肝靶向氟尿嘧啶类脂纳米粒的研究

目的　为了提高氟尿嘧啶(5-Fu)的疗效,降低其毒副作用,制备具肝靶向的5-Fu类脂纳米粒。方法　利用氟尿嘧啶与硬脂酰氯进行反应,制备了5-Fu前体药物N₁-硬脂酰-5-Fu,通过红外光谱及核磁共振谱对合成的目标化合物进行结构确认。同时研究了前体药物的性质及稳定性。采用物理凝聚法制备类脂纳米粒,并研究其形态、粒径及粒径分布、载药量、体外释药特征、动物体内分布与药代动力学参数等。结果　平均粒径d_av=240.19 nm,载药量为20.53%。体外释药速率符合一级动力学模型。与5-Fu水针剂比较,类脂纳米粒组在肝脏中药物含量平均增加了一倍以上。家兔体内主要药动学参数为：V_c=0.04336 L.kg^-1,T_1/2β=1.2834 h,CL=0.1632 L.h^-1。结论　利用前体药物可提高药物的脂溶性,首次以物理凝聚法制备类脂纳米粒,小鼠体内分布研究表明类脂纳米粒有明显的肝靶向,有一定的优越性和参考价值。     

冬凌草甲素固态类脂纳米粒在小鼠体内的组织分布及兔体内的药代动力学

目的考察冬凌草甲素固态类脂纳米粒在动物体内的组织分布及药代动力学特性。方法建立生物样品中冬凌草甲素的HPLC测定法，比较冬凌草甲素普通注射液和固态类脂纳米粒注射液的体内分布特点与药代动力学参数。结果冬凌草甲素固态类脂纳米粒在肝、脾、肺、心及肾中的相对摄取率分别为4.25%，3.44%，1.19%，0.52%和0.60%。静脉注射后的药-时曲线表明体内过程符合三室模型，其各相半衰期分别为T_1/2π=0.087 h，T_1/2α=1.65 h，T_1/2β=32.36 h，中心分布容积V_C=0.66 mL·kg^-1。结论冬凌草甲素固态类脂纳米粒能够增强药物的肝脾靶向性，提高药物生物利用度，并在一定程度上延长药物在动物体内的循环时间。固态类脂纳米粒可能成为冬凌草甲素的一种新型药物载体。     

他扎司特胶囊的人体相对生物利用度

目的 :研究国产他扎司特胶囊与日本产同类产品的人体相对生物利用度和生物等效性。方法 :采用 HPL C法测定 12名男性健康志愿者随机交叉单剂量 po75 m g两种他扎司特胶囊后体内活性代谢物 MTCC的血药浓度变化情况 ,计算药物动力学参数与相对生物利用度。结果 :试验品与参比胶囊的各项药物动力学参数分别为 cmax:(1.18± 0 .2 8)和 (1.11± 0 .38) ︼g/ml,tmax:(0 .92± 0 .48)和 (0 .86± 0 .2 9) h;T1 / 2 :(2 .48± 1.31)和 (2 .45± 1.47) h;AU C0 - t:(2 .18± 0 .44 )和 (2 .11± 0 .5 5 ) ︼g/m l· h。经统计分析 ,两种制剂的药物动力学参数均无显著性差异 (P>0 .0 5 )。国产他扎司特胶囊的相对生物利用度为 (10 6 .5±2 1.5 ) %。结论 :两种胶囊具有生物等效性     

吡喹酮长循环纳米粒在家兔体内的药动学

健康成年家兔18只,随机分为3组,分别静注吡喹酮溶液、吡喹酮纳米粒和吡喹酮长循环纳米粒(10 mg/kg).以地西泮为内标,采用HPLC法测定家兔血浆中的吡喹酮.吡喹酮注射液和吡喹酮纳米粒的体内过程符合二房室模型,吡喹酮长循环纳米粒的体内过程符合三房室模型,3种制剂的主要药动学参数分别为:t1/2(1.27±1.56)、(1.13±0.66)和(23.82±8.94)h,CL(5.29±0.78)、(2.38±1.00)和(1.16±0.16)L·h-1·kg-1,AUC0→t(1.48±0.2 7)、(3.52±1.79)和(4.93±1.27) mg·h·ml-1,MRT(0.44±0.30)、(0.41±0.10)和(16.12±1.38) h.     

