Xanthine oxidase (XO) is an important therapeutic target for the treatment of hyperuricemia and gout. Based on the previously identified potent XO inhibitor 1, seventeen oxadiazoles and their ring-opening analogues were designed and synthesized via the bioisostere replacement strategy. Among them, compounds 2l, 2n, and 3b showed obvious XO inhibitory activity at the concentration of 10 μmol·L^-1, and compound 3b exhibited an IC₅₀ value of 1.45 μmol·L^-1.

Aim To analyze the anti-A549 and HI299 lung ade-nocarcinoma activities via using examples of baicalin, astragalo-side, hesperidin and cisplatin based on real time cellular analysis (RTCA) technology, and to build a new strategy for EC50 e-valuation reflecting the time-dimensional characteristic. Methods Using RTCA Software Pro for data analysis and GraphPad Prism and Origin Pro plotting, the in vitro anti-A549 and H1299 lung adenocarcinoma activities of baicalin, astragaloside, hesperidin, and cisplatin were characterized using the endpoint method and time dimension, respectively. Results (X) There were significant differences in EC50 values of A549 and H1299 cells at 24 h and 48 h endpoint methods. (2) The correlation coefficient of the curve fitted with the four-parameter equation was > 0. 9, and the dynamic change of EC50 remained relatively stable (the linear fitting of EC50 at adjacent 4 points I slope 1^1) used to calculate the EC50 value within this time dimension. The EC50 of baicalin, astragaloside, hesperidin and cisplatin on A549 cells was 52. 97 ±1.75 плпо! • L~1(16~48 h) , 62.88 ± 2.91 ijunol • L"1 (32.25 -48 h) , 78.84 ±0.33 плпо1 • L"1 (21.5 -29.75 h), 13.57 ±1.54 плпо1 • L_1(27.5 -48 h), respectively; the EC50 of baicalin, astragaloside, hesperidin and cisplatin on H1299 cells was 43. 71 ± 1. 26 |лто1 • L_1 ( 19. 5 -48 h), 47.23 ±1. 19 |лто1 • L_1(14 -48 h) , 39.45 ±0.24 плпо1 • L"1 (12.75 -46.25 h), 25.97 ±4.76 плпо1 • L"1 (10. 25 -48 h) , respectively. The results showed that the time window for the anti-tumor effect of the test solution/drug was different. Conclusions Based on RTCA technology, it is more accurate and reasonable to select EC50 data that exhibit better fitting, stable changes, and time-dimensional characteristics for the evaluation of anti-tumor activity. In addition, this method of distinguishing different effective time of antitumor drugs can provide a reference for the timing of clinical combination drugs, and this approach will also provide a reference for further related studies.

Objective To make an epidemiological investigation on traditional Chinese medicine(TCM)dampness syndrome manifestations in the population at risk of cerebrovascular diseases in Guangdong area.Methods A cross-sectional study was conducted to analyze the clinical data related to the risk of cerebrovascular diseases in 330 Guangdong permanent residents.The diagnosis of dampness syndrome,quantitative scoring of dampness syndrome and rating of the risk of stroke were performed for the investigation of the distribution pattern of dampness syndrome and its influencing factors.Results(1)A total of 306(92.73%)study subjects were diagnosed as dampness syndrome.The percentage of dampness syndrome in the risk group was 93.82%(258/275),which was slightly higher than that of the healthy group(48/55,87.27%),but the difference was not statistically significant(χ2 = 2.91,P = 0.112).The quantitative score of dampness syndrome in the risk group was higher than that of the healthy group,and the difference was statistically significance(Z =-2.24,P = 0.025).(2)Among the study subjects at risk of cerebrovascular disease,evaluation time(χ2 = 26.11,P = 0.001),stroke risk grading(χ2= 8.85,P = 0.031),and history of stroke or transient ischemic attack(TIA)(χ2 = 9.28,P = 0.015)were the factors influencing the grading of dampness syndrome in the population at risk of cerebrovascular disease.Conclusion Dampness syndrome is the common TCM syndrome in the population of Guangdong area.The manifestations of dampness syndrome are more obvious in the population with risk factors of cerebrovascular disease,especially in the population at high risk of stroke,and in the population with a history of stroke or TIA.The assessment and intervention of dampness syndrome should be taken into account for future project of stroke prevention in Guangdong.

