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The test drug, a recombinant humanized monoclonal antibody, is a biosimilar candidate for the reference drug. The purpose of this study was to evaluate the bioequivalence of these two drugs. The study was divided into two parts, a pre-study and a formal trial. The pre-study included two subjects who were each given a single intravenous infusion of 6 mg/kg test drug. The formal trial was designed to be a randomized, double-blind, parallel controlled trial in which 70 subjects were randomly assigned 1:1 to receive either test or reference drug as a single 6 mg/kg intravenous infusion. In the pre-study, the immunogenicity was negative in both subjects and the safety of the test drug was considered to be good. The two groups in the formal trial had similar demographic characteristics. The 90% confidence interval of geometric mean ratios of area under the serum concentration-time curve from the time 0 to the time of last quantifiable concentration, area under the serum concentration-curve from time 0 to infinity, and maximum observed serum concentration between the test group and the reference group fell between 80% and 125% and the bioequivalence was recognized. There was no significant difference in the positive rate of antidrug antibodies. The treatment-emergent adverse events in the test group were similar to those in the reference group. This study showed that the test drug has similar pharmacokinetics, immunogenicity, and safety to the reference drug in healthy male subjects. more...

The continuous emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants led to a rapid decline in protection efficacy and neutralizing titers even after three doses of COVID-19 vaccines. Here, we report an open-labeled Phase I clinical trial of a modified mRNA vaccine (SYS6006) as a fourth-dose booster in healthy adults. Eighteen eligible participants, who had completed three doses of inactivated COVID-19 vaccines, received a fourth boosting dose of SYS6006-20 μg. Eighteen convalescent COVID-19 patients were enrolled for the collection of serum samples as a comparator of immunogenicity. The primary endpoint of this trial was titers of anti-receptor binding domain of spike glycoprotein (RBD) antibodies of the Omicron strain (BA.2 and BA.4/5) in serum; titers of neutralizing antibodies against pseudovirus of the Omicron strain (BA.2 and BA.4/5). The secondary endpoint was the incidence of adverse events within 30 days after the boosting. The exploratory endpoint was the cellular immune responses (interferon gamma, IFN-γ). This trial was registered with the Chinese Clinical Trial Registry website. No serious adverse events were reported within 30 days after vaccination. No Grade 3 fever or serious adverse event was reported in the SYS6006 group. Notably, SYS6006 elicited higher titers and longer increases in anti-RBD antibodies and neutralizing antibodies (>90 days) compared with the convalescent group (P < 0.0001) against Omicron strain (BA.2 and BA.4/5). Besides, higher positive spots of T-cell-secreting IFN-γ were observed in the SYS6006 group than those in the convalescent group (P < 0.05). These data demonstrated that SYS6006 was well tolerated and highly immunogenic, generating a stronger and more durable immune response against different variants of SARS-CoV-2. more...

Jie Cheng,1,&ast; Siyang Wang,2,&ast; Jingying Jia,3 Qian Chen,3 Yunxiao Song,4 Junsheng Li1 1Department of Urinary Surgery, Shanghai Xuhui Central Hospital, Shanghai, People’s Republic of China; 2Department of Geratology, Shanghai Xuhui Central Hospital, Shanghai, People’s Republic of China; 3Department of Central Laboratory, Shanghai Xuhui Central Hospital, Shanghai, People’s Republic of China; 4Department of Clinical Laboratory, Shanghai Xuhui Central Hospital, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Junsheng LiDepartment of Urinary Surgery, Shanghai Xuhui Central Hospital, No. 966 Huaihai Road, Shanghai, 200031, People’s Republic of ChinaTel +86-21 31270810Email lijunshengdy@163.comPurpose: Red cell distribution width (RDW), an inflammation biomarker, has been linked to poor outcomes in patients with different types of cancers. The present study aimed to investigate the relationship between pre-/post-treatment 3-month RDW levels and changes in RDW with 3-year prognosis of prostate cancer.Patients and Methods: A total of 348 patients with prostate cancer were recruited between June 1, 2012 and June 1, 2017 and were followed up for at least 3 years. RDW was measured with the Mindray BC-6800Plus automatic blood counting system at pre- and post-treatment 3-month. Demographic and clinical information of the participants were also collected. The overall survival (OS) and cancer-specific survival (CSS) were analyzed using the Kaplan–Meier method. Cox regression and competing risk regression analyses were performed.Results: During the follow-up period, 51 (14.66%) deaths occurred. The levels of pre- and post-treatment RDW levels were significantly higher in the death group than in the survival group (p< 0.001). In the death group, the level of RDW continued to rise in most subjects, and the mean level of RDW was significantly higher at post-treatment than pre-treatment, contrary to the results observed in the survival group. Multivariate Cox regression analysis revealed that high pre-treatment RDW, high post-treatment RDW, and persistently higher RDW were independently associated with OS and CSS (p< 0.001). Similar results were observed in the competing risk regression analysis. Kaplan–Meier analysis revealed that patients with higher pre-treatment RDW levels, higher post-treatment RDW levels, and persistently higher RDW levels had poorer 3-year OS and CSS rates (p< 0.05).Conclusion: The levels of and changes in RDW before and after treatment were associated with the 3-year prognosis of prostate cancer, suggesting that RDW might be an efficient prognostic predictor in patients with prostate cancer.Keywords: red cell distribution width, prostate cancer, prognostic, overall survival, cohort study more...

