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1.
Proportion of participants with type 2 diabetes achieving a metabolic composite endpoint with once-weekly semaglutide treatment versus comparators: Post hoc pooled analysis from SUSTAIN 1-5, 7-10 and SUSTAIN China.
Ji, L, Ahmann, AJ, Ahrén, B, Capehorn, MS, Hu, P, Lingvay, I, Liu, W, Rodbard, HW, Shen, Z, Sorli, C
Diabetes, obesity & metabolism. 2024;(1):233-241
Abstract
AIM: To compare the proportion of participants with type 2 diabetes (T2D) treated with once-weekly (OW) subcutaneous (SC) semaglutide versus comparators who achieved a composite metabolic endpoint. MATERIALS AND METHODS SUSTAIN 1-5, 7-10 and SUSTAIN China trial data were pooled. Participants with T2D (aged ≥18 years) and glycated haemoglobin ≥7.0% (≥53 mmol/mol) who had been randomized to OW SC semaglutide (0.5 or 1.0 mg) or comparator in addition to background medication. Using patient-level data pooled by treatment, proportions of participants achieving the metabolic composite endpoint, defined as glycated haemoglobin <7% (<53 mmol/mol), blood pressure <140/90 mmHg and non-high-density lipoprotein cholesterol <130 mg/dl (<3.37 mmol/L), were evaluated following baseline adjustments. Endpoints were analysed per trial using a binomial logistic regression model with treatment, region/country and stratification factor as fixed effects and baseline value as covariate. Pooled analysis used logistic regression with treatment and trial as fixed effects and baseline value as covariate. RESULTS This post hoc analysis included data from 7633 participants across 10 trials. The proportion of participants who achieved the metabolic composite endpoint was significantly higher with OW SC semaglutide 0.5 and 1.0 mg versus comparators (23.7% and 32.0% vs. 11.5%, respectively; p < .0001). Likewise, when the OW SC semaglutide doses were pooled, significantly higher proportions of patients receiving semaglutide achieved the composite metabolic endpoint versus comparators (29.1% vs. 11.4%, respectively; p < .0001). CONCLUSIONS Treatment with OW SC semaglutide versus comparators was associated with increased proportions of participants with T2D meeting the composite metabolic endpoint.
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2.
Multicenter Randomized Double-Blind Phase III Trial of Donafenib in Progressive Radioactive Iodine-Refractory Differentiated Thyroid Cancer.
Lin, Y, Qin, S, Yang, H, Shi, F, Yang, A, Han, X, Liu, B, Li, Z, Ji, Q, Tang, L, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2023;(15):2791-2799
Abstract
PURPOSE The phase II/III study of donafenib was initiated when there was no available treatment indicated for Chinese patients with progressive radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC). Donafenib, an oral tyrosine kinase inhibitor (TKI), showed good efficacy and tolerability in the phase II study. We aimed to further evaluate the antitumor activity and safety of donafenib in Chinese patients with RAIR-DTC. PATIENTS AND METHODS This multicenter, double-blind, placebo-controlled, phase III study enrolled 191 patients with progressive RAIR-DTC and randomized in a ratio of 2:1 to donafenib (300 mg twice daily, n = 128) or matched placebo (n = 63). An open-label donafenib treatment period was allowed upon disease progression. The primary endpoint was progression-free survival (PFS) assessed by the independent review committee. The second endpoints include objective response rate (ORR), disease control rate (DCR), safety, etc. RESULTS Donafenib demonstrated prolonged median PFS over placebo [12.9 vs. 6.4 months; hazard ratio (HR), 0.39; 95% confidence interval (CI), 0.25-0.61; P < 0.0001] in Chinese patients with RAIR-DTC. Improved ORR (23.3% vs. 1.7%; P = 0.0002) and DCR (93.3% vs. 79.3%; P = 0.0044) were observed in the donafenib group over placebo. For donafenib, the most common grade ≥ 3 treatment-related adverse events (AE) included hypertension (13.3%) and hand-foot syndrome (12.5%), 42.2% underwent dose reduction or interruption, and 6.3% experienced discontinuation. CONCLUSIONS Donafenib was well-tolerated and demonstrated clinical benefit in terms of improved PFS, ORR, and DCR in patients with RAIR-DTC. The results suggest that donafenib could be a new treatment option for patients with RAIR-DTC.
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3.
Pharmacokinetics and bioequivalence of two methylprednisolone tablet formulations in healthy Chinese subjects under fasting and fed conditions.
