川芎嗪对大鼠低压低氧性肺动脉高压的预防作用及初步机制探讨

摘 要 目的：研究川芎嗪（TMP）对慢性低压低氧性肺动脉高压模型大鼠的防治作用及其机制。方法: 将雄性SD大鼠随机分为3组,即正常对照组、低压低氧组与川芎嗪组（100 mg·kg^-1·d^-1）。建立低压低氧性肺动脉高压大鼠模型,观察TMP干预后大鼠平均肺动脉压力（mPAP）、左颈总动脉插管测平均颈动脉压（mCAP）、右心室肥厚指数（RVHI）和肺血管形态学的改变,计算肺细小动脉管壁厚度占血管外径的百分比（WT%）和管壁面积占血管总面积的百分比（WA%）,以及大鼠血清中一氧化氮（NO）、内皮素-1（ET-1）、缺氧诱导因子-1α（HIF-1α）与血管内皮生长因子（VEGF）水平。结果: 检测TMP干预21 d,大鼠mPAP、RVHI、WT%和WA%各指标比较,低压低氧组显著高于正常对照组（P＜0.05或P＜0.01）,川芎嗪组显著低于低压低氧组（P＜0.05或P＜0.01）。低压低氧条件对颈动脉压力mCAP影响不大,组间比较差异均无统计学意义（P＞0.05）。血清中NO含量比较,低压低氧组显著低于正常对照组（P＜0.05）,川芎嗪组显著高于低压低氧组（P＜0.05）。血清中ET-1、HIF-1α与VEGF含量比较,低压低氧组显著高于正常对照组（P＜0.05）,川芎嗪组显著低于低压低氧组（P＜0.05）。结论:TMP可有效预防大鼠低压低氧导致的肺动脉高压和肺小动脉的结构重建,其作用机制可能与上调大鼠血清NO含量和下调ET-1、HIF-1α与VEGF活性有关。     

7-羟乙基白杨素对低压低氧致脑组织损伤的保护作用

目的 研究7-羟乙基白杨素（7-HEC）对低压低氧诱导大鼠脑组织损伤的保护作用。方法 将52只健康♂ Wistar大鼠随机分为正常组、模型组、乙酰唑胺组、7-HEC组，每组13只。连续灌胃给药5 d，末次给药后，除正常组，将其余3组置于低压低氧动物实验舱，升至8 000 m海拔缺氧处理24 h。HE染色观察脑组织病理改变，酶标法检测脑组织中过氧化氢（H₂O₂）和丙二醛（MDA）水平，以及超氧化物歧化酶（SOD）、过氧化氢酶（CAT）、谷胱甘肽过氧化物酶（GSH-Px）和ATP酶的活力；Western blotting检测蛋白B细胞淋巴瘤-2（Bcl-2）、Bcl-2相关X蛋白抗体（Bax）及半胱氨酸天冬氨酸特异性蛋白酶3（caspase-3）的表达。结果 与正常组相比，低压低氧导致大鼠脑组织出现明显损伤，H₂O₂和MDA水平显著升高，抗氧化酶SOD、CAT和GSH-Px以及Na⁺-K⁺-ATPase和Ca²⁺-Mg²⁺-ATPase的活力显著降低。7-HEC预处理能够逆转这些变化。此外，低压低氧能够显著升高脑组织中促凋亡蛋白Bax和cleaved caspase-3表达，降低抗凋亡蛋白Bcl-2的表达，而7-HEC能够下调Bax和cleaved caspase-3表达，上调Bcl-2的表达。结论 7-HEC对低压低氧致脑组织损伤具有明显的保护作用，其作用机制可能与其缓解氧化应激，抑制细胞凋亡，改善能量代谢有关。     

