尿酸酶-过氧化氢酶复合纳米脂质体对高尿酸血症小鼠的治疗作用

目的 考察硼酸-硼砂缓冲液制备的尿酸酶(UA)-过氧化氢酶(CA)复合纳米脂质体(UCLP)对高尿酸血症小鼠的治疗作用.方法 采用pH8.5的硼酸-硼砂缓冲液,运用逆向蒸发法制备UCLP,并考察测定UCLP中UA的最适温度和最适pH;建立小鼠高尿酸血症模型后,给予UCLP治疗,用相应试剂盒测定小鼠体内尿酸和过氧化氢的浓度.结果 UCLP中UA的最适温度为40℃,最适pH为8.0;UCLP组小鼠体内尿酸和过氧化氢的浓度均较UA组低.结论 UCLP能有效降低高尿酸血症小鼠体内的尿酸水平,同时降低体内过氧化氢的浓度.     

羧甲基壳聚糖包衣尼莫地平纳米脂质体药效学研究

目的：研究羧甲基壳聚糖（CMC）包衣尼莫地平（NMD）纳米脂质体对小鼠脑缺氧及脑栓塞的影响。方法：采用亚硝酸钠所致小鼠脑缺氧实验以及诱导剂致小鼠脑栓塞实验,观察CMC包衣NMD纳米脂质体对小鼠脑缺氧及脑栓塞的影响,并与市售NMD注射液,普通NMD脂质体,CMC包衣NMD脂质体,NMD纳米脂质体进行比较。结果：CMC包衣NMD纳米脂质体能显著延长小鼠亚硝酸钠中毒后的存活时间,提高小鼠对抗脑栓塞的能力。结论：CMC包衣NMD纳米脂质体对小鼠脑缺氧以及脑栓塞有明显的预防保护作用。     

天麻素纳米脂质体的制备及其体外释药特性研究

目的:研制天麻素（GTD）纳米脂质体,提高GTD的脑靶向性。方法:用正交设计筛选GTD纳米脂质体的最优处方,对其质量进行评定,并考察其体外释药特性。结果:GTD最优处方组成为:药脂比为1:20,胆固醇:卵磷脂为3:3,药物浓度为60%（w/w）,水化介质为PBS,pH 6.5。由最优制得的GTD纳米脂质体外形圆整,平均粒径为（77.13±7.60）nm,Zeta电位为（-8.35±0.35）mV（n=3）,平均包封率为（65.22±1.63）%（n=9）。体外释药符合Higuchi方程:Q=-0.201 2+0.412 4t^1/2（r=0.980 0）,具有明显的缓释特性。结论:GTD处方组成简单,质量较好,具有缓释性,为进一步体内脑靶向性研究奠定了基础。     

环孢素纳米脂质体的制备及在小鼠体内的组织分布

目的 :研究小鼠灌胃给予环孢素纳米脂质体后药物在主要脏器中的分布。方法 :利用旋转薄膜 超声法制备环孢素纳米脂质体、考察其形态、含量、包封率、粒径、多分散指数及Zeta电位。并以环孢素微乳软胶囊内容物为对照 ,小鼠灌胃给药 ,考察环孢素在全血及心、肝、脾、肺、肾、皮肤的分布特征。结果 :环孢素纳米脂质体均匀圆整 ,含量为 (3.14±s0 .0 6 ) g·L- 1,包封率为 (98.91± 0 .0 8) % ,粒径(6 4± 5 )nm ,多分散指数为 (43± 6 ) % ,Zeta电位为 13mv。给予环孢素纳米脂质体后药物在全血及各组织的AUC0 2 4 低于环孢素微乳软胶囊内容物的AUC0 2 4 ,而MRT值则较大。结论 :环孢素纳米脂质体未能进一步促进环孢素的吸收 ,但在一定程度上改变了它的体内分布 ,延长了MRT     

