OBJECTIVE To provide scientific basis for establishing the evaluation index system of professional and specialized drug inspectors in China. METHODS Through the method of literature research， group discussions and behavioral event interview， combined with the practice situation of drug inspection at home and abroad， in accordance with the requirements of Chinese laws and regulations and department rules， the evaluation indexes for drug inspectors were extracted and screened. In addition， the Delphi method was used to conduct correspondence with experts in relevant fields so as to determine the evaluation index system of drug inspectors. RESULTS & CONCLUSIONS Finally， 62 experts completed two rounds of anonymous online questionnaires， including 29 experts in the first round and 33 experts in the second round. The questionnaire recovery rates were 96.67% and 94.29% respectively， and the expert authority coefficients were 0.81 and 0.79， indicating a high level of authority among experts. After expert consultation， evaluation index system for professional and specialized drug inspectors had been constructed， including five first-level indexes （personal characteristics， professional knowledge， professional skills， professional behavior and professional ethics） and their corresponding 27 second-level indexes. The average score of the importance of second-level indexes was 4.224- 4.879， the full score ratio was 81.8%-100%， the coefficient of variation was 0.067-0.177， and Kendall’s W was 0.643 （P＜0.001）. It indicates that this evaluation index system is relatively reliable and is expected to become a management tool for promoting the construction of professional and specialized drug inspector team and ensuring the quality of drug inspection.

Abstract As a non-invasive drug delivery method, nasal drug delivery has many advantages, such as rapid onset, easy use, high compliance, no first pass effect, fewer adverse reactions, mucosal immunity, and provides a new convenient route to deliver drugs to the brain through nose-to-brain delivery. Nasal formulations are increasingly becoming a research and development hotspot, focusing on addressing unmet clinical needs. However, due to the special structure and physiology of the nasal cavity, there are still many challenges in the development and evaluation of nasal preparations.

Abstract OBJECTIVE To introduce the scientific progress in the regulation of nasal preparations by the US Food and Drug Administration(FDA), and provide reference and inspiration for the development, manufacture, quality control and supervision of nasal preparations in China. METHODS Regulations and literature relevant to the nasal preparations were translated and collated, and research projects and latest developments of FDA regulatory science were introduced. The difficulties encountered in the development of nasal preparations and the future development direction were analyzed. RESULTS The main directions of FDA nasal regulatory science were to evaluate potential bioequivalence(BE) methods as an alternative to comparative clinical endpoint BE studies, to employ digital technology to establish computer models, to study the factors influencing nasal absorption, pharmacokinetics and pharmacodynamics characteristics, as well as pediatric drug use studies, nasal-brain delivery, and to develop new tools, new methods, and new standards. It provided a scientific basis for optimizing regulatory strategy and improving regulatory efficiency. CONCLUSION This article summarizes the latest research on the regulatory science of nasal preparation, provides a reference for the management personnel of regulatory agencies, and provides new ideas and new methods for improving the quality and efficiency of China's drug regulation and realizing international standards.

Abstract This paper focuses on the regulatory strategy of drug-led drug device combination products, comparing and analyzing the definition, scope and management mode of drug device combination products in the United States, the European Union, Japan, Canada and China; summarizing and analyzing the types of combination products in the Product-specific Guidances for Generic Drug Development(PSGs) of the US FDA's scientific and technical reports in the past five years, the results show that the top three PSGs newly added to the FDA were transdermal system, nasal sprays, and single-dose prefilled syringes/pens(including auto-injectors). As of March 1, 2023, the National Medical Products Administration(NMPA) had cumulatively announced the results of 339 combination products applied for attribute definition by enterprises, of which 88 were "drug-led drug device combination products", accounting for 26%; and 78 were "device-led drug device combination products", accounting for 23%; the results of "not belonging to drug device combination products" accounted for more than half (51.0%), which indicated that there was a big difference between the industry and the regulatory understanding of the definition of drug-device combination products, and that the existing guideline and documents were unable to provide clear and predictable positioning of the combination products under research and development for the time being. This paper also puts forward suggestions for solving the problems in the development of drug-device combination products in China, in order to improve the consistency, predictability and transparency of the classification and definition of drug-device combination products in China, and to provide references for the development and scientific supervision of this kind of products.

