阿立哌唑

[通用名称]aripiprazole,阿立哌唑 [化学名称]7-{4-[4-(2,3-二氯苯)-1-哌嗪]丁氧}-3,4-二氢-2(1H)-喹啉。     

阿立哌唑不良反应临床分析

目的探讨阿立哌唑的不良反应。方法对使用阿立哌唑治疗精神病患者的不良反应进行观察与分析。结果阿立哌唑的不良反应的发生率主要集中在用药后的前2个星期,以第2个星期的新发生不良反应的人数最多。不良反应的类型由高到低依次为:兴奋激越、静坐不能、心动过速、视物模糊、其他。结论阿立哌唑是一种疗效肯定、不良反应相对较少的药物,以服药后的第2个星期的新发生不良反应的患者最多。建议护理人员应对这些患者及家属开展个性化的心理护理和生活指导,必要时应用药物以消除或降低其不良反应。     

阿立哌唑的合成工艺

目的　考察阿立哌唑的合成路线。方法　以7-羟基- 3,4 -二氢- 2 (1H) -喹喏酮为原料,经O -溴丁基化和缩合反应合成阿立哌唑。结果　阿立哌唑总收率为81%,经元素分析、红外光谱确证化学结构正确。结论　该合成路线适于工业化生产。     

阿立哌唑的制备工艺研究

目的:优化阿立哌唑的制备工艺。方法:以7-羟基-3,4-二氢-2-(1H)-喹啉酮为起始原料,经与1,4-二溴丁烷醚化后,再与1-(2,3-二氯苯基)哌嗪缩合,制得阿立哌唑。结果:醚化时用丙酮替代DMF作溶剂,反应副产物减少;由中间体Ⅲ制备终产物Ⅰ原工艺采用萃取法纯化,溶剂消耗多,成本高,本文中改由直接大量多次水洗产品,操作简便,产物纯度符合要求,总收率达到71.3%。结论:优化后的制备工艺稳定可行,适合工业化生产要求。     

HPLC-MS法测定人血浆中的阿立哌唑

目的:建立HPLC-MS法测定人血浆中阿立哌唑浓度的方法。方法:以盐酸洛哌丁胺为内标,采用Thermo Hypersil-HyPURITY C18(150 mm×2.1 mm,5μm)色谱柱;以20 mmol.L-1醋酸铵溶液(0.7%乙酸,0.1%TFA)-甲醇-乙腈(37∶50∶13)为流动相;柱温:40℃;流速:0.3 mL.min-1。结果:标准曲线线性范围为1.0~200ng.mL-1;萃取回收率为72.03%~74.35%;方法回收率为97.00%~100.80%;日内RSD在5.74%~10.69%;日间RSD在5.87%~11.26%。结论:本方法快速、灵敏、准确、简便,适用于阿立哌唑血药浓度测定及药动学研究。     

阿立哌唑治疗精神分裂症临床对照研究

目的探讨阿立哌唑治疗精神分裂症的疗效和安全性。方法以氯氮平为对照,将符合CCMD-3中精神分裂症诊断标准住院满8周、BPRS总分≥30分的124例患者,随机分为阿立哌唑组、氯氮平组各62例。结果完成病例98例,阿立哌唑组脱落12例、氯氮平组脱落14例。阿立哌唑的有效率为87%,氯氮平的有效率为85%。结论两组疗效相当,无一例血糖、尿糖升高者。阿立哌唑治疗精神分裂症疗效安全可靠,依从性好,是有效的抗精神病药物。     

阿立哌唑的合成

1-(2,3-二氯苯基)哌嗪盐酸盐与4-溴丁酸乙酯经N-烷基化、硼氢化钠还原制得1-[(4-羟基)丁基]-4-(2,3-二氯苯基)-哌嗪(5),5经对甲苯磺酰化得到的对甲苯磺酸4-[4-[(2,3-二氯苯基)哌嗪-1-基]丁酯(6)与7-羟基-3,4-二氢-2(1H)-喹啉酮缩合得到阿立哌唑,总收率约76%.     

阿立哌唑的合成

间氨基酚和3-氯丙酰氯制得的酰胺在无水三氯化铝作用下环合得7-羟基-3,4-二氢-2(1H)-喹诺酮,与1,4-二溴丁烷成醚后与1-(2,3-二氯苯基)哌嗪进行取代反应制得抗精神病药阿立哌唑,总收率25%.     

