硫酸茯苓多糖对抑郁症大鼠海马AMPA受体表达的影响

目的探讨硫酸茯苓多糖(SP)是否通过调节α-氨基-3-羟基-5-甲基-4-异恶唑丙酸(AMPA)受体的表达而生产抗抑郁作用。方法实验设假手术组、抑郁症模型组、SP(25,50和100 mg·kg~(-1))剂量组及SP(100 mg·kg~(-1))+GYKI 52466(3 mg·kg~(-1))剂量组,每组12只。大鼠卵巢摘除加慢性不可预知性温和应激(CUMS)法诱导抑郁症动物模型。连续灌胃和腹腔注射给药21 d。糖水消耗、强迫游泳及敞箱试验观察大鼠行为变化。尼氏染色观察大鼠海马神经元病理变化。免疫组化法观察海马脑源性神经营养因子(BDNF)的表达。Western蛋白印迹法检测海马AMPA受体GluR1、磷酸化GluR1及c AMP反应元件结合蛋白(CREB)、p-CREB和BDNF蛋白表达。结果与模型组相比,SP各给药组大鼠强迫游泳不动时间明显降低而自发活动明显增加,同时糖水摄入量及糖水偏爱百分比明显升高(P<0.05,P<0.01),海马神经元损伤显著减轻,GluR1和GluR1磷酸化水平及p-CREB和BDNF表达均明显升高。但与SP(100 mg·kg~(-1))剂量组相比,SP+GYKI 52466组大鼠强迫游泳不动时间又明显增加而自发活动又明显减少,糖水摄入量及糖水偏爱百分比又明显降低,海马GluR1和p-GluR1及p-CREB和BDNF表达又明显降低(P<0.01)。结论 SP具有抗抑郁作用,其机制可能通过增强海马GluR1受体功能,进而上调海马p-CREB和BDNF蛋白表达有关。     

雷公藤内酯醇对应激小鼠抑郁样行为及脑源性神经营养因子的调节作用

目的研究雷公藤内酯醇对抑郁模型小鼠抑郁样行为的改善及脑源性神经营养因子(BDNF)的影响。方法成年雄性ICR小鼠,每天选取8种刺激中的1种进行刺激应激,每日1次,共计14 d,制备慢性不可预知应激抑郁模型。每天应激前10 min,ip给予雷公藤内酯醇20,40,80和160μg·kg-1,第15天起,给予药物处理10 min后,每天检测一个行为学指标。采用自发活动实验测定运动总路程,强迫游泳实验和悬尾实验测定累计不动时间。采用Western蛋白印迹法检测小鼠海马和前额叶中磷酸化c AMP反应元件结合蛋白(p-CREB)和BDNF的蛋白表达。结果雷公藤内酯醇不影响小鼠的自主活动能力。慢性应激组表现出明显的抑郁样行为,给予雷公藤内酯醇80和160μg·kg-1后在强迫游泳实验的不动时间分别由慢性应激组的(160±18)s下降为(102±14)s(P<0.05)和(83±14)s(P<0.01),而丙米嗪(10 mg·kg-1)和氟西汀组(10 mg·kg-1)分别为(77±11)s(P<0.01)和(96±9)s(P<0.01)。给予雷公藤内酯醇40,80和160μg·kg-1后在悬尾实验中的不动时间分别由慢性应激组的(128±8)s下降为(93±9)s(P<0.05),(85±8)s(P<0.01)和(77±11)s(P<0.01),丙米嗪和氟西汀组分别为(64±9)s(P<0.01)和(72±6)s(P<0.01)。雷公藤内酯醇80和160μg·kg-1组海马内p-CREB蛋白表达增加(P<0.05),前额叶内p-CREB蛋白表达亦显著性增加(P<0.05)。雷公藤内酯醇80和160μg·kg-1组海马和前额叶中BDNF的表达显著性增加(P<0.05)。结论雷公藤内酯醇对慢性不可预知应激引起的小鼠抑郁样行为有一定程度的改善作用,且这种改善作用可能与其参与调节p-CREB-BDNF通路有关。     