阿霉素磁纳米脂质体的制备研究

目的采用超小超顺磁纳米粒(USPIOs)作为内部磁性物质,制备阿霉素磁纳米脂质体,并探讨如何得到高效磁包封和药物包封的阿霉素磁纳米脂质体。方法采用逆相蒸发法,以USPIOs为磁核,制备阿霉素磁纳米脂质体,以透射电镜观察到的形态、磁纳米脂质体的粒径、其中包裹的铁含量、药物包封率为指标,考察阿霉素磁纳米脂质体制备时最佳的脂质和磁纳米粒比例。结果当USPIOs用量为1 mg·m L-1时,磷脂用量在6.5 mg·m L-1时,可形成包裹较完全的磁纳米脂质体。得到的磁纳米脂质体粒径为274.3 nm,包裹的铁含量可达(51.43±2.69)%,药物包封率可达(63.38±15.29)%。在4℃条件下放置1个月以内,形态仍较稳定。结论阿霉素磁纳米脂质体的形成与脂质体浓度和磁纳米粒浓度有很大关系,通过摸索条件,可得到最佳磁纳米粒包封率和药物包封率的磁纳米脂质体,这为下一步阿霉素磁纳米脂质体的性质考察奠定基础。     

紫杉醇纳米脂质体的制备及其在小鼠体内组织分布

目的制备紫杉醇新型纳米脂质体并研究其在小鼠体内组织分布。方法采用薄膜分散超声结合冷冻干燥制备紫杉醇纳米脂质体。小鼠尾静脉注射紫杉醇脂质体及市售紫杉醇注射液Anzatax,RP-HPLC检测小鼠各组织中紫杉醇浓度。梯形法计算紫杉醇在小鼠各组织的蓄积情况。结果紫杉醇纳米脂质体粒径<100 nm,药物包封率>80%。小鼠经iv给予剂量为3 mg.kg-1的紫杉醇脂质体和普通紫杉醇注射液,紫杉醇纳米脂质体在肝脾系统轻微蓄积,肝脏AUC0→8h仅仅提高34%,脾脏AUC0→8h提高6%。结论紫杉醇纳米脂质体基本没有改变紫杉醇注射液的组织分布,有望为临床提供更安全有效的紫杉醇新制剂。     

正交试验法优选鬼臼毒素纳米脂质体的制备工艺

目的确立鬼臼毒素纳米脂质体的最佳制备工艺。方法以包封率作为评价指标,正交试验法L9(34)优选制备条件。结果优选出鬼臼毒素纳米脂质体的制备工艺为磷脂∶胆固醇=4∶1,药物∶胆固醇=2∶5,PBS溶液浓度为1×PBS,旋转蒸发温度为30℃。结论所选工艺制备的成品符合脂质体的质量标准。     

紫杉醇纳米脂质体的制备与大鼠体内药动学

目的:制备紫杉醇新型纳米脂质体并研究其在大鼠体内的药动学。方法:采用薄膜分散超声结合冷冻干燥制备紫杉醇纳米脂质体。大鼠尾静脉注射紫杉醇脂质体及市售紫杉醇注射液Anzatax,血浆样品经乙醚提取后用反相高效液相色谱法(RP-HPLC)检测血浆紫杉醇浓度,并用3P87软件包估算药动学参数。色谱条件如下:色谱柱为Gemini ODS(150 mm×4.6 mm,5μm),流动相为0．035mol·L-1乙酸铵缓冲液(pH 5．0)-乙腈(45:50),流速1．0 mL·min,检测波长230 nm,地西泮为内标。结果:制备的紫杉醇纳米脂质体的体积权重粒径为(54.1±26．0)nm,包封率大于80％,符合药典规定,且24 h内与葡萄糖注射液配伍稳定。紫杉醇脂质体及市售紫杉醇注射液Anzatax经大鼠尾静脉注射后均符合二室模型,脂质体组的消除半衰期(t1/2β)显著长于Anzatax组[(3．38±0．39)vs．(2．49±0．63)h,P<0．05];其他药动学参数经方差分析均无显著性差异。紫杉醇脂质体与Anzatax的AUC0-8h比值为88．13％。结论:制备的紫杉醇纳米脂质体在大鼠体内的药动物参数与市售紫杉醇注射液Anzatax比较,t1/2β稍有延长,AUC0-8h值相近。     

尼莫地平纳米脂质体包封率测定方法的研究

目的　建立尼莫地平纳米脂质体的包封率测定方法。方法　以高效液相色谱法为分析手段 ,采用反透析法测定尼莫地平纳米脂质体的包封率。结果　反透析法透析平衡时间为 6h ,游离药物回收率符合要求 ;此法测得自制尼莫地平纳米脂质体的平均包封率为 85 6 9%± 3 13% ,10h内无渗漏 ,方法重现性好。结论　反透析法便捷、准确 ,适用于脂溶性药物尼莫地平纳米脂质体的包封率测定。     

