-
1.
Sorafenib plus triplet therapy with venetoclax, azacitidine and homoharringtonine for refractory/relapsed acute myeloid leukemia with FLT3-ITD: A multicenter phase 2 study.
Yu, S, Zhang, Y, Yu, G, Wang, Y, Shao, R, Du, X, Xu, N, Lin, D, Zhao, W, Zhang, X, et al
Journal of internal medicine. 2024;(2):216-228
Abstract
BACKGROUND Patients with relapsed or refractory acute myeloid leukemia (R/R AML) and FLT3-internal tandem duplication (FLT3-ITD) respond infrequently to salvage chemotherapy. OBJECTIVE To investigate the efficacy of sorafenib plus triplet therapy with venetoclax, azacitidine, and homoharringtonine (VAH) as a salvage therapy in this population. METHODS This multicenter, single-arm, phase 2 study was conducted at 12 hospitals across China. Eligible patients had R/R AML with FLT3-ITD (aged 18-65 years) who were treated with VAH. The primary endpoint was composite complete remission (CRc) after two cycles. Secondary outcomes included the overall response rate (ORR), safety, and survival. RESULTS Between July 9, 2020, and March 19, 2022, 58 patients were assessed for eligibility, 51 of whom were enrolled. The median patient age was 47 years (interquartile range [IQR] 31-57). CRc was 76.5% with ORR of 82.4%. At a median follow-up of 17.7 months (IQR, 8.7-24.7), the median duration of CRc was not reached (NR), overall survival was 18.1 months (95% confidence interval [CI], 11.8-NR) and event-free survival was 11.4 months (95% CI, 5.6-NR). Grade 3 or 4 adverse events occurring in ≥10% of patients included neutropenia in 47 (92.2%), thrombocytopenia in 41 (80.4%), anemia in 35 (68.6%), febrile neutropenia in 29 (56.9%), pneumonia in 13 (25.5%), and sepsis in 6 (11.8%) patients. Treatment-related death occurred in two (3.9%) patients. CONCLUSIONS The sorafenib plus VAH regimen was well tolerated and highly active against R/R AML with FLT3-ITD. This regimen may be a suitable therapeutic option for this population, but larger population trials are needed to be explored. TRIAL REGISTRATION Clinical Trials Registry: NCT04424147.
-
2.
A first-in-human phase 1 study of simnotrelvir, a 3CL-like protease inhibitor for treatment of COVID-19, in healthy adult subjects.
Yang, XM, Yang, Y, Yao, BF, Ye, PP, Xu, Y, Peng, SP, Yang, YM, Shu, P, Li, PJ, Li, S, et al
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. 2023;:106598
-
-
Free full text
-
Abstract
Safe and efficacious antiviral therapeutics are in urgent need for the treatment of coronavirus disease 2019. Simnotrelvir is a selective 3C-like protease inhibitor that can effectively inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We evaluated the safety, tolerability, and pharmacokinetics of dose escalations of simnotrelvir alone or with ritonavir (simnotrelvir or simnotrelvir/ritonavir) in healthy subjects, as well as the food effect (ClinicalTrials.gov Identifier: NCT05339646). The overall incidence of adverse events (AEs) was 22.2% (17/72) and 6.3% (1/16) in intervention and placebo groups, respectively. The simnotrelvir apparent clearance was 135-369 L/h with simnotrelvir alone, and decreased significantly to 19.5-29.8 L/h with simnotrelvir/ritonavir. The simnotrelvir exposure increased in an approximately dose-proportional manner between 250 and 750 mg when co-administered with ritonavir. After consecutive twice daily dosing of simnotrelvir/ritonavir, simnotrelvir had a low accumulation index ranging from 1.39 to 1.51. The area under the curve of simnotrelvir increased 44.0 % and 47.3 % respectively, after high fat and normal diet compared with fasted status. In conclusion, simnotrelvir has adequate safety and tolerability. Its pharmacokinetics indicated a trough concentration above the level required for 90 % inhibition of SARS-CoV-2 in vitro at 750 mg/100 mg simnotrelvir/ritonavir twice daily under fasted condition, supporting further development using this dosage as the clinically recommended dose regimen.
-
3.
Efficacy and safety of cetagliptin as monotherapy in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled phase 3 trial.
