十一酸睾酮二元醇质体凝胶剂体内外透皮特性研究

摘 要 目的：对十一酸睾酮（TU）二元醇质体凝胶进行体内外透皮考察。方法: 采用注入法制备TU二元醇质体,以卡波姆941为凝胶基质,制备TU二元醇质体凝胶剂;以小鼠皮肤为屏障,采用Franz扩散池法对其体外透皮特性进行考察;以大鼠为实验动物,背部给予TU二元醇质体凝胶剂后,于设定的时间点测定血浆中TU浓度,计算药动学参数,并与TU二元醇质体进行比较。结果: TU二元醇质体及其凝胶的体外累积透皮百分率Q与时间t均符合一级动力学模型,线性方程分别为：Q=8.68t+6.78（r=0.998 2）和Q=6.09t+3.09（r=0.999 3）,稳态透皮速率分别为8.68 μg·cm^-2·h^-1和6.09 μg·cm^-2·h^-1,24 h后TU在皮肤中的滞留量分别为（208.80±55.26）μg·g^-1和（225.60±38.90）μg·g^-1;大鼠体内TU二元醇质体及其凝胶的主要药动学参数分别为：Cmax（18.50±2.75）mg·L^-1和（20.80±2.42）mg·L^-1;tmax（6.20±0.14）h和（9.54±0.52）h;AUC0-48h（336.74±2.05）h和（486.30±1.68）h。结论:TU二元醇质体及其凝胶均呈现较好的体内外透皮特性,且在缓释性上凝胶剂表现更优。     

HPLC-MS/MS法测定大鼠血浆中长春花碱的浓度及药动学研究

摘 要 目的： 建立HPLC MS/MS法测定大鼠血浆中长春花碱的浓度。方法: 血浆样本加入适量内标,经乙腈直接沉淀蛋白后采用HPLC MS/MS进行分析。色谱柱采用Ultimate C18柱 (150 mm×2.1 mm,5.0 μm);流动相由乙腈 10 mmol·L^-1醋酸铵(含0.1%甲酸) (49:51)组成,柱温40℃;流速0.3 ml·min^-1;采用电喷雾离子源(ESI),以多反应监测方式(MRM)进行定量分析。长春花碱和内标长春新碱在正离子模式下定量分析离子对分别为m/z 811.4→m/z 224.2和m/z 825.4→m/z 807.4。结果: 长春花碱在0.475~ 950 ng·ml^-1内线性关系良好（r=0.997 1）,最低定量限为0.475 ng·ml^-1,提取回收率为89.15%~95.28%,日内、日间精密度RSD均不高于7.95%。药动学研究结果表明,长春花碱在大鼠体内的t1/2为（5.86 ±2.37）h,AUC(0-t)和AUC(0-∞)分别为（68.45±14.51）,（95.03±33.09）μg·L^-1·h。 结论:该方法分析速度快、灵敏、准确,为临床进一步研究长春花碱和药物转运体提供了基础。长春花碱在大鼠体内的浓度较低,半衰期较长。     

多西他赛长循环脂质体的制备与大鼠体内药动学评价

摘 要 目的：制备多西他赛长循环脂质体,并评价大鼠尾静脉给药的药动学特性。方法: 采用薄膜分散 挤出法制备多西他赛长循环脂质体,并对其粒径分布、Zeta电位和微观形态进行表征。将12只Wistar大鼠随机分为多西他赛注射液组和多西他赛长循环脂质体组,尾静脉给药剂量均为7.5 mg·kg^-1,采用HPLC法测定大鼠血中多西他赛的药物浓度,采用3P97程序计算多西他赛大鼠体内药动学参数。结果: 多西他赛长循环脂质体平均粒径为（109.2±28.6）nm,Zeta电位为（-15.8±2.7）mV。多西他赛注射液和多西他赛长循环脂质体在大鼠体内的t_1/2(α)分别为（0.19±0.05）h和（0.36±0.07）h;t_1/2(β)分别为（1.82±0.33）h和（17.93±1.37）h;AUC_0-t分别为（4.42±0.76）μg·mL^-1·h^-1和（33.73±3.52）μg·mL^-1·h^-1。结论:多西他赛长循环脂质体与市售多西他赛注射液相比,延长了药物在血浆中的滞留时间,能达到长循环目的。     

