七甲川菁染料与醋酸阿比特龙的化合物应用于小鼠前列腺癌的活体成像和治疗研究

目的 研究七甲川菁(heptamethine carbocyanine)近红外(near-infrared fluorescence,NIRF)荧光染料与醋酸阿比特龙(abiraterone acetate,ABi)合成化合物(DZ1-ABi和783-ABi)对前列腺癌的治疗及其在活体成像中的应用.方法 化学合成两种化...     

HPLC测定醋酸阿比特龙的含量与有关物质

本实验建立HPLC测定醋酸阿比特龙的含量与有关物质,为醋酸阿比特龙质量综合评价和控制提供参考。采用Eclipse plus C18 (5μm,4.6 mm×250 mm),流动相A:乙腈溶液(含2%异丙醇)B:0.01 mol/L的醋酸铵溶液,流速:1.0 mL/min,波长:254 nm,梯度洗脱。实验结果显示,其在0.3033～1.0111 mg/mL范围内,具有良好的线性关系,平均回收率为99.41%(RSD=1.10%),且能与有关物质可实现很好分离。在16 h内溶液稳定性良好,RSD=0.33%;定量限为0.97 ng,检测限为0.291 ng。该法简单、便捷、精准、灵敏度高,适用于醋酸阿比特龙含量与有关物质测定。     

单室模型的最佳给药方案

药物剂量和给药间隔时间的确定是临床给药方案设计中的关键问题。给药剂量过小无药效;剂量过大容易引起药物中毒。药物动力学用房室模拟人体,把给药后药物能迅速在周身各部位达到动态平衡的整个机体视为一个房室。针对单室模型的最佳给药方案问题,首先利用常微分方程建立"静注+静滴"的联合给药数学模型,在上次滴注与下次滴注初始剂量相同且等于首剂量的条件下确定重复给药体内药量的表达式;然后构建用积分来表示药量在人体内积蓄程度的目标函数,采用最优化方法,确定给药时间间隔、首次剂量、滴注时间和每天滴注次数等参数,进而得到使体内的毒素积蓄最小、安全有效的最佳给药方案。最后仿真结果表明,该方法可行有效。     

甲强龙不同途径给药治疗突发性聋其内耳药物浓度分布的临床对比研究

目的 观察不同途径给药(全身给药/鼓室内给药),甲强龙在内耳中药物浓度的分布及药代动力学改变(药物作用的起效时间、持续时间等),以寻求一种治疗突发性聋更为有效的方法.方法 将60例患者随机分为A、B两组,A组采用全身给药(静脉注射),B组为鼓室内给药,分别检测两组患者血中和内耳的药物浓度、药物持续时间,进行临床听力检测与疗效对比观察.结果 甲强龙鼓室内给药内耳药物浓度较全身给药内耳药物浓度高、药物起效时间快、药效持续时间较长、不良反应相对较少.A、B两组听力恢复总有效率分别为66.67％、86.67％,可见经鼓室内给药治疗的总有效率明显高于全身给药治疗(p＜0.05).结论 在常规治疗基础上鼓室内注射甲强龙治疗突发性聋,其内耳药物浓度较全身给药高,其疗效优于全身给药,且不良反应相对较少.     

冰片对反式白藜芦醇药动学的影响研究

为了研究冰片对反式白藜芦醇(resveratrol,Res)药代动力学的影响,将雄性SD大鼠分为灌胃给药和尾静脉注射给药两大组,灌胃给药组和尾静脉注射给药组均包括反式白藜芦醇(30 mg/kg)单用组,反式白藜芦醇与低、中、高剂量冰片(50、100和200 mg/kg)合用组.大鼠给药后不同时间点Res的血药浓度用高效液相色谱法测定,并用DAS3.0软件处理计算Res药动学参数.结果表明,不管是灌胃给药,还是静脉注射给药,冰片对反式白藜芦醇大鼠体内药动学均有明显影响.尾静脉注射给药中,单用Res对照组的药-时曲线下面积AUC0~∞为(127.04±29.84)mg/(L·min),血浆药物总清除率CLz为(0.088±0.029)L/(min·kg).低、中剂量冰片对Res的药代动力学无显著影响,高剂量冰片使血浆中Res的AUC(0~∞)增大了73.6%,CLz降低了42.1%,且与对照组相比差异具有统计学意义(P0.05).表明高剂量冰片可促进Res的吸收,降低Res的体内清除.1     