Ji, L, Lu, J, Gao, L, Ying, C, Sun, J, Han, J, Zhao, W, Gao, Y, Wang, K, Zheng, X, et al
Diabetes, obesity & metabolism. 2023;(12):3671-3681
Abstract
AIM: To assess the efficacy and safety of the dipeptidyl peptidase-4 inhibitor, cetagliptin, as monotherapy in Chinese patients with type 2 diabetes (T2D) and inadequate glycaemic control. MATERIALS AND METHODS In total, 504 eligible patients with T2D were enrolled and randomized to cetagliptin 50 mg once daily, cetagliptin 100 mg once daily or placebo at a ratio of 2:2:1 for 24 weeks of double-blind treatment, then all patients received cetagliptin 100 mg once daily for 28 weeks of open-label treatment. The primary efficacy endpoint was the change in HbA1c level from baseline at week 24. RESULTS After 24 weeks, HbA1c from baseline was significantly reduced with cetagliptin 50 mg (-1.08%) and cetagliptin 100 mg (-1.07%) compared with placebo (-0.35%). The placebo-subtracted HbA1c reduction was -0.72% with cetagliptin 50 mg and 100 mg. Patients with a baseline HbA1c of 8.5% or higher had a greater HbA1c reduction with cetagliptin than those patients with a baseline HbA1c of less than 8.5%. Both doses studied led to a significantly higher proportion of patients (42.3% with 100 mg and 45.0% with 50 mg) achieving an HbA1c of less than 7.0% compared with placebo (12.9%). Cetagliptin also significantly lowered fasting plasma glucose and 2-hour postmeal plasma glucose relative to placebo. The incidence of adverse experiences was similar between cetagliptin and placebo. No drug-related hypoglycaemia was reported. CONCLUSIONS Cetagliptin monotherapy was effective and well tolerated in Chinese patients with T2D who had inadequate glycaemic control on exercise and diet.
-
4.
Efficacy and safety of tafolecimab in Chinese patients with heterozygous familial hypercholesterolemia: a randomized, double-blind, placebo-controlled phase 3 trial (CREDIT-2).
Chai, M, He, Y, Zhao, W, Han, X, Zhao, G, Ma, X, Qiao, P, Shi, D, Liu, Y, Han, W, et al
BMC medicine. 2023;(1):77
Abstract
BACKGROUND Heterozygous familial hypercholesterolemia (HeFH) is largely underdiagnosed and undertreated in China where few patients achieved recommended target levels of low density lipoprotein cholesterol (LDL-C). We conducted the first randomized, placebo-controlled clinical trial in Chinese patients with HeFH to assess the efficacy and safety of tafolecimab, a novel fully human proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody. METHODS Patients diagnosed with HeFH by Simon Broome criteria and on a stable lipid-lowering therapy for at least 4 weeks were randomized 2:2:1:1 to receive subcutaneous tafolecimab 150 mg every 2 weeks (Q2W), tafolecimab 450 mg every 4 weeks (Q4W), placebo Q2W or placebo Q4W in the 12-week double-blind treatment period. After that, participants received open-label tafolecimab 150 mg Q2W or 450 mg Q4W for 12 weeks. The primary endpoint was the percent change from baseline to week 12 in LDL-C levels. Secondary endpoints included proportion of participants achieving ≥50% LDL-C reductions and proportion of participants with LDL-C <1.8 mmol/L at week 12 and 24, the change from baseline to week 12 in non-high density lipoprotein cholesterol (non-HDL-C), apolipoprotein B and lipoprotein(a) levels, as well as the change from baseline to week 24 in lipid levels. RESULTS In total, 149 participants were randomized and 148 received at least one dose of the study treatment. At week 12, tafolecimab treatment induced significant reductions in LDL-C levels (treatment difference versus placebo [on-treatment estimand]: -57.4% [97.5% CI, -69.2 to -45.5] for 150 mg Q2W; -61.9% [-73.4 to -50.4] for 450 mg Q4W; both P <0.0001). At both dose regimens, significantly more participants treated with tafolecimab achieved ≥50% LDL-C reductions or LDL-C <1.8 mmol/L at week 12 as compared with corresponding placebo groups (all P <0.0001). Meanwhile, non-HDL-C, apolipoprotein B and lipoprotein(a) levels were significantly reduced in the tafolecimab groups at week 12. The lipid-lowering effects of tafolecimab were maintained till week 24. During the double-blind treatment period, the most commonly-reported adverse events in the tafolecimab groups included upper respiratory tract infection, increased blood creatine phosphokinase, increased alanine aminotransferase, increased aspartate aminotransferase and hypertension. CONCLUSIONS Tafolecimab administered either 150 mg Q2W or 450 mg Q4W yielded significant and persistent reductions in LDL-C levels and showed a favorable safety profile in Chinese patients with HeFH. TRIAL REGISTRATION ClinicalTrials.gov, NCT04179669.