阿立哌唑的合成

4-（2，3-二氯苯基）-1-哌嗪盐酸盐与1，4-二溴丁烷缩合得到1-（4-溴丁基）-4-（2，3-二氯苯基）哌嗪，再与3-氯-N-（3-羟基苯基）丙酰胺反应得3-氯-N-[3-[4-[4-（2，3-二氯苯基）]-1-哌嗪基]丁氧基]苯丙酰胺，最后经闭环制得阿立哌唑，总收率25％。     

漆树叶皮肤刺激性与致敏性的实验研究

目的:研究漆树叶对动物的皮肤刺激性与致敏性。方法:采集新鲜漆树叶(不含叶轴)冻存后粉碎,室温下将漆树叶屑用蒸馏水制成糊剂,叶和水的比例为1:1。皮肤刺激实验:新西兰纯种家兔6只,脊柱两侧备皮(3cm×3cm)后,将漆树叶糊1.0g涂敷在左侧皮肤上,覆盖4h后清洗,右侧皮肤涂0.5ml蒸馏水作为对照。清洗后1、24、48、72h观察涂敷漆树叶糊部位皮肤反应并评分。皮肤致敏实验:白化豚鼠50只,分为实验组(20只,雌雄各半)、阳性对照组(20只,雌雄各半)和阴性对照组(10只,雌雄各半)。脊柱两侧备皮(2cm×2cm)。实验开始即刻和第7、14天时,实验组背部左侧备皮处涂敷0.8g漆树叶糊,阳性对照组涂敷2.5%2,4-二硝基氯苯0.2g,阴性对照组涂蒸馏水0.4ml,均覆盖6h后清洗;实验第28天时,实验组和阴性对照组豚鼠背部左侧备皮处涂敷0.8g漆树叶糊,阳性对照组涂敷1.0%2,4-二硝基氯苯0.2g,覆盖6h后清洗。其后24、48h分别计算致敏率、判定致敏程度。结果:皮肤刺激实验:有3只家兔在涂敷漆树叶糊后皮肤出现红斑,评分平均值为0.67分(24h),刺激反应程度为轻度。皮肤致敏实验:实验组与阴性对照组所有豚鼠涂敷漆树叶糊后24、48h均未出现红斑、水肿等反应,致敏反应积分平均值为0,致敏率为0,致敏程度为弱。阳性对照组豚鼠出现红斑、水肿,48h皮肤致敏反应总积分平均值为3.65分,致敏率为100%,致敏程度为极强。结论:漆树叶对实验动物皮肤有轻度刺激性,无致敏性。     

中日肌肉刺激性试验的比较研究及探讨

肌肉刺激性试验是以肌内注射类药物为主的新药开发研制和新药申报中重要的安全性评价检查项目之一。我国已有一些试验方法被广泛使用,但内容多属于指导性原则,较简约;日本厚生省于1984年推出了更加详实、完善的注射用药的局部刺激性试验的试验方法的修改案。多年来,随着药物临床前试验的发展,安全评价理念的深入以及动物实验研究的进展,有一些值得参考借鉴之处。结合多年动物实验和病理学研究的心得,本文在全面比较中日在肌肉刺激性试验的异同的基础上,全面遵循局部刺激性试验的指导原则,做了进一步探讨并提出建议性的试验方法,仅供参考。     

Assessment of dermal safety of oil extracted from Periplaneta americana: acute dermal toxicity,irritation, and sensitization

Abstract

Introduction

The American cockroach (Periplaneta americana) is used in traditional Chinese medicine. Periplaneta americana (P. americana) is rich in oil that has shown potential antioxidant and antibacterial activities in vitro.     

Evaluation of dermal and eye irritation and skin sensitization due to carbon nanotubes

The present paper summarizes the results of our studies on dermal and eye irritation and skin sensitization due to carbon nanotubes (CNTs), whose potential applications and uses are wide and varied, including CNT-enhanced plastics, electromagnetic interference/radio-frequency (EMI/RFI) shielding, antistatic material, flexible fibers and advanced polymers, medical and health applications, and scanning probe microscopy. Skin and eyes have the highest risk of exposure to nanomaterials, because deposition of nanomaterials to the surficial organs has the potential to be a major route of exposure during the manufacturing, use, and disposal of nanomaterials. Two products composed of single-walled carbon nanotubes (SWCNTs) and two products composed of multi-walled carbon nanotubes (MWCNTs) were tested regarding acute dermal and acute eye irritation using rabbits, and skin sensitization using guinea pigs. The concentrations of the CNTs in the substances were the maximum allowable for administration. The two products of SWCNTs and one of the products of MWCNTs were not irritants to the skin or eyes. The other product of MWCNTs caused very slight erythema at 24 h, but not at 72 h, after patch removal in the dermal irritation experiments and conjunctival redness and blood vessel hyperemia at 1 h, but not at 24 h, in eye irritation experiments. These findings showed that one product of MWCNTs was a very weak acute irritant to the skin and eyes. No products of SWCNTs and MWCNTs exhibited skin-sensitization effects. Our knowledge of the toxicological effects of CNTs is still limited. Further information is needed to clarify the potential for irritation and sensitization given the complex nature of CNTs.     

