pH梯度结合逆向蒸发法制备槐定碱纳米脂质体及体外释放度研究

目的:采用pH梯度结合逆向蒸发法制备槐定碱纳米脂质体,对影响包封率和粒径的因素进行考察,并对其体外释放进行评价。方法:以正交设计及单因素实验考察影响脂质体包封率及粒径的主要因素,同时对优化后的脂质体进行了质量评价及体外释放度研究。结果:磷脂的浓度为5 mg.mL-1,药脂比为1∶15,胆脂比为1∶4,内水相的pH值为2.0,均质压力为100 bar时,制备的脂质体包封率可达(90.30±0.63)%,脂质体外观圆整均匀,平均粒径为(117±6)nm。结论:pH梯度结合逆向蒸发法制备的槐定碱纳米脂质体包封率高,粒径均匀,稳定性好,具有一定的缓释作用。     

紫杉醇磁性脂质体的制备与抗肿瘤作用研究

目的制备紫杉醇磁性纳米脂质体,并研究其对3种肿瘤细胞的抑制效果。方法应用超声薄膜分散法制备紫杉醇磁性纳米脂质体,通过正交设计来优化制备工艺,噻唑蓝（MTT）法研究其对肿瘤细胞的抑制效果。结果最佳处方和工艺条件为：磷脂酰胆碱：胆固醇为4：1,紫杉醇：（磷脂酰胆碱+胆固醇）为1：30,超声处理时间30 min,磁粉：紫杉醇为1：1,聚山梨酯 80：紫杉醇为4：1,聚乙二醇1 000：紫杉醇为8：1;制备的紫杉醇磁性纳米脂质体包封率约85.8%,平均粒径约150 nm;对3种肿瘤细胞均有良好的抑制效果,并呈现一定的缓释作用。结论该方法制备的紫杉醇磁性纳米脂质体包封率较高,分布均匀,对3种肿瘤细胞抑制效果较好,符合靶向制剂的要求。     

甘草次酸固体脂质纳米凝胶的制备及体外透皮效应

目的制备甘草次酸固体脂质纳米凝胶并考察其体外透皮效应。方法采用微乳液法制备甘草次酸固体脂质纳米粒并考察其包封率、粒径与表面电位,以研和法制备固体脂质纳米粒凝胶;采用改良Franz立式扩散池法进行体外透皮实验,HPLC法测定甘草次酸含量,评价甘草次酸固体脂质纳米粒凝胶的经皮渗透结果。结果甘草次酸固体脂质纳米粒外观为圆球形或椭球形;甘草次酸固体脂质纳米粒的包封率为64.75%±1.36%,粒径范围(46.13±20.10)nm,电位分布范围为(-53.4±7.11)mV。24h甘草次酸固体脂质纳米粒凝胶较甘草次酸固体脂质纳米粒的累积透过量提高66%。结论甘草次酸固体脂质纳米粒凝胶能提高甘草次酸的透皮速率,有望成为甘草次酸透皮给药的新型制剂。     

甲氨蝶呤柔性纳米脂质体凝胶的构建及体外经皮渗透性研究

目的 制备甲氨蝶呤(methotrexate,MTX)柔性纳米脂质体凝胶,并研究其体外经皮渗透行为.方法 采用逆向蒸发法制备MTX柔性纳米脂质体,以卡波姆940为基质制成脂质体凝胶,并考察其初步稳定性;Franz扩散池研究MTX柔性纳米脂质体凝胶与普通凝胶的经皮渗透规律.结果 脂质体凝胶4℃下稳定性良好;体外透皮试验表明,MTX柔性纳米脂质体凝胶的累积透过量明显＜MTX普通凝胶(P＜0.05),皮肤滞留量＞MTX普通凝胶(P＜0.05).结论 MTX柔性纳米脂质体凝胶可显著提高药物的皮肤滞留量,而不增加药物进入血液循环的量,能有效降低药物潜在的全身毒性,有望成为MTX局部治疗的新剂型.     

羟基喜树碱包衣纳米脂质体的制备及体外释药研究

目的:进行羟基喜树碱氯化壳聚糖包衣纳米脂质体(Nanoliposome,N-liposome)的制备及体外释药考察,以提高包封率和稳定性.方法:采用薄膜分散法制备羟基喜树碱脂质体并用氯化壳聚糖包衣,经高压均质机多次乳匀得到纳米脂质体(＜100nm),用激光粒度分析仪测定其zeta电位、粒径大小及分布,用不同冻干保护剂进行冷冻干燥,用透析法考察药物体外释药性质.结果:包衣纳米脂质体zeta电位为 55.1mV,平均粒径(ZAve)为91.9 nm,粒径分布为20～120 nm;以15%(W/V)的海藻糖做冻干保护剂的脂质体冻干前后粒径变化最小,再水化后平均粒径为98.2 nm,包封率为(61.2±1.2)%(n=3);氯化壳聚糖包衣脂质体外释药曲线符合Higuchi方程(Q=0.055 0.0228t1/2).结论:本试验制备的羟基喜树碱包衣纳米脂质体具有包封率高,稳定性好,大小均匀,以及体外能显著延缓药物的释放的性质.     