NVP-BEZ235对低氧大鼠肺血管管周肥大细胞的影响

目的 评价PI3K/mTOR双重抑制剂NVP-BEZ235对低压、低氧诱导的大鼠肺血管管周肥大细胞的分布以及脱颗粒状态的影响。方法 低氧组SD雄性大鼠于低压低氧培养箱（50.5 kPa）内培养,治疗组隔天给予NVP-BEZ235（35 mg/kg）干预,对照组匹配饲养条件并在当地气压常氧环境饲养,21 d后全部动物以5%戊巴比妥钠麻醉后取材。肺组织固定后进行石蜡包埋并行苏木素伊红染色和甲苯胺蓝染色。结果 低氧组大鼠肺血管管周肥大细胞数量较对照组增多,聚集明显。低氧组不同管径的肺血管（<50 μm,50~100 μm,>100 μm）管周的肥大细胞聚集情况及脱颗粒细胞比例较对照组增多,具有统计学差异（P<0.05）,而NVP-BEZ235干预组较低氧组肺血管管周肥大细胞数量减少（P<0.05）,且能降低管径50~100 μm的肺血管周围低氧组脱颗粒的肥大细胞比例（P=0.000 3）。结论 NVP-BEZ235可以抑制低压低氧诱导的大鼠肺血管管周肥大细胞的聚集及中等管径血管管周脱颗粒细胞比例。     

格列本脲检测方法的研究进展

目的 总结和探讨格列本脲分析方法的研究发展方向。方法 通过查阅相关文献和归纳总结,对检测格列本脲的多种分析方法进行阐述,比较不同方法的优缺点,并介绍格列本脲降解产物的分析现状。结果 目前格列本脲检测技术有了很大提高,测定方法更加丰富。结论 高灵敏度、高选择性、联用技术是格列本脲分析方法的发展方向。关键词:格列本脲;检测方法;研究进展     

耐甲氧西林金黄色葡萄球菌血流感染危险因素的系统评价

目的 系统评价耐甲氧西林金黄色葡萄球菌（MRSA）血流感染危险因素，为各级医疗机构预防MRSA血流感染提供依据。方法 计算机检索中国学术期刊全文数据库（CNKI）、万方数据库（Wanfang Data）、维普中文期刊全文数据库（VIP）、中国生物医学文献数据库（CBM）、PubMed、Embase等数据库，检索时限为建库至2023年6月6日，收集国内外MRSA血流感染危险因素的病例对照研究，采用RevMan 5.3软件进行Meta分析。结果 共纳入16篇病例对照研究，涉及感染危险因素49个。结果显示年龄（年龄≥65、60岁），医院感染，合并脑梗死、慢性肝胆疾病、消化性溃疡、感染性休克、肺部感染，中心静脉置管、留置导尿管、气管插管，入住ICU，感染前使用碳青霉烯类、糖肽类、第3代头孢菌素类，感染来源于呼吸道、皮肤软组织、腹腔、导管、感染来源大于2个部位，住院时间，MRSA血流感染组与甲氧西林敏感金黄色葡萄球菌（MSSA）血流感染组相比，差异有统计学意义（P<0.05）。结论 MRSA血流感染危险因素多，临床诊疗活动中应重视患者基础疾病，规范化进行侵入性操作，重视病区环境的消杀和医务人员手卫生，合理使用抗菌药物，动态评估患者生命体征，根据危险因素制定感控策略，从而降低MRSA血流感染发生率。     

藏药三果汤治疗糖尿病作用机制的网络药理学与分子对接技术分析

目的 基于网络药理学及分子对接对三果汤治疗糖尿病靶点及通路进行分析，并通过分子对接进行验证，为基础研究及临床用药提供科学依据。方法 通过中药系统药理学数据库与分子平台（TCMSP）、有机小分子生物活性数据库（PubChem）及文献查阅筛选三果汤中诃子、毛诃子、余甘子的活性成分及作用靶点，使用Genecard数据库、DRUGBANK数据库筛选糖尿病相关靶点，构建“药物-成分-靶点-疾病”网络，取药物疾病靶点交集，使用STRING构建蛋白PPI网络，运用Matescape数据库对交集靶点基因进行GO、KEGG富集分析。将筛选出的有效成分与靶点进行分子对接验证。结果 通过网络药理学收集三果汤及糖尿病靶点信息，采用GO富集分析和KEGG通路分析发现，三果汤和糖尿病共同作用靶点共269个，靶点作用最为突出的为AKT1、HAS2、MAP2、CDH1、PRKCG、PLAT，三果汤作用于糖尿病的通路主要在癌症通路、脂质和动脉粥样硬化、MAPK信号通路。分子对接结果显示，鞣花酸和没食子酸对AKT1、HAS2、MAP2存在亲和力，鞣花酸对HAS2亲和力最好。结论 通过本研究中网络药理学分析及分子对接分析，三果汤中鞣花酸、没食子酸对AKT1、HAS2、MAP2通路靶点具有亲和力，为后续实验提供研究思路。     