Objective To observe the regulatory mechanism of drug-containing serum of Jinghou Zengzhi Prescription based on qi and blood replenishing method on the expression of growth and differentiation factor 9(GDF9)and apoptosis of ovarian granulosa cells in rats with controlled ovarian hyperstimulation(COH).Methods Serum of COH rats(blank serum)and serum of COH rats gavaged by the Jinghou Zengzhi Prescription were prepared.A COH rat model was established and ovarian granulosa cells were collected.The experiment was divided into 5 groups:blank serum group,drug-containing serum group,drug-containing serum+SB203580[p38 mitogen-activated protein kinase(p38MAPK)inhibitor]group,drug-containing serum + PDTC[nuclear transcription factor κB(NF-κB)inhibitor]group,drug-containing serum + SB203580 + PDTC group.The mRNA expression levels of p38MAPK,casein kinase 2(CK2),nuclear transcription factor κB inhibitor α(IκBα),NF-κB and GDF9 were detected by real-time quantitative polymerase chain reaction(qRT-PCR),and GDF9 protein expression level was detected by Western Blot,and ovarian granulosa cell apoptosis was detected by terminal-deoxynucleoitidyl transferase mediated nick end labeling(TUNEL).Results The drug-containing serum of Jinghou Zengzhi Prescription decreased the mRNA expressions of p38MAPK and NF-κB,elevated the mRNA expressions of CK2 and IκBα,increased the mRNA and protein expression levels of GDF9,and decreased the apoptosis rate of ovarian granulosa cells in COH rats.The addition of p38MAPK inhibitor SB203580 alone and the addition of NF-κB inhibitor PDTC alone both promoted the mRNA and protein expressions of GDF9 and reduced the apoptosis rate of granulosa cells.Conclusion The drug-containing serum of Jinghou Zengzhi Prescription based on qi and blood replenishing method can promote the expression of GDF9 and inhibit the apoptosis of ovarian granulosa cells in rats with COH,and its mechanism may be related to the regulation of the expression of genes of the dual signaling pathways of p38MAPK and NF-κB.

Objective To evaluate tolerability,safety and pharmacokinetics of JS026 and JS026-JS016 single dose intravenous infusion in healthy adults.Methods This phase 1,randomized,double-blind,placebo-controlled,dose-escalation study totally included 48 participants:32 healthy subjects were enrolled in JS026 single intravenous infusion groups and 16 healthy subjects were enrolled in JS026-JS016 groups.JS026 was sequentially administered from low dose to high dose(30-1 000 mg),with intravenous infusion of JS026 or placebo in JS026 single-dose groups,and intravenous infusion of JS026-JS016 or placebo in the combination drug groups.Blood was collected according to the time point designed for trial.Serum concentrations of JS026 and JS016 were determined by enzyme linked immunosorbnent assay(ELISA),and pharmacokinetics parameters were calculated by WinNonlin 8.2.The power model method was used to evaluate the linear analysis of dose and drug exposure.Results 47 subjects completed trial and 1 subject lost to follow-up.After a single intravenous injection of JS026 of 30 mg,100 mg,300 mg,600 mg,and 1 000 mg,mean Cmax were(9.47±1.53),(33.20±4.95),(96.10±13.70),(177.00±22.20)and(353.00±56.70)μg·mL-1,respectively;mean AUC0-∞ were(4 225.00±607.00),(1.78 × 104±3 268.00),(5.83 × 104±1 038.00),(1.07 × 105±152.00),(1.66 × 105±327.00)μg·h·mL-1,respectively;mean t1/2 of JS026 were 563-709 h.The Cmax and AUC0-∞ of JS026 were basically similar alone or in combination with JS016.The results of Power model showed that Cmax and AUC0-∞ increased approximately linearly with the increasing dose of JS026.Treatment emergent adverse event was not increasing when dose increased and most of adverse event associated with drugs were abnormal on laboratory tests and haematuria,thus JS026 and JS016 was well tolerated in all groups.Conclusion The single intravenous infusion of JS026 can almost be thought to be a linear relationship between the doses and drug serum exposure.JS016 had no significant effect on serum concentration of JS026 and JS026 was well tolerated and safe in healthy subjects within 30-1 000 mg.