肉苁蓉多糖对衰老过程中学习记忆影响的体内外作用

目的探讨肉苁蓉多糖对急性衰老模型保护作用的机制。方法 (1)采用D-半乳糖诱导PC12细胞损伤建立亚急性衰老模型,MTT法检测细胞存活率;(2)采用D-半乳糖建立亚急性衰老小鼠模型,Morris水迷宫实验观察肉苁蓉多糖对衰老所致小鼠学习记忆能力的影响;(3) ELISA法检测SOD和MDA含量及环腺苷酸(c AMP)、c AMP依赖蛋白激酶(PKA)和脑源性神经营养因子(BDNF)的含量;(4) Western蛋白印迹法及免疫组化检测CREB和p-CREB蛋白的表达;(5) HE染色观察脑组织神经元细胞形态学的变化。结果 (1)D-半乳糖16 g·L-1暴露PC12细胞40 h后,MTT检测细胞存活率达(46.67±6.59)%,与对照组比较差异具有统计学意义,表明成功建立了细胞衰老模型;(2)在水迷宫实验中,给药组小鼠逃避潜伏期及第1次到达站台时间明显缩短而穿越站台次数显著增加;(3)与模型组比较,给药组SOD水平提高,MDA水平下降。阻断剂H-89干预1 h后SOD水平提高,MDA水平下降;与模型组比较,给药组c AMP,PKA和BDNF均增加。阻断剂H-89干预1 h后c AMP,PKA和BDNF均减少;(4)与模型组比较,给药组p-CREB表达增加。阻断剂H-89干预1 h后p-CREB表达减少;(5)与模型组比较,给药组脑组织海马CA1区神经元数量增加,病理改变减轻。结论肉苁蓉多糖对衰老的神经细胞有明显的保护作用,并且可明显改善衰老模型小鼠的学习记忆能力,其机制与其抗氧化、抗凋亡和上调c AMP/PKA/CREB信号通路有关。     

西酞普兰联合石杉碱甲对老年抑郁模型大鼠的改善作用

目的:研究西酞普兰联合石杉碱甲对老年抑郁大鼠的改善作用。方法:将老年大鼠随机分为空白对照组、模型组、石杉碱甲组(0.3 mg/kg)、西酞普兰组(5 mg/kg)及联用组(石杉碱甲0.3 mg/kg~+西酞普兰5 mg/kg),每组10只。除空白对照组外,其余各组大鼠采用慢性不可预知温和应激方式建立抑郁模型,成模后每天ig给予相应药物1次,连续给药2周。通过旷场实验、糖水消耗实验、悬尾实验、强迫游泳实验、Morris水迷宫实验观察各组大鼠的抑郁和学习记忆行为变化。结果:与空白对照组比较,模型组大鼠水平穿格次数和直立次数、糖水偏好率、站台穿越次数、目标象限路程百分比、目标象限时间百分比均明显减少或降低(P<0.05或P<0.01),悬尾不动时间、游泳不动时间和逃避潜伏期均明显延长(P<0.05或P<0.01)。与模型组比较,西酞普兰组和联用组大鼠抑郁相关指标均明显改善(P<0.05或P<0.01),其中联用组效果更好;联用组大鼠学习记忆相关指标均明显改善(P<0.05或P<0.01),石杉碱甲组和西酞普兰组大鼠仅站台穿越次数明显增加(P<0.05或P<0.01),其他学习记忆相关指标无明显变化(P>0.05)。结论:西酞普兰联合石杉碱甲能明显改善老年抑郁模型大鼠的抑郁行为和学习记忆能力,效果优于单用西酞普兰。     

