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。     

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。     

毛菊苣总倍半萜磁性纳米脂质体在小鼠体内组织分布和靶向效果

目的研究毛菊苣总倍半萜有效部位、脂质体和磁性纳米脂质体在小鼠体内的组织分布和靶向效果。方法采用高效液相色谱法,以山莴苣素的含量为评价指标,研究毛菊苣总倍半萜有效部位溶液组、脂质体溶液组和磁性纳米脂质体溶液组(加磁场)在小鼠体内不同组织器官的药物浓度;并以AUC0-12 h、平均滞留时间(MRT)和靶向效率(TE)、相对靶向效率(RTE)、靶向指数(TI)为指标评价不同剂型的靶向作用。结果尾静脉注射给药10 min后,磁性纳米脂质体组在心、肝、脾、肺、肾脏组织中山莴苣素浓度较有效部位组、脂质体组显著提高;在动物的肝部体外施加磁场,磁性纳米脂质体组肝部位的AUC0-12 h明显高于其他部位,MRT明显的延长,差异具有显著性(P0.01);TE仅在肝部有增加,且TI大于10。结论在外加磁场的作用下,毛菊苣总倍半萜磁性纳米脂质体可改变药物在动物体内的分布,延长药物的作用时间,提高药物在肝部位的特异性和靶向性。     

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     

甲基莲心碱纳米脂质体在小鼠体内组织分布的研究

目的：考察甲基莲心碱（Nef）纳米脂质体在小鼠体内的组织分布。方法：对小鼠尾静脉注射同剂量的Nef注射液和Nef纳米脂质体,于预定时间测定血浆及心,肝,脾,肺,肾,脑组织中的药物浓度,计算相关靶向参数：TI=（AUC0→∞）lip／（AUC0→∞）inj×100％,RTE：（TElip—TEinj）／TEinj×100％。结果：Nef纳米脂质体与注射液相比,脑组织中的TI,RTE分别为298．89％,64．08％。结论：本实验割备的Nef纳米脂质体具有较好的脑靶向性,值得进一步研究。     

HPLC测定紫杉醇纳米脂质体凝胶剂在小鼠皮肤中的含量

目的 考察紫杉醇纳米脂质体凝胶剂给药4 h后在小鼠皮肤各层中的含量分布情况。方法 采用胶带粘贴技术剥脱角质层,以HPLC测定紫杉醇在皮肤各层中的含量,比较紫杉醇脂质体凝胶剂以及紫杉醇凝胶剂在皮肤各层中的分布特点。结果 紫杉醇纳米脂质体给药4 h后在角质层和活性皮肤层中的药物含量分别为3.41,5.35 μg·cm^-2,与紫杉醇凝胶剂比较,能显著提高药物在皮肤中的滞留量（P<0.05）。结论 与紫杉醇凝胶剂相比,紫杉醇纳米脂质体能增加药物的皮肤滞留量。     

紫杉醇纳米脂质体在大鼠体内的药动学

目的对紫杉醇纳米脂质体在大鼠体内的药动学进行研究.方法大鼠尾静脉注射紫杉醇纳米脂质体及紫杉醇注射液,建立液相-质谱联用分析(LC-MS/MS)方法测定血浆中的紫杉醇药物浓度.结果血药浓度在0.2～1 000 μg·L-1范围内线性良好(r=0.999 6),方法回收率及提取回收率均大于90%,日内,日间精密度RSD＜15%.紫杉醇纳米脂质体及市售紫杉醇注射液血浓经时曲线均符合二室模型.t1/2α分别为(0.71±0.25)h和(0.438±0.023)h,t1/2β分别为(13.2±1.2)h和(7.8±1.4)h,AUC分别为(4 519.7±791.3)μg·L-1·h和(2 679.2±530.7 μg·L-1·h).结论本法灵敏度高,准确、可靠.与市售紫杉醇注射液相比,紫杉醇纳米脂质体有一定的长循环作用且可提高在大鼠体内的生物利用度.     

环孢素脂质微粒经小鼠皮肤给药的渗透机理研究

目的　研究普通纳米脂质体、柔性纳米脂质体及胆酸钠-磷脂混合胶团对环孢素经小鼠皮肤给药的渗透机理。方法　将含药载体非封闭性应用于离体或在体小鼠皮肤,测定了皮肤、接收介质和血液中环孢素含量。结果 离体条件下,应用柔性纳米脂质体和混和胶团后均能在接收液中检测到药物,但普通脂质体却不能。在体条件下,应用柔性纳米脂质体后8 h血药浓度到达峰值,而应用普通脂质体和混合胶团后在血中几乎未检测到药物。结论 柔性纳米脂质体在皮肤水合压力下发生变形,携药透过皮肤;普通脂质体主要与皮肤发生融合产生蓄积作用;混合胶团在水溶液状态下发挥其渗透促进作用。     

槐定碱纳米脂质体在大鼠体内药代动力学及组织分布研究

目的:研究槐定碱纳米脂质体静脉给药后在大鼠体内药代动力学及组织分布。方法:大鼠尾静脉注射给药后,采用HPLC法测定血浆药物浓度,比较盐酸槐定碱注射液、槐定碱纳米脂质体的药代动力学;另HPLC法测定各组大鼠心脏、肝、脾、肺、肾中4 h内的槐定碱浓度,分析药物组织分布情况。结果:槐定碱纳米脂质体的大鼠药时曲线AUC是普通注射液的2.42倍,体内滞留时间延长;各组织中槐定碱浓度均在0.5 h达最高后开始降低;与槐定碱注射液比较,静脉注射槐定碱纳米脂质体后4 h内的平均浓度在肝、脾中均升高,在其他组织中的浓度均降低。结论:槐定碱纳米脂质体能提高药物在肝、脾中的分布,具有肝、脾靶向性,尤其是肝靶向性。     

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。     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

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Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

In vitro studies on sterically stabilized liposomes (SL) as enzyme carriers in organophosphorus (OP) antagonism

This study describes a new approach for organophosphorous (OP) antidotal treatment by encapsulating an OP hydrolyzing enzyme, OPA anhydrolase (OPAA), within sterically stabilized liposomes. The recombinant OPAA enzyme was derived from Alteromonas strain JD6. It has broad substrate specificity to a wide range of OP compounds: DFP and the nerve agents, soman and sarin. Liposomes encapsulating OPAA (SL)* were made by mechanical dispersion method. Hydrolysis of DFP by (SL)* was measured by following an increase of fluoride ion concentration using a fluoride ion selective electrode. OPAA entrapped in the carrier liposomes rapidly hydrolyze DFP, with the rate of DFP hydrolysis directly proportional to the amount of (SL)* added to the solution. Liposomal carriers containing no enzyme did not hydrolyze DFP. The reaction was linear and the rate of hydrolysis was first order in the substrate. This enzyme carrier system serves as a biodegradable protective environment for the recombinant OP-metabolizing enzyme, OPAA, resulting in prolongation of enzymatic concentration in the body. These studies suggest that the protection of OP intoxication can be strikingly enhanced by adding OPAA encapsulated within (SL)* to pralidoxime and atropine.     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.     

Steroidal sapogenin contents in some domestic plants

In order to find out the values of the steroid resources for the future use. the compositions and contents of steroidal sapogenins from 13 domestic plants have been investigated. As a result,Dioscorea nipponica, D. quinqueloba andSmilax china were found to have large amount of diosgenin. And pennogenin inTrillium kamtschaticum andParis verticillata, yuccagenin inAllium fistulosum, hecogenin inAgave americana and neochlorogenin inSolanum nigum were appeared to be major steroidal sapogenins.