OBJECTIVE To establish the quality risk management mode based on failure mode and effect analysis (FMEA),and explore the application effect in the collinear production of external solution preparations. METHODS FMEA was performed on each link during the whole process of collinear production of external solution preparations. The high and medium risk failure modes were identified according to risk priority number (RPN), and failure causes were analyzed for formulating and implementing improvement measures. The risk level and the continuous verification effect of cleaning verification were evaluated before and after the implementation of control measures, the incidence of equipment failure, the qualified rate of first clearance, the rate of quality control compliance and the frequency of deviation treatment before and after the application of quality risk management mode were compared, and the improvement effect was examined. RESULTS A total of 21 failure modes were identified in the whole process of collinear production, of which 4 were high-risk, 11 were medium-risk and 6 were low-risk. The 15 items of medium and high risk failure modes were downgraded to low risk, and all cleaning verification indicators are controlled within the limits by continuous improvement of pollution and cross-contamination control measures, continuous supervision and research of collinear production risk control measures, continuous confirmation of equipment cleaning effect and other measures. Moreover, after the implementation of quality risk management mode, the incidence of equipment failure and the frequency of deviation treatment were reduced markedly, and the qualified rate of the first clearance and the quality control compliance rate were significantly increased, and the differences were statistically significant (P<0.05). CONCLUSION Applying the quality risk management model in the whole process of collinear preparation production can effectively reduce the risk of confusion, contamination and cross contamination, ensure the quality of collinear preparation products, and improve the operation level of the quality management system.

OBJECTIVE To prepare hydrogels containing antimicrobial peptide PMAP-24KK and evaluate antibacterial activity. METHODS The antimicrobial peptide PMAP-24KK was combined with sodium alginate, calcium carbonate, and gluconic acid-δ-lactone to form the PMAP-24KK hydrogel. Firstly, the formation time, swelling rate, moisture content, water retention rate, and release rate of PMAP-24KK hydrogel were analyzed. Then, the effect of PMAP-24KK hydrogel on the antibacterial activity in vitro, the sustained release, and the antibacterial barrier were determined by drug sensitivity test and skin wound healing in mice was analyzed. RESULTS The results showed that the PMAP-24KK hydrogel could form a gel state with network structure in about 2 min, and the swelling rate and moisture content reached equilibrium at 10 h, which were (158.83±3.26)% and (61.01±2.41)%, respectively. The water retention rate and release rate were about 55% and 81% after 24 h, respectively. The PMAP-24KK hydrogel showed the inhibitory effect on Staphylococcus aureus, Listeria monocytogenes, Salmonella choleraesuis, and Salmonella typhimurium. The sustained-release activity of PMAP-24KK hydrogel had no significant difference in 18 h, and gradually decreased after 18 h to 36 h without antibacterial activity. The PMAP-24KK hydrogel can effectively act as an antibacterial barrier and contribute to wound healing in mouse wound model. CONCLUSION Antimicrobial peptide PMAP-24KK hydrogel with good physicochemical properties and antibacterial activity is successfully prepared in this study, and it has good sustained-release and antibacterial barrier and promote wound healing, the study laid a foundation for further application research of antimicrobial peptide hydrogel.

OBJECTIVE To observe the effects of curcumin on the gastric tissue morphology and inflammatory microenvironment in mice with gastric epithelia dysplasia (GED), and to evaluate the preventive and therapeutic effects of curcumin on GED. METHODS Normal control group, model group, low, medium, and high dose groups of curcumin, and positive control group were set up. Except for the normal control group, all other groups were induced to establish GED animal models using a compound factor modeling method. After 8 weeks of modeling, the low, medium, and high dose groups of curcumin and the positive control group were respectively given curcumin at doses of 38, 75, 150 mg·kg^-1 and vitacoenzyme 350 mg/kg for intervention, continued for 8 weeks. At the end of the experiment, the gastric levels of pepsinogen PGⅠ, IFN-γ, IL-1β, IL-6, and the relative expression levels of p-JAK2, p-STAT3, Cyclin D1 in each experimental group were detected. HE staining and PCNA antibody immunohistochemistry were performed to observe the gastric mucosal tissue morphology and cell proliferation in each group. The pathological scores of GED and inflammatory cell infiltration were evaluated, and the proliferation index (PI) was calculated. RESULTS Compared with the normal control group, the serum concentration of PGⅠ in mice in the model group decreased, while the levels of IL-1β, IFN-γ, and IL-6 in gastric tissue increased (P<0.05). The scores of GED and gastric mucosal inflammatory cell infiltration, as well as the proliferation index (PI), all increased (P<0.01). Histopathological observations revealed changes such as epithelial dysplasia and inflammatory cell infiltration in the gastric mucosa, enhanced cell proliferation activity, and upregulation of p-JAK2, p-STAT3, and Cyclin D1 expression (P<0.05). Compared with the model group, the medium and high dose groups of curcumin showed an increase in serum PG1 concentration, a decrease in the inflammatory factors IFN-γ and IL-6 levels in gastric tissue (P<0.05), a decrease in GED and gastric mucosal inflammatory cell infiltration scores, as well as PI (P<0.05 or 0.01). The curcumin treatment alleviated gastric mucosal dysplasia and inflammatory cell infiltration, inhibited cell proliferation activity, and downregulated the expression of p-JAK2, p-STAT3, and Cyclin D1 (P<0.05). In the low dose group of curcumin, the expression of p-JAK2 protein was downregulated, and in the high dose group, IL-1β decreased (P<0.05). CONCLUSION Curcumin has a preventive and alleviating effect on the epithelial dysplasia of the gastric mucosa in mice, and can improve the tissue morphology of the gastric mucosa in GED mice. Its mechanism of action may be related to the downregulation of the JAK2/STAT3/Cyclin D1 pathway signaling, inhibiting excessive cell proliferation.

