克班宁透皮贴剂对佐剂性关节炎大鼠的抗炎作用

目的：考察克班宁制备成透皮贴剂后对佐剂性关节炎大鼠的抗炎作用。方法：将60只雄性Wistar大鼠随机分为6组,分别为正常组、模型组、甲氨蝶呤（MTX）组、克班宁贴剂低、中、高剂量组,每组10只。除正常组外,其余大鼠右后足趾皮下注射0.1 mL弗氏完全佐剂（CFA）造模,给药组于腹部脱毛区域给予克班宁透皮贴剂,MTX组腹腔注射给予甲氨蝶呤,正常组、模型组给予空白透皮贴剂,隔天给药1次,连续给药20 d。观察各组大鼠体质量、关节肿胀度、关节炎指数和免疫器官指数的变化,检测血清中肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6）水平,苏木素伊红（HE）染色观察大鼠踝关节病理变化情况。结果：与正常组相比,模型组体质量增长较慢,关节炎指数明显升高,右后肢关节严重肿胀,血清TNF-α、IL-1β和IL-6水平显著升高（P<0.01）,踝关节可见严重滑膜炎症、软骨侵蚀及骨破坏。与模型组相比,各给药组大鼠体质量增加较快,关节肿胀度降低（P<0.01）、关节炎指数降低（P<0.01）,血清中TNF-α、IL-1β、IL-6水平降低（P<0.01）,踝关节炎细胞浸润减轻,软骨破坏减弱。结论：克班宁透皮贴剂能明显改善佐剂性关节炎大鼠关节炎症和病理损伤,降低血清中炎症因子水平,说明克班宁透皮贴剂对佐剂性关节炎具有一定的治疗作用。     

瘦素在佐剂性关节炎大鼠血清中的表达及其在关节炎发病机制中的作用初探

目的：研究瘦素（leptin）在佐剂性关节炎（AA）大鼠血清中的表达，以及与IL-6的关系。以探讨leptin在类风湿关节炎（RA）发病机制中的作用。方法：通过给大鼠右后足足跖部皮下注射完全弗氏佐剂（CFA）建立类风湿关节炎（RA）的动物模型-AA。用放免法（RIA）测定AA大鼠血清中leptin，IL-6的表达水平。结果；AA组大鼠血清中leptin水平高于正常组，IL-6水平高于正常组，且血清中leptin的表达水平与IL-6呈显著正相关。结论：AA大鼠血清中leptin水平增高。并与IL-6呈显著正相关，leptin可能参与了RA的发病，为RA的治疗提供了新的途径。     

来氟米特与柳氮磺吡啶分别联合甲氨蝶呤治疗强直性脊柱炎对患者血清 IL-33、瘦素水平的影响

目的：观察来氟米特与柳氮磺吡啶分别联合甲氨蝶呤治疗强直性脊柱炎对患者血清白介素-33（IL-33）、瘦素水平的影响。方法将304例强直性脊柱炎患者随机分为 A 组（102例）、B 组（102例）、C 组（100例）。其中 A 组采用来氟米特联合甲氨蝶呤治疗,B 组采用柳氮磺吡啶联合甲氨蝶呤治疗,C 组采用单纯甲氨蝶呤治疗,比较3组患者治疗前后血清 IL-33、瘦素水平。结果治疗后3组患者血清 IL-33、瘦素均较治疗前明显下降（P ﹤0.05）,且治疗后 A、B 组血清 IL-33、瘦素水平均低于 C 组（P ﹤0.05）,而 A、B 组血清 IL-33、瘦素水平差异均无统计学意义（P ﹥0.05）。结论来氟米特与柳氮磺吡啶分别联合甲氨蝶呤治疗强直性脊柱炎的疗效均优于单纯甲氨蝶呤,且联合治疗的2组疗效未见显著性差异。     

蓍草总倍半萜内酯对类风湿性关节炎模型大鼠保护作用的实验研究

目的 探讨蓍草总倍半萜内酯对类风湿性关节炎（RA）模型大鼠的抗炎作用,并初步探讨其作用机制。方法 大鼠右后足跖皮下注射弗氏完全佐剂建立佐剂性关节炎大鼠模型,给予不同剂量蓍草总倍半萜内酯和雷公藤多苷药物干预21 d。通过检测大鼠关节肿胀度、关节炎指数和血清白介素（IL）-6、IL-1β、肿瘤坏死因子（TNF）-α水平等指标,观察蓍草总倍半萜内酯片对佐剂性RA大鼠的影响。结果 与模型组比较,蓍草总倍半萜内酯中、高剂量组在14、21、28 d大鼠足跖肿胀度显著低于模型组（P<0.05,P<0.01）,明显抑制了RA大鼠足关节肿胀度。蓍草总倍半萜内酯中、高剂量组在14、21、28 d大鼠关节指数显著低于模型组（P<0.05,P<0.01）。与模型组比较,蓍草总倍半萜内酯低、中、高剂量组均能够显著降低IL-6、IL-1β、TNF-α水平（P<0.05,P<0.01）,各剂量组的抑制作用呈剂量依赖性。结论 蓍草总倍半萜内酯具有较好的治疗大鼠RA作用,其作用机制可能与下调炎症因子IL-6、IL-1β、TNF-α水平有关。     