紫杉醇纳米脂质体凝胶剂的制备及体外透皮研究

目的制备紫杉醇纳米脂质体凝胶剂,考察其粒径、粒径分布、包封率、体外释放度及透皮特性。方法采用薄膜蒸发高压微射流法制备紫杉醇纳米脂质体,以卡波姆为凝胶基质,研制紫杉醇纳米脂质体凝胶剂,采用正交试验探索最佳工艺。用粒径测定仪测定脂质体的粒径及其粒径分布,低速-超速相结合法测定包封率,透析膜扩散法进行体外释放试验,以离体小鼠皮结合改良Franz扩散装置考察其体外透皮特性。结果紫杉醇纳米脂质体的最佳工艺:卵磷脂的含量为2%,药物与磷脂质量比为1∶30,磷脂与胆固醇的质量比为10∶1。测得的粒径为81.8 nm;粒径分布系数为0.180;平均包封率73.2%。纳米脂质体凝胶剂72 h累积释放百分率为79.04%;48 h的单位面积累积渗透量为429.68μg·cm?2。结论该制剂制备工艺简单,易于涂布,具有较高的包封率,粒径较小且分布均匀,体外释放缓慢。纳米脂质体能促进脂溶性药物紫杉醇透过皮肤。     

Preparation,optimization, and pharmacokinetic study of nanoliposomes loaded with triacylglycerol-bound punicic acid for increased antihepatotoxic activity

Punicic acid of pomegranate oil (PAP) has gained heightened interest due to several health benefits, such as anticarcinogenic, antidiabetic, and antiatherosclerotic properties. However, these bioactivities have been hampered by chemical instability, poor water solubility, rapid metabolism, and low bioavailability of PAP. Therefore, this study was aimed at optimizing the liposomal formulation of Triacylglycerol-bound punicic acid with its regioisomers (TPAR) for improved oral bioavailability and increased hepatoprotection through antioxidation and anti-inflammation. Herein, the optimized TPAR nanoliposome (TPAR-NL) was developed using thin-film dispersion method and subsequently characterized with appropriate indices. The optimized TPAR-NL produced fairly stable spherical nanoparticles (˂ 200 nm) with encapsulation efficiency (%EE) of 85.77%, as well as enhanced in vitro release and improved oral bioavailability. The TPAR-NL exhibited profound antihepatotoxic effect in mice pretreated with carbon tetrachloride (CCl₄) via reduction of serum alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels compared with free TPAR. The TPAR-loaded liposome also significantly reduced oxidative stress by increasing superoxide dismutase and glutathione levels while lowering malonaldehyde concentration compared with the free TPAR. The TPAR-LNF further exhibited remarkable anti-inflammatory activity compared with the free drug via inhibition of interleukin-6 and tumor necrosis factor-alpha generation. Thus, the developed nanoliposomes potentiated the antihepatotoxic activity of TPAR via antioxidation and anti-inflammation.     

牙周用交联淀粉碘微球软膏初步药效学研究

目的 对牙周用交联淀粉碘微球软膏(抗牙周炎药)进行初步药效学研究.方法 目测观察探诊出血(BOP)、牙龈指数(GI)指标,定期从实验部位取样,光学显微镜观测炎症部位的情况.结果 软膏对家兔的刺激性实验结果表明,软膏对家兔完整皮肤基本无刺激性;对于破损皮肤有轻度的刺激性;但是随着皮肤的愈合,刺激性减少并最终消失,说明软膏并不妨碍破损皮肤的愈合;软膏对家兔眼睛有轻微刺激性,使结膜轻度充血,症状在停药72 h之后基本消失.结论 交联淀粉碘微球软膏可以考虑作为治疗牙周炎的药物,适合长期给药.     