表柔比星在肿瘤患者体内的药物动力学

目的;研究表柔比星(Epi)在肿瘤患者体内的药物动力学.方法:11例肿瘤患者单次iv 60mg/m~2Epi,用HPLC测定Epi血药浓度,数据用3P87药物动力学程序进行模型拟合并计算药物动力学参数.结果:Epi的药-时曲线符合三室模型,其主要药物动力学参数分别为:T_(1/2p)=(0.052±0.018)h,T_(1/2(?))=(1.25±1.18)h,T_(1/2p)=(31.1±13.7)h,Vc=(23.9±11.2)ml,AUC=(2009±429)ng·h/ml,CL=(50.1±12.1)ml/h.结论:Epi在肿瘤患者体内分布迅速,消除缓慢.     

表面修饰的灯盏花素聚乳酸纳米粒的制备和大鼠体内药动学*

目的:制备灯盏花素聚乳酸纳米粒并对其进行了表面修饰,同时考察了游离药物和纳米药物经大鼠尾静脉注射后在动物体内的药动学。方法:采用自乳化溶剂扩散法制备灯盏花素聚乳酸纳米粒,并用泊洛沙姆188对纳米粒进行表面修饰,采用反相高效液相色谱法(RP-HPLC)测定纳米粒的包封率、载药量和血浆样品中灯盏花素的含量,药时数据采用DASver 1.0药代计算程序处理。结果:载药纳米粒平均粒径为177.2和319.6 nm,多分散指数分别为(0.11±0.01)和(0.12±0.02),平均包封率及载药量分别为(86.9±0.9)%,(8.0±0.2)%和(93.1±0.6)%,(8.5±0.1)%,游离灯盏花素iv后呈二室模型,t1/2β为(0.81±0.14)m in,纳米组则呈一室模型,2种粒径的纳米粒的t1/2β分别为(8.90±0.16)m in(177.2 nm)和(13.90±0.07)m in(319.6 nm)。游离灯盏花素和2种粒径的灯盏花聚乳酸纳米粒的AUC0~t分别为(158.82±69.96),(1 476.25±51.22)和(704.95±25.39)mg.m in.L-1。经t检验,游离药物与纳米药物之间的t1/2β和AUC0~t均有统计学差异(P<0.01)。结论:灯盏花素制成纳米粒后明显增加了药物在动物体内的半衰期,延长了药物在体内的循环时间,且不同粒径的纳米粒对药动学有一定的影响。     

解热药YL2000中小檗碱在正常和发热大鼠体内的药物动力学比较

目的　探讨解热药YL2 0 0 0中小檗碱在正常和发热大鼠体内的药物动力学。方法　采用高效液相技术分别测定正常大鼠和干酵母致发热大鼠血浆中小檗碱的含量 ,使用3P87软件处理小檗碱的时量数据 ,计算各药代动力学参数。结果　在正常和发热大鼠体内 ,小檗碱的达峰时间分别为(3 4± 0 3)h和 (0 3± 2 1)h(P <0 0 5 ) ,峰值血药浓度分别达 (0 15 4± 0 0 2 3)mg·L-1和 (0 2± 0 6 )mg·L-1,T1/ 2(ke)分别长达 (6± 3)h和 (6± 5 )h ,T1/ 2 (ka)分别为 (1 2±0 4 )h和 (0 1± 2 8)h ,CL/F(s)值分别为 (4 0± 1 9)mg·kg-1·h-1/ (mg·L-1)和 (6± 6 )mg·kg-1·h-1/ (mg·L-1) ,AUC( 0～T) 值分别为 (1 8± 0 3)mg·L-1·h-1和 (0 7± 0 5 )mg·L-1·h-1(P <0 0 5 )。结论　发热降低小檗碱在体内的AUC( 0～T) 。     