The National Medical Products Administration have become an official applicant of the Pharmaceutical Inspection Co-operation Scheme(PIC/S)in 2023,and the good manufacturing practice appendix and inspection memorandum are key documents of PIC/S.Based on the analysis of the history,framework and main contents of the appendix and inspection memorandum of PIC/S investigational medicinal products,this paper discusses the key contents of the appendix and inspection memorandum of PIC/S clinical trial drugs,and provides reference for the inspection work.

Objective To compare the efficacy and safety of different courses of caffeine citrate injection in the treatment of very low birth weight infants.Methods Very low birth weight infants were divided into long course group and routine course according to cohort method.2 groups of children were given intravenous infusion of caffeine citrate injection loading dose(20 mg·kg-1)within 3 days after birth,and the dose was maintained at 5 mg·kg-1 after 24 hours(qd).In the long course group,caffeine citrate injection was used to correct gestational age＞34 weeks,and in the routine course,caffeine citrate injection was used to correct gestational age 33-34 weeks.The use of caffeine citrate injection,clinical efficacy,neonatal behavioral neurological scale(NBNA)score and the occurrence of adverse drug reactions were compared between the two groups.Results 116 cases were included in this study,64 cases in the long course group and 52 cases in the routine course.After treatment,the total clinical effective rate of the long course group and the routine course was 92.19％and 94.23％,respectively,with no statistical significance(P＞0.05).The total duration of caffeine citrate injection were(60.53±8.92)and(48.17±5.24)days,respectively;the corrected gestational age at withdrawal were(36.02±1.56)and(33.18±1.27)weeks,respectively.The corrected gestational age were(34.31±0.48)and(32.06±0.51)weeks;the milk volume were(32.69±2.14)and(23.85±1.69)mL,respectively,with statistical significance(all P＜0.05).The starting age of caffeine citrate injection were(59.65±3.42)and(58.35±3.11)h in the long course group and the routine course,respectively,with no statistical significance(P＞0.05).Before treatment,the NBNA score of the long course and routine courses were 36.49±6.78 and 35.58±4.22,respectively;the NBNA score of long course and conventional course after treatment were 43.25±6.88 and 44.12±7.42,respectively.Compared with before treatment,NBNA score in both groups were higher after treatment,with statistical significance(all P＜0.05).There was no significant difference in NBNA score between the long course group and the routine course(P＞0.05).The incidence of bronchopulmonary dysplasia(84.38％vs 51.92％)and decreased hemoglobin concentration(17.75％vs 5.77％)in the long course group were significantly higher than those in the routine course(all P＜0.05).Conclusion Long-term use of caffeine citrate injection to correct gestational age＞34 weeks has no significant effect on clinical treatment,neurological function and intellectual development of very low birth weight infants.

Objective This study employs the Geographically and Temporally Weighted Regression(GTWR)model to assess the impact of meteorological elements and imported cases on dengue fever outbreaks,emphasizing the spatial-temporal variability of these factors in border regions. Methods We conducted a descriptive analysis of dengue fever's temporal-spatial distribution in Yunnan border areas.Utilizing annual data from 2013 to 2019,with each county in the Yunnan border serving as a spatial unit,we constructed a GTWR model to investigate the determinants of dengue fever and their spatio-temporal heterogeneity in this region. Results The GTWR model,proving more effective than Ordinary Least Squares(OLS)analysis,identified significant spatial and temporal heterogeneity in factors influencing dengue fever's spread along the Yunnan border.Notably,the GTWR model revealed a substantial variation in the relationship between indigenous dengue fever incidence,meteorological variables,and imported cases across different counties. Conclusion In the Yunnan border areas,local dengue incidence is affected by temperature,humidity,precipitation,wind speed,and imported cases,with these factors'influence exhibiting notable spatial and temporal variation.