Evaluation of electric arc furnace‐processed steel slag for dermal corrosion,irritation, and sensitization from dermal contact

Electric arc furnace (EAF) steel slag is alkaline (pH of ~11–12) and contains metals, most notably chromium and nickel, and thus has potential to cause dermal irritation and sensitization at sufficient dose. Dermal contact with EAF slag occurs in many occupational and environmental settings because it is used widely in construction and other industrial sectors for various applications including asphaltic paving, road bases, construction fill, and as feed for cement kilns construction. However, no published study has characterized the potential for dermal effects associated with EAF slag. To assess dermal irritation, corrosion and sensitizing potential of EAF slag, in vitro and in vivo dermal toxicity assays were conducted based on the Organisation for Economic Co‐operation and Development (OECD) guidelines. In vitro dermal corrosion and irritation testing (OECD 431 and 439) of EAF slag was conducted using the reconstructed human epidermal (RHE) tissue model. In vivo dermal toxicity and delayed contact sensitization testing (OECD 404 and 406) were conducted in rabbits and guinea pigs, respectively. EAF slag was not corrosive and not irritating in any tests. The results of the delayed contact dermal sensitization test indicate that EAF slag is not a dermal sensitizer. These findings are supported by the observation that metals in EAF slag occur as oxides of low solubility with leachates that are well below toxicity characteristic leaching procedure (TCLP) limits. Based on these results and in accordance to the OECD guidelines, EAF slag is not considered a dermal sensitizer, corrosive or irritant. Copyright © 2014 John Wiley & Sons, Ltd.     

Analysis for the potential of polystyrene and TiO2 nanoparticles to induce skin irritation, phototoxicity, and sensitization

The human skin equivalent model (HSEM) is well known as an attractive alternative model for evaluation of dermal toxicity. However, only limited data are available on the usefulness of a HSEM for nanotoxicity testing. This study was designed to investigate cutaneous toxicity of polystyrene and TiO₂ nanoparticles using cultured keratinocytes, a HSEM, and an animal model. In addition, we also evaluated the skin sensitization potential of nanoparticles using a local lymph node assay with incorporation of BrdU. Findings from the present study indicate that polystyrene and TiO₂ nanoparticles do not induce phototoxicity, acute cutaneous irritation, or skin sensitization. Results from evaluation of the HSEMs correspond well with those from animal models. Our findings suggest that the HSEM might be a useful alternative model for evaluation of dermal nanotoxicity.     

复方甲硝唑克林霉素乳膏的皮肤刺激性、致敏试验及离体透皮释药特性

目的：制备复方甲硝唑克林霉素乳膏,并了解乳膏的皮肤刺激性、致敏性及离体透皮释药特性。方法：采用乳化法将甲硝唑、盐酸克林霉素、螺内酯和维生素B₆制备成复方甲硝唑克林霉素乳膏,并采用HPLC法测定乳膏中的4种主要成分的含量。评价乳膏对大鼠的皮肤毒性和刺激性,评价乳膏对豚鼠的皮肤致敏性。采用离体大鼠皮肤进行离体皮肤透皮释药试验,分别测定1,2,3,6,9、12,24,48 h各时间点甲硝唑、盐酸克林霉素、螺内酯、维生素B₆的单位面积透皮释药量Q及透皮吸收百分率Q%。结果：制得的复方甲硝唑克林霉素乳膏呈乳白色,均匀细腻,无颗粒感,易于涂布。采用梯度洗脱法能同时测定乳膏中4种主要成分的含量。离体透皮释药试验结果表明,给药12 h后甲硝唑、盐酸克林霉素、螺内酯、维生素B₆的Q、Q%均达到稳态值。给药6,12,24 h后,甲硝唑、盐酸克林霉素、螺内酯、维生素B₆均能不同程度地滞留在离体皮肤内。皮肤毒性试验结果可见,在7 d内均未出现死亡大鼠,未观察到急性毒性反应。皮肤刺激性试验结果可见,复方甲硝唑克林霉素乳膏的评分均值0.17,小于0.5,对大鼠皮肤无刺激性。皮肤致敏试验结果显示,复方甲硝唑克林霉素乳膏被评定为Ⅰ级致敏度,实际使用中对豚鼠并无致敏危险。结论：复方甲硝唑克林霉素乳膏的制备工艺简单可行,无皮肤毒性、刺激性和致敏性,且具有良好的透皮释药特性。     

