SAN against NPC. The target-protein interaction network map was constructed using the STRING database, and the core target genes of SAN against NPC were obtained via topological network analysis. "R" language gene ontology (GO) function and Kyoto encyclopedia of genes and genome (KEGG) pathway enrichment analyses were used to dock the core target genes with SAN with the help of AutodockVina. Cell proliferation was detected using MTT and xCELLigence real-time cell analysis. Apoptosis was identified via Hoechst 33342 staining, JC-1 mitochondrial membrane staining, and annexin V-FITC/PI double fluorescence staining, while protein expression was quantified using western blotting. RESULTS: A total of 95 SAN against NPC targets were obtained using target intersection, and 8 core targets were obtained by topological analysis and included EGFR, TP53, F2, FN1, PLAU, MMP9, SERPINE1, and CDK1. Gene ontology enrichment analysis identified 530 items, and 42 items were obtained by Kyoto encyclopedia of genes and genome pathway enrichment analysis and were mainly related to the PI3K/AKT, MAPK, and p53 signaling pathways. Molecular docking results showed that SAN had good binding activity to the core target. SAN inhibited the proliferation of NPC cells, induced apoptosis, reduced the expression levels of survivin and Bcl2, and increased the expression levels of Bax and cleaved caspase-8. It also decreased the expression levels of the key proteins p-c-Raf, p-MEK, and p-ERK1/2 in the MAPK/ERK signaling pathway in NPC cells. CONCLUSION: SAN inhibits the proliferation and induces the apoptosis of NPC cells through the MAPK/ERK signaling pathway.

Highly Selective Coextraction of H+/SO42- Using a Strapped Calix[4]pyrrole.

We report on the synthesis of a cage-type calix[4]pyrrole (1) bearing an additional basic pyridinebisthiazolamine group on the strap. The receptor in its protonated form shows strong affinity and selectivity for sulfate over a wide range of inorganic anions. With receptor 1 as a liquid-liquid extractant, H+/SO42- in the form of H2SO4 is almost quantitatively extracted from an aqueous solution containing HNO3 at a high concentration to CH2Cl2 in a recyclable manner.

Dose findings of antofloxacin hydrochloride for treating bacterial infections in an early clinical trial using PK-PD parameters in healthy volunteers.

AIM: To find an appropriate dose regimen of the novel antibacterial agent antofloxacin for a phase II clinical trial using a population pharmacokinetic (PPK) study in healthy volunteers and the minimum inhibitory concentration (MIC) as pharmacodynamic (PD) parameters. METHODS: Twenty-four healthy volunteers were enrolled in a double-blind crossover study and received antofloxacin (200 or 400 mg/d, po) for consecutive 5 d with 10 d washout between two separate periods. Blood concentrations were analyzed using HPLC with a UV-Vis detector. The values of area under the curve (AUC) with covariates were obtained from a PPK model, and the MICs came from the previous in vitro studies. The dose regimen was determined for the phase II clinical trial according to the ratio (>20) of AUC/MIC, and the efficacy of the dose was evaluated by the trial. RESULTS: A two-compartment model best described the time-concentration data with first-order absorption. The PPK parameter estimates for CL, V(c), Q, V(p) and K(A) are 8.34 L/h, 142 L, 15.9 L/h, 52.2 L and 4.64 1/h, respectively. The covariates sex for K(A), weight for CL, weight for V(c) and interoccasion variability were included in the final model. The AUC/MIC was calculated based on the PPK model and the MIC of antofloxacin for Escherichia coli, Klebsiella pneumonia, Staphylococcus aureus and Staphylococcus epidermidis were determined in previous researches. The 400 mg loading dose with 200 mg/d maintenance dose was recommended and confirmed by the phase II trial. CONCLUSION: The ratio of AUC from the PPK model vs MIC as the PD parameter can be applied in a dose-finding trial of antofloxacin in treatment of bacterial infections. The PPK model suggests that sex and body weight may be considerations in regards to individual therapy, which should be investigated in larger clinical trials and serve as a potential reference for clinical therapies.

Race differences: modeling the pharmacodynamics of rosuvastatin in Western and Asian hypercholesterolemia patients.

AIM: To evaluate race differences in the pharmacodynamics of rosuvastatin in Western and Asian hypercholesterolemia patients using a population pharmacodynamic (PPD) model generated and validated using published clinical efficacy trials. METHODS: Published studies randomized trials with rosuvastatin treatment for at least 4 weeks in hypercholesterolemia patients were used for model building and validation. Population pharmacodynamic analyses were performed to describe the dose-response relationship with the mean values of LDL-C reduction (%) from dose-ranging trials using NONMEM software. Baseline LDL-C and race were analyzed as the potential covariates. Model robustness was evaluated using the bootstrap method and the data-splitting method, and Monte Carlo simulation was performed to assess the predictive performance of the PPD model with the mean effects from the one-dose trials. RESULTS: Of the 36 eligible trials, 14 dose-ranging trials were used in model development and 22 one-dose trials were used for model prediction. The dose-response of rosuvastatin was successfully described by a simple E(max) model with a fixed E(0), which provided a common E(max) and an approximate twofold difference in ED(50) for Westerners and Asians. The PPD model was demonstrated to be stable and predictive. CONCLUSION: The race differences in the pharmacodynamics of rosuvastatin are consistent with those observed in the pharmacokinetics of the drug, confirming that there is no significant difference in the exposure-response relationship for LDL-C reduction between Westerners and Asians. The study suggests that for a new compound with a mechanism of action similar to that of rosuvastatin, its efficacy in Western populations plus its pharmacokinetics in bridging studies in Asian populations may be used to support a registration of the new compound in Asian countries.

