阿魏酸-磷脂复合物的制备及其物理特性

目的制备阿魏酸-磷脂复合物,提高阿魏酸的脂溶性,以期进行进一步的制剂研究。方法采用溶剂挥发法制备阿魏酸-磷脂复合物,并以单因素法优化制备工艺,对复合物进行红外及X-衍射分析,考察阿魏酸表观油水分配系数的变化。结果阿魏酸磷脂复合物的制备工艺为:以无水乙醇为溶剂,药物-磷脂投料摩尔比为1∶1,室温下磁力搅拌4 h,真空干燥;红外及X-衍射图谱验证了复合物的形成;阿魏酸-磷脂复合物在0.1 mol.L-1HCl中的表观油水分配系数显著提高。结论阿魏酸磷脂复合物提高了阿魏酸的脂溶性。     

人参皂苷Rb1磷脂复合物的制备及其理化性质研究

目的:制备人参皂苷Rb1磷脂复合物,并研究其理化性质。方法:以人参皂苷Rb1与磷脂的复合率为评价指标,对制备工艺进行单因素考察,并采用正交实验设计对处方进行优化。利用紫外光谱法、差示扫描量热法等对所得的磷脂复合物进行鉴定。测定磷脂复合物中Rb1的含量,并考察磷脂复合物在不同体系中的表观油水分配系数。结果:人参皂苷Rb1与磷脂形成了分子型复合物。最佳制备方法的复合率为99.92%±0.14%,其中Rb1的含量在99.00%以上。磷脂复合物在不同体系中的表观油水分配系数与原药相比均显著增加。结论:确定了人参皂苷Rb1磷脂复合物的最佳制备工艺,并且其磷脂复合物明显的提高了原药的脂溶性。     

羟甲香豆素磷脂复合物的制备工艺及形成机制

目的：提高羟甲香豆素的脂溶性,将其制备成磷脂复合物并研究形成机制。方法：采用溶剂挥发法制备羟甲香豆素磷脂复合物;以复合率为考察指标,采用单因素和Box-Behnken响应面试验优化工艺条件;采用差示扫描量热分析（differential scanning calorimetry,DSC）和傅里叶变换红外光谱法（Fourier transform infrared spectrometer,FTIR spectrometer）等探讨复合物形成机制。结果：确定羟甲香豆素磷脂复合物的最佳制备工艺为：反应溶剂为无水乙醇,药磷比为1：3,反应物质量浓度为10 mg·mL^-1,反应温度为50℃,反应时间为2.54 h。复合率为（95.72±0.35）%;DSC和FTIR表明羟甲香豆素磷脂复合物的形成主要依靠氢键作用;磷脂复合物可显著增加羟甲香豆素在水和正辛醇中的表观溶解度和油水分配系数。结论：羟甲香豆素与大豆磷脂通过氢键作用形成复合物并提高了药物的脂溶性,为后续制备成高包封率纳米粒奠定基础。     

匹维溴铵磷脂复合物的制备及其理化性质研究

采用单因素试验考察了反应溶剂、投料比、浓度、反应温度和反应时间对匹维溴铵磷脂复合物形成的影响.所得优化制备工艺条件为:以无水乙醇为反应溶剂,匹维溴铵浓度为5 mg/ml,匹维溴铵-大豆磷脂投料比为1:5,60℃反应2h.对制得的复合物进行紫外扫描、差示扫描量热及X-射线衍射分析,并考察了其溶解性能.结果表明,复合物中药物以无定形形态存在,且该复合物提高了匹维溴铵的表观油水分配系数.     

葛根素磷脂复合物的制备及其质量评价

目的:优化葛根素磷脂复合物的制备工艺,改善其理化性质。方法:采用正交设计优化复合物制备工艺,以溶剂法制备葛根素磷脂复合物,以IR表征复合物的结构。结果:葛根素磷脂复合物的优化制备条件为:无水乙醇作溶剂,卵磷脂为药物的1.5倍,30℃搅拌1h。测定葛根素的溶解度提高了2.18,油水表观分配系数提高了1.61倍。结论:磷脂可提高葛根素的溶解度、油水表观分配系数。     

人参皂苷磷脂复合物的制备与质量评价初步研究

目的确定人参皂苷与磷脂形成复合物的最佳工艺,并进行质量评价.方法以人参皂苷与磷脂的复合率为评价指标,采用正交实验设计,考察反应溶剂类型、药-脂比、药物浓度、反应时间、反应温度等因素对磷脂复合物形成的影响.考察人参皂苷磷脂复合物的外观、紫外吸收特点.结果确定人参皂苷磷脂复合物的最佳制备条件:30℃,以四氢呋喃为反应溶剂,反应时间为1 h,药-脂比为1∶1,药物浓度为20mg·mL-1.在此条件下复合率为94.5%.结论磷脂复合物显著改善了人参皂苷的理化性质.     