盐地碱蓬幼苗水提取物对小鼠非特异性免疫功能的影响

通过小鼠刚果红吞噬试验,初步研究了盐地碱蓬幼苗水提取物对小鼠非特异性免疫功能的影响.在采用相同剂量、不同时间间隔和不同给药次数的试验方法下,将盐地碱蓬幼苗水提取物A,B,C分别灌胃给药,结果表明水提取物A和C具有显著增强机体非特异性免疫的功能,其中以C（间隔12h给药,共给药4次）的效果最为显著,而B的效果不明确.初步揭示了盐地碱蓬幼苗水提取物的一些药效学和药物代谢动力学特点.     

复方氨酚右敏溶液在健康人体的药代动力学研究

研究复方氨酚右敏溶液在健康人体的药代动力学.12名健康受试者以自身为对照采用随机交叉给药方式,单次空腹口服3个剂量复方氨酚右敏溶液(低、中、高3个剂量分别为7.5、15、30 mL,每mL含对乙酰氨基酚32 mg、马来酸右氯苯那敏0.1 mg).用液相色谱-串联质谱法(LC-MS/MS)测定血浆中对乙酰氨基酚和马来酸右氯苯那敏的浓度,计算2种药物的药代动力学参数,评价其药代动力学特征.对乙酰氨基酚在人体内的动力学过程符合二室模型,低、中、高3个剂量主要药代动力学参数消除半衰期t1/2分别为(2.93±0.47)、(3.08±0.43)、(3.01±0.49) h,血药质量浓度时间曲线下面积AUC0～t分别为(12.29±3.91)、(27.80±7.64)、(60.41±17.24) μg·h·mL-1;右氯苯那敏在人体内的动力学过程符合一室模型,低、中、高3个剂量主要药代动力学t1/2分别为(20.49±7.86)、(19.66±5.05)、(19.96±6.48) h;AUC0～t分别为(32.61±13.65)、(67.58±23.31)、(158.12±56.44) ng·h·mL-1.对乙酰氨基酚和右氯苯那敏药动学参数ρmax、AUC0～t、AUC0～∞均与给药剂量呈线性相关(P<0.001),复方氨酚右敏溶液在7.5～30 mL剂量范围内呈线性人体药代动力学特征.     

药物载体新技术——“分子伞”

迄今,已上市的药物其剂型虽然种类繁多,但绝大多数药物在到达病灶之前都会遭到体内消化系统或其它系统的分解与破坏。为达到预期的治疗效要,药(?)学家不得不加大药物剂量。可是,加入用药剂量不仅增加厂药物对人体的副作用,而且还加重了病者的药费负担。那么,有无一种剂量小、药效高的给药新途径呢?美国科研人员经过多年的研究,终于找到解决这一难题的方法,这就是“分子伞”给药新技术。     

盐地碱蓬幼苗水提取物对小鼠非特异性免疫功能 …

通过小鼠刚果红吞噬试验，初步研究了盐地碱蓬幼苗水提取物地小鼠非特异性免疫功能的影响。在采用相同剂量、不同时间间隔和不同给药次数的试验方法下，将盐地碱蓬幼苗水提取物Ａ，Ｂ，Ｃ分别灌胃给药，结果表明：水提取物Ａ和Ｃ具有显著增强机体非特异性免疫的功能，其中以Ｃ（间隔１２ｈ给药，共给药４次）的效果最为显著，而Ｂ的效果不明确。初步揭示了盐地碱蓬幼苗水提取物的一些药效学和药物代谢动力学特点。     

纳微多药给药系统的设计与研究

化疗是肿瘤等重大疾病的主要治疗手段,但由于肿瘤复杂的发病机制以及耐药性的产生极大地限制了传统单一化疗药物的临床应用.基于联合给药策略的多药给药系统,具有同时装载多种药物和药物释放行为的可控性等特点.主要就纳微多药给药系统的背景以及设计研究现状展开综述,希望为后来的研究给以启发.     