槲皮素长循环纳米脂质体的制备与质量评价

目的 制备槲皮素长循环纳米脂质体,并进行质量评价.方法 采用乳化蒸发-低温固化法制备槲皮素长循环纳米脂质体;以形态、粒径、包封率和载药量等作为纳米脂质体质量评价指标.结果 采用乳化蒸发-低温固化法制备的槲皮素长循环纳米脂质体平均粒径为172.63 nm,包封率为85.90%,载药量为23.55%.结论 该试验制备的槲皮...     

去氢骆驼蓬碱长循环磁纳米脂质体的制备及体外性质的研究

目的制备去氢骆驼蓬碱长循环磁纳米脂质体并对其体外性质进行考察。方法采用紫外分光光度法测定去氢骆驼蓬碱的质量浓度;采用逆相蒸发法制备去氢骆驼蓬碱磁纳米脂质体,并用被动载药法包裹去氢骆驼蓬碱;测定脂质体的粒径、电位、包封率、Fe2+质量浓度、释放度并进行电镜观察。结果建立了紫外分光光度法测定去氢骆驼蓬碱质量浓度的方法,去氢骆驼蓬碱在2.0~12.0μg·mL~(-1)范围内线性关系较好(r=0.999 6),回收率为102.0%。去氢骆驼蓬碱磁纳米脂质体的粒径为297.7nm;药脂比1∶10和1∶20的包封率分别为69.22%和84.55%;Fe2+质量浓度为189.1μg·mL~(-1),体外释放度符合Wuibull方程。结论被动载药法制备的去氢骆驼蓬碱长循环磁纳米脂质体包封率较高,粒径较好,体外释放度符合Wuibull方程。     

槲皮素纳米脂质体冻干粉针的制备及其质量评价

目的:研究槲皮素纳米脂质体冻干粉针的制备方法,并对其进行初步的质量评价。方法:以乳化蒸发-低温固化法和冷冻干燥法制备含有不同冻干保护剂的槲皮素纳米脂质体(QUE-NL)冻干粉,以包封率为评价指标,对制备工艺和处方进行单因素考察,并考察其理化性质,筛选出最佳配方。并对冻于粉针进行稳定性影响因素试验。结果:该法制得的脂质体包封率较佳;制备过程中,槲皮素纳米脂质体的包封率受药脂比影响较大,受胆固醇磷脂比影响较小;采用5%甘露醇+5%麦芽糖作为冻干保护剂冻干效果更好;所得冻于粉针对温度、光照较为敏感,也易受湿度影响。结论:5%甘露醇+5%麦芽糖是槲皮素纳米脂质体较合适的冻干保护剂,初步的稳定性考察结果表明,槲皮素纳米脂质体冻干粉针宜低温、避光、密封保存。以本试验方法制备的槲皮素纳米脂质体冻干粉粒径较小,包封率高,稳定性好,制备工艺合理可行。     

响应曲面法优化原花青素柔性纳米脂质体的制备

目的采用薄膜分散-超声法制备原花青素柔性纳米脂质体。方法以包封率为指标,采用响应面分析法设计试验,优化原花青素柔性纳米脂质体的制备工艺。结果原花青素柔性纳米脂质体最佳工艺参数为超声时间9 min,大豆卵磷脂与Tween 80的质量比10:1、大豆卵磷脂与药物的质量比17:1,在此优化条件下,测得的包封率为80.93%,平均粒径为(150.6±11)nm,zeta电位为(-23.76±2.3)m V,具有较好的体外缓释作用和较高的体外透皮性。结论响应曲面优选的原花青素柔性纳米脂质体的制备工艺实用可行。     

复方克林霉素脂质体凝胶的制备及体外透皮释药研究

目的制备复方克林霉素脂质体凝胶并考察其粒径分布、包封率及体外透皮特性。方法采用薄膜分散法制备复方克林霉素脂质体,利用透射电镜观察其形态,用激光纳米粒度仪测定其粒径大小及分布,用HPLC法测定其包封率。将脂质体进一步制成凝胶剂后,考察其体外透皮情况。结果复方克林霉素脂质体的粒径在240nm左右,分布均匀,平均包封率为51.24%;脂质体中的克林霉素能缓慢透过大鼠皮肤,缓释效果明显。结论该制剂制备工艺简单,性质稳定,药物包封率较高,定量测定方法简便、准确;药物透皮速率缓慢,释药稳定。     

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.     

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.

     

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.     

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.     

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.