半乳糖化棕榈酰壳聚糖的分子量及取代度对载10-羟基喜树碱聚合物胶束包封率的影响

目的以10-羟基喜树碱(10-HCPT)为模型药物,研究壳聚糖分子量、棕榈酰基取代度对棕榈酰壳聚糖(P-CS)及半乳糖化棕榈酰壳聚糖(GP-CS)载药胶束包封率的影响。方法以不同分子量和棕榈酰基取代度的P-CS及GP-CS为载体材料,用透析法制备10-HCPT聚合物胶束,紫外分光光度法测定包封率,考察药物/载体比例对包封率的影响。结果在药物/载体质量比为0.04:1时,壳聚糖分子量为3万时,以棕榈酰基取代度为0.5mol的GP-CS(30Q-0.5-GP-CS)的胶束包封率较高,达到36.8%;壳聚糖分子量为5千时,以棕榈酰基取代度为0.9mol的GP-CS(5Q-0.9-GP-CS)的胶束包封率最高,达到35.7%。结论 30Q-0.5-GP-CS及5Q-0.9-GP-CS的聚合物胶束具有较高的载药包封率,可作为聚合物胶束材料。     

N-正辛基-N′-琥珀酰基壳聚糖胶束的制备及特征研究

目的:制备两亲性的N-正辛基-N′-琥珀酰基壳聚糖(OSC)胶束,并研究其制剂学特征。方法:采用超声方法制备OSC胶束,并考察OSC的胶束化行为、胶束的形态、粒径及ξ电位。结果:OSC胶束具有较低的临界胶束浓度,胶束粒子呈较规则的球形,粒径为200～250 nm,ξ电位在-40.0～-30.0 mV,且疏水链段取代度增加,粒径变大,临界胶束浓度降低。结论:OSC胶束具有较好的物理稳定性。     

TPGS修饰的羧甲基壳聚糖-大黄酸聚合物胶束的制备与表征

目的合成TPGS修饰的羧甲基壳聚糖-大黄酸(TPGS-CR)偶联物,其能在水中自组装成聚合物胶束,为难溶性抗肿瘤药物递送提供一个新型载体材料。方法通过酰化反应,将TPGS与大黄酸(R)接枝于羧甲基壳聚糖(CMCS)上,经FT-IR与~1H-NMR验证其结构。通过UV法测R取代度,HPLC法测定TPGS的取代度,荧光分光光度法测定CMC值,DLS法测定胶束的粒径、分布及电位,综合各因素,确定最佳合成工艺,并通过TEM和AFM观察其形态特征。通过MTT法评估TPGS-CR偶联物对HepG-2细胞毒性。用透析法初步考察其载药性能。结果 TPGS与R通过酰胺键接枝于CMCS上,形成TPGS-CR偶联物,确定n(TPGS)∶n(CMCS)∶n(R)=0.75∶1∶1为最佳合成投料比,此时R的摩尔取代度为(5.73±0.23)%,TPGS摩尔取代度为(0.28±0.05)%,粒径为(117.1±24.9) nm,Zeta电位为负值,对HepG-2细胞毒性较小,载药性能较好。结论所设计合成的TPGS-CR偶联物能在水中自组装成具有壳-核结构的胶束,粒径较小,可作为递送难溶性药物的载体材料。     

N-正辛基-N′-琥珀酰基壳聚糖胶束的制备及特征研究*

目的：制备两亲性的N-正辛基-N’-琥珀酰基壳聚糖（OSC）胶束，并研究其制剂学特征。方法：采用超声方法制备OSC胶束，并考察OSC的胶束化行为、胶束的形态、粒径及￡电位。结果：OSC胶束具有较低的临界胶束浓度，胶束粒子呈较规则的球形，粒径为200～250nm，￡电位在-40．0～-30．0mV，且疏水链段取代度增加，粒径变大，临界胶束浓度降低。结论：OSC胶束具有较好的物理稳定性。     

色胺酮纳米胶束的制备及其性质研究

目的制备色胺酮纳米胶束,改善色胺酮的水溶性,并进行体外性质考察。方法以二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000(DSPE-PEG2000)为载体,用溶剂挥发法制备色胺酮纳米胶束,通过正交实验筛选制备胶束的最佳条件,核磁共振氢谱(1 HNMR)验证色胺酮包载于纳米胶束,用芘荧光探针法测定其临界胶束浓度(CMC),用紫外分光光度计测定其包封率和载药率,动态光散射法测定胶束的粒径,以粒径、外观形态和包封率为指标考察胶束的稳定性。结果色胺酮纳米胶束的CMC为8.93×10-6mol·L~(-1),色胺酮与聚合物投药比为0.442 9∶1(mol∶mol),真空干燥1h,水化5min时,胶束的包封率为32.24%±1.37%,载药率为5.468%±0.39%。色胺酮纳米胶束平均粒径为112.5nm,平均分散系数为0.208,4℃条件下胶束可稳定15d以上。结论制备色胺酮纳米胶束,将色胺酮的溶解度提高至1.625mmol·L~(-1),为改善色胺酮生物利用度的研究奠定了基础。     