快速老化小鼠脑内能量代谢及学习记忆能力的研究

目的观察快速老化小鼠(SAM)这一较理想的阿尔茨海默病模型,其脑内能量代谢及学习记忆能力随增龄的动态变化情况,研究脑内能量代谢与学习记忆能力的关系。方法选择2,6和12月龄雄性快速老化小鼠(SAMP8)为研究对象,同月龄的抗快速老化小鼠(SAMR1)作为对照。应用新物体识别、Morris水迷宫、穿梭箱等实验研究快速老化小鼠学习记忆能力的变化;应用小动物氟脱氧葡萄糖正电子断层扫描(FDG-PET)技术检测小鼠脑内葡萄糖摄取水平;应用高效液相色谱法检测小鼠海马内ATP,ADP和AMP等能量物质的增龄性变化;应用Western蛋白印迹法检测糖酵解及三羧酸循环葡萄糖代谢关键酶己糖激酶(HK)和丙酮酸脱氢酶(PDH)及葡萄糖转运蛋白的表达情况;应用分光光度法检测HK和PDH的活性。结果在新物体识别实验中,2,6和12月龄SAMP8的1和24 h优先指数显著低于同月龄SAMR1(P<0.05)。在Morris水迷宫实验中,学习期6月龄和12月龄SAMP8的逃避潜伏期显著高于同月龄SAMR1(P<0.05);测试期6月龄和12月龄SAMP8穿环次数显著少于同月龄SAMR1(P<0.05)。在穿梭箱实验中,6月龄和12月龄SAMP8的学习期成功回避次数显著低于同月龄SAMR1(P<0.05),SAMP8的测试期成功回避次数显著低于同月龄SAMR1(P<0.05),表明SAMP8的物体识别记忆能力、空间学习记忆能力及主动回避反应能力呈增龄性衰退。FDG-PET结果显示,2,6和12月龄SAMP8全脑、海马、皮层葡萄糖摄取低于同月龄SAMR1,且SAMP8葡萄糖摄取随着增龄而减少。与同月龄SAMR1比较,6月龄和12月龄SAMP8海马的ATP,ADP和AMP含量均显著降低(P<0.05)。2,6和12月龄SAMP8小鼠海马中HK和PDH的蛋白表达和活性均随着增龄而逐渐降低,其中12月龄SAMP8海马的HK和PDH活性显著低于同月龄SAMR1(P<0.01)。结论 SAMP8学习记忆能力随增龄进行性衰退,SAMP8脑内能量代谢随增龄逐渐降低,其学习记忆能力的衰退可能与其脑内能量代谢的异常相关。     

从DHA代谢角度探讨当归芍药散治疗APP/PS1阿尔茨海默病模型小鼠的作用及机制

目的研究当归芍药散水提液(DSS)对APP/PS1阿尔茨海默病(AD)双转基因模型小鼠认知功能的影响,并从脑内二十二碳六烯酸(DHA)代谢及对DHA代谢信号通路神经炎症、氧化应激探讨DSS治疗AD的作用机制。方法选择6月龄APP/PS1双转基因小鼠,随机分为模型组、当归芍药散高、中、低剂量组以及阳性药组,选择同背景同月龄转基因阴性雄性小鼠作为正常对照组。当归芍药散组分别为1.6,3.2和6.4 g·kg~(-1)。阳性药组(多奈哌齐)给药剂量为3 mg·kg~(-1)。每天灌胃1次,连续给药1个月后开始行为学测试。行为学测试结束次日,小鼠称重,10%的水合氯醛腹腔注射麻醉,分离全脑并称重,采用液质联用技术对脑内未酯化的DHA进行含量测定;采用Western蛋白印迹法对DHA从细胞膜释放、代谢的酶i PLA2和15-LOX以及参与炎症介质释放、代谢的酶c PLA2,COX-1,COX-2,5-LOX和12-LOX蛋白表达量进行检测;ELISA测定炎症介质PGE2,TXB2和LTB4;试剂盒检测小鼠脑内抗氧化酶MDA,SOD,GSH和ROS。结果 Morris水迷宫定位航行结果提示:与正常组相比,同背景同月龄的APP/PS1模型组逃避潜伏期明显延长(P<0.05);阳性药组(P<0.05)以及DSS 1.6,3.2和6.4 g·kg~(-1)组(P<0.01)可明显缩短AD模型小鼠的逃避潜伏期。Morris水迷宫空间探索结果提示:与对照组相比,模型组第一次穿越平台时间明显延长(P<0.01)、穿越平台次数明显减少(P<0.01);阳性药组、DSS 1.6,3.2和6.4 g·kg~(-1)组可明显缩短AD模型小鼠第一次穿越平台的时间(P<0.01)、增加其穿越平台的次数(P<0.05,P<0.01)。与模型组相比,阳性药组、DSS1.6,3.2和6.4 g·kg~(-1)组小鼠脑内未酯化的DHA含量明显增多(P<0.05);除DSS 1.6 g·kg~(-1)外,阳性药、DSS 3.2和6.4 g·kg~(-1)组可明显上调小鼠海马、皮质内15-LOX和i PLA2蛋白的表达(P<0.05,P<0.01),下调参与炎症介质释放、代谢的酶c PLA2,COX-1,COX-2,5-LOX和12-LOX蛋白表达(P<0.05,P<0.01);与模型组相比,阳性药组、DSS 1.6,3.2和6.4 g·kg~(-1)组海马、皮质内的神经炎症介质PGE2,TXB2和LTB4明显减少(P<0.05,P<0.01),MDA和ROS明显降低(P<0.05,P<0.01),SOD活性增加(P<0.05)。结论当归芍药散能改善APP/PS1双转基因AD模型小鼠的学习记忆障碍,改善血脂水平,能提高AD模型小鼠海马、皮质内未酯化DHA的含量并且上调DHA经酶代谢产生NPD1有关到15-LOX和i PLA2蛋白的表达,减少神经介质PGE2,TXB2和LTB4的生成,并且下调与神经介质生成有关的c PLA2,5-LOX,12-LOX,COX-1和COX-2蛋白的表达,并且还能改善AD模型小鼠脑内的氧化应激状态。     