-
5.
Sex differences in the association of physical activity levels and vitamin D with obesity, sarcopenia, and sarcopenic obesity: a cross-sectional study.
Jia, S, Zhao, W, Hu, F, Zhao, Y, Ge, M, Xia, X, Yue, J, Dong, B
BMC geriatrics. 2022;(1):898
Abstract
BACKGROUND The relationship between vitamin D and sarcopenia was inconsistent between men and women. Physical activity (PA) may interact with vitamin D on sarcopenia. However, the sex-specific relationships of vitamin D, PA and sarcopenia have yet elucidated. We aimed to examine the sex differences in the relation between vitamin D status, PA levels, obesity and sarcopenia in community-dwelling middle-aged and older adults, as well as whether vitamin D status is a modifier in the relationship between PA and sarcopenia. METHODS The current study was a cross-sectional study based on the baseline survey of the West China Health and Aging Trend (WCHAT) study. A total of 3713 participants aged ≥ 50y were included in our study. Sarcopenia was defined according to the Asian Working Group for Sarcopenia (AWGS) 2019 consensus. Obesity was defined by body mass index (BMI) (≥ 28 kg/m2) and body fat mass percentage (≥ 60th percentile in each sex group). 25-hydroxyvitamin D was measured by chemiluminescent microparticle immunoassay and PA was evaluated by a validated China Leisure Time Physical Activity Questionnaire (CLTPAQ). Multinomial logistic regression was performed to examine the relationship between PA, vitamin D and sarcopenia and obesity. RESULTS Low PA was significantly associated with higher odds of sarcopenia in women only (OR = 1.70,95%CI:1.18,2.46, p < 0.01). Vitamin D deficiency was only associated with sarcopenia in men (OR = 1.85,95%CI: 1.27,2.69, p < 0.01). Low PA was significantly associated with obesity, sarcopenia, and sarcopenic obesity only in participants with serum 25(OH)D < 20 ng/ml. CONCLUSIONS The role of vitamin D and PA in obesity and sarcopenia was different between men and women, and the relationship between PA and sarcopenia was modified by serum vitamin D status. These findings highlighted the need to supplement vitamin D in individuals with physical inactivity and provide different interventions strategies to sarcopenia in men and women. TRIAL REGISTRATION Clinical trial number: ChiCTR1800018895.
-
6.
Dynamic evaluation of the prognostic value of 18F-FDG PET/CT in extranodal NK/T-cell lymphoma, nasal type.
Xu, P, Guo, R, You, J, Cheng, S, Li, J, Zhong, H, Sun, C, Xu, H, Huang, H, Li, B, et al
Annals of hematology. 2021;(4):1039-1047
Abstract
Extranodal natural killer/T-cell lymphoma, nasal-type (ENKTL) is a type of rare and distinct entity of non-Hodgkin lymphoma with poor prognosis. It is important to evaluate the early treatment response accurately to decide further treatment strategy. 18F-FDG PET/CT plays an important role in response evaluation and prognostic prediction in some kinds of lymphomas. However, data available regarding patients with ENKTL are limited. Thus, in this prospective study, we analyzed the prognostic value of 18F-FDG PET/CT in ENKTL. Thirty-four patients with newly diagnosed ENKTL were enrolled in this phase 2 study (NCT02825147, July 7, 2016). The patients received pre-, mid-, and end-treatment 18F-FDG PET/CT scans. Deauville score (DS), maximal standardized uptake values (SUVmax), and the change in SUVmax (ΔSUVmax) were recorded for response assessment. The median follow-up period was 42.2 months. The 2-year overall survival (OS) and progression-free survival (PFS) were 82.4% and 73.5%, respectively. Univariate analysis revealed that Ann Arbor stage (P < 0.002), mid-treatment DS (P = 0.005), mid-SUVmax (P = 0.001), mid-∆SUVmax (P = 0.004), end-treatment DS (P < 0.001), and end-SUVmax (P = 0.014) were prognostic factors for OS. Ann Arbor stage (P = 0.001), mid-treatment DS (P = 0.008), mid-SUVmax (P = 0.029), mid-∆SUVmax (P < 0.001), and end-treatment DS (P =0.021) were of prognostic significance for PFS. Multivariate analysis showed that mid-SUVmax (P = 0.042) and DS at the middle (P = 0.050) and end (P = 0.044) of treatment were significant independent predictors of PFS. 18F-FDG PET/CT is useful for predicting the prognosis of ENKTL.