辛伐他汀固体脂质纳米粒的制备及在大鼠体内的药动学研究

摘 要 目的： 制备辛伐他汀固体脂质纳米粒,并研究其经灌胃给药后在大鼠体内的药动学特征。方法: 采用热熔乳化超声 低温固化法制备辛伐他汀固体脂质纳米粒,考察辛伐他汀固体脂质纳米粒的粒径分布、Zeta电位、包封率、微观形态及体外药物释放特性。研究辛伐他汀固体脂质纳米粒经灌胃给药后在大鼠体内的药动学特征。结果: 辛伐他汀固体脂质纳米粒平均粒径为(242.5±62.1) nm,多聚分散系数为0.225±0.031,Zeta电位为(-32.1±4.2) mV,包封率为(95.7±2.6) %,在24 h内平稳缓慢释药。辛伐他汀固体脂质纳米粒在大鼠体内的Cmax和AUC0 t分别为辛伐他汀混悬液的2.89倍和1.83倍。结论:辛伐他汀固体脂质纳米粒在大鼠体内能快速吸收,显著提高了药物在大鼠体内的生物利用度。     

黄芪、灯盏花素复方制剂对阿尔茨海默病大鼠记忆能力及血、脑组织中超氧化物歧化酶、过氧化脂质和乳酸脱氢酶的影响

摘 要 目的：探讨黄芪、灯盏花素复方制剂（HDs）对阿尔茨海默病（AD）大鼠红细胞、脑组织中超氧化物歧化酶（SOD）、过氧化脂质丙二醛（MDA）以及乳酸脱氢酶（LDH）的影响。方法: 随机将50只大鼠分为正常对照组、脑复康阳性对照组（0.15 g·kg^-1·d^-1,灌胃）、模型组以及HDs低剂量（HDs1,1.5 ml·kg^-1·d^-1,腹腔注射）、HDs高剂量组（HDs 2,3.0 ml·kg^-1·d^-1,腹腔注射）,以三氯化铝（5 mg·kg^-1·d^-1,灌胃）和D 半乳糖（40 mg·kg^-1·d^-1,腹腔注射）建立AD大鼠动物模型。90 d后,测定各组大鼠的近期学习记忆能力,检测各组大鼠红细胞、脑组织SOD、MDA以及LDH水平。结果: 与AD模型组比较,HDs各剂量组大鼠学习记忆能力明显提高,红细胞及脑组织中SOD、LDH的活性明显升高,MDA含量明显降低,差异均有统计学意义(Ｐ<0.05或Ｐ<0.01);但尚未恢复至正常水平（Ｐ<0.05或Ｐ<0.01）。HDs2组部分指标明显优于脑复康阳性对照药组和HDs1组(Ｐ<0.05或Ｐ<0.01)。结论:黄芪、灯盏花素复方制剂对AD大鼠的学习记忆障碍有明显的改善,能有效提高AD大鼠红细胞及脑组织SOD、及LDH的活性,降低MDA的浓度。     

HPLC测定大鼠血浆中雪胆甲素的浓度及其药动学研究

摘 要 目的： 建立灵敏、快捷测定大鼠血浆中雪胆甲素浓度的高效液相色谱法(HPLC),并应用于体内药动学特征研究。方法: 色谱条件：色谱柱：Dikma Diamonsil C₁₈(250 mm×4.6 mm, 5 μm),流动相：乙腈∶水(45∶55 ,v/v),检测波长: 212 nm,柱温: 35℃,流速: 1.0 ml·min^-1。采取大鼠静脉注射给药途径,于不同时间点采血测定血浆药物浓度,并用DAS2.0计算药动学参数。结果: 雪胆甲素血药浓度在0.146～ 14.060 μg·ml^-1范围内线性关系良好（r=0.999 3）;方法回收率为99.02% ～104.22%;提取回收率为84.74%～86.80%;日内、日间精密度RSD均＜5%,稳定性考察符合要求。应用此法测定大鼠尾静脉注射给药后的血药浓度并计算主要药动学参数,1.0,2.0,4.0 mg·kg^-1三个剂量组静脉给药后在大鼠体内均符合三室模型,主要药动学参数分别为t_1/2β(h):0.732±0.151,0.681±0.055,0.667±0.064; Vd(L·kg^-1):0.147±0.089, 0.131±0.095,0.153±0.047; CL(L·h^-1·kg^-1): 0.287±0.031,0.304±0.063, 0.318±0.029和AUC_0→∞(mg·h·L^-1): 3.646±1.124, 4.916±1.227,9.385±1.419。结论:该法快速、简便、准确,符合生物样品测定需求,可用于药动学研究。雪胆甲素静脉注射给药后在体内呈三室模型,代谢较快,具有线性动力学特征。     