硫化氢通过抗氧化作用改善脑缺氧导致的小鼠空间记忆障碍(英文)

目的观察外源性H2S对缺氧性脑损伤小鼠空间学习记忆障碍的影响,并探究其作用机制。方法连续4 d sc给予NaNO2 120 mg.kg-1.d-1制备缺氧模型;氢硫化钠(NaHS)治疗组在制备模型的同时ip给予NaHS 1 mg.kg-1.d-1。每天给药前进行Morris水迷宫实验,测定逃避潜伏期、原平台象限停留时间和穿越平台次数。比色法检测小鼠脑组织中超氧化物歧化酶(SOD)活性及丙二醛(MDA)含量。HE染色观察海马组织切片CA1区神经元形态学改变。结果水迷宫实验第3天和第4天,模型组小鼠逃避潜伏期分别为(26.0±7.3)s和(23.3±8.7)s,明显长于正常对照组的(16.1±9.6)s(P<0.05)和(11.1±6.2)s(P<0.01)。第5天,模型组小鼠穿越平台次数为4.1±1.9,在原平台象限停留时间为(20±8)s,与正常对照组穿越平台次数(7.2±1.6)次和在原平台象限停留时间(28±8)s比较明显减少(P<0.01)。与正常对照组相比,模型组小鼠脑组织中SOD活性降低12.6%(P<0.01),MDA含量升高43.9%(P<0.01)。在模型组小鼠海马CA1区,锥体细胞出现明显的核固缩、胞浆深染和排列紊乱等变性改变。与模型组比较,NaHS组小鼠在水迷宫实验的第3天和第4天逃避潜伏期明显缩短(P<0.05),分别为(17.9±7.0)s和(15.8±8.5)s;在平台所在象限停留时间和穿越平台次数明显增加(P<0.01),分别为(30±9)s和(6.7±2.5)次;SOD活性升高了8.9%(P<0.05),MDA含量显著下降了29.6%(P<0.01);海马CA1区神经元变性改变较模型组得到显著缓解。结论 NaHS减轻了脑缺氧损伤诱发的小鼠学习记忆的损害,其作用机制可能与H2S衰减海马区神经元损伤和抗氧化作用有关。     