睾酮贴剂在性腺机能低下患者的药代动力学及药效学研究

目的研究性腺机能低下患者单次和多次外用睾酮贴剂的药代动力学和药效学。方法用多剂量、三周期、剂量递增、连续给药设计方案,12名原发性或继发性性腺机能低下的中国男性受试者外用2,4,6贴睾酮贴剂,用化学发光免疫试剂盒方法测定血清总睾酮浓度,计算其主要药代动力学参数。结果 7名受试者完成全部试验,单次外用2,4,6贴睾酮贴剂的主要药代动力学参数分别如下:Cmax为(5.65±3.47),(30.13±47.59),(37.64±41.55)nmoL.L-1;Tmax为(10.86±2.54),(8.00±1.63),(10.86±5.98)h;AUC0-t为(91.96±62.49),(197.01±144.75),(321.49±172.82)nmoL.h.L-1。多次外用睾酮贴剂后,血清总睾酮的主要药代动力学参数分别如下:Csmsax为(6.74±5.12),(16.89±11.15),(36.13±44.32)nmoL.L-1;Tmax为(8.86±3.44),(5.71±2.93),(7.71±2.43)h;AUC0ss-t为(110.92±60.49),(238.72±104.26),(416.62±278.66)nmoL.h.L-1。结论总睾酮的Cmax和AUC0-t随给药剂量的增加而增大。多次外用睾酮6贴后0～24 h血清总睾酮浓度均达到正常值范围。     

瑞舒伐他汀钙治疗中国高脂血症人群的药效动力学探索

目的：建立舒伐他汀钙治疗中国高脂血症人群的群体药效学模型,考察单位体重用药剂量和低密度脂蛋白胆固醇（LDL-C）的量效关系。方法：从已有的临床研究中,选择合适的受试者,提取其主要疗效指标（服用瑞舒伐他汀钙8周后LDL-C下降率）,及潜在的可能对LDL-C下降率有影响的指标（包括受试者所属试验、年龄、性别、体重和LDL-C基线值等）。用NONMEM软件进行模型拟合和群体药效学参数的估算。用Bootstrap法和蒙特卡洛模拟法分别对最终群体药效学模型进行验证和预测。结果：SigmoidalEmax药效学模型较好地拟合了瑞舒伐他汀钙治疗中国高脂血症人群的量效关系,所属试验、年龄、性别、体重和LDL-C基线值等因素对其无影响,最终模型的药效学参数Emax、ED50和γ分别为53.9%,0.072mg/kg和3.76,且参数的相对标准误均较小。Bootstrap法证明了最终模型具有较好的稳定性,蒙特卡洛模拟预测药效的95%可信区间包含了约50%受试者的实测药效。结论：本研究用群体分析方法建立了中国高脂血症人群应用瑞舒伐他汀钙的药效学模型,反映了约50%受试者用药后的药效学特征,说明除剂量外,影响药效因素众多,有待进一步探索。     

刺五加茎叶药效学研究

本文介绍了刺五加茎叶的药理作用,通过实验证明,刺五加茎叶有与刺五加根相同的药理作用,与盐水对照组比较各项指标均有显著差异。     

Pharmacokinetics and pharmacodynamics of azosemide

Azosemide is used in the treatment of oedematous states and hypertension. The exact mechanism of action is not fully understood, but it mainly acts on both the medullary and cortical segments of the thick ascending limb of the loop of Henle. Delayed tolerance was demonstrated in humans by homeostatic mechanisms (principally an increase in aldosterone secretion and perhaps also an increase in the reabsorption of solute in the proximal tubule). After oral administration to healthy humans in the fasting state, the plasma concentration of azosemide reached its peak at 3-4 h with an absorption lag time of approximately 1 h and a terminal half-life of 2-3 h. The estimated extent of absolute oral bioavailability in humans was approximately 20.4%. After oral administration of the same dose of azosemide and furosemide, the diuretic effect was similar between the two drugs, but after intravenous administration, the effect of azosemide was 5.5-8 times greater than that in furosemide. This could be due to the considerable first-pass effect of azosemide. The protein binding to 4% human serum albumin was greater than 95% at azosemide concentrations ranging from 10 to 100 microg/ml using an equilibrium dialysis technique. The poor affinity of human tissues to azosemide was supported by the relatively small value of the apparent post-pseudodistribution volume of distribution (Vdbeta), 0.262 l/kg. Eleven metabolites (including degraded products) of azosemide including M1, glucuronide conjugates of both M1 and azosemide, thiophenemethanol, thiophencarboxylic acid and its glycine conjugate were obtained in rats. Only azosemide and its glucuronide were detected in humans. In humans, total body clearance, renal clearance and terminal half-life of azosemide were 112 ml/min, 41.6 ml/min and 2.03 h, respectively. Azosemide is actively secreted in the renal proximal tubule possibly via nonspecific organic acid secretory pathway in humans. Thus, the amount of azosemide that reaches its site of action could be significantly modified by changes in the capacity of this transport system. This capacity, in turn, could be predictably changed in disease states, resulting in decreased delivery of the diuretic to the transport site, as well as in the presence of other organic acids such as nonsteroidal anti-inflammatory drugs which could compete for active transport of azosemide. The urinary excretion rate of azosemide could be correlated well to its diuretic effects since the receptors are located in the loop of Henle. The diuretic effects of azosemide were dependent on the rate and composition of fluid replacement in rabbits; therefore, this factor should be considered in the evaluation of bioequivalence assessment.     

