豆豉溶栓酶肠溶片剂的制备及体外释放度

采用均匀设计优化豆豉溶栓酶肠溶片片芯的制备工艺。结果表明，按优化处方经工艺过程制得的片芯酶活性损失仅6％。包肠溶衣后的制品在0．1mol／L盐酸中2h平均累积释放率为2．1％；在0．2mol/L磷酸钠缓冲液（pH6．8）中，23．4min累积释药50％，45min释药86．3％，释药规律符合Weibull分布模型。     

麦考酚钠肠溶颗粒剂的研制

目的采用挤出-滚圆法制备麦考酚钠肠溶颗粒剂。方法以微晶纤维素KG802为填充剂,交联羧甲基纤维素钠为崩解剂,聚维酮K30为黏合剂,以丙烯酸树脂Ⅱ号、丙烯酸树脂Ⅲ号为肠溶衣膜材料,对不同配方组成进行湿法制粒、挤出、滚圆,制得肠溶颗粒。结果所制麦考酚钠肠溶颗粒剂在pH2.0盐酸溶液中2 h内累积释放率<1%,在pH6.8磷酸盐缓冲液中30 min累积释放率≥95%。结论以微晶纤维素KG802为填充剂、交联羧甲基纤维素钠为崩解剂、聚维酮K30为黏合剂,丙烯酸树脂Ⅱ号/丙烯酸树脂Ⅲ号(1∶1)混合物为肠溶材料,通过挤出-滚圆法能直接制得释放度符合要求的麦考酚钠肠溶颗粒剂。     

载葛根素的海藻酸镁胃内滞留释药系统的研究

采用滴制法制备微丸,选取海藻酸钠为载体材料,氯化镁为交联剂,碳酸氢钠为制泡剂,海藻酸钠与镁离子发生交联反应制得胃漂浮微丸,考察微丸的外观、粒径、微观结构、漂浮性以及释药行为。为延长药物在胃靶向长时间的释放,在单因素实验的基础上,以Eudragit L100和Eudragit RSALO作为载体材料制备载药固体分散体,粉碎过筛后加入海藻酸钠溶液中,依法制备载药固体分散体胃漂浮微丸,以Eudragit L100、Eudragit RSALO和药物的质量比为考察因素,评价其漂浮性和释放度。结果表明制得的载药固体分散体胃漂浮微丸持续9 h有超过95%的漂浮率,载药固体分散体微丸累积释放在5 h达到76% ~ 83%。本文制备的载药固体分散体胃漂浮微丸可在模拟胃液中持续漂浮并缓慢释放药物,为这类药物的胃漂浮给药系统的发展提供了思路。     

去氢骆驼蓬碱脂质体的制备和体外释放特性

目的：研究去氢骆驼蓬碱（harmine,HM）脂质体的制备工艺和体外释放特性。方法：运用薄膜分散-pH值梯度法制备HM．脂质体以及高速离心法分离脂质体与游离药物,并测定其包封率;借助综合评分法,评价其粒径、多分散系数、包封率、载药量指标;运用正交优化实验法考察磷脂-胆固醇与药-脂比、超声时间、外相pH值对脂质体的影响,述选最优工艺处方,评价脂质体与原料药的体外释放情况。结果：最优处方因素为磷脂-胆固醇比值为4：1,超声时间为300S,药-脂比值为1：5,外相pH值为6,8,即X13X23X32X43,经实验验证其粒径为（155.0±14．5）nm,多分散系数为（0．148±0．011）,包封率为（80．90±0．01）％,载药量为（11．16±0．01）％;其原料药0．5h累积释放百分比大于50％,不到2h已全部释放,而优化后的脂质体在1h内其累积释放百分比大于50％,4h后释放完成。结论：采用薄膜分散-pH值梯度法,以最优处方制得HM-脂质体,其粒径大小适中、形态均匀,包封率和载药量相对较高,体外释放显示具有较好的缓释特性。     

盐酸坦洛新胃漂浮缓释小丸的制备与体外释放

目的研制盐酸坦洛新胃漂浮缓释小丸并考察其体外释放特性。方法采用液中干燥法制备胃漂浮小丸,以收率、圆整度、平均粒径、释放度和漂浮性为指标,考察处方工艺因素对小丸性能的影响。结果圆整度较好,小丸收率质量分数在75%以上,随搅拌速度增加粒径减小,体外缓释8 h,漂浮效果较好。结论盐酸坦洛新胃漂浮缓释小丸具有较好的漂浮及缓释性能,是一种较理想的口服缓释制剂。     