OBJECTIVE To systematically review the background of bioequivalence assessment of nasal sprays and nasal aerosols and the guiding considerations for the bioequivalence assessment of these complex drug-device combination products by regulatory authorities in the United States, the European Union(EU) and China. METHODS This article provided detailed explanations on the innovative weight of evidence assessment approach adopted by the US Food and Drug Administration(FDA), and the statistical rationale, methods and considerations for the bioequivalence assessment of nasal sprays and nasal aerosols. Using the calculation methods described in the draft guidance for budesonide inhalation suspension and the draft guidance for fluticasone nasal spray propionate issued by FDA, the statistical parameters of two-sided and one-sided population bioequivalence calculation were realized through R language programming, and pseudo-code for the population bioequivalence (PBE) calculation programs was provided. This article also presented a comprehensive review of published guidelines and summaries review principles of the EU and China for nasal sprays and nasal aerosols equivalence assessment. RESULTS & CONCLUSION Nasal sprays/nasal aerosols is the focus of innovative and generic drug development in recent years. This paper provided valuable considerations references for the research and development, quality control and bioequivalence evaluation of generic preparations of nasal sprays/nasal aerosols.

Objective:To evaluate the role of miR-188-5p in oxygen-glucose deprivation and restoration (OGD/R) injury to mouse neuroblastoma (N2a) cells and its relationship with small ubiquitin-like modifier-specific proteases 3 (SENP3).Methods:N2a cells were cultured and divided into 5 groups ( n=23 each) using a random number table method: control group (group C), OGD/R group, group NC, transfection of mir-188-5p agonist group (group M) and transfection of mir-188-5p inhibitor group group (group I). Cells in group C were cultured routinely.Cells in group NC, group M and group I were transfected with mir-188-5p negative control miRNA, agonist and inhibitor, respectively.N2a cells were subjected to OGD for 3 h followed by restoration of oxygen-glucose supply to establish the model of OGD/R injury.At 24 h of oxygen-glucose restoration, the cell viability was recorded by the cell counting kit-8 assay, the amount of lactic dehydrogenase (LDH) released was detected, the expression of miR-188-5p and SENP3 mRNA was detected by quantitative real-time polymerase chain reaction, and SENP3 expression was determined by Western blot.The targeting relationship between miR-188-5p and SENP3 mRNA was detected using dual luciferase reporter assay. Results:Compared with group C, the cell viability was significantly decreased, amount of LDH released was increased, and expression of SENP3 and its mRNA was up-regulated in the other 4 groups, miR-188-5p expression was down-regulated in OGD/R and I groups, and miR-188-5p expression was up-regulated in group M ( P<0.05 or 0.01). Compared with group OGD/R, the cell viability was significantly decreased, amount of LDH released was increased, and expression of SENP3 and its mRNA was up-regulated, and miR-188-5p expression was down-regulated in group I, and the cell viability was increased, amount of LDH released was decreased, expression of SENP3 and its mRNA was down-regulated, and miR-188-5p expression was up-regulated in group M ( P<0.05 or 0.01). The dual luciferase reporter assay showed that miR-188-5p could act directly on SENP3. Conclusion:miR-188-5p is involved in OGD/R injury, which is associated with targeted down-regulation of SENP3 expression in N2a cells.

Drug-drug interactions (DDI) change dose-response relationships, and may result in low efficacy or high toxicity, which are important considerations especially in medical practice with multiple-drug therapies. Predicting clinically significant drug interactions during new drug development is an important part of benefit and risk assessment in drug development and review. This article summarizes the purpose and significance of drug interactions in new drug development, the main content and precautions of DDI studies in vivo and in vitro. Drug interaction studies on novel drug approvals for 2020 in the National Medical Products Administration (NMPA) and US Food and Drug Administration (USFDA) are examined, respectively. It aims to provide reference for DDI studies and regulatory reviews in new drug development in our country.