Fan, L, Zhang, P, Gan, C, Huang, Q, Shen, Z, Xiao, X, Yang, Y, Qiu, D, Mai, G, Shentu, J
International journal of clinical pharmacology and therapeutics. 2023;(1):37-44
Abstract
AIMS: The aims of this study were to evaluate and compare the pharmacokinetic profiles and bioequivalence of two tablet formulations of methylprednisolone (test formulation: Zhejiang Xianju Pharmaceutical Co., Ltd., China; reference formulation: Medrol, Pfizer Italia SRL) in healthy Chinese subjects under fasting and fed conditions. MATERIALS AND METHODS Subjects were randomly allocated to either the fasting group or the fed group and also to one of two sequences (test-reference or reference-test), according to which they received a single 16-mg dose of the test or reference methylprednisolone tablet in the study periods. Blood samples were collected pre dose and at intervals up to 16 hours after administration. Plasma methylprednisolone concentrations were determined using a validated liquid chromatography tandem mass spectrometry method. The safety of the medications was monitored throughout the study. The primary pharmacokinetic parameters measured were Cmax, AUC0-t, and AUC0-∞. RESULTS A total of 56 subjects were enrolled, and all completed the study. The 90% confidence intervals for Cmax, AUC0-t, and AUC0-∞, measured under both fasting and fed conditions, fell within the acceptable range for bioequivalence of 80 - 125%. Analysis of variance showed that there were no significant differences in the primary pharmacokinetic parameters (Cmax, AUC0-t, and AUC0-∞) between the test and reference formulation measured under both fasted and fed conditions. No serious or unexpected adverse drug reactions occurred during the study period. CONCLUSION The test methylprednisolone 16 mg tablet produced in China is bioequivalent to the reference formulation (Medrol) in healthy Chinese subjects measured under both fasting and fed conditions. Both formulations were well tolerated by all study participants.
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4.
Effectiveness of butylphthalide on cerebral autoregulation in ischemic stroke patients with large artery atherosclerosis (EBCAS study): A randomized, controlled, multicenter trial.
Guo, ZN, Yue, BH, Fan, L, Liu, J, Zhu, Y, Zhao, Y, Zhong, J, Lou, Z, Liu, XL, Abuduxukuer, R, et al
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2023;(10):1702-1712
Abstract
Finding appropriate drugs to improve cerebral autoregulation (CA) in patients with acute ischemic stroke (AIS) is necessary to improve prognosis. We aimed to investigate the effect of butylphthalide on CA in patients with AIS. In this randomized controlled trial, 99 patients were 2:1 randomized to butylphthalide or placebo group. The butylphthalide group received intravenous infusion with a preconfigured butylphthalide-sodium chloride solution for 14 days and an oral butylphthalide capsule for additional 76 days. The placebo group synchronously received an intravenous infusion of 100 mL 0.9% saline and an oral butylphthalide simulation capsule. The transfer function parameter, phase difference (PD), and gain were used to quantify CA. The primary outcomes were CA levels on the affected side on day 14 and day 90. Eighty patients completed the follow-up (52 in the butylphthalide group and 28 in the placebo group). The PD of the affected side on 14 days or discharge and on 90 days was higher in the butylphthalide group than in the placebo group. The differences in safety outcomes were not significant. Therefore, butylphthalide treatment for 90 days can significantly improve CA in patients with AIS.Trial registration: ClinicalTrial.gov: NCT03413202.
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Development and validation of a novel diagnostic model for initially clinical diagnosed gastrointestinal stromal tumors using an extreme gradient-boosting machine.
Hu, B, Wang, C, Jiang, K, Shen, Z, Yang, X, Yin, M, Liang, B, Xie, Q, Ye, Y, Gao, Z
BMC gastroenterology. 2021;(1):481
Abstract
INTRODUCTION Gastrointestinal stromal tumor (GIST) is the most common gastrointestinal soft tissue tumor. Clinical diagnosis mainly relies on enhanced CT, endoscopy and endoscopic ultrasound (EUS), but the misdiagnosis rate is still high without fine needle aspiration biopsy. We aim to develop a novel diagnostic model by analyzing the preoperative data of the patients. METHODS We used the data of patients who were initially diagnosed as gastric GIST and underwent partial gastrectomy. The patients were randomly divided into training dataset and test dataset at a ratio of 3 to 1. After pre-experimental screening, max depth = 2, eta = 0.1, gamma = 0.5, and nrounds = 200 were defined as the best parameters, and in this way we developed the initial extreme gradient-boosting (XGBoost) model. Based on the importance of the features in the initial model, we improved the model by excluding the hematological features. In this way we obtained the final XGBoost model and underwent validation using the test dataset. RESULTS In the initial XGBoost model, we found that the hematological indicators (including inflammation and nutritional indicators) examined before the surgery had little effect on the outcome, so we subsequently excluded the hematological indicators. Similarly, we also screened the features from enhanced CT and ultrasound gastroscopy, and finally determined the 6 most important predictors for GIST diagnosis, including the ratio of long and short diameter under CT, the CT value of the tumor, the enhancement of the tumor in arterial period and venous period, existence of liquid area and calcific area inside the tumor under EUS. Round or round-like tumors with a CT value of around 30 (25-37) and delayed enhancement, as well as liquid but not calcific area inside the tumor best indicate the diagnosis of GIST. CONCLUSIONS We developed a model to further differential diagnose GIST from other tumors in initially clinical diagnosed gastric GIST patients by analyzing the results of clinical examinations that most patients should have completed before surgical resection.