OBJECTIVE To identify and evaluate the risk signals of tislelizumab in non-small-cell lung cancer (NSCLC) patients, so as to provide basis for future management of irAEs and better tumor immunotherapy in NSCLC patients. METHODS The clinical data of NSCLC patients who received tislelizumab in Peking University People's Hospital from April 2021 to April 2023 were retrospectively analyzed. The occurrence of irAEs during tislelizumab treatment was observed, the incidence of irAEs was summarized, and the clinical features of irAEs and non-irAEs groups were compared. RESULTS Sixty-eight NSCLC patients received tislelizumab, of whom 22 (32.35%) developed 32 irAEs. The main manifestations were pulmonary toxicity (17.65%), skin toxicity (11.76%), endocrine toxicity (5.88%), gastrointestinal toxicity (4.41%), cardiovascular toxicity (4.41%), and hematological toxicity (2.94%). The median duration of irAEs was 79 d (1-706 d). Thirteen cases (59.09%) were treated with glucocorticoids. Comparison of the clinical characteristics of irAEs group and non-irAEs group showed that the incidence of irAEs in patients with hepatic insufficiency was higher (P<0.05), the other differences were not statistically significant (P>0.05). CONCLUSION irAEs involve multiple systems/organs, so attention should be paid to the management of immune-related toxicity, timely detection, and treatment of irAEs, to achieve better effects of tumor immunotherapy.

Active ingredients in Chinese medicine have great potential to be used in breast cancer treatment to improve the efficacy of existing breast cancer treatment strategies. By influencing different signaling pathways to produce different mechanisms of action, active ingredients in Chinese medicine enhance the sensitivity of tumor cells to the effects of chemical, hormonal or gene therapeutic agents, reduce toxic side effects or inhibit the efflux of anticancer drugs. In this paper, it is reviewed the strategies for the combination of Chinese herbal active ingredients with other breast cancer therapeutic agents, such as chemotherapeutic agents, hormones, gene agents, small molecule inhibitors and inorganic mixtures, and intelligently design nano-delivery systems to co-deliver Chinese herbal active ingredients and other breast cancer therapeutic agents for the synergistic treatment of breast cancer. Nanocarriers offer various advantages including improved solubility, increased stability and enhanced tumor targeting, thus overcoming the clinical application limitations of the active ingredients of TCM.

OBJECTIVE To analyze the key contents of paediatric regulation in the European Union (EU) and identify the characteristics of the European regulation for paediatric medicines. METHODS A literature review was conducted to analyze the EU paediatric regulation, relevant guidance documents and published literatures. RESULTS The EU has established the paediatric medicines committee, which is specifically responsible for issues related to the regulation of paediatric medicines. Moreover, the EU has systematically designed the regulation around four aspects including obligations, rewards and incentives, other initiatives for paediatric medicines research and information and transparency measures. CONCLUSION The EU attaches great importance to building a professional team for the regulation of paediatric medicines, focusing on both mandatory and incentives, and emphasizing the concepts of the whole life cycle of medicines and dynamic adjustments, which provide a comprehensive guarantee for promoting the development and availability of paediatric medicines. It deserves to be studied and learned from.