Purpose Henagliflozin is a highly selective and effective sodium glucose co-transporter (SGLT)-2 inhibitor developed for the treatment of patients with type 2 diabetes mellitus (T2DM). This study aimed to investigate the effects of meal intake on the pharmacokinetic properties of henagliflozin, and to understand the excretion pathways of henagliflozin in humans. Methods In this Phase I, randomized, open-label, single-dose, two-period crossover study, 12 healthy male Chinese volunteers were randomized to receive either henagliflozin 10 mg in the fasted condition followed by henagliflozin 10 mg in the fed condition, or the reverse schedule, with the two administrations separated by a washout period of at least 7 days. Samples of blood, urine, and feces were collected and analyzed for the investigation of the pharmacokinetic profile and excretion pathways in the fasted and fed conditions. Any adverse events that occurred throughout the study were recorded for tolerability assessment. Findings After the administration of a single oral dose of henagliflozin, mean (SD) plasma AUC0–∞ and Cmax were 1200 (274) h · ng/mL and 179 (48.8) ng/mL, respectively, in the fasted state and were decreased to 971 (245) h · ng/mL and 115 (34.2) ng/mL in the fed state. The fed/fasted ratios (90% CIs) of the geometric mean values of Cmax, AUC0–t, and AUC0–∞ were 64% (54%–76%), 80% (76%–85%), and 80% (76%–85%), respectively. The median (range) Tmax was prolonged from 1.5 (1–3) hours in the fasted condition to 2 (1.5–6) hours in the fed condition. Mass-balance testing revealed that henagliflozin was eliminated primarily as the parent drug in feces and as glucuronide metabolites in urine. In the fasted state, the cumulative excretion percentages of the parent drug and its metabolites to dose in feces and urine were 40.6% and 33.9%, respectively. The values in the fed condition were changed to 50.4% and 25.5%, respectively. These findings suggest that postprandial administration decreases the absorption rate and the extent of henagliflozin exposure in humans, but has no effect on the metabolism or elimination of the drug. Implications In the present study, the consumption of a high-fat meal prior to henagliflozin administration was associated with reductions in AUC0–∞ and Cmax of 19.4% and 36.4%, respectively. However, based on the analysis of the pharmacokinetic/pharmacodynamic findings on henagliflozin, this slight change may not have clinical significance. Mass balance of henagliflozin in humans was achieved with ∼75% of the administered dose recovered in excretions within 4 days after administration whether in the fasted or fed state. These findings suggest that henagliflozin tablets can be administered with or without food. more...

The aim of this study was to investigate the effect of a high-fat and high-calorie meal on the single-dose pharmacokinetics (PK) and tolerability of savolitinib. The study included two phases: safety run-in phase and food effect assessment phase. In the safety run-in phase, 9 healthy male volunteers were divided into three groups to be administered a single oral dose of savolitinib tablets at 200, 400, and 600 mg. In the food effect assessment phase, 16 healthy male volunteers received a single 600 mg dose of savolitinib tablets following an overnight fast or a high-fat and high-calorie breakfast prior to dosing. Blood samples were collected at the designated time points for pharmacokinetic analysis. Safety and tolerability were assessed throughout the study by clinical assessments and adverse events (AEs). A total of 25 healthy male volunteers were enrolled in the study, including 9 in the safety run-in phase and 16 in the food effect assessment phase. In the food effect assessment phase, the geometric mean ratios (90% confidence interval) for savolitinib dosed under the fed condition compared with that dosed under the fasting condition were 102.7% (84.9%, 124.2%) and 117.1% (103.9%, 131.9%) for Cmax and AUC0-inf of savolitinib, respectively. The Tmax was delayed significantly (p = 0.023) under fed condition. The most common AEs possibly related to the study drug were dizziness, nausea, and emesis. The study indicated that a high-fat and high-calorie meal has no clinically relevant impact on the PK and bioavailability of savolitinib in healthy male volunteers. more...