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Effects of Food and Antacids on Pharmacokinetics and Pharmacodynamics of Lesinurad, a Selective Urate Reabsorption Inhibitor.
Shen, Z, Lee, CA, Valdez, S, Yang, X, Wilson, DM, Flanagan, T, Gillen, M
Clinical pharmacology in drug development. 2019;(5):647-656
Abstract
Two clinical studies were performed in healthy volunteers to investigate food and antacid effects on lesinurad, a novel selective uric acid reabsorption inhibitor approved for treatment of hyperuricemia associated with gout in combination with xanthine oxidase inhibitors. Study 1 evaluated a high-fat, high-calorie meal or high doses of antacids (3000 mg calcium carbonate or 1600 mg magnesium hydroxide/1600 mg aluminum hydroxide) on the pharmacokinetics (PK) and pharmacodynamics (PD) of 400 mg oral lesinurad. Study 2 evaluated low doses of antacids (1250 mg calcium carbonate or 800 mg magnesium hydroxide/800 mg aluminum hydroxide) on the PK and PD of 400 mg lesinurad. Food did not alter the plasma AUC of lesinurad and only reduced its Cmax by 18%. In the fasted conditions, high-dose calcium carbonate reduced the Cmax and AUC of lesinurad by 54% and 38%, respectively, whereas high-dose magnesium hydroxide/aluminum hydroxide reduced Cmax and AUC by 36% and 31%, respectively. Food enhanced the maximum serum urate (sUA)-lowering effect of lesinurad by approximately 20% despite reducing the Cmax of lesinurad. High-dose calcium carbonate decreased the urate-lowering effect approximately 20% in the first 6 hours, whereas high-dose magnesium hydroxide/aluminum hydroxide reduced the effect by 26%. Low-dose calcium carbonate or magnesium hydroxide/aluminum hydroxide in the presence of food did not significantly affect plasma lesinurad Cmax and AUC or the sUA lowering and renal handling of uric acid. In summary, study results suggest food did not meaningfully alter lesinurad PK and PD. High doses of antacids reduced lesinurad AUC up to 40% and reduced the lesinurad uric acid-lowering effect.
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7.
Enhanced recovery after surgery for radical cystectomy with ileal urinary diversion: a multi-institutional, randomized, controlled trial from the Chinese bladder cancer consortium.
Lin, T, Li, K, Liu, H, Xue, X, Xu, N, Wei, Y, Chen, Z, Zhou, X, Qi, L, He, W, et al
World journal of urology. 2018;(1):41-50
Abstract
PURPOSE Enhanced recovery after surgery (ERAS) has played an important role in recovery management for radical cystectomy with ileal urinary diversion (RC-IUD). This study is to evaluate ERAS compared with the conventional recovery after surgery (CRAS) for RC-IUD. METHODS From October 2014 and July 2016, bladder cancer patients scheduled for curative treatment from 25 centers of Chinese Bladder Cancer Consortium were randomly assigned to either ERAS or CRAS group. Primary endpoint was the 30-day complication rate. Secondary endpoints included recovery of fluid and regular diet, flatus, bowel movement, ambulation, and length of stay (LOS) postoperatively. Follow-up period was 30-day postoperatively. RESULTS There were 144 ERAS and 145 CRAS patients. Postoperative complications occurred in 25.7 and 30.3% of the ERAS and CRAS patients with 55 complications in each group, respectively (p = 0.40). There was no significant difference between groups in major complications (p = 0.82), or type of complications (p = 0.99). The ERAS group had faster recovery of bowel movements (median 88 versus 100 h, p = 0.01), fluid diet tolerance (68 versus 96 h, p < 0.001), regular diet tolerance (125 versus 168 h, p = 0.004), and ambulation (64 versus 72 h, p = 0.047) than the CRAS group, but similar time to flatus and LOS. CONCLUSIONS ERAS did not increase 30-day complications compared with CRAS after RC. ERAS may be better than CRAS in terms of bowel movement, tolerance of fluid and regular diet, and ambulation.
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8.
Pharmacokinetics, pharmacodynamics, and tolerability of verinurad, a selective uric acid reabsorption inhibitor, in healthy adult male subjects.