益妇散治疗更年期综合征的实验研究

摘 要 目的： 通过观察益妇散的中药复方对去势大鼠血清性激素水平、下丘脑单胺类神经递质的影响,研究其治疗更年期综合征的作用效果。方法: 将60只SD大鼠随机分成5组：假手术组、去卵巢对照组、尼尔雌醇组、益妇散低、高剂量组。连续给药4周,然后测定下丘脑单胺类神经递质,测定血清性激素水平以及测定肾上腺、子宫和胸腺指数等。结果: 益妇散高剂量组去势大鼠的血清E2水平为(4.768±2.548)pmol·L^-1,肾上腺、子宫指数分别为(0.375±0.039)mg·g^-1,（1.572±0.194）mg·g^-1,与去卵巢对照组大鼠的血清E2水平（1.976±0.945）mg·g^-1,肾上腺、子宫指数（0.282±0.039）mg·g^-1,（1.236±0.423）mg·g^-1比较,差异有统计学意义。益妇散高剂量组能够有效地降低去势大鼠异常增高的5 羟色胺硫酸肌肝(5 HT)和5 羟吲哚乙酸(5 HIAA)水平,提高多巴胺(DA)的含量水平,与对照组相比,差异有统计学意义(P<0.01)。结论: 益妇散能够从多方面调节生殖内分泌功能,具有缓解更年期综合征的作用。     

前列康和非那雄胺治疗良性前列腺增生的对比研究

摘 要 目的： 比较前列康和非那雄胺治疗大鼠良性前列腺增生的疗效。方法: 36只Wistar大鼠随机分成3组,去势14 d后皮下注射丙酸睾丸酮5 mg·kg^-1,前列康组按成人剂量10倍剂量灌胃给药,非那雄胺组按0.1 mg·kg^-1灌胃给药,对照组给予等量的蒸馏水,21 d后处死,称取前列腺湿质量,量取前列腺体积,光镜观察前列腺组织病理学改变。结果: 前列康和非那雄胺组大鼠前列腺湿质量分别为 （0.467±0.061）g,（0.408±0.058）g;大鼠前列腺体积分别为（0.371±0.059）ml,（0.365±0.054）ml,均显著低于对照组大鼠（P＜0.05）。结论: 前列康能显著抑制模型大鼠的良性前列腺增生,其机制可能是通过抑制前列腺细胞的增殖而实现的。     

伏立康唑白蛋白纳米粒大鼠体内药动学与组织分布

摘 要 目的：制备伏立康唑白蛋白纳米粒,并考察其在大鼠体内药动学与及组织分布。 方法: 采用超高压微射流技术制备伏立康唑白蛋白纳米粒,并评价了白蛋白纳米粒的粒径分布、Zeta电位、外观形态以及体外释药行为;考察了伏立康唑白蛋白纳米粒在大鼠体内的药动学与组织分布特征。 结果: 本研究制备的伏立康唑白蛋白纳米粒平均粒径为（121.9±41.6）nm,PdI为0.197,Zeta电位为（-42.1±0.9）mV,呈球形或类球形分布;伏立康唑白蛋白纳米粒在0.5%吐温80磷酸盐缓冲液（pH 7.4）中24 h累积释放67.5%;大鼠体内药动学研究表明,伏立康唑白蛋白纳米粒和伏立康唑注射剂的AUC0-24分别为（98.27±1.42）和（105.32±1.45）g?h?L^-1,MRT0-24分别为（4.48±0.38）和（4.86±0.51）h;伏立康唑白蛋白纳米粒能增加药物在大鼠肝、脾、脑中的靶向性。 结论:伏立康唑白蛋白纳米粒在大鼠体内具有良好的肝、脾、脑中靶向性,可以提高药物治疗疗效。     