MAOA 在诱导前列腺癌神经内分泌分化中的作用

摘要:目的 建立神经内分泌性前列腺癌( neuroendocrine prostate cancer,NEPC) 细胞模型和动物模型,探讨单胺氧化酶 A( monoamine oxidase A,MAOA)在前列腺癌神经内分泌分化( neuroendocrine transdifferentiation,NED) 中的作用及机制。 方法 选取人前列腺癌细胞系 C4-2,通过恩杂鲁胺( enzalutamide,ENZ)长期诱导获得 NEPC 细胞模型;通过酶活性实验、Real-time PCR 和 Western blot 技术检测 NED 过程中 MAOA 的水平变化;使用 MAOA 抑制剂氯吉灵( clorgyline,CLG)检测 MAOA 对神经内分泌标志物的影响并探讨其潜在机制;建立前列腺癌异种移植模型,体内实验验证 MAOA 与 NED 之间的相关性。 结果 ENZ 可作为诱导 NEPC 模型的方法;在 ENZ 引起的 NED 过程中,MAOA 的表达和活性增加;抑制 MAOA 的活性可以延缓 NED 的发生,这可能是 MAOA 通过抑制缺氧信号实现的。结论 MAOA 是促进 NED 和维持神经内分泌细胞特性的关键靶点,MAOA 抑制剂 CLG 可以延缓 NEPC 发生,可能作为前列腺癌患者的潜在治疗药物。     

并联机构动力学建模和控制方法分析

并联机构的动力学建模是其实现高速、高精度运动控制的前提条件．根据并联机构特点分析了4种动力学建模方法,即牛顿一欧拉方法、拉格朗日方法、拉格朗日一达朗贝尔方法和微分几何原理．分类阐述了并联机构的不同运动控制策略,其中包括基于运动学模型的控制、基于动力学模型的控制、基于性能的控制和冗余驱动控制．认为完备的动力学建模、动态参数辨识、自适应控制以及多目标优化控制等理论和技术是并联机构控制研究中需要解决的关键性问题．     

Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001

Cytochrome P450 17A1 (also known as CYP17A1 and cytochrome P450c17) catalyses the biosynthesis of androgens in humans. As prostate cancer cells proliferate in response to androgen steroids, CYP17A1 inhibition is a new strategy to prevent androgen synthesis and treat lethal metastatic castration-resistant prostate cancer, but drug development has been hampered by lack of information regarding the structure of CYP17A1. Here we report X-ray crystal structures of CYP17A1, which were obtained in the presence of either abiraterone, a first-in-class steroidal inhibitor recently approved by the US Food and Drug Administration for late-stage prostate cancer, or TOK-001, an inhibitor that is currently undergoing clinical trials. Both of these inhibitors bind the haem iron, forming a 60° angle above the haem plane and packing against the central I helix with the 3β-OH interacting with aspargine 202 in the F helix. Notably, this binding mode differs substantially from those that are predicted by homology models and from steroids in other cytochrome P450 enzymes with known structures, and some features of this binding mode are more similar to steroid receptors. Whereas the overall structure of CYP17A1 provides a rationale for understanding many mutations that are found in patients with steroidogenic diseases, the active site reveals multiple steric and hydrogen bonding features that will facilitate a better understanding of the enzyme's dual hydroxylase and lyase catalytic capabilities and assist in rational drug design. Specifically, structure-based design is expected to aid development of inhibitors that bind only CYP17A1 and solely inhibit its androgen-generating lyase activity to improve treatment of prostate and other hormone-responsive cancers.     

Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer

Recently, we identified recurrent gene fusions involving the 5' untranslated region of the androgen-regulated gene TMPRSS2 and the ETS (E26 transformation-specific) family genes ERG, ETV1 or ETV4 in most prostate cancers. Whereas TMPRSS2-ERG fusions are predominant, fewer TMPRSS2-ETV1 cases have been identified than expected on the basis of the frequency of high (outlier) expression of ETV1 (refs 3-13). Here we explore the mechanism of ETV1 outlier expression in human prostate tumours and prostate cancer cell lines. We identified previously unknown 5' fusion partners in prostate tumours with ETV1 outlier expression, including untranslated regions from a prostate-specific androgen-induced gene (SLC45A3) and an endogenous retroviral element (HERV-K_22q11.23), a prostate-specific androgen-repressed gene (C15orf21), and a strongly expressed housekeeping gene (HNRPA2B1). To study aberrant activation of ETV1, we identified two prostate cancer cell lines, LNCaP and MDA-PCa 2B, that had ETV1 outlier expression. Through distinct mechanisms, the entire ETV1 locus (7p21) is rearranged to a 1.5-megabase prostate-specific region at 14q13.3-14q21.1 in both LNCaP cells (cryptic insertion) and MDA-PCa 2B cells (balanced translocation). Because the common factor of these rearrangements is aberrant ETV1 overexpression, we recapitulated this event in vitro and in vivo, demonstrating that ETV1 overexpression in benign prostate cells and in the mouse prostate confers neoplastic phenotypes. Identification of distinct classes of ETS gene rearrangements demonstrates that dormant oncogenes can be activated in prostate cancer by juxtaposition to tissue-specific or ubiquitously active genomic loci. Subversion of active genomic regulatory elements may serve as a more generalized mechanism for carcinoma development. Furthermore, the identification of androgen-repressed and insensitive 5' fusion partners may have implications for the anti-androgen treatment of advanced prostate cancer.     

Translating cancer research into targeted therapeutics

The emphasis in cancer drug development has shifted from cytotoxic, non-specific chemotherapies to molecularly targeted, rationally designed drugs promising greater efficacy and less side effects. Nevertheless, despite some successes drug development remains painfully slow. Here, we highlight the issues involved and suggest ways in which this process can be improved and expedited. We envision an increasing shift to integrated cancer research and biomarker-driven adaptive and hypothesis testing clinical trials. The goal is the development of specific cancer medicines to treat the individual patient, with treatment selection being driven by a detailed understanding of the genetics and biology of the patient and their cancer.     

龙葵活性成分的研究

龙葵为我国传统的中草药.这种植物具有治疗多种疾病的药理作用,尽管这种植物药理活性的作用机制目前尚未完全阐明.近年来在抗肿瘤作用机制方面,无论是单味药物还是复方制剂,以及其提取物等,已受到了学者的广泛重视,特别是龙葵醇提取物在对抑制肿瘤生长机制方面的研究.     

参考模型自适应方法在主从对策中的应用

用参考模型自适应方法,处理两类参数未知的线性动态主从对策,得出相应的自适应鼓励策略,并指出了算法的收敛性。讨论建立在波波夫超稳定性与李雅普诺夫稳定性基础上。     

实现适应性系统管理的分布式多智能体框架

为了应对动态、多变环境给管理系统带来的复杂性，提出了基于分布式范型的多智能体框架．该框架由多个分布式智能体结点组成，结点间通过消息传递与会话机制来实现分布式的合作与协同．结点内的功能主体使用了基于信念机制的内核结构，使得每个结点在以目标驱动的方式展开各种诊断与恢复的同时，仍能以反应驱动的方式对环境的变化做出反应，从而高效地实现了本地适应性管理．通过一个网络资源管理实例的分析证明，在复杂、动态的环境下所提框架能有效地实现可扩展的适应性系统管理．     

Bioinformatics Analysis of the Relationship between Lifestyle and Prostate Cancer

In this study, we assessed the relationship between lifestyle and prostate cancer. We selected the Gene Expression Omnibus(GEO) dataset GSE10306 to analyze the expression levels of ataxin10(ATXN10), interferon related developmental regulator 1(IFRD1), formin-binding protein 1 like(FNBP1 L) and THO complex 2(THOC2) in prostate biopsies pre and post intensive nutrition and lifestyle intervention. Following a three-month intervention of nutrition and lifestyle, these genes showed a significant down-regulation. ONCOMINE database analysis showed that the four genes exhibited high expression in prostate cancer tissues compared with normal prostate tissues, which indicated that comprehensive lifestyle changes may modify the progression of prostate cancer mediated by altering the expression of ATXN10, FNBP1 L, THOC2 and IFRD1. Among the four genes, the high expression of IFRD1 was found to indicate a worse overall survival(OS) and disease-free survival(DFS). FNBP1 L and THOC2 were associated with CD8+ T cell infiltration of prostate cancer. We also speculated a possible regulatory network for lifestyle to influence miRNA, subsequently influencing the expression of relevant genes. Our findings suggested that these genes may be used as potential target sites for the treatment of prostate cancer.