Qingqing Wu,1,2 Xiaodong Wang,3 Qian Chen,1,2 Yang Zou,1,2 Xiaoyan Xu,1,2 Tingting Li,1,2 Chen Yu,1,2 Fu Zhu,1,2 Kanyin E Zhang,4 Jingying Jia,1,2 Yanmei Liu1,2 1Center Laboratory, Shanghai Xuhui Central Hospital, Shanghai, People’s Republic of China; 2Shanghai Engineering Research Center of Phase I Clinical Research & Quality Consistency Evaluation for Drugs, Shanghai, People’s Republic of China; 3Changzhou Siyao Pharmaceuticals Co., Ltd, Jiangsu, People’s Republic of China; 4ViaClinical Ltd, Shanghai, People’s Republic of ChinaCorrespondence: Yanmei LiuCenter Laboratory, Shanghai Xuhui Central Hospital, No. 966, Huaihai Road(M), Shanghai, People’s Republic of ChinaTel/Fax +86-21-54030254Email ymliu@shxh-centerlab.comPurpose: To compare the bioequivalence of two formulations of valsartan (80 mg capsules) under fasting and fed conditions in healthy Chinese volunteers using a full-replicate study design.Methods: A total of 78 Subjects were randomly assigned to fasting cohort (n = 48) or fed cohort (n = 30). Each cohort includes 4 single-dose observation periods and 3-day washout periods. Blood samples were collected at designed time point. Plasma concentration of valsartan was analyzed by a validated LC-MS/MS method. Noncompartmental analysis method was employed to determine the pharmacokinetic parameters. Based on the within-subject standard deviation (SWR) of the reference formulation, either reference-scaled average bioequivalence (RSABE) or average bioequivalence (ABE) method was used to evaluate the bioequivalence of the two formulations.Results: Under fasting conditions, the RSABE method was used to evaluate the bioequivalence of Cmax (SWR> 0.294), while ABE method was used to evaluate the bioequivalence of AUC0-t and AUC0-∞. The geometric mean ratio (GMR) of the test/reference for Cmax was 99.52%, and the 95% upper confidence bound was < 0. For AUC0-t and AUC0-∞ comparisons, GMRs were 102.07% and 101.92%, and the 90% CIs of the test/reference were 96.28%– 108.21%, 96.28%– 107.88%, respectively. Under fed conditions, the SWR value of Cmax, AUC0-t and AUC0-∞ all exceeded the cutoff value of 0.294 and therefore, the RSABE method was used. The GMRs for Cmax, AUC0-t and AUC0-∞ were 98.78%, 103.33% and 103.08%, respectively, while the 95% upper confidence bound values were all < 0. These results all met the bioequivalence criteria for highly variable drugs. All adverse events were mild and transient.Conclusion: In this study, the generic formulation of valsartan 80 mg capsule was considered to be bioequivalent to the reference product under both fasting and fed conditions, and satisfied the requirements for marketing in China.NMPA Registration No: CTR20181422.Keywords: valsartan, bioequivalence, replicate, pharmacokinetics, safety more...

Purpose Surufatinib is a potent and orally active small-molecule tyrosine kinase inhibitor targeting VEGFRs 1 to 3, FGFR-1, and CSF-1R, and thus may exert antitumor and antiangiogenic effects. The objective of this study was to determine the tolerability and effects of food intake on the pharmacokinetic properties of surufatinib in healthy Chinese subjects. Methods A total of 24 healthy Chinese male subjects aged between 18 and 55 years were enrolled. Subjects were administered a single dose of surufatinib 250–mg capsules in the fasted and fed states in succession. Pharmacokinetic analysis was performed through the collection of blood samples at predose and at several time points after surufatinib administration. Tolerability assessments comprised physical examination including vital sign measurements, laboratory testing, and ECG to determine adverse events (AEs). Findings The 90% CIs of the geometric mean ratios of AUC0–t and AUC0–∞ in the fasted and fed states was within 0.80 to 1.25; and for Cmax, within 0.70 to 1.43, indicating that food had no effect on the bioavailability of surufatinib in these healthy Chinese male subjects. Food intake delayed the time to peak absorption of surufatinib, as the median Tmax in the fed state was longer than that in the fasted state (4.0 vs 2.0 h). Surufatinib was marginally excreted from urine (mean [SD] cumulative excretion fraction, 1.2% [0.4%]). AEs occurred in 7 of the 24 subjects (29.2%) and included upper respiratory tract infection, dizziness, merycism, intervertebral disc protrusion, influenza-like disease, hematuria, prostatitis, and elevated blood urea nitrogen. All AEs were grade 1 or 2. Implications The bioavailability of surufatinib was not affected by food intake prior to dosing. However, food intake led to delated Tmax of surufatinib. The tolerability of a single oral dose of surufatinib 250 mg in the fasted and fed states was favorable in these healthy Chinese male subjects. These results indicate that surufatinib capsules could be administered before or after meals. ClinicalTrials.gov identifier: NCT02320409. more...

The purpose of this study was to tendency the expression of microRNA and xenomiR in hay of two alfalfa varieties (cv.Zhongmu No.1, cv.Xinyan No.52), and analyze the expression level of miR-168c, miR-156a and miR-166e of alfalfa in cow serum, milk and colostrum. The miRs in fresh and dry samples of two alfalfa varieties were sequenced by high-throughput RNA sequencing technology, RT-qPCR was used to analyze the expression levels of miR-156a, miR-166e and miR-168c. In addition, the target gene of miR168c in dairy cows was verified by Double-Luciferase Report.The results showed that: (1) 771 miRs were detected, 113 and 84 miRs expression levels in dry samples were up- and down-regulated, 8855 target genes were predicted. (2) miR-156a, miR-166e and miR-168c expression levels in dry samples of two alfalfa varieties were opposite, which were down-regulated in cv.Zhongmu 1 and up-regulated in cv.Xinyan 52. (3) The expression levels of miR-168c, miR-156a and miR-166e in high producing dairy cow serum were significantly higher than low producing dairy cow (p more...