来氟米特药物代谢酶和转运体的基因组学研究进展

来氟米特是一种用于治疗免疫系统疾病的免疫调节剂,但由于存在药物不良反应,超过50%的患者在用药1年后停用该药。目前,药物遗传学研究表明单核苷酸多态性（SNPs）对来氟米特血药浓度有一定的影响,与类风湿性关节炎（RA）患者的有效性和耐受性存在潜在相关。体外研究表明,细胞色素P450酶CYP1A2、CYP2C19和CYP3A4参与来氟米特在机体内的代谢,CYP1A2*1F等位基因可能与RA患者的来氟米特不良反应相关。此外,二氢乳清酸脱氢酶（DHODH）基因rs3213422（19C>A）的C等位基因和雌激素受体（ESR1/2）的基因多态性可能与来氟米特的不良反应和治疗效果相关。本文总结了参与来氟米特体内过程相关代谢酶及转运体的基因多态性与来氟米特及其活性代谢物特立氟胺血药浓度、临床疗效以及药物不良反应的相关性,为深入研究来氟米特临床合理用药提供参考信息。     

四妙勇安方水提物对大鼠急性痛风性关节炎的治疗作用及其对外周血 IL-1β、TNF-α和 MIF 水平的影响

目的：探讨四妙勇安方水提物（SMYA）对急性痛风性关节炎（ AGA）大鼠的治疗作用及其对血清巨噬细胞移动抑制因子（MIF）、白介素-1β（IL-1β）、肿瘤坏死因子-α（TNF-α）水平的影响。方法将40只 SD 雄性大鼠随机分为4组：SMYA 组、秋水仙碱（COL）组、模型组、正常组,每组10只。SMYA 组与 COL 组每日分别予 SMYA 相当于生药1 g / kg、COL 0.8 mg / kg 灌胃,模型组与正常组每日给予等量生理盐水灌胃。药物干预第5天,于模型组、COL 组、SMYA 组大鼠左踝关节腔注射 PBS 配制的微晶尿酸钠结晶（25 mg / ml）100μl,复制 AGA 模型。分别于造模后1、2、4、6、8、12、24 h 使用游标卡尺记录每组大鼠踝关节肿胀程度。造模后24 h 对各组大鼠腹主动脉采血,离心,留取血清,采用酶联免疫吸附实验（ELISA）检测血清 MIF、IL-1β、TNF-α水平。结果 SMYA 组、COL 组及模型组踝关节肿胀度均于造模后8 h 达到高峰,之后缓慢下降。造模后4、6、8、12、24 h SMYA 组、COL 组及模型组踝关节肿胀度显著高于正常组（P ﹤0.05）,SMYA 组和 COL 组踝关节肿胀度显著低于模型组（ P ﹤0.05）,上述差异以8 h 时更为显著（ P ﹤0.01）;造模后12、24 h SMYA 组踝关节肿胀度显著低于 COL 组（P ﹤0.05）。与模型组比较,SMYA 组、COL 组 MIF、IL-1β、TNF-α表达显著减弱（P ﹤0.05）;与 COL 组比较,SMYA 组 MIF、IL-1β表达更强,TNF-α表达更弱（ P ﹤0.05）。结论 SMYA 对大鼠 AGA 具有显著治疗效应,其作用机制与抑制促炎细胞因子 MIF、IL-1β、TNF-α的表达有关。     

来氟米特对糖尿病肾病大鼠肾脏VEGF表达的影响

目的：研究氟米特对糖尿病肾病大鼠肾脏血管内皮生长因子（VEGF）表达的影响。方法：将48只清洁级雄性Wistar大鼠随机分为正常对照组（A组）、模型对照组（B组）、来氟米特组（C组）和氯沙坦组（D组）。分别于糖尿病成模后8、12周处死,观察24h尿蛋白排泄量、尿素氮（BUN）、肌酐（Scr）、肾脏病理组织学改变、免疫荧光检测肾组织VEGF蛋白的表达,RT—PCR方法检测肾组织VEGF mRNA表达。结果：8、12周末糖尿病模型大鼠（B、C、D组）的Scr、BUN及24h尿蛋白较正常对照组（A组）均有显著增高（P〈0．01）;12周末时B、C、D组大鼠的Scr、BUN及24h尿蛋白均较8周时有所增加;来氟米特（LEF）干预组及氯沙坦干预组上述指标均低于B组,差异有统计学意义（P〈0．01）．但LEF干预组及氯沙坦干预组之间差异无统计学意义。结论：来氟米特和氯沙坦均对糖尿病大鼠肾脏损害有保护作用,其机制可能是通过增加VEGF表达而实现。     