复方丹参片对APP/PS1转基因小鼠焦虑样行为的调节作用

目的探讨复方丹参片对阿尔采末病(AD)APP/PS1转基因小鼠焦虑样行为的作用及机制。方法4月龄野生型小鼠(正常组)和APP/PS1转基因小鼠分别灌胃给予溶剂(模型组)或复方丹参片低剂量(180 mg·kg~(-1))、中剂量(360 mg·kg~(-1))、高剂量(720 mg·kg~(-1))和阳性药物舍曲林(15 mg·kg~(-1))60 d后,采用Morris水迷宫实验、新奇抑制摄食实验和高架十字迷宫实验评价复方丹参片对小鼠记忆障碍和焦虑样行为学表现的影响,采用高效液相色谱法(HPLC)和ELISA分别检测小鼠前额皮质、海马和杏仁核γ-氨基丁酸(GABA)和脑源性神经营养因子(BDNF)的含量。结果复方丹参片中、高剂量明显缩短小鼠找到平台的潜伏期,明显增加小鼠原有平台象限的探索时间(P<0.05,P<0.01)。高架十字迷宫试验结果显示,复方丹参片高剂量显著增加APP/PS1转基因小鼠在开臂的时间百分比和进入开臂的次数(P<0.01);新奇抑制摄食实验结果显示,复方丹参片中、高剂量显著缩短APP/PS1转基因小鼠摄食潜伏期(P<0.05,P<0.01)。HPLC和ELISA结果显示,复方丹参片中、高剂量可显著增加APP/PS1转基因小鼠不同脑区如前额皮质、海马和杏仁核GABA和BDNF含量(P<0.05,P<0.01)。结论复方丹参片改善AD转基因小鼠的学习记忆损伤和焦虑样行为,可能与增加脑组织GABA和BDNF水平有关。     

3,6'-二芥子酰基蔗糖联合tenuifoliside A协同抗抑郁作用及其机制的研究

目的研究远志中3,6'-二芥子酰基蔗糖(DISS)和tenuifoliside A(TFSA)协同抗抑郁作用及其初步作用机制。方法采用经典的行为绝望抑郁模型——小鼠悬尾实验,随机分为对照组、阳性药组、DISS 5、10 mg·kg~(-1)、TFSA 5、10mg·kg~(-1)、DISS 5 mg·kg~(-1)+TFSA 5 mg·kg~(-1)、DISS 5 mg·kg~(-1)+TFSA 10 mg·kg~(-1)、DISS 10 mg·kg~(-1)+TFSA 5 mg·kg~(-1)和DISS 10 mg·kg~(-1)+TFSA 10 mg·kg~(-1);灌胃给药7 d,观察DISS和TFSA单体及其合用对小鼠悬尾不动时间的影响;免疫组织化学方法检测小鼠海马及皮层内BDNF的表达;蛋白质印记法检测小鼠海马内CRTC1、CREB、p-CREB及BDNF的表达。结果 DISS和TFSA及其二者合用均可缩短悬尾小鼠的不动时间,其中DISS(10 mg·kg~(-1))和TFSA(10 mg·kg~(-1))组与单剂量药物组相比明显,并稳定缩短小鼠悬尾不动时间(P<0.05)。免疫组化实验中,DISS和TFSA及其合用组均可提高海马及皮层内BDNF的表达量(P<0.05),同时DISS和TFSA及其合用组可增加海马中CRTC1、CREB、p-CREB及BDNF蛋白的含量,其中合用组明显高于单药组(P<0.05)。结论 DISS与TFSA双药合用启动CREB共转录因子CRTC1,激活海马内CREB的磷酸化,进而增加其下游BDNF表达,发挥协同抗抑郁作用。     

