基于UPLC-Q-TOF-MS/MS和网络药理学方法探讨短梗五加改善失眠的潜在药效成分及作用机制

目的:研究短梗五加改善失眠的药效物质基础及潜在的作用机制。方法:运用UPLC-Q-TOF-MS/MS技术,结合文献,对短梗五加化学成分进行分析鉴定,使用SwissADME对成分进行筛选,通过 Swiss Target Prediction数据库预测活性成分潜在靶点,GeneCards、DRUGBANK、OMIM和DisGeNET数据库搜集疾病靶点,使用VENNY软件收集成分-靶点交集,Cytoscape软件构建靶点蛋白相互作用网络,利用DAVID数据库进行GO和KEGG富集,使用微生信平台进行可视化分析。随后利用Cytoscape构建成分-靶点-通路图,运用AutoDock Vina和Pymol软件进行分子对接。进一步建立斑马鱼睡眠剥夺模型对活性成分进行验证。结果:异嗪皮啶、金合欢素、东莨菪碱内酯、丁香酸、川芎哚等16个成分为短梗五加改善睡眠药效成分,可能作用于ESR1、AKT1、EGFR、PTGS2和PPARG等靶点,成分与靶点结合能小于-4.25kJ·mol^-1的占总数94%,显示良好的结合活性。短梗五加通过雌激素、PI3K-Akt、ErbB、HIF-1等信号通路改善失眠。总提物、金合欢素、异嗪皮啶和东莨菪碱内酯均可改善失眠并具有一定的镇静作用(P＜0.01,P＜0.05)。结论:短梗五加改善失眠可能是通过多靶点、多成分起作用,本研究为产品的质量评价及深度开发提供科学依据。     

美罗培南在化脓性脑膜炎新生儿血浆和脑脊液中药动学和药效学的关联研究

目的 探讨美罗培南在化脓性脑膜炎的新生患儿血浆和脑脊液中的药动学和药效学的关联。方法 试验招募2016年5月—2021年5月在扬州大学附属医院诊断为化脓性脑膜炎的58例新生儿患者,均获得血浆样品,其中17人获得脑脊液样品。出生后2～4周的新生儿以及4～6周的婴幼儿使用8 h的剂量间隔,美罗培南使用剂量为40 mg·kg^-1,输注时间超过30 min。使用带有DIGITAL FORTRAN编译器的NONMEM软件包分析数据。超高效液相色谱联用串联质谱（UHPLC-MS/MS）测定血浆和脑脊液中的美罗培南浓度。使用最终模型估计值的蒙特卡罗模拟（n＝1 000）用于生成不同给药方案的游离血药浓度水平维持在目标菌群的最低抑菌浓度（MIC）之上的时间（fT＞MIC）占1个给药间隔的百分比（% fT＞MIC）和最小抑菌浓度（MIC）值：1、2、4、8 mg·L^-1。结果 美罗培南在血浆中的峰浓度（C_max）、曲线下面积（AUC）、清除率（CL）、表观分布容积（V_d）高于脑脊液中的各项数据,差异有统计学意义（P＜0.05）;血浆中的半衰期（t_1/2）低于脑脊液,差异有统计学意义（P＜0.05）。用蒙特卡罗模拟10 000例患者目标获得概率,随着MIC值增加,血浆目标获得概率降低;血浆中40%最低抑菌浓度（MIC）的时间百分比（40% TMIC）、60% TMIC、80% TMIC、100% TMIC目标获得概率逐渐降低。随着MIC值增加,脑脊液目标获得概率降低;脑脊液中40% TMIC、60% TMIC、80% TMIC、100% TMIC目标获得概率逐渐降低。结论 模拟试验表明,当MIC为2 μg·mL^-1时,美罗培南在血浆中的目标获得概率可以达标,其在脑脊液中的目标获得概率不能达标,治疗时需要增加美罗培南的剂量或缩短给药间隔,以达到治疗目标。     

Pharmacokinetics and pharmacodynamics of intravenous ilaprazole in healthy subjects after single ascending doses

1.?Ilaprazole is a novel proton pump inhibitor and this is the first study to investigate the pharmacokinetics, pharmacodynamics and safety of intravenous ilaprazole in healthy volunteers.