-
7.
Developmental Pharmacogenetics of SLCO2B1 on Montelukast Pharmacokinetics in Chinese Children.
Li, Q, Wang, K, Shi, HY, Wu, YE, Zhou, Y, Kan, M, Zheng, Y, Hao, GX, Yang, XM, Yang, YL, et al
Drug design, development and therapy. 2019;:4405-4411
Abstract
BACKGROUND Montelukast, a potent oral selective leukotriene-receptor antagonist, inhibits the action of cysteinyl-leukotriene in patients with asthma. Although pharmacokinetic studies of montelukast have been reported in Caucasian adults and children, and showed large inter-individual variability on pharmacokinetics, none of these studies has been explored in Chinese children. Given the potential inter-ethnic difference, the purpose of the present study was to evaluate the effects of developmental factors and pharmacogenetics of CYP2C8 and SLCO2B1 on montelukast clearance in Chinese pediatric patients. METHODS After the administration of montelukast, blood samples were collected from children and plasma concentrations were determined using an adapted micro high-performance liquid chromatography coupled with the fluorescence detection (HPLC-FLD) method. A previously published pharmacokinetic model was validated using the opportunistic pharmacokinetic samples, and individual patient's clearance was calculated using the validated model. Population pharmacokinetic analysis was performed using a nonlinear mixed-effects model approach (NONMEM V 7.2.0) and variants of CYP2C8 and SLCO2B1 were genotyped. RESULTS Fifty patients (age range: 0.7-10.0 years) with asthma were enrolled in this study. The clearance of montelukast was significantly higher in children with the SLCO2B1 c.935GA and c.935AA genotypes compared with that of children with the SLCO2B1 c.935GG genotype (0.94 ± 0.26 versus 0.77 ± 0.21, p = 0.020). The patient's weight was also found to be significantly corrected with montelukast clearance (p <0.0001). CONCLUSION The developmental pharmacology of montelukast in Chinese children was evaluated. Weight and SLCO2B1 genotype were found to have independent significant impacts on the clearance of montelukast.
-
8.
Pretreatment PET/CT imaging of angiogenesis based on 18F-RGD tracer uptake may predict antiangiogenic response.
Li, L, Ma, L, Shang, D, Liu, Z, Yu, Q, Wang, S, Teng, X, Zhang, Q, Hu, X, Zhao, W, et al
European journal of nuclear medicine and molecular imaging. 2019;(4):940-947
Abstract
PURPOSE To explore the relationship between metabolic uptake of the 18F-ALF-NOTA-PRGD2 (18F-RGD) tracer on positron emission tomography/computerized tomography (PET/CT) and the antiangiogenic effect of apatinib in patients with solid malignancies. MATERIALS AND PATIENTS Patients with measurable lesions scheduled for second- or third-line single-agent therapy with apatinib were eligible for this prospective clinical trial. All patients underwent 18F-RGD PET/CT examination before the start of treatment. Standardized uptake values (SUVs) of contoured tumor lesions were computed and compared using independent sample t-tests or the Mann-Whitney U test. Receiver-operating characteristic (ROC) curve analysis was used to determine accuracy in predicting response. Survival curves were compared using the Kaplan-Meier method. RESULTS Of 38 patients who consented to study participation, 25 patients with 42 measurable lesions met the criteria for inclusion in this response assessment analysis. The median follow-up time was 3 months (range, 1-10 months), and the median progression-free survival (PFS) was 3 months (95% confidence interval, 1.04-4.96). The SUVpeak and SUVmean were significantly higher in responding tumors than in non-responding tumors (4.98 ± 2.34 vs 3.59 ± 1.44, p = 0.048; 3.71 ± 1.15 vs 2.95 ± 0.49, P = 0.036). SUVmax did not differ between responding tumors and non-responding tumors (6.58 ± 3.33 vs 4.74 ± 1.83, P = 0.078). An exploratory ROC curve analysis indicated that SUVmean [area under the ROC curve (AUC) = 0.700] was a better parameter than SUVpeak (AUC = 0.689) for predicting response. Using a threshold value of 3.82, high SUVmean at baseline was associated with improved PFS (5.0 vs. 3.4 months, log-rank P = 0.036). CONCLUSION 18F-RGD uptake on PET/CT imaging pretreatment may predict the response to antiangiogenic therapy, with higher 18F-RGD uptake in tumors predicting a better response to apatinib therapy.