间苯三酚磷脂复合物的制备工艺筛选及其理化性质研究

目的:筛选制备间苯三酚磷脂复合物的工艺并考察其磷脂复合物的理化性质。方法:以间苯三酚与磷脂的摩尔比(A)、反应温度(B)及反应时间(C)为因素,间苯三酚与磷脂的复合率为指标,通过正交试验法优化间苯三酚磷脂复合物的制备工艺,检测复合物在不同溶剂中的溶解度及油水分配系数并与原料药比较,采用紫外、红外光谱扫描验证复合物的理化性质。结果:优选工艺条件A为1∶2、B为60℃、C为2h,复合率均为98%以上。与间苯三酚原料药相比,磷脂复合物在水、氯仿中溶解度以及油水分配系数均有增大。紫外、红外光谱证实药物与磷脂未形成新的化合物。结论:优选工艺后所制复合物可显著提高药物的溶解度和亲脂性。     

水飞蓟宾磷脂复合物自微乳给药系统研究

目的研制水飞蓟宾（SLB）磷脂复合物自微乳化胶囊并对其进行体外评价。方法通过单因素考察结合正交设计将SLB制成磷脂复合物,测定了该复合物的溶解度和油水分配系数,进一步制成自微乳给药系统。结果 SLB磷脂复合物的最佳工艺条件为,反应温度50℃,反应时间2 h,比例1∶2。按此最佳工艺条件制备SLB磷脂复合物,复合率为100%,其溶解度和油水分配系数分别为126.3μg.mL-1,166.64,其最佳自微乳给药系统（PMC）组成及比例为,复合物∶油酸乙酯∶吐温80∶丙二醇=12∶30∶45∶13。按最佳处方制备的SLB磷脂复合物-PMC在人工胃液中36 min内累积溶出百分率已达到80%。结论将水飞蓟宾制成磷脂复合物自微乳化胶囊能显著提高其体外溶出度。     

茶多酚磷脂复合物的制备及其抗氧化性能的研究

目的制备茶多酚磷脂复合物（TP-ph）,考察它的脂溶性和脂质过氧化性能,为实际应用提供依据。方法以茶多酚与茶多酚磷脂复合物在茶多酚特征吸收峰位置的吸收值差;以表观油水分配系数K值的测定考察茶多酚磷脂复合物包埋构成及完整性。考察对二苯代苦味肼自由基的抑制率;抗油脂脂质过氧化性能的测定考察比较茶多酚磷脂复合物的抗氧化性能。结果包埋构成及完整性指标显示茶多酚磷脂复合物显著降低了茶多酚在其特征峰位置的吸收值。茶多酚磷脂复合物与茶多酚的表观油水分配系数在两种脂溶性有机溶剂中的K值分别为27．4和4及115．9和0．00037。抗氧化指标考察显示茶多酚磷脂复合物和茶多酚对二苯代苦味肼自由基的单位质量抑制率分别为50％和94．1％。单位质量抗POV性能方面,在98％,78h末,T80-ph、迷迭香提取物、T80和Ve的POV值分别为106．67、165．3、200．3和202．8。结论用磷脂包埋茶多酚从构成和完整性指标看是切实可行的,茶多酚磷脂复合物显著增加了茶多酚的脂溶性。且茶多酚磷脂复合物显著增加了茶多酚的抗脂质过氧化性能。     

甘草黄酮磷脂复合物制备工艺研究

目的 采用正交试验法优化甘草黄酮磷脂复合物的制备工艺,改善其理化性质.方法 以甘草黄酮与磷脂的复合率为指标,在单因素法考察复合溶剂、复合温度、复合时间、初始浓度和投料比例对复合率的影响的基础上,采用正交设计法优化复合物制备工艺;并对所得磷脂复合物的表观溶解度进行考察.结果 甘草黄酮磷脂复合物的最佳制备工艺为:甘草黄酮与磷脂按1∶1.5 的质量比投料,于30 ℃ 乙醇中复合1.5 h,甘草黄酮的浓度为5 g· L-1.验证试验表明,在优化得到的工艺条件下,甘草黄酮与磷脂的复合率在96% 以上.复合物在水中的表观溶解度是甘草黄酮原料药的10.7倍.结论 优化得到的工艺稳定,磷脂复合物改善了甘草黄酮的溶解性质.     

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.