藤茶提取物中二氢杨梅素对大鼠急性痛风性关节炎模型的影响

目的研究藤茶提取物中二氢杨梅素对大鼠急性痛风性关节炎模型中血清IL-1β、IL-8、TNF-α的影响,初步探讨其治疗急性痛风性关节炎的作用机制。方法采用踝关节腔内注射尿酸钠建立急性痛风性关节炎大鼠模型,以秋水仙碱为对照,观察藤茶提取物中二氢杨梅素对各组大鼠的踝关节肿胀度及血清TNF-α、IL-1β及IL-8水平的调节作用。结果模型组关节肿胀度、IL-1β、IL-8和TNF-α的水平明显高于空白对照组(P<0.05或P<0.01);中高剂量的二氢杨梅素能明显抑制急性痛风性关节炎大鼠的踝关节肿胀度,降低血清TNF-α、IL-1B及IL-8的水平。结论藤茶提取物中二氢杨梅素对急性痛风性关节炎具有良好的治疗作用,其作用机制与抑制血清IL-1β、IL-8和TNF-α的产生有关。     

来氟米特治疗类风湿性关节炎36例临床观察

目的观察来氟米特治疗类风湿性关节炎（RA）的临床效果。方法72例RA患者随机分为治疗组和对照组,各36例。治疗组给予来氟米特治疗,对照组给予甲氨蝶呤治疗。观察2组症状、体征改善情况,比较2组临床疗效及不良反应发生情况。结果2组患者主要症状及体征较治疗前均有显著改善,差异均有统计学意义（P〈0.01和P〈0.05）,治疗组治疗后关节疼痛度、压痛指数明显低于对照组,差异有统计学意义（P〈0.05）;2组总有效率比较差异无统计学意义（P〉0.05）。结论来氟米特治疗RA能够显著缓解症状,改善病情,安全有效,值得临床推广应用。     

基于PPAR-γ/NF-κB信号通路探究芍甘附子汤对胶原诱导性关节炎大鼠的干预作用及作用机制

目的观察芍甘附子汤对胶原诱导性关节炎(CIA)大鼠的干预作用并探讨其作用机制。方法 Wistar大鼠随机选取12只为正常组,其余大鼠制备CIA大鼠模型。于首次免疫后第14日,依据分层分配原则将造模成功的大鼠分为模型组,芍甘附子汤低(1.05 g·kg-~1)、中(2.1 g·kg-~1)、高(4.2 g·kg-~1)剂量组,雷公藤多苷片组(9 mg·kg-~1),每组15只。于首次免疫后第15日各组按相应剂量进行药物干预,正常组及模型组灌胃同等量生理盐水,连续4周。分别于首次免疫后第14、21、28、35、42日进行关节炎指数(AI)评分。于末次给药24 h后麻醉大鼠,收集血清,并取踝关节,采用HE染色和Micro-CT扫描观察其病理及影像学改变。检测血清PGE_2、TNF-α、IL-1β、IL-6、NO含量,免疫组织化学法检测踝关节组织PPAR-γ、NF-κB p65、p-NF-κB p65、COX-2、iNOS蛋白表达。结果同正常组相比,模型组大鼠足跖出现明显肿胀,血清PGE_2、TNF-α、IL-1β、IL-6、NO水平升高(P<0.01),踝关节滑膜增生,炎细胞浸润,骨质破坏,踝关节NF-κB p65、p-NF-κB p65、COX-2、iNOS蛋白表达上调,PPAR-γ蛋白表达显著降低。同模型组相比,芍甘附子汤可不同程度降低AI,降低血清PGE_2、NO、TNF-α、IL-1β、IL-6水平,改善踝关节病理损害,降低病理评分,下调踝关节NF-κB p65、p-NF-κB p65、COX-2、iNOS蛋白表达,上调PPAR-γ蛋白表达。结论芍甘附子汤对CIA大鼠关节肿胀及病理损害具有改善作用,作用机制可能与其调节PPAR-γ/NF-κB信号通路有关。     

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.     

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.