Objective:To compare the post-operative outcomes between extended lateral approach and L-shaped lateral approach in surgical treatment of Sanders type III intra-articular calcaneal fractures.Methods:A retrospective case-control study was made on clinical data of 34 patients with fresh Sanders type III intra-articular calcaneal fractures hospitalized in Langfang Hospital of Traditional Chinese Medicine from October 2014 to October 2017. There were 33 males and 1 female, with the age of 18-56 years [(42.5±9.4)years]. All fractures were fresh. Seventeen patients were fixed by the extended lateral approach (extended approach group) and seventeen patients by L-shaped lateral approach (L-shaped approach group). Operation duration, intraoperative bleeding volume, length of hospital stay, one-stage wound healing rate and complication rate were observed. B?hler and Gissane angle were measured before operation, one week after operation and 12 months after operation. American Orthopedic Foot and Ankle Society (AOFAS) ankle-hindfoot scale was applied to evaluate function recovery.Results:There were no significant differences between groups in operative time and intraoperative bleeding volume ( P>0.05). There were significant differences between extended approach group and L-shaped approach group in length of hospital stay [(15.7±4.0)days vs.(22.4±9.6)days], one-stage wound healing rate [88%(15/17) vs. 47%(8/12)] and postoperative complication rate [12%(2/17) vs. 47%(8/17)] ( P<0.05). The B?hler and Gissane angles did not differ significantly between groups before operation and one week and 12 months after operation ( P>0.05). At postoperative 12 months, the B?hler and Gissane angles were improved from preoperative (8.2±6.0)°, (85.3±10.5)° to (23.9±6.1)° and (119.3±6.2)° respectively in extended approach group, and those from preoperative (9.4±3.9)°, (85.5±7.1)° to (25.8±3.7)° and (122.2±5.6)° respectively in L-shaped approach group (all P>0.05). At 12 months after operation, the AOFAS score was (86.9±7.5)points in extended approach group, with the excellent and good rate of 88%; and was (83.3±12.5)points in L-shaped approach group, with the excellent and good rate of 76% ( P>0.05). While the score of hindfoot joint activity in extended approach group was (5.8±0.7)points, significantly higher than (3.4±1.0)points in L-shaped approach group ( P<0.05). Conclusion:For Sanders III intraarticular calcaneal fractures, compared with L-shaped approach group, plate fixation via extended approach can promote fracture healing, shorten hospital stay, reduce incidence of complications and facilitate function recovery of subtalar joint.

OBJECTIVETo investigate the synergistic effect between the N-terminus domain of the a2 isoform of vacuolar ATPase (a2NTD) and macrophage colony-stimulating factor (M-CSF) on modulating macrophage polarization and the impact of polarized macrophages on proliferation of gastric cancer cells.

METHODSPeripheral blood mononuclear cells were derived from healthy donor and induced into macrophages. Then macrophages were randomly divided into four groups: the control group (RPMI 1640), the experimental group I (M-CSF 100 μg/L), the experimental group II (a2NTD 500 μg/L) and the experimental group III (a2NTD 500 μg/L plus M-CSF 100 μg/L). After stimulation for 48 hours, double color immunofluorescence cytochemistry was adopted to detect the expression of cell membrane molecules on macrophages; ELISA was used to measure the secretion of cytokines IL-10 and IL-12; CCK-8 assay was used to evaluate the impact of macrophages on proliferation ability of gastric cancer cell strain SGC-7901.

RESULTSThe expression of CD68, also known as macrophage surface antigen, was detected on macrophage membrane in all four groups (+). The mean absorbance (A) was 0.092 ± 0.005 in control group, 0.095 ± 0.006 in group I, 0.094 ± 0.005 in group II, 0.094 ± 0.005 in group III, and no significant differences were observed among 4 groups (all P>0.05). Meanwhile, the expression of CD206, which mainly exists on M2 macrophage membrane, was hard to detect in control group (-) with A 0.025 ± 0.004; it was normal in groupI and group II (+) with A 0.191 ± 0.012 in group I and 0.197 ± 0.136 in group II (P=0.212), and it was up-regulated significantly in group III (+++) with A 0.285 ± 0.011. There were significant differences between either two groups except group I and group II (all P<0.01). Secretion of IL-10 in group I and group II [(85.65 ± 13.64) ng/L and (87.77 ± 14.25) ng/L] was significantly higher compared with control group [(71.67 ± 7.56) ng/L, P<0.01]. Secretion of IL-12 in group I and group II [(9.91 ± 1.50) ng/L and (10.15 ± 1.80) ng/L] was significantly lower compared with control group [(16.87 ± 1.10) ng/L, P<0.01]. Secretion of IL-10 in group III [(116.98 ± 14.27) ng/L] was the highest, and secretion of IL-12 [(5.31 ± 0.88) ng/L] was the lowest (all P<0.01). There was a synergistic effect between a2NTD and M-CSF on the secretion of both IL-10 and IL-12. Elevated proliferation of gastric cancer cell strain SGC-7901 was detected in all four groups, in which group III showed the greatest impact compared with other 3 groups (P<0.01).

CONCLUSIONSa2NTD and M-CSF show a synergistic effect in modulating macrophage phenotype and the secretion of IL-10 and IL-12. The polarized macrophage can significantly enhance proliferation of gastric cancer cell strain SGC-7901.

Cell Proliferation ; Humans ; Interleukin-10 ; metabolism ; Interleukin-12 ; metabolism ; Macrophage Colony-Stimulating Factor ; pharmacology ; Macrophages ; cytology ; Phenotype ; Stomach Neoplasms ; pathology ; Tumor Cells, Cultured ; Vacuolar Proton-Translocating ATPases ; pharmacology

Cardiovascular System ; drug effects ; Humans ; Hydrocarbons, Brominated ; toxicity ; Occupational Exposure ; adverse effects