This study aimed to evaluate the pharmacokinetics (PK), safety, and immunogenicity of the infliximab biosimilar CMAB008 compared to the reference product (Remicade) in healthy Chinese male subjects to provide the basis for the similarity evaluation of the 2 drugs. In this phase I randomized, double-blind, parallel-controlled, single-dose study, a total of 90 subjects were randomized 1:1 to receive CMAB008 or infliximab reference product with single intravenous injections (5 mg/kg). Blood samples were collected at designed time points for PK and immunogenicity assessment. If the 90%CI of the geometric mean ratio of area under the plasma concentration-time curve from 0 to the time of the last observation, maximum observed plasma concentration, area under the plasma concentration-time curve from 0 to infinity was completely within the range of 80% to 125%, the PK bioequivalence was established. Other PK parameters including time to maximum plasma concentration more...

Daboia russelii siamensis accounts for most of snakebite mortalities in China, yet, specific treatment against the venom toxins is absent in clinical practice. The F(ab')

Hongjie Qian,1,2 Qian Chen,1,2 Liyu Liang,1,2 Yang Zou,1,2 Huahua Pu,1,2 Liang Xin,1,2 Rong Song,1,2 Tingting Li,1,2 Huijuan Zhu,1,2 Yu Wang,3 Guanghui Tian,4 Jingshan Shen,2,3 Hualiang Jiang,2,3 Chen Yu,1,2 Zhen Wang,2,3 Jingying Jia1,2 1Central Laboratory, Shanghai Xuhui Central Hospital, Shanghai, 200031, People’s Republic of China; 2Shanghai Engineering Research Center of Phase I Clinical Research & Quality Consistency Evaluation for Drugs, Shanghai, 200031, People’s Republic of China; 3CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People’s Republic of China; 4Vigonvita Life Science Co., Ltd., Suzhou, 215123, People’s Republic of ChinaCorrespondence: Jingying JiaShanghai Xuhui Central Hospital, No. 966, Huaihai Road(M), Shanghai, 200031, People’s Republic of ChinaTel/Fax +86 21 54030254Email jyjia@shxh-centerlab.comZhen WangShanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zu Chong Zhi Road, Pudong, Shanghai, 201203, People’s Republic of ChinaTel +86 21 20231000Fax +86 21 20231962Email wangzhen@simm.ac.cnPurpose: TPN171H is a novel, potent and selective phosphodiesterase type 5 (PDE5) inhibitor for the treatment of pulmonary arterial hypertension (PAH). The objective of this study was to evaluate the safety, tolerability, and pharmacokinetics of TPN171H in healthy subjects after single and multiple dosing, in addition, to investigate the food effect on pharmacokinetics and safety of TPN171H.Methods: The entire study was comprised of three parts: Part I (single ascending-dose study), Part II (food effect study), and Part III (multiple ascending-dose study). A total of 63 healthy subjects were enrolled in the study. TPN171H tablet or placebo was administered per protocol requirements. Blood samples were collected at the designated time points for pharmacokinetic analysis. Safety was assessed by clinical examinations and adverse events.Results: In Part I, AUC and Cmax were proved to be linear within the 5– 30 mg dose range. T1/2 of TPN171H was 8.02– 10.88 h. In Part II, we figured out that TPN171H administration under fed condition could decrease Cmax, prolong Tmax, but had no effect on AUC. In Part III, the accumulation ratio at steady-state for AUC and Cmax indicated that TPN171H has a slight accumulation upon repeated dosing. Subjects were generally tolerable after TPN171H administration. Compared with other PDE5 inhibitors, TPN171H was found to have no impact on blood pressure and color discrimination.Conclusion: TPN171H was safe and generally tolerated in healthy subjects. Based on the half-life, food effect, and safety profile of TPN171H, we recommend a once-daily, post-meal administration of TPN171H in subsequent clinical studies in healthy subjects and patients with PAH.Keywords: TPN171H, PDE5 inhibitor, safety, pharmacokinetics, food effect, healthy subjects more...

The bioequivalence and safety of levetiracetam granules (test formulation) and oral solution (reference formulation) were evaluated in Chinese healthy volunteers under a fasting condition. A total of 24 subjects randomly received the test or reference formulation at the rate of 1:1. The alternative formulation was administered after a 7-day washout period. The blood samples were collected at designated time points. Liquid chromatography-tandem mass spectrometry was applied to determine the plasma concentrations of levetiracetam. Adverse events were monitored and recorded. The 90% CIs for the geometric mean ratios of maximum plasma concentration, area under the plasma concentration-time curve from time 0 to the last quantifiable concentration, and area under the plasma concentration-time curve from time 0 to infinity between test preparation and reference preparation were 95.5% to 110.7%, 100.2% to 105.3%, and 100.3% to 105.7%, respectively, all within an acceptable bioequivalence range of 80.00% 125.00%. Both test and reference preparations were well tolerated. The trial confirmed that a single dose of 500-mg levetiracetam granules was bioequivalent to oral solution under a fasting condition, and may serve as a new dosage form of levetiracetam for clinical practice. more...