Objective:To assess the effectiveness of a 6-month Ba Duan Jin exercise program in improving the balance of community-dwelling older adults.Methods:A two arms, parallel-group, cluster randomized controlled trial was conducted in 1 028 community residents aged 60-80 years in 40 communities in 5 provinces of China. Participants in the intervention group (20 communities, 523 people) received Ba Duan Jin exercise 5 days/week, 1 hour/day for 6 months, and three times of falls prevention health education, and the control group (20 communities, 505 people) received falls prevention health education same as the intervention group. The Berg balance scale (BBS) score was the leading outcome indicator, and the secondary outcome indicators included the length of time of standing on one foot (with eyes open and closed), standing in a tandem stance (with eyes open and closed), the closed circle test, and the timed up to test.Results:A total of 1 028 participants were included in the final analysis, including 731 women (71.11%) and 297 men (28.89%), and the age was (69.87±5.67) years. After the 3-month intervention, compared with the baseline data, the BBS score of the intervention group was significantly higher than the control group by 3.05 (95% CI: 2.23-3.88) points ( P<0.001). After the 6-month intervention, compared with the baseline data, the BBS score of the intervention group was significantly higher than the control group by 4.70 (95% CI: 4.03-5.37) points ( P<0.001). Ba Duan Jin showed significant improvement ( P<0.05) in all secondary outcomes after 6 months of exercise in the intervention group compared with the control group. Conclusions:This study showed that Ba Duan Jin exercise can improve balance in community-dwelling older adults aged 60-80. The longer the exercise time, the better the improvement.

AIM: To observe the imaging characteristics of the affected eyes of patients with central serous chorioretinopathy(CSC)of different ages and their asymptomatic fellow eyes.METHODS: Retrospective study. A total of 76 cases(88 eyes)of CSC patients diagnosed in the ophthalmology department of our hospital from April to September, 2023 and 35 cases(35 eyes of asymptomatic fellow eyes of patients with unilateral CSC)were selected for the study. According to age, they were divided into young and middle-aged groups(<40 years old), middle-aged groups(40-50 years old)and middle-aged and elderly groups(>50 years old). The imaging features of the affected eyes of CSC patients of different ages and their asymptomatic fellow eyes were observed.RESULTS: The subfoveal choroidal thickness(SFCT)of CSC eyes in the young and middle-aged patients(487.30±83.33 μm)was significantly greater than that of the middle-aged group(414.17±96.02 μm, P<0.05)and the middle-aged and elderly group(409.4±107.42 μm, P<0.05). The incidence of choroidal neovascularization(CNV)in CSC patients of the middle-aged and elderly group was significantly higher than that in the young and middle-aged group(P<0.0167). The SFCT of the asymptomatic fellow eye of the unilateral CSC patient in the young and middle-aged group(511.29±40.89 μm)was significantly larger than that of the middle-aged and elderly group(364.76±82.26 μm, P<0.05). Among them, the vortex vein anastomosis rate in eyes with CSC is higher than 90%, and vortex vein anastomosis or dilatation is present in all asymptomatic fellow eyes of CSC patients.CONCLUSION: There are differences in the imaging manifestations of CSC-affected eyes and their asymptomatic fellow eyes of different age groups. SFCT is generally thickened and gradually becomes thinner with the growth of age. The incidence of CNV in CSC-affected eyes is the highest in the middle-aged and elderly group. In addition, vortex vein anastomosis and dilatation are common in CSC-affected eyes and asymptomatic fellow eyes.