2.?In this open-label, single-dose, randomized and four-period crossover study, 16 healthy Chinese subjects received ilaprazole 5, 10 or 20?mg intravenously, or 10?mg orally. Serial blood and urine samples were collected and intragastric pH was recorded within 24?h. The percentage time of intragastric pH?>?6 was the major index. Safety was assessed throughout the study.

3.?Plasma exposure of intravenous ilaprazole increased proportionally over the dose of 5–20?mg. Clearance and volume of distribution were independent of dose. Ilaprazole was not eliminated through urine and the absolute bioavailability was 55.2%. For the intravenous dose of 5, 10, 20?mg, and oral dose of 10?mg, the mean percentages time of intragastric pH?>?6 were 47.3%, 52.8%, 68.2% and 47.5%, respectively.

4.?Ilaprazole showed linear pharmacokinetics over the dose of 5–20?mg. Intravenous ilaprazole provided rapid onset of action and the potency of effect were exhibited in a dose-dependent manner. Intravenous ilaprazole was safe and well tolerated except for elevated activated partial thromboplastin time (APTT) and prothrombin time (PT).     

Comparative assessment of clinical response in patients with rheumatoid arthritis between PF‐05280586, a proposed rituximab biosimilar,and rituximab

AimsTo evaluate potential differences between PF‐05280586 and rituximab sourced from the European Union (rituximab‐EU) and USA (rituximab‐US) in clinical response (Disease Activity Score in 28 Joints [DAS28] and American College of Rheumatology [ACR] criteria), as part of the overall biosimilarity assessment of PF‐05280586.MethodsA randomised, double‐blind, pharmacokinetic similarity trial was conducted in patients with active rheumatoid arthritis refractory to anti‐tumour necrosis factor therapy on a background of methotrexate. Patients were treated with 1000 mg of PF‐05280586, rituximab‐EU or rituximab‐US on days 1 and 15 and followed over 24 weeks for pharmacokinetic, clinical response and safety assessments. Key secondary end points were the areas under effect curves for DAS28 and ACR responses. Mean differences in areas under effect curves were compared against respective reference ranges established by observed rituximab‐EU and rituximab‐US responses using longitudinal nonlinear mixed effects models.ResultsThe analysis included 214 patients. Demographics were similar across groups with exceptions in some baseline disease characteristics. Baseline imbalances and group‐to‐group variation were accounted for by covariate effects in each model. Predictions from the DAS28 and ACR models tracked the central tendency and distribution of observations well. No point estimates of mean differences were outside the reference range for DAS28 or ACR scores. The probabilities that the predicted differences between PF‐05280586 vs. rituximab‐EU or rituximab‐US lie outside the reference ranges were low.ConclusionsNo clinically meaningful differences were detected in DAS28 or ACR response between PF‐05280586 and rituximab‐EU or rituximab‐US as the differences were within the pre‐specified reference ranges. TRIAL REGISTRATION Number: {"type":"clinical-trial","attrs":{"text":"NCT01526057","term_id":"NCT01526057"}}NCT01526057.     