Objective To investigate the associations between interleukin (IL) gene polymorphisms and susceptibility to gastric cancer in the Qinghai population, China. Methods Patients with gastric cancer and cancer-free controls were enrolled into the study from Qinghai Provincial People’s Hospital between September 2016 and September 2018. Single nucleotide polymorphisms (SNPs) were genotyped with the Sequenom MassARRAY® SNP genotype system. The Hardy–Weinberg equilibrium in allele and genotype frequencies, and general characteristics between patients with gastric cancer and cancer-free controls, were evaluated using χ2-test. Potential associations between interleukin gene variants and the risk of gastric cancer were analysed by logistic regression. Results Among eight candidate SNPs, the allele and genotype frequency distribution of IL-1B rs1143634 polymorphism was significantly different between patients with gastric cancer ( n = 190) and cancer-free controls ( n = 186). The IL-1B rs1143634 GA genotype and IL-1B rs1143634 GA + AA genotype were associated with a reduced risk of gastric cancer, however, the remaining SNPs were not statistically associated with gastric cancer risk in the Qinghai population. Conclusion The IL-1B rs1143634 polymorphism might be associated with a decreased risk of gastric cancer, and may be a protective factor against gastric cancer. more...

Background Henagliflozin, a novel selective inhibitor of sodium–glucose cotransporter 2, is under development as a treatment for type 2 diabetes mellitus. Purpose To evaluate the tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of henagliflozin in healthy Chinese volunteers. Methods Two clinical studies were conducted. One was a single ascending dose (SAD) study (2.5–200 mg) involving 80 healthy subjects, and the other was a multiple ascending dose (MAD) study (1.25–100 mg for 10 days) involving 48 healthy subjects. The tolerability, PK profiles of henagliflozin and its main metabolites, and the urinary glucose excretion over 24 h were characterized in these 2 studies. Findings No serious adverse events were observed in the healthy subjects after single- and multiple-dose oral administration of henagliflozin, suggesting that this drug was well tolerated. Henagliflozin was rapidly absorbed, with a Tmax of 1.5–3 h, and then eliminated from plasma with a half-life of 11–15 h. It was not accumulated following once-daily oral administration. Plasma exposure of henagliflozin exhibited dose-proportional PK properties over the dose ranges of 2.5–200 mg (SAD) and 1.25–100 mg (MAD). The excretion of henagliflozin in urine was found to be very low, with 3.00%–5.13% of the dose. The glucuronide metabolites M5-1, M5-2 and M5-3 were the main metabolites detected in plasma samples, which accounted for up to 54.3%, 19.8%, and 27.5%, respectively, of the parent drug at steady state. Both the SAD and MAD studies demonstrated that the urinary glucose excretion over 24 h was dose-dependently increased and displayed saturation kinetics at >25 mg. No significant changes in the levels of serum glucose and urine electrolytes were found following a single or multiple doses of henagliflozin administration. Implications Henagliflozin was well tolerated and showed predictable PK/PD profiles in these healthy subjects. Henagliflozin did not affect blood glucose level or urinary electrolyte excretion. It is best characterized for once-daily administration with a maximum dose of 25 mg. ChinaDrugTrials.org.cn identifiers: CTR20131986 and CTR20140132. more...

A simple, rapid and accurate method for quantitative analysis of a highly selective phosphodiesterase-5 inhibitor (PDE5), TPN171 by high performance liquid chromatography and tandem mass spectrometry in human plasma was proposed and validated successfully using D3-TPN171 as internal standards (ISTD). An aliquot of 100 μL of plasma was mixed with internal standard and was precipitated with acetonitrile. Gradient elution was performed on a ACQUITY HSS T3 column (50 × 2.1 mm, 1.8 μm) coupled with a ACQUITY column in-line filter at 40℃, by 5 mM ammonium acetate in water containing 0.1 % formic acid and 0.1 % formic acid in acetonitrile as the mobile phase. The total analytical run time was 3.5 min. The analyte was monitored using multiple reaction monitoring (MRM) scan in positive polarity mode. The ion transition was m/z 442.2→113.2 and 445.2→116.2 for TPN171 and D3-TPN171 respectively. The method was validated for specificity, sensitivity, precision, accuracy, and other analytical parameters. The results found were satisfactory over the linear calibration range of 1-500 ng/mL. Within-day precisions ranged from 1.8 to 7.3 %, and between-day precisions from 2.3 to 4.9 %, accuracies were 95.5-99.8 %.The validated method was successfully applied to determine the plasma concentration after oral administration of 10 mg TPN171 in six healthy volunteers. more...