完全疏水化酰化壳聚糖的制备及反应条件的研究

制备了完全疏水化的脂肪长链酰化壳聚糖,并用元素分析、红外光谱和核磁共振进行表征.研究了反应条件对酰化度的影响,结果表明:在吡啶-氯仿(2:1)介质中,分子量最低的壳聚糖酰化度最高.通过对完全酰化产物进行选择性还原,可获得两亲性N,N-双酰化壳聚糖.     

pH敏感释药两亲性壳聚糖共聚物胶束的制备及其性质考察

目的在合成了两亲性接枝共聚物丁酰基-羧甲基-壳聚糖(butyryl-carboxymethyl-chitosan,BR-CM-CS)的基础上,采用化学键合载药方式结合透析法制备了阿霉素pH敏感两亲性共聚物胶束并对其相关性质进行考察。方法利用芘荧光探针技术测定胶束的临界胶束浓度(CMC);通过透析法结合紫外分光光度法测定胶束的载药量及包封率;分别利用透射电镜(TEM)、扫描电镜(SEM)、动态光散射法(DLS)和zeta电位分析仪对胶束及其冷冻干燥产品的形态、粒径和表面电位进行了表征;采用透析法考察了载药聚合物胶束的体外释放行为。结果胶束的CMC值为1.0 mg.L-1,载药量可达12.5%,包封率为89.1%;胶束的粒度分布很窄,平均粒径为205.2 nm;胶束粒子为类球形且分散良好,其表面zeta电位值为25.94 mV;胶束释药行为体现pH敏感性。结论以壳聚糖为载体的化学腙键释药胶束作为抗肿瘤药物的传递系统具有可行性及良好的应用前景。     

S-[2,3-二(棕榈酰基氧基)丙基]-N-棕榈酰半胱氨酸合成工艺的改进

以胱氨酸为原料，经N-酰化、还原、S-烃化及酯化等6步反应得到S-[2，3-二(棕榈酰基氧基)丙基]-N-棕榈酰半胱氨酸。其中还原反应用锌粉取代二硫苏糖醇，在二环己基碳二亚胺和二甲氨基吡啶条件下酯化，最后用三氟乙酸脱保护基得标题化合物。本法操作简单，总收率18．3％。     

N-辛基-O,N-羧甲基壳聚糖聚合物胶束对紫杉醇的增溶、缓释及其安全性初步评价

本文合成了一系列两亲性壳聚糖衍生物N-辛基-O,N-羧甲基壳聚糖(OCC),以透析法制备紫杉醇(PTX)-OCC载药聚合物胶束,并考察疏水烷基取代度对包封率、载药量、粒径和zeta电位的影响,通过透射电镜(TEM)观察其形态结构,并以市售制剂为对照;通过体外溶血实验、豚鼠急性过敏实验及小鼠尾静脉注射急性毒性实验初步评价其安全性.结果表明,OCC对PTX有良好的增溶效果,在疏水基取代度为37.9%～58.6%时,载药量为24.9%～34.4%,包封率为56.3%～89.3%,且随着疏水辛基取代度的增加,载药量和包封率皆显著提高.疏水烷基链进一步提高则可能破坏胶束亲水疏水平衡而导致载药能力降低;载药胶束粒径为186.4～201.1 nm,随疏水烷基取代度的增加而减小,zeta电位为-47.5～-50.9 mV,疏水烷基取代度对其无显著影响,TEM照片显示该聚合物胶束为规则球形结构,粒径分布均匀.OCC对紫杉醇具有优良的缓释效果,未见突释,15 d累计药物释放量在60%～95%,缓释能力随疏水基取代度的增加而增强.溶血实验、豚鼠急性过敏实验和小鼠尾静脉注射急性毒性实验结果表明,PTX-OCC溶血性和急性过敏反应低于市售制剂,PTX-OCC小鼠尾静脉注射的LD50及95%可信限为134.4(125.0～144.6)mg·kg-1,为市售制剂LD50的2.7倍.初步认为PTX-OCC是安全可靠的静脉注射用纳米制剂.     

叶酸介导肿瘤细胞靶向紫杉醇聚合物胶束的制备与表征

以叶酸-聚乙二醇-二硬脂酰磷脂酰乙醇胺(FA-PEG 3350-DSPE)和甲氧基聚乙二醇-二硬脂酰磷脂酰乙醇胺(mPEG 2000-DSPE)(摩尔比1:100)作为混合载体材料,采用固体分散-水化法,制备包载紫杉醇(1)的聚合物胶束,以星点设计-效应面法进行处方优化,并考察了聚合物胶束的理化性质、体外抑制肿瘤细胞生长效果及对巨噬细胞摄取的影响.结果表明,优化所得胶束的包封率为81%、载药量为2.7%、平均粒径为12～16 nm,可持续释放24 h;制品可有效提高1体外抑制肿瘤细胞生长的效果,加入1%的FA-PEG 3350-DSPE可略减弱mPEG 2000-DSPE规避巨噬细胞吞噬的效果.     

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.