氟尿嘧啶炭纳米粒新型制剂在大鼠体内的药物动力学研究

目的对氟尿嘧啶(5-Fu)炭纳米粒新型制剂在大鼠体内进行药物动力学研究。方法采用高效液相色谱法测定大鼠经腹腔注射5-Fu炭纳米粒新剂型与普通剂型(20mg/kg体质量)后在大鼠体内的血药浓度,得出药-时曲线图及相关药物动力学参数。结果 5-Fu在0.1～100mg/L范围内,浓度与峰面积线性关系良好(r=0.9998),方法回收率为98.12%,日内和日间RSD均<12.0%。2种制剂药物体内处置均符合二室模型(W=1/C/C)。结论本文建立的5-Fu血药浓度测定方法及所获得的药物动力学参数,可为5-Fu相关制剂的临床研究提供参考;炭纳米粒新型制血药峰浓度显著大于普通剂型,且在较长时间内维持相对较高水平,有助于提高临床治疗效果。     

9-硝基喜树碱半固体脂质纳米粒的制备及大鼠的药动学研究

采用高温乳化蒸发-低温固化法制备9-硝基喜树碱(1)半固体脂质纳米粒,并考察其形态、粒径、包封率、z电位及大鼠静脉给药后体内药物动力学行为。结果表明,1半固体脂质纳米粒为圆形,具有明显可见的亲水性聚乙二醇“外壳”,粒径为223.3～249.1nm,包封率为77.9%～83.5%,z电位为-28.4～-22.2mV。分别用1半固体脂质纳米粒和溶液对大鼠静脉给药,体内药物动力学参数分别为:t1/2 (14.9±0.3)h和(1.2±0.6)h,AUC0～t(486±37)mg·h·L-1和(117±64)mg·h·L-1,MRT (19.3±0.7)h和(1.7±1.0)h。表明1半固体脂质纳米粒可延长体循环时间,提高生物利用度。     

大鼠血浆中环丙沙星的HPLC荧光分析检测法及其体内药物动力学研究

建立测定大鼠血浆中环丙沙星的RP HPLC荧光检测法和研究其体内的药物动力学。以格帕沙星为内标 ,血浆样品经乙腈沉淀蛋白 ,取上清夜进行HPLC检测。流动相为 0 0 5mol/L磷酸盐缓冲液( pH3 0 )—乙腈—甲醇 ( 77∶13∶10 ,v/v/v) ,荧光检测 ,λEX=2 76nm ,λEM=448nm。血浆样品在 0 0 0 2 5～ 0 5μg/ml范围内线性关系良好 ,平均提取回收率为 97 1% ,日间和日内精密度RSD均小于 8 0 % ,最低检测限达到 1 0ng/ml。环丙沙星在大鼠体内的过程符合双隔室开放型一级吸收动力学模型、药动学参数分别为 :T1/2(ka) =0 44h ,T1/2 (α) =0 92h ,T1/2 ( β) =5 6 6h ,Tmax=1 0 4h ,Cmax=0 35 μg/ml,AUC =1 86h·μg/ml。     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

Lung disease and PKCs

The lung offers a rich opportunity for development of therapeutic strategies focused on isozymes of protein kinase C (PKCs). PKCs are important in many cellular responses in the lung, and existing therapies for pulmonary disorders are inadequate. The lung poses unique challenges as it interfaces with air and blood, contains a pulmonary and systemic circulation, and consists of many cell types. Key structures are bronchial and pulmonary vessels, branching airways, and distal air sacs defined by alveolar walls containing capillaries and interstitial space. The cellular composition of each vessel, airway, and alveolar wall is heterogeneous. Injurious environmental stimuli signal through PKCs and cause a variety of disorders. Edema formation and pulmonary hypertension (PHTN) result from derangements in endothelial, smooth muscle (SM), and/or adventitial fibroblast cell phenotype. Asthma, chronic obstructive pulmonary disease (COPD), and lung cancer are characterized by distinctive pathological changes in airway epithelial, SM, and mucous-generating cells. Acute and chronic pneumonitis and fibrosis occur in the alveolar space and interstitium with type 2 pneumocytes and interstitial fibroblasts/myofibroblasts playing a prominent role. At each site, inflammatory, immune, and vascular progenitor cells contribute to the injury and repair process. Many strategies have been used to investigate PKCs in lung injury. Isolated organ preparations and whole animal studies are powerful approaches especially when genetically engineered mice are used. More analysis of PKC isozymes in normal and diseased human lung tissue and cells is needed to complement this work. Since opposing or counter-regulatory effects of selected PKCs in the same cell or tissue have been found, it may be desirable to target more than one PKC isozyme and potentially in different directions. Because multiple signaling pathways contribute to the key cellular responses important in lung biology, therapeutic strategies targeting PKCs may be more effective if combined with inhibitors of other pathways for additive or synergistic effect. Mechanisms that regulate PKC activity, including phosphorylation and interaction with isozyme-specific binding proteins, are also potential therapeutic targets. Key isotypes of PKC involved in lung pathophysiology are summarized and current and evolving therapeutic approaches to target them are identified.     