尼达尼布在家兔体内的药动学研究

摘 要 目的： 建立家兔血浆尼达尼布检测的高效液相色谱方法,研究尼达尼布在家兔体内的药动学。方法: 采用ZORBAX SB-C₁₈色谱柱为分离柱,以乙腈-0.1%三氟乙酸-水（35∶20∶45）为流动相,流速为1.0 ml·min^-1,检测波长为286 nm,柱温为35℃;以卡马西平为内标,血浆在碱性条件下经乙酸乙酯萃取后检测。雄性家兔6只,按20 mg·kg^-1的剂量耳缘静脉注射给予尼达尼布;分别在给药前和给药后不同时间点耳缘静脉采集血液,分离血浆待测。用DAS 3.0计算药动学参数。结果: 尼达尼布浓度在0.05～10.00 μg·mL^-1范围内线性关系良好（r=0.999 8）;低中高三个浓度（0.10,2.50,7.50 μg·mL^-1）的日内精密度RSD分别为5.55％、4.53％和2.74％,日间精密度RSD分别为6.15％、5.45％和3.15％;相对回收率分别为（98.50±5.47）％、（100.25±4.54）％和（99.94±2.74）％。6只家兔血浆尼达尼布浓度经DAS 3.0计算,尼达尼布的主要药动学参数如下：C_max为（3.01±0.35） μg·mL^-1,t_1/2为（4.38±1.53）h,AUC_0-t为（11.67±1.71）μg·h·mL^-1。结论:该方法简便、快速、准确,适用于家兔血浆尼达尼布浓度的测定及其药动学研究。尼达尼布在家兔体内呈一级动力学消除。     

Nachweis einiger Heilmittel in der Kniegelenksynovialflüssigkeit

Zusammenfassung Mittels Gaschromatographie und Dünschichtchromatographie wiesen die Autoren 11 Substanzen nach, welche durch Injektion oder nach Verabreichung per os in die Kniegelenksynovialflüssigkeit eindrangen. In ihrer Aufstellung konnten sie eine direkte Beziehung zwischen Struktur sowie chemischphysikalischen Eigenschaften der Substanz und ihrer Fähigkeit, aus dem Blut in die Kniegelenksynovialflüssigkeit einzudringen, nicht nachweisen, außer der Tatsache, daß Substanzen mit starker Affinität zu Eiweißstoffen erst in höheren Dosen nachweisbar waren.     

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.     

Emerging drugs for epilepsy

Epilepsy affects ≤ 1% of the world's population. Antiepileptic drugs (AEDs) are the mainstay of treatment, although more than a third of patients are not rendered seizure free with existing medications. Uncontrolled epilepsy is associated with increased mortality and physical injuries, and a range of psychosocial morbidities, posing a substantial economic burden on individuals and society. Limitations of the present AEDs include suboptimal efficacy and their association with a host of adverse reactions. Continued efforts are being made in drug development to overcome these shortcomings employing a range of strategies, including modification of the structure of existing drugs, targeting novel molecular substrates and non-mechanism-based drug screening of compounds in traditional and newer animal models. This article reviews the need for new treatments and discusses some of the emerging compounds that have entered clinical development. The ultimate goal is to develop novel agents that can prevent the occurrence of seizures and the progression of epilepsy in at risk individuals.     

盐酸达泊西汀中甲磺酸甲酯、甲磺酸乙酯及甲磺酸异丙酯的顶空毛细管GC-ECD法测定

建立了衍生化顶空毛细管气相色谱-电子捕获检测器(ECD)法测定盐酸达泊西汀中的甲磺酸甲酯(MMS)、甲磺酸乙酯(EMS)和甲磺酸异丙酯(IMS).应用碘化钠衍生技术,使用PW-5毛细管柱,载气为氮气,ECD检测,程序升温.MMS、EMS和IMS分别在0.03～0.30、0.05～0.50和0.05～0.50 μg/ml浓度范围内线性关系良好,平均回收率分别为63.5％、100.3％和96.2％,最低检测限分别为0.30、0.50和0.50 ng/ml.     

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.