Search

You Zhai,1,2 Lihua Wu,1,2 Yunliang Zheng,1,2 Minglan Wu,1,2 Yujie Huang,1,2 Qian Huang,1,2 Jianzhong Shentu,1– 3 Qingwei Zhao,1,2 Jian Liu1,2 1Research Center for Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 2Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 3College of Medicine, Zhejiang University, Hangzhou, People’s Republic of ChinaCorrespondence: Jian LiuResearch Center for Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, People’s Republic of ChinaTel +86 571 87236537Fax +86 571 87214223Email lindaliu87@zju.edu.cnPurpose: This study compares the pharmacokinetic and safety profiles between a new generic and a branded reference formulation of amitriptyline hydrochloride tablets, and assesses the bioequivalence of the two products in healthy Chinese volunteers to obtain sufficient evidence for the marketing approval of the generic drug.Materials and Methods: A randomized, open-label, two-period crossover study (clinicaltrials.gov, NCT03646526) was conducted under both fasting and fed conditions in healthy Chinese volunteers (24 subjects/condition). Eligible subjects randomly received a single 25 mg dose of either the test or the reference formulation, followed by a 3-week washout period. Blood samples were collected until 144 h following administration. The pharmacokinetic parameters were acquired based on the concentration-time profiles, including the areas under the plasma concentration-time curve (AUC0-t, AUC0-∞), the peak plasma concentration (Cmax), the time to achieve Cmax (Tmax), and the elimination half-life (t1/2). The geometric mean ratios (GMRs) and the corresponding 90% confidence intervals (CIs) of amitriptyline were acquired for bioequivalence analysis, and values of these parameters for nortriptyline were used for comparison of therapeutic outcomes. Safety assessments included laboratory tests, physical examination, vital signs, and incidence of adverse events (AEs).Results: The values of t1/2 and Tmax for amitriptyline were not significantly different between the test and reference products under both fasting and fed conditions (P > 0.05). The GMRs of Cmax, AUC0–t, and AUC0-∞ between the two products, and corresponding 90% CIs, were all within the range of 80% to 125% under both fasting and fed conditions. The test and reference products were well tolerated and did not elicit serious adverse events.Conclusion: This study demonstrated that the generic and reference products were well tolerated by the subjects and bioequivalent, according to the rate and extent of the drug absorption.Keywords: bioequivalence, pharmacokinetics, amitriptyline hydrochloride, nortriptyline

Jian Liu,1,2 You Zhai,1,2 Lihua Wu,1,2 Guolan Wu,1,2 Yunliang Zheng,1,2 Xingjiang Hu,1,2 Jianzhong Shentu1– 3 1Research Center for Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 2Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 3College of Medicine, Zhejiang University, Hangzhou, People’s Republic of ChinaCorrespondence: Jianzhong ShentuResearch Center for Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, People’s Republic of ChinaTel +86 571 87236560Fax +86 571 87214223Email stjz@zju.edu.cnBackground: Cefotetan is highly stable to penicillinase and cephalosporin produced by gram-negative bacteria, and it has strong antimicrobial activity against most gram-negative bacteria, some anaerobic bacteria and streptococcus. The objective of this study was to evaluate the pharmacokinetic profile and tolerability of single and multiple intravenous doses of cefotetan disodium in healthy Chinese volunteers.Methods: In this single-center, open-label, dose-escalating study, subjects were randomized to receive a single dose of cefotetan disodium 0.5, 1.0, or 2.0 g administered as a 1 h intravenous infusion. After completion of the single-dose phase, subjects continued into the multiple-dose phase, in which they received 1.0 g cefotetan disodium BID for 7 consecutive days. Plasma samples were assayed by a validated high-performance liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were calculated and analyzed statistically. Tolerability was assessed based on physical examinations, vital signs, laboratory tests, and subject interviews.Results: After intravenous administration of single doses of 0.5, 1.0, and 2.0 g cefotetan disodium, the pharmacokinetics of cefotetan were as follows: Cmax was 69.49± 12.10 μg·mL− 1, 132.03± 22.56 μg·mL− 1 and 237.75± 42.12 μg·mL− 1, respectively; AUClast was 278.29± 51.13 μg·mL− 1·h, 543.25± 92.44 μg·mL− 1·h and 1003.8± 172.39 μg·mL− 1·h, respectively; AUC∞ was 284.42± 50.76 μg·mL− 1·h, 551.38± 95.83 μg·mL− 1·h and 1020.18± 181.19 μg·mL− 1·h, respectively; t1/2 was 4.21± 0.83 h, 4.39± 0.53 h and 4.27± 0.74 h, respectively; CL was 1.81± 0.33 L·h− 1, 1.86± 0.32 L·h− 1 and 2.02± 0.38 L·h− 1, respectively; Vd was 10.80± 1.89L, 11.78± 2.20L and 12.25± 1.99L, respectively. In the multiple-dose study, the pharmacokinetics of cefotetan were as follows: Cmax,ss was 147.58± 22.71 μg·mL− 1; Cmin,ss was 12.92± 3.70 μg·mL− 1; Cavg was 45.10± 7.78 μg·mL− 1; AUCτ,ss was 541.15± 93.36 μg·mL− 1·h; AUC∞ was 612.06± 114.23 μg·mL− 1·h; t1/2 was 4.30± 0.63 h; CL was 1.90± 0.35L·h− 1; Vd was 8.91± 1.57L; DF was 300.92± 33.28%; Accumulation Index was 1.17± 0.05. No serious adverse events were reported. Adverse events were generally mild.Conclusion: Cefotetan disodium showed favorable tolerability in this study. The Cmax and AUCs of cefotetan disodium demonstrated dose-dependent pharmacokinetic characteristics after single dose over a dose range (0.5– 2.0 g) in healthy subjects, whereas the t1/2 was independent of dose. Except for Vd, there was no difference in other pharmacokinetic parameters between multiple and single administration.Keywords: cefotetan disodium, pharmacokinetics, healthy volunteers, plasma, single-dose, multiple-dose