Gender-related symptoms and correlates of alcohol dependence among men and women with a lifetime diagnosis of alcohol use disorders

This study explored gender-related symptoms and correlates of alcohol dependence in a crosssectional study of 150 men and 150 women with a lifetime diagnosis of alcohol use disorders (AUD). Participants were recruited in equal numbers from treatment settings, correctional centres and the general community. Standardized measures were used to determine participants' use of substances, history of psychiatric disorders and psychosocial stress, their sensation seeking and family history of substance use and mental health disorders. Multivariate analyses were used to detect patterns of variables associated with gender and the lifetime severity of AUD. Men had a longer history of severe AUD than women. Women had similar levels of alcohol dependence and medical and psychological sequelae as men, despite 6 fewer years of AUD. More women than men had a history of severe psychosocial stress, severe dependence on other substances and antecedent mental health problems, especially mood and anxiety disorders. There were differences in family history of alcohol-related problems approximating same-gender aggregation. The severity of a lifetime AUD was predicted by its earlier age at onset and the occurrence of other disorders, especially anxiety, among both men and women. The limitations in the generalizability of these findings due to sample idiosyncrasies are discussed.     

Biochemical and molecular characterisation of cubozoan protein toxins

Class Cubozoa includes several species of box jellyfish that are harmful to humans. The venoms of box jellyfish are stored and discharged by nematocysts and contain a variety of bioactive proteins that are cytolytic, cytotoxic, inflammatory or lethal. Although cubozoan venoms generally share similar biological activities, the diverse range and severity of effects caused by different species indicate that their venoms vary in protein composition, activity and potency. To date, few individual venom proteins have been thoroughly characterised, however, accumulating evidence suggests that cubozoan jellyfish produce at least one group of homologous bioactive proteins that are labile, basic, haemolytic and similar in molecular mass (42-46 kDa). The novel box jellyfish toxins are also potentially lethal and the cause of cutaneous pain, inflammation and necrosis, similar to that observed in envenomed humans. Secondary structure analysis and remote protein homology predictions suggest that the box jellyfish toxins may act as α-pore-forming toxins. However, more research is required to elucidate their structures and investigate their mechanism(s) of action. The biological, biochemical and molecular characteristics of cubozoan venoms and their bioactive protein components are reviewed, with particular focus on cubozoan cytolysins and the newly emerging family of box jellyfish toxins.     

Dose tolerability of chronically inhaled voriconazole solution in rodents

Invasive pulmonary aspergillosis (IPA) is a fungal disease of the lung associated with high mortality rates in immunosuppressed patients despite treatment. Targeted drug delivery of aqueous voriconazole solutions has been shown in previous studies to produce high tissue and plasma drug concentrations as well as improved survival in a murine model of IPA. In the present study, rats were exposed to 20 min nebulizations of normal saline (control group) or aerosolized aqueous solutions of voriconazole at 15.625 mg (low dose group) or 31.25 mg (high dose group). Peak voriconazole concentrations in rat lung tissue and plasma after 3 days of twice daily dosing in the high dose group were 0.85 ± 0.63 μg/g wet lung weight and 0.58 ± 0.30 μg/mL, with low dose group lung and plasma concentrations of 0.38 ± 0.01 μg/g wet lung weight and 0.09 ± 0.06 μg/mL, respectively. Trough plasma concentrations were low but demonstrated some drug accumulation over 21 days of inhaled voriconazole administered twice daily. Following multiple inhaled doses, statistically significant but clinically irrelevant abnormalities in laboratory values were observed. Histopathology also revealed an increase in the number of alveolar macrophages but without inflammation or ulceration of the airway, interstitial changes, or edema. Inhaled voriconazole was well tolerated in a rat model of drug inhalation.