槲皮素通过SIRT1/NLRP3通路改善db/db糖尿病模型小鼠的认知功能障碍

目的流行病学研究发现,糖尿病与认知功能障碍密切相关。槲皮素已被证实具有改善糖尿病和认知障碍功能,但是其相关机制仍然不清楚。本研究采用db/db糖尿病模型小鼠,探讨槲皮素是否可以通过SIRT1/NLRP3途径来改善糖尿病模型小鼠的认知功能障碍。方法将10月龄的雌性db/db小鼠随机分成3组(每组8只),模型组、槲皮素低剂量组(35 mg·kg~(-1))和槲皮素高剂量组(70 mg·kg~(-1));相同月龄雌性野生型db/m小鼠8只设为正常对照组。连续给药12周后进行学习记忆相关的行为学检测(Morris水迷宫测试和新物体识别测试)、葡萄糖耐量OGTT和胰岛素耐量ITT。行为学测试结束,取材,免疫印迹检测小鼠脑中神经和突触相关蛋白及SIRT1/NLRP3通路相关蛋白的表达。结果 Moriss水迷宫实验结果显示,槲皮素组较模型组逃避潜伏期明显缩短(P<0.01),穿越平台的次数和目标象限停留的时间显著提高(P<0.05);新物体识别实验结果显示槲皮素组较模型组对于新物体的识别指数明显提高(P<0.05),表明槲皮素能够增加db/db小鼠的学习记忆能力。同时,胰岛素耐量实验和葡萄糖耐量实验结果显示,槲皮素组较模型组胰岛素抵抗和空腹血糖水平显著降低(P<0.05)。蛋白质印迹分析还表明,槲皮素组较模型组小鼠脑中神经和突触相关蛋白(PSD93,PSD95,BDNF和NGF)的表达显著增加(P<0.01,P<0.05),同时槲皮素还显著改善了SIRT1的蛋白质表达(P<0.05),降低了NLRP3炎症相关蛋白(NLRP3,ASC,Cleaved Caspase-1,IL1β,IL18)的表达水平(P<0.05,P<0.01)。结论 SIRT1/NLRP3通路可能是槲皮素对糖尿病脑病神经保护作用的关键机制。     

Safety assessment of poloxamers 101, 105, 108, 122, 123, 124, 181, 182, 183, 184, 185, 188, 212, 215, 217, 231, 234, 235, 237, 238, 282, 284, 288, 331, 333, 334, 335, 338, 401, 402, 403, and 407, poloxamer 105 benzoate, and poloxamer 182 dibenzoate as used in cosmetics

Poloxamers are polyoxyethlyene, polyoxypropylene block polymers. The impurities of commercial grade Poloxamer 188, as an example, include low-molecular-weight substances (aldehydes and both formic and acetic acids), as well as 1,4-dioxane and residual ethylene oxide and propylene oxide. Most Poloxamers function in cosmetics as surfactants, emulsifying agents, cleansing agents, and/or solubilizing agents, and are used in 141 cosmetic products at concentrations from 0.005% to 20%. Poloxamers injected intravenously in animals are rapidly excreted in the urine, with some accumulation in lung, liver, brain, and kidney tissue. In humans, the plasma concentration of Poloxamer 188 (given intravenously) reached a maximum at 1 h, then reached a steady state. Poloxamers generally were ineffective in wound healing, but were effective in reducing postsurgical adhesions in several test systems. Poloxamers can cause hypercholesterolemia and hypertriglyceridemia in animals, but overall, they are relatively nontoxic to animals, with LD(50) values reported from 5 to 34.6 g/kg. Short-term intravenous doses up to 4 g/kg of Poloxamer 108 produced no change in body weights, but did result in diffuse hepatocellular vacuolization, renal tubular dilation in kidneys, and dose-dependent vacuolization of epithelial cells in the proximal convoluted tubules. A short-term inhalation toxicity study of Poloxamer 101 at 97 mg/m(3) identified slight alveolitis after 2 weeks of exposure, which subsided in the 2-week postexposure observation period. A short-term dermal toxicity study of Poloxamer 184 in rabbits at doses up to 1000 mg/kg produced slight erythema and slight intradermal inflammatory response on histological examination, but no dose-dependent body weight, hematology, blood chemistry, or organ weight changes. A 6-month feeding study in rats and dogs of Poloxamer 188 at exposures up to 5% in the diet produced no adverse effects. Likewise, Poloxamer 331 (tested up to 0.5 g/kg day(-1)), Poloxamer 235 (tested up to 1.0 g/kg day(-1)), and Poloxamer 338 (at 0.2 or 1.0 g/kg day(-1)) produced no adverse effects in dogs. Poloxamer 338 (at 5.0 g/kg day(-1)) produced slight transient diarrhea in dogs. Poloxamer 188 at levels up to 7.5% in diet given to rats in a 2-year feeding study produced diarrhea at 5% and 7.5% levels, a small decrease in growth at the 7.5% level, but no change in survival. Doses up to 0.5 mg/kg day(-1) for 2 years using rats produced yellow discoloration of the serum, high serum alkaline phosphatase activity, and elevated serum glutamicpyruvic transaminase and glutamic-oxalacetic transaminase activities. Poloxamers are minimal ocular irritants, but are not dermal irritants or sensitizers in animals. Data on reproductive and developmental toxicity of Poloxamers were not found. An Ames test did not identify any mutagenic activity of Poloxamer 407, with or without metabolic activation. Several studies have suggested anticarcinogenic effects of Poloxamers. Poloxamers appear to increase the sensitivity to anticancer drugs of multidrug-resistant cancer cells. In clinical testing, Poloxamer 188 increased the hydration of feces when used in combination with a bulk laxative treatment. Compared to controls, one study of angioplasty patients receiving Poloxamer 188 found a reduced myocardial infarct size and a reduced incidence of reinfarction, with no evidence of toxicity, but two other studies found no effect. Poloxamer 188 given to patients suffering from sickle cell disease had decreased pain and decreased hospitilization, compared to controls. Clinical tests of dermal irritation and sensitization were uniformly negative. The Cosmetic Ingredient Review (CIR) Expert Panel stressed that the cosmetic industry should continue to use the necessary purification procedures to keep the levels below established limits for ethylene oxide, propylene oxide, and 1,4-dioxane. The Panel did note the absence of reproductive and developmental toxicity data, but, based on molecular weight and solubility, there should be little skin penetration and any penetration of the skin should be slow. Also, the available data demonstrate that Poloxamers that are introduced into the body via routes other than dermal exposure have a rapid clearance from the body, suggesting that there would be no risk of reproductive and/or developmental toxicity. Overall, the available data do not suggest any concern about carcinogenesis. Although there are gaps in knowledge about product use, the overall information available on the types of products in which these ingredients are used, and at what concentration, indicates a pattern of use. Based on these safety test data and the information that the manufacturing process can be controlled to limit unwanted impurities, the Panel concluded that these Poloxamers are safe as used.     