番荔素纳米混悬剂的制备及其抗肿瘤作用研究

目的 制备高载药量番荔素纳米混悬剂（ACGs-NSPs）,并研究其对小鼠乳腺癌4T1移植肿瘤的生长抑制作用,为强效抗肿瘤药物ACGs的临床应用提供可用注射剂型。方法 番荔素、TPGS、SPC（质量比7:5:2）采用超声-沉淀法制备ACGs-NSPs,并用动态光散射法测定ACGs-NSPs的粒径,透射电镜观察其形态;稳定剂TPGS、SPC组成比例对ACGs-NSPs的溶血性考察;透析法考察其体外释放;采用MTT比色法评价ACGs-NSPs对4T1细胞细胞毒性;建立4T1乳腺癌皮下小鼠肿瘤模型,以紫杉醇注射液（PTX）为阳性对照,考察不同剂量ACGs-NSps静脉注射给药对4T1肿瘤的抗肿瘤药效。结果 ACGs-NSPs为表面光滑的球形,平均粒径为(129.03±1.03）nm,多分散指数PDI为0.134±0.03,zeta为（-17.7±0.16）mV,HPLC法测得番荔素线性回归方程为Y=0.157 2 X-0.363 2（R²=0.999）,在5~200 μg/mL范围内显性关系良好,载药量高达（45.03±0.72）%;体外释放较为缓慢;MTT试验中,ACGs-NSPs对4T1乳腺癌的细胞毒性显著强于游离药物（IC⁵⁰,3.221 μg/mL vs 4.464 μg/mL,P<0.05）;4T1荷瘤小鼠的药效学实验中,ACGs-NSPs表现出剂量相关性的抑瘤作用,高、中、低剂量组（0.4、0.2、0.1 mg/kg）抑瘤率分别为76.09%、74.34%、42.03%;但高剂量组小鼠有死亡（3/10）。结论 成功制备高载药量的ACGs-NSPs,且其对4T1乳腺癌有显著的抑制作用;从药效和小鼠存活率来看,0.2 mg/kg为合适的给药剂量。     

Controlled release recombinant human interferon‐α2b for treating patients with chronic hepatitis C genotype 1: a phase 2a clinical trial

Summary. Better convenience and tolerability and sustained therapeutic concentrations might improve interferon (IFN) treatment for chronic hepatitis C virus (HCV) infection. In an open‐label, randomized study, controlled release free (chemically unmodified) recombinant human IFN‐α_2b in poly(ether–ester) microspheres (CR‐rhIFN‐α_2b), was injected at doses of 160, 320, 480 or 640 μg every 2 weeks for 12 weeks with concomitant weight‐based oral ribavirin in 32 treatment‐naïve patients with chronic HCV genotype 1. Treatment was well tolerated, with 31 patients (97%) successfully completing the study. Full doses of CR‐rhIFN‐α_2b were administered on 96% of scheduled occasions. Flu‐like symptoms were generally mild and brief. Injection site reactions developed in 13 patients (41%), and neutropenia occurred in six of eight patients receiving 640 μg. In the 320, 480 and 640 μg groups, 62–75% of patients achieved a ≥2 log₁₀ HCV RNA reduction by 4 weeks and 88–100% by 12 weeks. For those groups, the pooled median time to ≥2 log₁₀ reduction was 11 days (95% confidence interval, 7–35 days). In those groups, viral reduction below the limit of detection was accomplished in 25% of patients by 4 weeks and in 62% by 12 weeks. The 160‐μg dose was less potent. After CR‐rhIFN‐α_2b injection, stable plateau levels of serum IFN‐α_2b were generally reached within 72 h. Treatment‐emergent neutralizing antibodies to IFN‐α_2b were observed in one patient. No antibodies to host plant proteins were detected. CR‐rhIFN‐α_2b with ribavirin cotherapy was well tolerated and displayed potent early antiviral activity in patients with chronic HCV genotype 1.     