Shen, Z, Gillen, M, Miner, JN, Bucci, G, Wilson, DM, Hall, JW
Drug design, development and therapy. 2017;:2077-2086
Abstract
PURPOSE Verinurad (RDEA3170) is a selective uric acid reabsorption inhibitor in clinical development for the treatment of gout and asymptomatic hyperuricemia. The aim of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of verinurad in healthy adult males. SUBJECTS AND METHODS This was a Phase I, randomized, double-blind, placebo-controlled, single and multiple ascending dose study. Panels of eight male subjects received a single oral dose of verinurad or placebo in either a fasted or fed state; panels of 10-12 male subjects received ascending doses of once-daily verinurad or placebo in a fasted state for 10 days. Serial blood and urine samples were assayed for verinurad and uric acid. Safety was assessed by adverse event (AE) reports, laboratory tests, vital signs, and electrocardiograms (ECGs). RESULTS A total of 81 adult males completed the study. Following single doses of verinurad, maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) increased in a dose-proportional manner; Cmax occurred at 0.5-0.75 hours and 1.25 hours in the fasted and fed states, respectively. Food decreased AUC by 23% and Cmax by 37%-53%. There was a modest accumulation of verinurad following multiple daily doses. Verinurad reduced serum urate levels by up to 62% (40 mg, single dose) and 61% (10 mg, multiple dose). The increase in urinary excretion of uric acid was greatest in the first 6 hours after dosing and was still evident ≥24 hours for verinurad doses ≥2 mg. Verinurad was well tolerated at all doses. No serious AEs, severe AEs, discontinuations due to AEs, or clinically significant laboratory or ECG abnormalities were reported. CONCLUSION Single and multiple doses of verinurad were well tolerated, absorption was rapid, and exposure was dose proportional. Verinurad increased urinary uric acid elimination and resulted in sustained reductions in serum urate. These data support further clinical evaluation of once-daily verinurad as a treatment for gout.
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9.
Pharmacokinetics, pharmacodynamics, and safety of lesinurad, a selective uric acid reabsorption inhibitor, in healthy adult males.
Shen, Z, Rowlings, C, Kerr, B, Hingorani, V, Manhard, K, Quart, B, Yeh, LT, Storgard, C
Drug design, development and therapy. 2015;:3423-34
Abstract
Lesinurad is a selective uric acid reabsorption inhibitor under investigation for the treatment of gout. Single and multiple ascending dose studies were conducted to evaluate pharmacokinetics, pharmacodynamics, and safety of lesinurad in healthy males. Lesinurad was administered as an oral solution between 5 mg and 600 mg (single ascending dose; N=34) and as an oral solution or immediate-release capsules once daily (qday) between 100 mg and 400 mg for 10 days under fasted or fed condition (multiple ascending dose; N=32). Following single doses of lesinurad solution, absorption was rapid and exposure (maximum observed plasma concentration and area under the plasma concentration-time curve) increased in a dose-proportional manner. Following multiple qday doses, there was no apparent accumulation of lesinurad. Urinary excretion of unchanged lesinurad was generally between 30% and 40% of dose. Increases in urinary excretion of uric acid and reductions in serum uric acid correlated with dose. Following 400 mg qday dosing, serum uric acid reduction was 35% at 24 hours post-dose, supporting qday dosing. A relative bioavailability study in healthy males (N=8) indicated a nearly identical pharmacokinetic profile following dosing of tablets or capsules. Lesinurad was generally safe and well tolerated.
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10.
[The prevention of primary liver cancer by selenium in high risk populations].
Li, W, Zhu, Y, Yan, X, Zhang, Q, Li, X, Ni, Z, Shen, Z, Yao, H, Zhu, J
Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine]. 2000;(6):336-8
Abstract
OBJECTIVE To study the preventive effects of selenium on primary liver cancer. METHODS After screening of blood samples in 18,000 males from 20 to 65 years-old in Qidong, Jiangsu province (a high risk area for liver cancer), 2,065 cases of HBsAg positive, AFP negative and normal liver function (normal ALT values) were found. The subjects were randomly divided into two groups, based on their residence areas; 1,112 subjects (experimental group) received one tablet of sodium selenite (0.5 mg Se) every day and 953 subjects (control group) received one placebo tablet every day. RESULTS During three years of intervention and follow up, the blood selenium concentration and glutathione peroxidase activity of the subjects in the experimental group were increased and had significant difference as compared with those of the control group (P < 0.01). At the same time, the prevalence rate of micronucleus cells in peripheral blood lymphocytes in the experimental group was significantly lower than that of the control group (P < 0.01), and the incidence of new liver cancer in the experimental group (3 057.55/10(6), 34 cases out of 1,112 subjects) was significantly lower than the control group (5 981.11/10(6); 57 cases out of 953 subjects) (P < 0.01). CONCLUSION The results confirms that selenium supplementation in general populations lived in high risk is effective in the prevention of liver cancer and the using of selenium tablets is simple and feasible.