HPLC法测定抗妇炎胶囊中木兰花碱、黄柏碱、药根碱、巴马汀、小檗碱、槐果碱、苦参碱、氧化槐果碱、槐定碱和氧化苦参碱

目的 采用高效液相色谱（HPLC）法同时测定抗妇炎胶囊中木兰花碱、黄柏碱、药根碱、巴马汀、小檗碱、槐果碱、苦参碱、氧化槐果碱、槐定碱和氧化苦参碱10种活性成分。方法 采用InerSustain AQ-C₁₈色谱柱（250 mm×4.6 mm,5 μm）,流动相A：乙腈–无水乙醇（80∶20）,流动相B：0.1%磷酸溶液,梯度洗脱,检测波长220 nm,体积流量1.0 mL/min,柱温30℃,进样量10 μL。结果 木兰花碱、黄柏碱、药根碱、巴马汀、小檗碱、槐果碱、苦参碱、氧化槐果碱、槐定碱和氧化苦参碱分别在2.69～134.50、1.95～97.50、0.63～31.50、0.86～43.00、11.95～597.50、0.59～29.50、6.08～304.00、4.85～242.50、1.66～83.00、19.79～989.50 μg/mL线性关系良好（r≥0.999 3）;平均回收率分别为99.11%、98.23%、96.95%、97.78%、100.02%、97.21%、99.66%、99.52%、98.81%、100.08%,RSD值分别为1.04%、1.23%、1.37%、1.65%、0.70%、1.28%、0.65%、0.81%、1.11%、0.63%。结论 建立的HPLC法可用于抗妇炎胶囊中10种活性成分的测定,作为抗妇炎胶囊质量控制方法。     

Arformoterol: (R,R)-eformoterol, (R,R)-formoterol, arformoterol tartrate, eformoterol-sepracor, formoterol-sepracor, R,R-eformoterol, R,R-formoterol