单宁酶的固定化及性质研究

比较几种固定化载体，确定以壳聚糖为载体，用戊二醛作交联剂制得固定化单宁酶。壳聚糖用量0．1g，用3％戊二醛5ml交联4h，然后加入酶58．4u，于4℃反应4h，固定化酶活回收率可达73％。单宁酶经固定化后，热稳定性、pH稳定性及最适温度均有所提高，最适pH降低。     

醋氯芬酸缓释胶囊的制备

目的制备醋氯芬酸缓释胶囊。方法采用包衣锅法制备含药微丸，再以乙基纤维为包衣材料，以PEG6000为致孔剂，用包衣锅包衣，制备醋氯芬酸缓释胶囊，测定其体外释放度并对释药曲线进行模型拟合。结果制得的醋氯芬缓释胶囊体外24h内药物释放曲线符合零级方程Q=4．07t＋7．13（r=0．9946），12h和24h的累积释放百分率分别为40％～60％和90％～100％。结论所用制备方法合理可行，制得的醋氯芬酸胶囊释放效果良好。     

盐酸环丙沙星胃漂浮缓释片的制备及体外释放

以体外漂浮性能和释放度为指标优化盐酸环丙沙星胃漂浮缓释片的处方。结果表明，每片用量HPMCK100M为120mg、碳酸氢钠为200mg和羧甲淀粉钠为100mg的片剂能在1min内起漂，持续漂浮时间达8．2h，8h累积释放率达90％。按优化处方制备的片剂在高温（60℃）、强光（4500lx）下贮存10d，均保持稳定，高湿（相对湿度75％）条件下有吸湿现象。     

新型壳聚糖海藻酸钠胃漂浮小丸的制备

目的采用两种新的配方制备壳聚糖-海藻酸钠小丸,考察小丸干燥方法(-50℃冷冻真空干燥和50℃烘箱干燥)对小丸漂浮及药物缓释性能的影响.方法采用锐孔凝固浴法制备壳聚糖-海藻酸钠小丸,体外释药实验考察小丸的漂浮和释药情况.结果通过改变小丸的配方,使烘干小丸在37℃人工胃液中漂浮率达到100%,雷尼替丁释放时间最长能达到5h.其漂浮效果与成本较高的冷冻干燥法相当,且药物释放时间得到延长.结论新配方制备小丸在口服胃漂浮释药上有一定应用前景.     

延胡索乙素胃漂浮微球的体外漂浮及释药特征评价

目的 制备延胡索乙素(tetrahydropalmatine,THP)胃漂浮微球,考察THP胃漂浮微球在不同条件下的体外漂浮性能与释药特征。方法 采用乳化溶剂挥发法制备THP胃漂浮微球,模拟胃肠道环境,通过直接观察法考察THP胃漂浮微球在0.1 mol·L^-1盐酸溶液、pH 3.0 PBS、pH 4.5醋酸缓冲液、pH 6.8 PBS释放介质,50,100,150 r·min^-1转速条件下的漂浮性能;采用转篮法考察THP胃漂浮微球在上述释放条件下的体外释放特征;以罗通定片为参比制剂,比较两者在模拟胃酸环境的体外释放特征;采用常见的动力学模型拟合延胡索乙素胃漂浮微球的释药曲线。结果 THP胃漂浮微球在不同介质中均能立即起漂,持漂12 h,漂浮率为100%;在4种释放介质中12 h累积释放度分别为(90.55±4.65)%,(81.48±5.92)%,(66.24±3.00)%,(51.93±2.35)%;在3种转速下,12 h累积释放度分别为(84.26±3.22)%,(90.55±4.65)%,(94.70±2.15)%。在模拟胃酸环境(0.1 mol·L^-1盐酸溶液)下,罗通定片0.5 h累积释放度为(78.31±11.01)%,2 h基本释放完全,而THP胃漂浮微球12 h内释药速度平稳而缓慢,无突释现象,且释药完全。结论 该研究制备的THP胃漂浮微球体外漂浮性能较好,具有较好的缓释效果,其体外释放行为符合Higuchi方程。     

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.