吡硫翁锌乳膏对银屑病样模型小鼠的药效学研究

目的：研究吡硫翁锌乳膏抗银屑病的作用。方法：采用小鼠雌激素期的阴道上皮模型和鼠尾鳞片表皮银屑病样皮损模型,观察吡硫翁锌乳膏抗银屑病的作用。在小鼠雌激素期的阴道上皮模型中,吡硫翁锌乳膏经小鼠阴道给药,连续给药14 d,观察小鼠阴道上皮分裂指数的变化。在鼠尾磷片表皮银屑病样皮损模型中,吡硫翁锌乳膏被涂抹于小鼠尾部,连续给药14 d,观察鼠尾含有颗粒层的鳞片数目的变化,及对小鼠上皮细胞有丝分裂及表皮细胞分化的影响。结果：经吡硫翁锌乳膏处理后,小鼠阴道上皮分裂指数明显降低,鼠尾含有颗粒层的鳞片数目明显增加。结论：吡硫翁锌乳膏能明显抑制阴道上皮细胞分裂,促进尾鳞片表皮颗粒层形成,具有潜在的抗银屑病样的作用。     

蝙蝠葛碱在犬体内的药代动力学和药效动力学研究

目的　应用药动学药效学结合模型方法研究蝙蝠葛碱在犬体内的药代动力学和药效动力学之间的关系。方法　4只beagle犬给蝙蝠葛碱6mg·kg-1静脉注射后,分时取血及行心电、血压及血流动力学变化观察。采用反相高效液相紫外法测定血浆中蝙蝠葛碱的浓度。结果　蝙蝠葛碱主要药动学参数T1 /2α,T1 /2β,Vd,AUC分别为(0 049±0 016)h,(2 .7±0. 6)h, (15. 8±3 5)L·kg-1和(1. 48±0. 17)mg·h·L-1。对Q Tc的最大延长率为( 25 5±9 4 )%;SBP,DBP,±(dp/dt)max的最大抑制率分别为( 23 .0±4. 9 )%,(21 .9±5. 9)%, ( 42. 8±6 .6 )%和( 39 .0±17 .1 )%。药理效应滞后于血药浓度10 ~15min。药理效应与效应室浓度之间的关系符合sigmoid Emax模型。结论　建立了蝙蝠葛碱在犬体内血药浓度、时间、药物效应三者之间的关系。     

Formulation and characterization of catalase in albumin microspheres

Abstract

Catalase in albumin microspheres were formulated for intravenous administration to antagonize the effects of over-production of reactive oxygenated species (ROS) such as hydrogen peroxide (H₂O₂) in septic shock. The aim was to increase effective half-life of catalase and take advantage of the phagocytic uptake of the encapsulated catalase by the vascular endothelium. Catalase microspheres were prepared by spray-drying. The microspheres were evaluated for particle size, particle shape and surface morphology by scanning electron microscopy (SEM), drug encapsulation efficiency, chemical stability, thermal stability and in vitro drug release characteristics. The microspheres had a mean particle size of 4.7 ± 2 µm, optimal for phagocytic uptake, as demonstrated by Makino et al. SEM revealed that microspheres were spherical with smooth surface morphology. An encapsulation efficiency of 91.5 ± 3% was achieved and the encapsulated catalase was chemically and thermally stable. Application of in vitro drug release data to the Higuchi kinetic equation indicated matrix diffusion-controlled catalase release from albumin microspheres.