Sulcardine sulfate (Sul) is a novel antiarrhythmic agent as a potential treatment for atrial fibrillation and ventricular arrhythmias. This study was conducted to investigate the pharmacokinetic profile, safety, and tolerability of Sul in healthy Chinese subjects. In this open-label, single-dose, randomized study, 10 healthy subjects were assigned to receive Sul doses of 200, 400, and 800 mg under fasting conditions (Cohorts A, B, and C, respectively) or 400 mg under fed conditions (Cohort D). The study incorporated a crossover design, separated by a 7-day washout period. Blood samples were collected before treatment and at successive time intervals up to 48 h after treatment. Sul concentrations in plasma samples were determined using a validated LC-MS/MS method. Tolerability was determined by clinical evaluation and adverse-event monitoring. Pharmacokinetic results demonstrated that Cmax and AUC(0-t) of Sul increased with an increasing dose. The mean t1/2 values for Cohorts A, B, and C were 16.85, 17.66, and 11.87 h, respectively. No statistically significant differences were observed between men and women for the main pharmacokinetic parameters, with the exception of t1/2 in Cohorts B and C. No significant differences were observed in the absorption and bioavailability of Sul between the fed and fasted states (P > 0.05). Four subjects reported mild AEs during the study. No serious AEs were reported. Sul was shown to be safe and well tolerated in healthy Chinese subjects. Pharmacokinetics studies demonstrated that Sul has adequate oral absorption and bioavailability properties. This article is protected by copyright. All rights reserved. more...

Sulcardine sulfate is a novel antiarrhythmic agent with mechanism of action as a multi-ion channel blocker. Preclinical studies in animal models have demonstrated that sulcardine sulfate is efficacious in atrial and ventricular arrhythmias, and consequently, leads to the prevention of sudden cardiac death.This study was conducted in healthy Chinese male subjects to investigate the pharmacokinetic profile and safety of sulcardine sulfate after repeated oral dose administration at 200, 400, and 800 mg for 5 days.Thirty-three male subjects were enrolled in this study. In the multiple dose phase, sulcardine sulfate was administered orally twice at the interval of q12 h since day 3. Sulcardine sulfate plasma concentration was determined using a validated LC-MS/MS method. Safety was assessed using clinical evaluation and AE monitoring.In this repeated dose study, pharmacokinetic parameters (CPharmacokinetic characteristics of sulcardine sulfate were shown to be non-linear, with the modest accumulation upon repeated dosing, and sulcardine sulfate was safe and well tolerated. more...

Only sporadic data are available on hair concentrations of diazepam and some of its metabolites (nordazepam, oxazepam, and temazepam) following a single controlled dose. The aim of this study was to investigate the deposition of diazepam and its metabolites in human hair after eight healthy volunteers (four women and four men, ages 24-26, East Asian) consumed 10 mg of diazepam. Hair was collected from all volunteers 1 month after exposure, and also 2 months post-exposure from men and 10 months post-exposure from women. Diazepam and the complete metabolite profile, including oxazepam glucuronide and temazepam glucuronide, were measured by ultra-high pressure liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) with limits of quantifications (LOQs) of 0.5-2.5 pg/mg for diazepam, nordazepam, oxazepam, and temazepam, and of 10 pg/mg for oxazepam glucuronide and temazepam glucuronide. There were no differences by gender in the amounts of diazepam or metabolites found. The concentration of the main metabolite nordazepam was consistently higher than that of diazepam at both 1 and 2 months after consumption. Oxazepam and temazepam traces were found in some volunteers' hair, but the glucuronides were not detected. Diazepam and nordazepam levels at 10 months post-exposure were extremely low (near the LOQ), indicating drug loss by personal hygiene and physical handling. To our knowledge, this is the first single-dose diazepam study using black hair and the first study to include measurements of oxazepam glucuronide and temazepam glucuronide in human hair. more...

Sulcardine sulfate is a newly developed candidate drug used to control arrhythmias. The aim of this research was to investigate the pharmacokinetics, bioavailability and excretion characteristics of sulcardine in animals. Sprague–Dawley rats were orally and intravenously given sulcardine at 20 and 40 mg/kg. Beagle dogs were also orally and intravenously dosed at 10 mg/kg. Both [3H]-labeled sulcardine and unlabeled sulcardine were given to rats. Feces, urine and bile were collected at 0–72 h for mass balance study. The contents of unlabeled sulcardine and radioactivity in samples were determined by a validated LC–MS/MS method and by liquid scintillation counting, separately. Sulcardine was rapidly eliminated in rats after dosing. The oral bioavailability was 34–35 % in rats, while a higher exposure was observed in dogs (bioavailability = 62.7 %). More than 90 % of dosed sulcardine was recovered, and approximately 20–40 % of the dose excreted into urine as the original form, and the remaining was found in feces and bile, most of which (about 40 %) was transformed into metabolites. No difference was observed between sexes. Metabolism may occur to a large extent after oral administration in rats but to a smaller extent in dogs. Sulcardine was extensively absorbed in both rats and dogs after oral administration. The mass balance data indicated that sulcardine was widely metabolized in rats after oral administration. more...