OBJECTIVE To discuss the occurrence and clinical characteristics of Kounis syndrome (KS) induced by antibacterial drugs containing sulbactam in order to provide references for clinical safety drug use. METHODS The case reports of KS induced by antibacterial drugs containing sulbactam were retrieved from PubMed, Embase, Cochrane Library, CNKI, Wanfang and VIP database from establishment of each database to October 2023. The relevant data were collected and analyzed. RESULTS A total of 11 cases from 11 articles were identified and included in the analysis. There were 7 males (63.6%) and 4 females (36.4%). The patients were aged from 44 to 89 years with an average age of (70.0±13.1) years old, and there were 9 patients aged 70 and above (81.8%). The drugs involved included cefoperazone sulbactam in 5 cases (45.5%), ampicillin sulbactam in 4 cases (36.4%) and piperacillin sulbactam in 2 cases (18.2%). The 81.8% of the patients developed acute anaphylaxis within 30 min after treatment and electrocardiogram indicated abnormal ST segment changes. Type Ⅰ, Ⅱ and Ⅲ KS were 8 cases (72.7%), 2 cases (18.2%) and 1 case (9.1%), respectively. After anti-allergic and anti-myocardial ischemia therapy, 10 patients (90.9%) had good prognosis, and 1 patient (9.1%) died of cardiogenic shock. CONCLUSION KS could be induced by a variety of antibacterial drugs containing sulbactam, especially in older patients and mostly within 30 min. KS should be highly suspected once acute anaphylaxis accompanied by abnormal changes in electrocardiogram. Timely withdrawal of medication and targeted treatment according to KS types are the key to improve the prognosis of patients.

OBJECTIVE To synthesize phytanetriol by epoxidation/ring-opening reaction under catalyst-free conditions using phytol as raw material, low concentration of hydrogen peroxide as oxidant, and formic acid as oxygen carrier. METHODS The effects of the molar ratios of formic acid and hydrogen peroxide to phytol, reaction temperature, and reaction time on the yield of phytanetriol were investigated using a single-factor test and verified by 3-batch reproducibility. The chromatographic purity and structure of phytanetriol were analyzed by gas-mass spectrometry, infrared spectroscopy, and nuclear magnetic resonance spectrometry. RESULTS The optimal conditions for the epoxidation reaction system were n(HCOOH):n(H₂O₂):n(phytol)=5∶1.3∶1, temperature 55 ℃, and reaction time 2 h. The optimal conditions for the ring-opening reaction system were pH=13, temperature 105 ℃, and reaction time 0.5 h. The phytanetriol synthesis process had a yield of 86.6% in the validated experiments. The chromatographic purity was 94.6%. CONCLUSION The synthesis process is stable and can produce phytanetriol with controllable quality and better purity than commercially available products.

OBJECTIVE To establish a method for bacterial endotoxin test of active pharmaceutical ingredient (API) of insoluble adrenaline. METHODS According to the bacterial endotoxin test (BET) method in the general rule 1143 in the Chinese Pharmacopoeia (2020 Edition, Volume Ⅳ), adrenaline API was dissolved with hydrochloric acid and diluted with BET water. The gel method and kinetic turbidimetric assay were used to carry out interference test and endotoxin recovery interference verification test. RESULTS Adrenaline API was dissolved with 0.1 mol·L^-1 hydrochloric acid to 10 mg·mL^-1, and then diluted 200 times or more by BET water, which had no interference effects to bacterial endotoxin test. CONCLUSION The BET method established in this study can be used for the bacterial endotoxin test of adrenaline API of adrenaline to control the product quality.

OBJECTIVE To investigate the penetration effect of solid microneedle in vivo and in vitro, the model drug ketoprofen was administered in the form of a patch. METHODS Using a rat skin penetration test, the effects of microneedle length, pre-treatment pressure, pre-treatment time, and types of needle on the penetration enhancement of ketoprofen in vitro were investigated. The pharmacokinetic characteristics of ketoprofen patches applied to the back of rats after different microneedle treatments were investigated, as well as the effect of the ketoprofen patch on promoting permeability in vivo. RESULTS In vitro, skin permeation tests revealed that after microneedle pretreatment, the permeation rate and permeation volume of the patch were significantly increased (P<0.05) and the permeation time lag was significantly shortened (P<0.05) after microneedle pretreatment, while the permeation promotion effect was related to the pressure, time, microneedle length and type of microneedle pretreatment. After microneedle pretreatment of the skin (pressure: 1-7 N, time: 1-5 min, microneedle length: 200 μm-300 μm), the cumulative permeation amount of the experimental drug for 24 hours increased by 1.16-3.09 times, and the permeation delay decreases by 0.20-2.50 h. As the results of in vivo pharmacokinetic in rats, ρ_max (10.86±0.80) μg·mL^-1 and AUC_0→t (108.10±17.06) μg·h·mL^-1 after 300 μm roller microneedle pretreatment of the skin, which were significantly greater than the control ρ_max (0.42±0.03) μg·mL^-1 and AUC_0→t (7.46±0.98) μg·h·mL^-1(P<0.05). ρ_max and AUC_0→t were increased by 25.9 times and 15 times. CONCLUSION Solid microneedle pretreatment of skin significantly improves in vitro penetration and in vivo skin absorption of ketoprofen patches through rat skin, with a more significant promotion effect in vivo penetration.