降低亲和力提高HER2-CAR-T细胞治疗的安全性

目的 探讨降低CAR-T细胞亲和力是否能有效提高其杀伤特异性,减少"脱靶效应"。方法 构建靶向HER2的中等亲和力和高亲和力的La-G3HER2-CAR和Ha-G3HER2-CAR并电穿孔转染T细胞,采用Western Blot、FCM技术和xCELLigence RTCA DP进行CAR载体表达和杀伤功能检测。结果 La-G3HER2-CAR-T细胞和Ha-G3HER2-CAR-T细胞分别表达43000和58000的外源CAR载体片段,转染效率分别为58.1%和69.0%。高亲和力的Ha-G3HER2-CAR-T细胞对高、中、低水平表达HER2的6种靶细胞均有效杀伤,而低亲和力的La-G3HER2-CAR-T细胞高效杀伤HER2高表达的SK-OV-3和BT474细胞,对HER2中表达的MDA-MB-231和HCC-202的杀伤作用较弱,而对低水平表达HER2的MCF-7和293细胞不杀伤。进一步的机制研究发现,HER2中水平表达的MDA-MB-231细胞共培养对La-G3HER2-CAR-T细胞和Ha-G3HER2-CAR-T细胞激活和细胞因子分泌诱导水平不同(CD107a:8.2% vs 71.6%; IFN-γ:66.3% vs 83.4%; TNF-α:73.4% vs 94.1%)。结论 中等亲和力La-G3HER2-CAR-T细胞比高亲和力的Ha-G3HER2-CAR-T细胞的杀伤作用特异性更强,降低CAR-T细胞的亲和力可以提高治疗的安全性。     

欧洲和美国药品标准数据库设计对中国的启示

目的 为中国构建统一、权威、规范的药品标准数据库提供参考。方法 通过查询欧洲药品质量管理局和美国药典委员会药品标准数据库应用建设情况,总结归纳其构建思路,功能设定与应用特点,并对中国药品标准数据库建设关键结构框架与功能设定进行简要分析。结果 欧洲与美国均构建了具有精准检索、知识辅助功能的药典数据库,并充分考虑了实际工作需要以及用户需求,建设了药典论坛、色谱图谱、药典培训等数据库,可以更好地满足药典编制工作需要和用户需求。结论 中国应当以《“十四五”国家药品安全及促进高质量发展规划》为契机,充分借鉴欧洲、美国药典数据库结构设计、功能设定、用户体验等特色与优势,尽快构建以国家药品标准为核心的数据库群,更好地满足国家药品标准智慧管理和公共服务需要。     

1例耐甲氧西林金黄色葡萄球菌感染患者抗菌药物治疗分析

摘 要 目的：通过参与1例耐甲氧西林金黄色葡萄球菌（MRSA）感染患者药物治疗,探讨临床药师在治疗团队中作用。方法: 根据患者感染部位、MRSA感染治疗原则及药物治疗特点,协助医师优化治疗方案,提供药学服务。结果: 临床医生采纳建议,患者症状好转,有效降低药品不良反应危害。结论:临床药师参与优化抗感染药物治疗方案,能提高临床药物治疗的疗效和安全性。     

曲美他嗪治疗微血管心绞痛疗效和安全性的系统评价

目的 系统评价曲美他嗪治疗微血管心绞痛（CMVA）的临床疗效和安全性。方法 检索中国学术期刊数据库（CNKI）、万方数据库（Wanfang）、中国生物医学文献服务系统（SinoMed）、维普中文期刊全文数据库（VIP）、PubMed和Web of Science（WOS）数据库从建库至2022年5月有关曲美他嗪治疗CMVA的临床随机对照试验（RCT）,采用ReviewManager 5.3软件进行Meta分析。结果 共纳入12项RCTs,包括1 195例患者,其中试验组609例、对照组586例。Meta分析结果显示,与对照组比较,试验组的心绞痛症状临床疗效提高,心绞痛症状改善的总有效例数增加［OR＝4.63,95% CI（3.20,6.72）,P＜0.000 01］、显效例数增加［OR＝1.94,95% CI（1.40,2.68）,P＜0.000 01］;平板运动试验总运动时间延长［MD＝1.31,95% CI（1.02,1.60）,P＜0.000 01］,平板运动试验心电图ST段压低0.1 mV时间延长［MD＝1.28,95% CI（0.98,1.59）,P＜0.000 01］,平板运动试验心电图ST段最大压低幅度降低［SMD=-1.19,95% CI（-1.72,-0.65）,P＜0.000 01］。结论 曲美他嗪可以改善CMVA患者心绞痛症状,延长CMVA患者平板运动时间和平板运动试验中心电图ST段压低0.1 mV所需时间、降低ST段压低的最大幅度。     