Effect of CYP2C19 genotypes on the pharmacokinetic/pharmacodynamic relationship of rabeprazole after a single oral dose in healthy Chinese volunteers.

AIMS: To explore the pharmacokinetic/pharmacodynamic relationship of rabeprazole and the role of CYP2C19 genotypes after a single oral dose in healthy Chinese volunteers by a population approach. METHODS: Plasma concentration time profile data and intragastric pH values of 19 genotyped healthy male adults after a single oral dose of rabeprazole in an open label randomized fashion were used for this population analysis. Simulation technology was performed to examine the rabeprazole response in subjects with different CYP2C19 genotypes to further investigate the effect of acid inhibition. RESULTS: The pharmacokinetics of rabeprazole was characterized by a two-compartment model with first order absorption and with an absorption lag-time. The results show that clearance of rabeprazole was affected by CYP2C19 genotypes (average clearances of homEM, hetEM, and PM were 13.9, 11.5, and 8.74 L·h(-1) respectively). An effect compartment with a sigmoidal Emax model was considered more rational for analyzing the relationship between rabeprazole concentrations and intragastric pH values. Simulated results suggest that rabeprazole 20 mg once daily for PMs is sufficient, but might be administered more frequently for other genotypes in treating gastro-esophageal reflux disease. CONCLUSION: The CYP2C19 genotype played a considerable role in the pharmacokinetic characteristics of rabeprazole, and this might need to be taken into account for clinical use.

[Limited sampling strategy models for estimating AUC for amlodipine in Chinese healthy volunteers].

This study aims to save cost of sampling for estimating the area under the amlodipine plasma concentration versus time curve in 24 hours (AUC(0-24 h)). Limited sampling strategy (LSS) models was developed and validated by mutiple regression model within 4 or fewer amlodipine concentration values. Absolute prediction error (APE), root of mean square error (RMSE) and visual predict check were used as criterion. The results of Jackknife validation showed that fifteen (9.4%) of the 160 LSS based on regression analysis were not within an APE of 15% by using one concentration-time point. 156 (97.5%), 159 (99.4%) and 160 (100%) of the 160 LSS model were capable of predicting within an APE 15% by using 2, 3, 4 points, separately. Limited sampling strategies have been developed and validated for estimating AUC(0-24 h) of amlodipine. The present study indicated that the implemention of both 5 mg and 10 mg dosage could enable accurate predictions of AUC(0-24 h) by the same LSS model. This study shows that 12, 4, 24, 2 h after administration are key sampling time points. The combination of (12, 4), (12, 4, 24) or (12, 4, 24, 2 h) might be chosen as sampling hours for predicting AUC(0-24 h) in practical application according to requirement.

Benzenebistriazole-strapped calix[4]pyrrole: a neutral anion receptor with CH and NH donor groups that exhibits high sulfate binding affinity and selectivity in aqueous solutions.

A calix[4]pyrrole strapped by benzenebistriazole has been prepared as an artificial anion binding receptor. This neutral anion receptor shows high sulfate binding affinity and selectivity in an aqueous solution. In solid state, the receptor binds the sulfate anion in a chair-like 3D cavity via multiple N-H and C-H hydrogen bonds.

Relationship between antofloxacin concentration and QT prolongation and estimation of the possible false-positive rate.

PURPOSE: To elucidate the relationship between antofloxacin (AT) plasma concentration and QT interval prolongation, compare the effects of different correction and analytical methods on conclusions, and estimate the possible false-positive rate in thorough QT (TQT) studies. METHODS: Twenty-four healthy Chinese volunteers from a four-period crossover TQT study orally received 200 mg/d AT, 400 mg/d AT, 400 mg/d moxifloxacin, and a placebo in a random order for 5 d for each. QT interval samples were collected on d 1 and d 5. Population models were established describing the relationship between QT and AT concentration. The yardstick from ICH E14 guidelines was used to measure the effect of drugs on QT prolongation both in biostatistical and modeling analyses. A possible false-positive rate was estimated by constructing a 1000-time bootstrap to obtain the rate-of-difference values between d 1 and d 5 over 5 ms in the placebo period. RESULTS: In the modeling analysis, the QT prolongation estimate at the mean maximal concentration of AT (4.51 µg/mL) was 3.84 ms, and its upper bound of the one-sided 95 % CI was 7.04 ms, which showed a negative effect on QT interval prolongation. The estimation for the false-positive rate was 31 % in this study. CONCLUSION: The effect of AT on QT interval prolongation may not have been significant at the dosage of 400 mg. Baseline and placebo adjustments were necessary in TQT studies. Population modeling has demonstrated clear superiority in making full use of data to accurately analyze the relationship between drugs and QT intervals.