Chimeric antigen receptor (CAR)-armed cell therapy has developed rapidly in recent years, especially in the treatment of leukemia. However, the treatment methods for solid tumors represented by glioma have not achieved the ideal therapeutic effect. This situation necessitates learning from chimeric antigen receptor T cell (CAR-T) treatment in other malignancies and discovering the differences between gliomas and other solid tumors. The current design idea is to enhance the targeting, regulatory effects, and adaptation of CAR-armed cells. This review traced not only clinical trials, but also several animal experiments, which might promote the development of CAR-T treatment in glioma. Furthermore, we have discussed the obstacles to CAR-T in the treatment of glioma and the current possible solutions.

Guan-Zhang Li,1,* Ke-Nan Zhang,1,* Zheng Wang,2 Hui-Min Hu,1 Zhi-Liang Wang,1 Ruo-Yu Huang,1 Hao-Yu Jiang,2 You Zhai,1 Yue-Mei Feng,1 Yuan-Hao Chang,1 Ren-Peng Li,2 Fan Wu,1 Fan Zeng,1 Tao Jiang,1–4 Wei Zhang2 1Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, People’s Republic of China; 2Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, People’s Republic of China; 3Center of Brain Tumor, Beijing Institute for Brain Disorders, Beijing 100070, People’s Republic of China; 4China National Clinical Research Center for Neurological Diseases, Beijing 100070, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei Zhang; Tao JiangDepartment of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, No. 119 South Fourth Ring Road West, Fengtai District, Beijing, People’s Republic of ChinaTel +86 180 1021 2611Email zhangwei_vincent@126.com; taojiang1964@163.comBackground: Inhibitors of immune checkpoints have shown little effect in clinical trials involving glioma patients. Here, we explored novel targets for use in future treatments. Previous studies showed the sialic acid-binding Ig-like lectin (Siglec) family to have a specific role in immunosuppression. We aimed to study the characteristics and immune function of Siglec family members.Methods: Transcriptome data from 1024 glioma samples and 1551 glioma single cells were used in our study. Clinical and molecular pathology information was also included. Statistical, bioinformatical methods, and single-cell sequencing analysis were applied to investigate the role of Siglec family members.Results: Siglecs-5, −7, −9, and −16 showed a significant correlation with immunosuppression in glioma. They are typically expressed in higher grade, IDH-wildtype, and mesenchymal subtype gliomas. Siglec-5, −7, and −9 had a similar immune function to TIM-3, while Siglec-16 was similar to PD-L1, suppressing tumor immunity via different mechanisms. Joint use of Siglec-inhibitors and immune checkpoint inhibitors could prolong the survival of glioma patients.Conclusion: Siglec-5, −7, −9, and −16 suppressed tumor immunity in different ways. Joint usage of inhibitors may be an effective means to improve the efficacy of glioma immunotherapy.Keywords: glioma, Siglec family, immunotherapy, single-cell sequencing analysis, prognosis

An effective geometrical method which can locate a source based on the time-of-arrival (TOA) measurements and the floor plan information is proposed in simple non-line-of-sight (NLOS) indoor environment where the multiple-bound scattering signal paths can be ignored. The novelty of our work resides in converting the NLOS problem into line-of-sight (LOS) problem based on the virtual stations (VSs), so that the localization algorithm for LOS conditions can be applied in simple NLOS conditions. The performance bound of the proposed method is also analyzed. Simulation results demonstrate the effectiveness of the proposed method.

Epidermal growth factor receptor (EGFR) and its ligands amphiregulin (AREG) and epiregulin (EREG) play a central role in the development of colorectal cancer, but the prognostic values of AREG and EREG are controversial. We conducted a meta-analysis of studies that investigated AREG and/or EREG mRNA levels in primary tumors to determine their prognostic value in metastatic colorectal cancer (mCRC). In addition, RAS status was assessed. Relevant articles were identified by searching the EMBASE, PubMed, and Cochrane Library databases. Hazard ratios (HR) with 95% confidence intervals (CIs) were calculated using a random-effects model. Nine studies involving 2167 patients were included in this meta-analysis. High AREG expression was associated with longer overall survival (OS) and progression-free survival (PFS). High EREG expression was also associated with prolonged OS and PFS. In RAS wild-type (WT) patients who received anti-EGFR therapy, high AREG and EREG expression was associated with longer OS. Our results indicate that high AREG and EREG mRNA expression are independent favorable prognostic biomarkers in mCRC. The expression of these ligands should be considered when evaluating prognoses in RAS-WT patients receiving anti-EGFR therapy.