-
9.
Prescription of statins at discharge and 1-year risk of major clinical outcomes among acute coronary syndromes patients with extremely low LDL-cholesterol in clinical pathways for acute coronary syndromes studies.
Sun, Y, Xie, G, Patel, A, Li, S, Zhao, W, Yang, X, Wu, T, Li, M, Li, X, Du, X, et al
Clinical cardiology. 2018;(9):1192-1200
Abstract
OBJECTIVE The aim of this study was to investigate statin description on discharge and the benefit on the long-term outcomes in acute coronary syndromes (ACS) patients with very low baseline LDL-cholesterol (LDL-c). METHODS This is a post-hoc analysis of 3374 ACS patients who were discharged alive and had baseline LDL-c levels below 70 mg/dL (1.8 mmol/L). The propensity score of using statin was estimated with a multivariable Logistic model including patient's demography, social economic status, cardiovascular risk factors, subtype of the diagnosis, and treatments received during hospitalization and current LDL-c level. The risk of major adverse cardiovascular events (MACEs) was compared between patients received and not-received statin with Cox-regression models adjusting for the propensity score plus other factors. A sensitivity analysis was done in propensity score matched patients. RESULTS Compared with nonstatin group, the incidence of MACE at 12 months after discharge was lower in the statin group (11.1% vs 5.8%; P < 0.001). The propensity score plus other factors-adjusted hazard ratios for MACEs was significant (0.58; 95% CI: 0.39, 0.87). The effect showed a significant dose-response relationship (P for trend = 0.02). The results in analyses with propensity-score matched participants were in consistent with above findings. Analyses on total mortality in 12 months showed similar results. CONCLUSIONS Among ACS survivors with a very low baseline LDL-c, low to moderate intensity statin therapy was associated significantly with lower risk of MACEs and total mortality at 12 months. The results suggested that ACS survivors should take statin regardless of the baseline of LDL-c.
-
10.
Arg913Gln of SLC12A3 gene promotes development and progression of end-stage renal disease in Chinese type 2 diabetes mellitus.
Zhang, R, Zhuang, L, Li, M, Zhang, J, Zhao, W, Ge, X, Chen, Y, Wang, F, Wang, N, Bao, Y, et al
Molecular and cellular biochemistry. 2018;(1-2):203-210
Abstract
Whether the Arg913Gln variation (rs11643718, G/A) of SLC12A3 contributes to diabetic nephropathy (DN) remains controversial. We undertook a case-control study to evaluate the association of the SLC12A3-Arg913Gln variation with the risk of end-stage renal disease (ESRD) in Chinese type 2 diabetes mellitus (T2DM) patients undergoing hemodialysis, and analyzed the genotype-phenotype interaction. Unrelated Chinese T2DM patients (n = 372) with diabetic retinopathy were classified into the non-DN (control) group (n = 151; duration of T2DM >15 years, no signs of renal involvement) and the DN-ESRD group (n = 221; ESRD due to T2DM, receiving hemodialysis). Polymerase chain reaction-direct sequencing was used to genotype the SLC12A3-Arg913Gln variation for all participants. The frequency of the GA+AA genotype in the DN-ESRD group was significantly higher than that of the non-DN group (23.1 vs. 9.9%; adjusted OR 2.2 (95% CI 1.3-4.5), P = 0.019). In the non-DN group, GA+AA carriers had a significantly higher urinary albumin excretion rate (UAER) and diastolic blood pressure compared with GG carriers (both P < 0.05). The SLC12A3-Arg913Gln variation may be associated with increased blood pressure and UAER and, therefore, could be used to predict the development and progression of DN-ESRD in Chinese T2DM patients undergoing hemodialysis.