Sepracor in the US is developing arformoterol [R,R-formoterol], a single isomer form of the beta(2)-adrenoceptor agonist formoterol [eformoterol]. This isomer contains two chiral centres and is being developed as an inhaled preparation for the treatment of respiratory disorders. Sepracor believes that arformoterol has the potential to be a once-daily therapy with a rapid onset of action and a duration of effect exceeding 12 hours. In 1995, Sepracor acquired New England Pharmaceuticals, a manufacturer of metered-dose and dry powder inhalers, for the purpose of preparing formulations of levosalbutamol and arformoterol. Phase II dose-ranging clinical studies of arformoterol as a longer-acting, complementary bronchodilator were completed successfully in the fourth quarter of 2000. Phase III trials of arformoterol began in September 2001. The indications for the drug appeared to be asthma and chronic obstructive pulmonary disease (COPD). However, an update of the pharmaceutical product information on the Sepracor website in September 2003 listed COPD maintenance therapy as the only indication for arformoterol. In October 2002, Sepracor stated that two pivotal phase III studies were ongoing in 1600 patients. Sepracor estimates that its NDA submission for arformoterol, which is projected for the first half of 2004, will include approximately 3000 adult subjects. Sepracor stated in July 2003 that it had completed more than 100 preclinical studies and initiated or completed 15 clinical studies for arformoterol inhalation solution for the treatment of bronchospasm in patients with COPD. In addition, Sepracor stated that the two pivotal phase III studies in 1600 patients were still progressing. In 1995, European patents were granted to Sepracor for the use of arformoterol in the treatment of asthma, and the US patent application was pending.     

欧洲刺柏（Juniper）

活性成分与药理作用欧洲刺柏药用部位是其浆果，具有促水排泄、防腐、抗胃肠胀气和抗风湿作用，还可改善胃功能。用作促水排泄药可增加尿量（水丢失），但不增加钠排泄。成分萜品烯-4-醇可增加肾小球滤过率，但刺激肾。欧洲刺柏浆果对单纯疱疹病毒体外显示抗病毒活性，并具抗真菌活性。动物实验显示，欧洲刺柏浆果提取物具有堕胎、抗生育、抗炎、抗胚胎植入、降血压、升血压和降血糖作用。欧洲刺柏浆果油具有兴奋子宫的活性，以及利尿、胃肠道抗菌和刺激作用，该油对平滑肌有阻止解痉作用。     

Oral Presentations (LDD, LPES, LNM, LPAT, LNT, LPPT, LPM)

Probiotic microorganisms have been shown to provide specific health benefits when consumed as food supplements or as food components. The main problem of such products is the poor survival of the probiotic bacteria in the low pH of gastric fluid. However the use of synthetic excipients for enteric coating to prevent the exposure of microorganisms to gastric fluid is limited in food supplementary industry. Therefore the aim of this study was to develop an enteric coating formulation containing shellac as a natural polymer. Shellac possesses good resistance to gastric juice; the major disadvantage of this polymer is its low solubility in the intestinal fluid [1, 2]. Thus films containing different ratios of shellac and water-soluble polymers (sodium alginate, hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidon (PVP)) or plasticizers (glycerol and glyceryl triacetate (GTA)) were prepared in order to analyse the films’ melting temperatures (T_m), the changes in enthalpy (ΔH), their capability of taking up water, and their solubility in different media. The release characteristics of the films were studied by loading pellets with Enterococcus faecium M74 and coating them with formulations containing different amounts of shellac and polymer or plasticized shellac. Using dissolution tests, performed according to USP XXXI paddle method, the resistance of the coatings to simulated gastric fluid (SGF, pH 1.2) and the release of cells in simulated intestinal fluid (SIF, pH 6.8) was investigated.The trials showed that an increasing amount of plasticizer results in a decrease of T_m and ΔH of the films whereat glycerol had a superior plasticization effect to GTA. The compatibility of films made of water-soluble polymers and shellac was also concentration dependent. HPMC and PVP showed superior compatibility with shellac compared to sodium alginate, since films containing shellac and more than 10% [w/w] sodium alginate tended to separate into two phases. In the end five formulations containing shellac and either 5% [w/w] glycerol, 10% [w/w] PVP, 20% [w/w] PVP, 10% [w/w] HPMC, or 5% [w/w] sodium alginate emerged as feasible for enteric coating purposes.