灵猫方药物血清体外抗乙肝病毒作用的研究

目的：观察灵猫方药物血清对HepG2.2.15细胞分泌HBsAg、HBeAg的抑制效果。方法：应用SD大鼠备置5倍和10倍灵猫方药物血清、生理盐水大鼠血清,将3种血清分别作用于HepG2.2.15细胞,在第72小时、96小时、144小时收集细胞培养上清液,采用ELISA法检测HBsAg、HBeAg。结果：与生理盐水大鼠血清相比较,灵猫方药物血清在72小时后即产生抑制HepG2.2.15细胞分泌HBsAg、HBeAg的作用,96小时时对乙肝病毒（HBV）的抑制率达到高峰,在144小时对HBV的抑制率有所下降;5倍灵猫方药物血清和10倍灵猫方药物血清在抑制HepG2.2.15细胞分泌HBsAg、HBeAg方面,差异无显著性意义。结论：灵猫方药物血清在体外具有一定的抗HBV的作用。     

Pharmacokinetics and pharmacodynamics of dapagliflozin, a novel selective inhibitor of sodium-glucose co-transporter type 2, in Japanese subjects without and with type 2 diabetes mellitus

Aims: Dapagliflozin, a selective, orally active inhibitor of the renal sodium–glucose co‐transporter type 2 (SGLT2) is in development for the treatment of type 2 diabetes mellitus (T2DM). Here, the pharmacokinetics (PK) and pharmacodynamics (PD) of dapagliflozin were evaluated in healthy Japanese subjects and in Japanese subjects with T2DM. Methods: Two studies were conducted: a single‐ascending dose (SAD) study (2.5–50 mg) in 32 healthy subjects and a multiple‐ascending dose (MAD) study (2.5–20 mg QD for 14 days) in 36 subjects with T2DM. Safety and tolerability were assessed in both studies. Single and multiple dose PK of dapagliflozin and its inactive major metabolite, dapagliflozin 3‐O‐glucuronide, and PD (urinary glucose parameters) were characterized. Plasma glucose parameters were assessed over 14 days in the MAD study. Results: No serious adverse events or discontinuations due to adverse events occurred in either study. In healthy and T2DM subjects, dapagliflozin was rapidly absorbed with a time to maximum plasma concentration of 0.5–1.3 h. Systemic exposure of dapagliflozin and dapagliflozin 3‐O‐glucuronide, measured by maximum plasma concentration and area under the plasma concentration–time curve, increased proportional to dose. On a molar basis, systemic exposure to dapagliflozin 3‐O‐glucuronide was similar to parent dapagliflozin. There was a dose‐related increase in the amount of glucose excreted in the urine (SAD and MAD), which was associated with dose‐related decreases in plasma glucose parameters in subjects with T2DM (MAD). Conclusions: Dapagliflozin was well tolerated and showed predictable dose‐proportional PK and PD parameters in both healthy and T2DM Japanese subjects.     

复方枸橼酸铋钾片药效学实验研究

目的观察复方枸橼酸铋钾片对胃炎胃溃疡的治疗作用。方法采用大鼠足爪肿胀、肉芽肿实验和小鼠扭体、热板法实验,观察复方枸橼酸铋钾片抗炎、镇痛作用;建立大鼠急性胃炎、胃溃疡和慢性胃炎模型,测定胃液量,胃酸度及胃蛋白酶活性,溃疡指数,并进行病理学检查,观察复方枸橼酸铋钾片对各类胃炎及胃溃疡的治疗作用。结果与模型组比较,复方枸橼酸铋钾片高、中、低剂量(0.44、0.22、0.11 g/kg)均能减轻大鼠的足爪肿胀度(P<0.05或P<0.01),高、中剂量组可明显减轻大鼠肉芽肿(P<0.01),减少小鼠的扭体次数(P<0.05),提高小鼠给药1 h后痛阈值(P<0.05);高、中剂量组可明显降低急性胃炎大鼠的溃疡指数及胃溃疡大鼠的溃疡面积(P<0.05或P<0.01),对慢性胃炎和胆汁反流性胃炎大鼠胃酸度的降低也有明显抑制作用(P<0.05);光学显微镜下示复方枸橼酸铋钾片高、中、低剂量组可改善慢性胃炎和胆汁反流性胃炎大鼠胃组织的病理改变。结论复方枸橼酸铋钾片对急性胃炎、胃溃疡、慢性胃炎及胆汁反流性胃炎具有一定的治疗作用。