阿替洛尔注射液对血管刺激、溶血和过敏的实验研究

目的 :观察阿替洛尔注射液血管刺激性和是否具有溶血、凝聚和过敏作用。方法 :兔耳缘静脉注射阿替洛尔 ,0 .2 5mg·kg- 1,qd× 3d ,停药 2 4h后做病理组织学检查 ,并与氯化钠注射液对照组比较 ;体外不同浓度的阿替洛尔注射液 0 .1～ 0 .5mL在 5mL兔红细胞氯化钠注射液中放置 0 .5～ 2 4h ,观察对兔红细胞悬液的溶血作用及有无红细胞凝聚作用 ;给豚鼠腹腔注射阿替洛尔 ,每只 0 .5mL ,qod× 3次 ,2wk和 3wk后分别再腹腔注射该药 ,每只2 .5mL- 1,然后观察 30min内是否出现过敏反应。结果 :阿替洛尔注射液对兔血管内皮没有损伤和刺激作用 ,与氯化钠注射液对照血管比较 ,两者无明显差异 ,对兔红细胞没有致溶血作用和凝聚作用 ,豚鼠未出现过敏反应。结论 :阿替洛尔注射液对用药血管没有刺激性反应 ,也无溶血及红细胞凝聚现象 ,对豚鼠无过敏反应。制剂有关安全性检测结果符合新药申报要求。     

葛根素注射液引起急性溶血机制的实验研究

目的：探讨葛根素注射液引起急性溶血的机制。方法：用Beagle犬和豚鼠进行葛根素注射液的体内外溶血试验如下：制剂的溶媒丙二醇和pH值对体外Beagle犬红细胞的溶血作用；静脉注射葛根素对豚鼠超氧化物歧化酶（SOD）、丙二醛（MDA）的含量及致敏豚鼠红细胞溶血率的影响；葛根素对Beagle犬和豚鼠红细胞的体外溶血作用和细胞形态的影响。结果：葛根素注射液最大浓度时（10g／L）的pH值为4．48，可致Beagle犬红细胞溶血；而同pH值的0．9％氯化钠注射液未见引起Beagle犬红细胞溶血。含5％和10％丙二醇的葛根素注射液可引起Beagle犬红细胞溶血；单纯5％和10％丙二醇溶液未见引起Beagle犬红细胞溶血。豚鼠静脉注射葛根素注射液组与0．9％氯化钠组比较，红细胞膜MDA含量明显下降（P〈0．01），未见引起氧化性溶血。葛根素注射液致敏豚鼠后与致敏前比较，未见红细胞溶血率升高，未见抗原抗体复合物产生。豚鼠静脉注射葛根素注射液能引起红细胞皱缩甚至破裂。体外非免疫性溶血试验显示葛根素注射液能直接致Beagle犬和豚鼠红细胞溶血，且与剂量相关。结论：葛根素注射液引起的溶血属于药物非免疫性溶血，可能与葛根素注射液直接作用于红细胞，引起红细胞稳定性改变有关。     

注射用七叶皂苷钠体外溶血作用试验研究

目的：探讨不同种类实验动物血细胞对七叶皂苷钠体外溶血活性的影响以及比较国内外同类品种体外溶血活性。方法：参照《中国药典》2005年版一部“溶血与凝聚”检查法。结果：用兔血细胞考核的9批产品,其中2批出现红细胞微溶无凝聚,采用羊血细胞则均未出现红细胞溶血与凝聚;用兔、羊、牛血细胞分别测得本公司2批产品的溶血指数（完全溶血浓度）为1／20．8万、1／15．6万、1／15．6万以上;用成年黄牛血细胞测得七叶皂苷钠国家对照品溶血指数为1／10万,略高于德国Reparil（1／20万）。结论：应采用同一来源的一种常用动物--家兔血细胞检测药品体外溶血活性以及在相同条件下检测国内同类品种体外溶血活性不高于国外。