Affective and Anxiety Disorders and Alcohol and Drug Dependence:

Depression and anxiety frequently coexist in patients with substance use disorders. This clinically-oriented article examiens the relationship between these conditions and emphasizes data showing that substances of abuse can cause signs and symptoms of both depression and anxiety. These substance-related syndromes appear to have a different course and prognosis than uncomplicated, independent anxiety and major depressive disorders, and clinicians should consider the role of alcohol and other drugs in all patients presenting with these complaints. The authors will also outline an approach for diagnosing and managing patients with the combination of a substance use and depressive or anxiety disorder.     

Synthesis and anti-nociceptive and anti-inflammatory effects of gaultherin and its analogs

The synthesis of gaultherin (1) and its analogs was carried out to provide 11 glycosides under phase-transfer catalytic conditions. The activities of all synthesized compounds were evaluated by nitric oxide production inhibitory assay in vitro. Methyl 2-O-(4-O-β-d-galactopyranosyl)-β-d-glucopyranosylbenzoate (5f) showed significantly anti-nociceptive and anti-inflammatory effects by the evaluation in vivo. Structure–activity relationships within these compounds were discussed.     

Modelling and simulation of variability and uncertainty in toxicokinetics and pharmacokinetics

Two important methodological issues within the framework of the variability and uncertainty analysis of toxicokinetic and pharmacokinetic systems are discussed: (i) modelling and simulation of the existing physiologic variability in a population; and (ii) modelling and simulation of variability and uncertainty when there is insufficient or not well defined (e.g. small sample, semiquantitative, qualitative and vague) information available. Physiologically based pharmacokinetic models are especially suited for separating and characterising the physiologic variability from the overall variability and uncertainty in the system. Monte Carlo sampling should draw from multivariate distributions, which reflect all levels of existing dependencies in the intact organism. The population characteristics should be taken into account. A fuzzy simulation approach is proposed to model variability and uncertainty when there is semiquantitative, qualitative and vague information about the model parameters and their statistical distributions cannot be defined reliably.     

成骨细胞的功能与损伤和骨质疏松的防治

骨质疏松是一种全身性骨骼疾病,导致骨折风险增加。成人的骨量通过破骨细胞的骨吸收和成骨细胞的骨形成作用来维持动态平衡,治疗骨质疏松症的理想策略是抑制破骨细胞的骨吸收和/或增强成骨细胞的骨形成功能。目前针对保护成骨细胞及增强其功能的骨质疏松疗法相对较少。因此,本文针对成骨细胞相关功能蛋白、各种细胞损伤机制（内质网应激、氧化应激、机械过载、微小RNA和长链非编码RNA的影响等）及骨质疏松的治疗与预防作一综述,以期为针对增强成骨细胞功能的骨质疏松治疗策略提供新思路。     

Self-stimulation and amphetamine: Tolerance to d and l isomers and cross tolerance to cocaine and methylphenidate

The effects of the d and l isomers of amphetamine on self-stimulation responding were tested following acute and chronic administration. Tolerance and post-drug depression of responding occurred in tests with both isomers, indicating no role for p-hydroxynorephedrine (PHN) which is one of the metabolites of d-amphetamine. In the second experiment, d-amphetamine, methylphenidate and cocaine all produced quantitatively and qualitatively similar effects on self-stimulation responding following acute administration. Following chronic administration of d-amphetamine, animals showed tolerance to all three drugs, indicating cross-tolerance among them. These data are consistent with an hypothesis that tolerance and post-drug depression following chronic amphetamine treatment are the result of decreases in postsynaptic receptor sensitivity, which would lead to a decreased effectiveness of all three drugs, regardless of their pre-synaptic mechanisms.     