The essence of ideological and political education is a kind of social practice education that cultivates, shapes, transforms, develops and perfects people. It has extensive and profound humanities heritage. The fundamental purpose of the ideological and political education is to enable people to have a high level of ideological qualifications and noble character. Over a long time, however, people often neglect the important role of humanities in ideological and political education in colleges and universities. They fail to understand the important role of humanities in shaping, training and perfecting people. Based on the analysis of the connotation of humanities in ideological and political education in colleges and universities, this paper, in close connection with the current situation of humanities in current ideological and political education, focuses on the emerging problems and analyzes their causes in detail, and puts forward some countermeasures in order to improve the practicality of ideological and political education in colleges and universities. By studying and integrating the research of humanities and ideological and political education in colleges and universities, it is bound to stimulate the coordinated progress and common development of the two. It will also push for the ideological and political education in universities in a new era to a new level. more...

Purpose Fruquintinib is a potent and highly selective oral small-molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor and demonstrates promising activity against a broad spectrum of cancer types. The objective of the study was to investigate the tolerability and effect of high-fat food on the pharmacokinetic profile of a fruquintinib capsule in healthy Chinese subjects. Methods Healthy Chinese male subjects aged between 18 and 45 years were enrolled in the study. The study included 2 phases: a dose-escalation phase and a food effect–assessment phase. In the dose-escalation phase, subjects were administered a single dose of fruquintinib (2, 3, or 4 mg) in the fasted state. In the food effect–assessment phase, subjects were administered a 4-mg fruquintinib capsule in the fasted and fed states, respectively, in 2 cycles. Blood samples for pharmacokinetic analysis were collected at the designated time points. Tolerability was assessed throughout the study by physical examination including vital sign measurements, clinical laboratory tests, 12-lead ECG, clinical assessments, and monitoring for and spontaneous reporting of adverse events. Findings Twenty-nine eligible male subjects were enrolled in the study, including 9 in the dose-escalation phase and 20 in the food effect–assessment phase. In the food effect–assessment phase, the ratios (90% CI) of the geometric mean AUC0-∞ and Cmax values for fruquintinib in the fed state to those observed in the fasted state were 97.2% (94.0%–100.4%) and 82.9% (76.7%–89.5%), respectively. The mean (SD) Tmax values of fruquintinib were 3.0 (1.0) and 5.6 (4.5) hours in the fasted and fed states, respectively. The most common adverse events possibly related to the study drug were elevated blood uric acid, diarrhea, and decreased white blood cell count. Implications The overall bioavailability of the evaluated formulation of fruquintinib was not affected by the consumption of a high-fat, high-calorie meal prior to dosing. However, the consumption of a high-fat, high-calorie meal prior to dosing prolonged the Tmax. These results indicate that the fruquintinib capsule can be administered with or without food. ClinicalTrials.gov identifier: NCT01955304. more...

Sulcardine sulfate (Sul), a novel antiarrhythmic agent, is currently in phase I and phase II clinical trials. To elucidate its clinical pharmacokinetic characteristics, a rapid and accurate liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed and validated for the quantification of Sul in human plasma. Plasma samples were precipitated by acetonitrile and isotope-labeled sulcardine was added as internal standard. The analysis was carried out on a Capcell Pak C18 MG III column (100 × 2.0 mm, 5 μm) with 0.1% formic acid in acetonitrile solution and water (17:83, v/v) as mobile phase. The linear range was 5.0-1000 ng/mL for Sul, with a lower limit of quantification of 5.0 ng/mL. The intra- and inter-batch CVs were within ±11.0% and the accuracies were 4.9-107.3%. Our method, for the first time, allows the rapid (only 3.0 min) and accurate quantification of Sul in human plasma. The method has been successfully applied in the pharmacokinetic study of Sul in a clinical trial following oral administration of Sul to healthy volunteers. Copyright © 2016 John Wiley & Sons, Ltd. more...

To investigate the QT/QTc effects of orally administered moxifloxacin in healthy Chinese volunteers. This was a single-blinded, randomized, single-dose, placebo-controlled, two-period cross-over study. A total of 24 healthy Chinese volunteers were enrolled, randomly assigned to two groups: one group received moxifloxacin (400 mg, po) followed by placebo with a 7-d interval, another group received placebo followed by moxifloxacin with a 7-d interval. On the days of dosing, 12-lead 24 h Holter ECGs were recorded and evaluated by an ECG laboratory blind to the treatments. Blood samples were collected to determine plasma concentrations of moxifloxacin. The orally administered moxifloxacin significantly prolonged the mean QTc at all time points except 0.5 h post-dose. The largest time-matched difference in the QTcI was 8.35 ms (90% CI: 5.43, 11.27) at 4 h post-dose. The peak effect on QTcF was 9.35 ms (90% CI: 6.36, 12.34) at 3 h post-dose. A pharmacokinetic-QTc model suggested a 2.084 ms increase in the QTc interval for every 1000 ng/mL increase in plasma concentration of moxifloxacin. In addition, the orally administered moxifloxacin was well tolerated by the subjects. Orally administered moxifloxacin significantly prolongs QTc, which supports its use as a positive control in ICH-E14 TQT studies in Chinese volunteers. more...