益生菌与肿瘤防治

益生菌广泛存在于自然界中,通过维持宿主体内菌群平衡、影响肠屏障功能和调节免疫应答等作用,提高宿主健康水平,被公认为"肠道健康卫士".一些益生菌可以增强机体的免疫功能,抑制致癌物质,影响肿瘤细胞的基因表达,对肿瘤具有拮抗作用.大量研究表明,益生菌在未来的肿瘤防治中有很好的应用和发展前景.     

Acamprosate and naltrexone treatment effects on ethanol and sucrose seeking and intake in ethanol-dependent and nondependent rats

Rationale  Two pharmacotherapies are approved for treating alcohol craving (acamprosate and naltrexone), but both have shown mixed findings in animals and humans. Objectives  The present experiments utilized a “reinforcer blocking” approach (i.e., rats were able to consume ethanol during treatment) to better understand the efficacy of these treatments for ethanol seeking and drinking using ethanol-dependent and nondependent rats. Materials and methods  In “nondependent” experiments, drugs (acamprosate 50, 100, and 200 mg/kg; naltrexone 0.1, 0.3, and 1.0 mg/kg) were administered over 3-week periods prior to operant sessions with a low response requirement to gain access to reinforcers for 20 min. For “dependent” experiments, rats were made dependent in vapor/inhalation chambers. Results  Acamprosate and naltrexone had similar effects on intake in nondependent and dependent rats; neither drug was selective for ethanol over sucrose drinking. In nondependent animals, naltrexone was more efficacious at more doses than acamprosate, and acamprosate’s effects were limited to a dose that also had adverse effects on body weight. Both pharmacotherapies showed more selectivity when examining reinforcer seeking. In nondependent rats, acamprosate and naltrexone had response-attenuating effects in ethanol, but not sucrose, groups. In dependent animals, acamprosate had selective effects limited to a decrease in sucrose seeking. Naltrexone, however, selectively decreased ethanol-seeking in nondependent rats. Conclusions  The naltrexone-induced decreases in seeking suggested a change in incentive motivation which was selective for ethanol in nondependent rats. The “nondependent” paradigm may model early stages of “problem drinking” in humans, and the findings suggest that naltrexone could be a good intervention for this level of alcohol abuse and relapse prevention.     

Antiinfective and encrustation-inhibiting materials--myth and facts

Catheters, urethral and ureteral stents and other urological implants are frequently affected by encrustration and infection due to their permanent contact with urine. Indwelling urinary catheters provide a haven for microorganisms and thus require extensive monitoring. Several surface modification techniques have been proposed to improve the performance of devices including the immobilization of biomolecules, the incorporation of hydrophilic grafts to reduce protein adsorption, the creation of hydrophobic surfaces, the creation of microdomains to regulate cellular and protein adhesion, new polymers and antimicrobial coatings. Physico-chemical explanation to elucidate the mechanism of such encrustation or infection inhibiting materials is still not available. Our series of experiments showed a marked decrease of silver-activity in biological fluids which corresponds with the controversial clinical results obtained with silver coated urinary catheters. Rifampicin/minocycline coated catheters had very low activity against Gram-negative rods, enterococci and Candida spp., the main causing organisms of urinary catheter infection. Surface engineered materials and antimicrobial drug delivery systems will be the next generation of sophisticated urinary catheters and stents, if both efficacy as well as efficiency has been proved clinically.     

Alprazolam and lorazepam single and multiple-dose effects on psychomotor skills and sleep

Summary The effects of alprazolam 0.5 mg and lorazepam 2 mg on cognitive and psychomotor skills were assessed in twelve normal volunteer subjects in a randomised, double-blind, crossover design. Single and multiple dose effects were monitored using a battery of tests comprising critical flicker fusion threshold (CFFT), choice reaction time (CRT), simulated car tracking, and subjective ratings of perceived sedation (LARS) and of sleep behaviour (LSEQ). Compared with placebo baseline scores, treatment with lorazepam 2 mg (both single and multiple doses) resulted in a widespread impairment of CRT, tracking accuracy, and CFFT. Single doses of alprazolam 0.5 mg reduced CFFT with respect to the placebo baseline. Single and multiple dose treatment with both drugs resulted in subjective reports of sedation, a reduction of sleep onset latency, and improved sleep quality. Only lorazepam 2 mg significantly disrupted the integrity of behaviour on waking from sleep. These results suggest important pharmacodynamic differences between the two drugs in the doses used.