The pharmacokinetics of lurasidone have been studied in healthy Japanese and Caucasian subjects, but not in Chinese subjects. The objective of this study was to evaluate the pharmacokinetics, safety, and tolerability of oral lurasidone in healthy Chinese subjects. This single-center, randomized, parallel-group, placebo-controlled, and double-blind study evaluated the pharmacokinetics, safety, and tolerability of oral lurasidone administered as a single dose (20, 40, and 80 mg) and multiple doses for 5 days (40 mg administered once daily) in healthy Chinese subjects. Serum lurasidone and its metabolites were quantified using high-performance liquid chromatography–mass spectrometry. Pharmacokinetic parameters for lurasidone and its metabolites were calculated using non-compartmental analysis of WinNonlin® version 6.2. Safety analyses were recorded using physical examinations, vital signs, electrocardiogram, and clinical laboratory tests. Serum concentrations of lurasidone reached maximum concentration (C max) within 1.0–3.0 h after each single dose, and then decreased biphasically, with a mean half-life (t ½) from 18.1 to 25.5 h over the dose range of 20–80 mg. The area under the concentration–time curve (AUC) and C max values increased approximately dose proportionally. Lurasidone steady state was achieved after 5 days of daily dosing and the accumulation index of the AUC during a dosage interval (AUCτ) was 1.25, smaller than theoretical cumulative coefficient (1.76). Similar results were observed for the metabolites (ID-14283, ID-14326, and ID-11614). No severe adverse events (AEs) were observed in the single- or multiple-dose studies and no subject discontinued from the study due to AEs. The most common reported AEs were somnolence, increased blood prolactin, and restlessness, with a higher rate as dose increased. Lurasidone was safe and well-tolerated in healthy Chinese subjects, following single doses in the range of 20 to 80 mg and multiple doses of 40 mg/day for 5 days. Linear increase in lurasidone C max and AUC values were seen following single doses from 20 to 80 mg. There was no unexpected accumulation after multiple administrations of lurasidone at 40 mg/day, and the pharmacokinetic characteristics were consistent with the conclusion obtained in the previous studies. Trial Registration: Clinicaltrials.gov identifiers NCT02174510 and NCT02174523. more...

Ulinastatin, is a broad-spectrum protease inhibitor purified from human urine, inhibits endogenous proteases such as trypsin, α-chymotrypsin, hyaluronidase, and plasmin. It is widely being used at increasingly higher doses for the treatment of acute or chronic pancreatitis, severe infection, and acute organ failure. We aimed to evaluate the safety and tolerability of high-dose ulinastatin in healthy volunteers in our single center, randomized, double-blind, placebo-controlled, single-dose escalation study. Fifty-one healthy Chinese subjects were enrolled in 9 dose cohorts (3×105 U, 6×105 U, 12×105 U, 20×105 U, 30×105 U, 45×105 U, 60×105 U, 70×105 U, or 80×105 U of ulinastatin) and randomized to UTI or matching placebo (n = 1). Each dose cohort was composed of 3–7 subjects. All subjects were required to have 2 h of intravenous infusion. Safety and tolerability were assessed throughout the study via monitoring of vital signs, physical examinations, clinical laboratory tests, 12-lead electrocardiograms, and interviews with the subjects about adverse events. Fifty-one subjects (35 men and 16 women) completed the study. A total of 13 AEs were reported by 10 subjects: 11 adverse events in the ulinastatin groups and 2 adverse events in the placebo group. Twelve of the adverse events were possibly related to the study drug. The most common drug-related adverse events included dizziness, pain at injection site, and a decrease in white blood cell count. All adverse events were of mild severity; none were serious. In conclusion, 2 hours of intravenous infusion of ulinastatin (3×105 to 80×105 U) was well tolerated by healthy Chinese subjects. more...

Dehydroandrographolide succinate (DAS) is extracted from herbal medicine Andrographis paniculata (Burm f) Nees. DAS injection is used in China for the treatment of viral pneumonia and upper respiratory tract infections. The aim of this study is to investigate the pharmacokinetics and tolerance of DAS injection in healthy Chinese volunteers.This was a single-center, randomized, single-dose, three-way crossover design study. Nine eligible subjects were randomly divided into 3 groups, and each group sequentially received 80, 160, or 320 mg of DAS infusion according to a three-way Latin square design. Plasma and urine samples were collected and determined using an LC-MS/MS method. Safety and tolerability were determined via clinical evaluation and adverse event monitoring.For the 80, 160, and 320 mg dose groups, the mean C(max) were 4.82, 12.85, and 26.90 mg/L, respectively, and the mean AUC(0-12) were 6.18, 16.95, and 40.65 mg·L(-1)·h, respectively. DAS was rapidly cleared, with a mean T(max) of 0.94-1.0 h and a t(1/2) of approximately 1.51-1.89 h. Approximately 10.1%-15.5% of the intravenous DAS dose was excreted unchanged in urine within 24 h in the 3 groups, and more than 90% of unchanged DAS was excreted between 0 and 4 h. The pharmacokinetic profile was similar between male and female subjects. No serious or unexpected adverse events were found during the study, but one mild adverse event (stomachache) was reported.This study shows that DAS has nonlinear pharmacokinetic characteristics. To guarantee the effective concentration, mul¬tiple small doses are recommended in clinical regimens. more...