注射用右旋兰索拉唑和兰索拉唑在氯化钠注射液中的稳定性研究

目的：对注射用右旋兰索拉唑和兰索拉唑在氯化钠注射液中的稳定性进行考察。方法：建立HPLC-UV法,采用Chiral PAK IC手性柱（4.6 mm×150 mm,5μm）;流动相：10 mmol·L-1乙酸铵（含0.05%乙酸）-乙腈（50∶50）;流速：0.6 mL·min-1;检测波长：284 nm;柱温：30℃;进样量：1μL。结果与结论：在室温下,注射用右旋兰索拉唑在氯化钠注射液中不发生手性转换;注射用右旋兰索拉唑和兰索拉唑在室内放置4 h标示含量>98%,暴露于日光下则发生明显的含量下降。     

兰索拉唑在正常及溃疡模型家兔体内药代动力学研究

目的:建立高效液相色谱法分析兔血浆中兰索拉唑的含量,并比较兰索拉唑在正常及溃疡模型家兔体内药代动力学行为的差异。方法:家兔于20℃水中浸泡8小时建立胃溃疡模型,耳缘静脉给予兰索拉唑注射剂后,分别在不同时间点收集血样,HPLC法测定,采用DASS2.0软件计算给药后的药物动力学参数。结果:兰索拉唑浓度在20~2000 ng.mL-1范围内线性关系良好,最低检测浓度为20 ng.mL-1。低、中、高3个浓度的提取回收率均大于85%,批内、批间相对标准差低于10%。与正常兔比较,溃疡模型家兔给予兰索拉唑药物后体内AUC(0-6.5)明显增加[(916.84±338.61)vs(522.72±172.16)μg.h.L-1,P<0.05]、体内平均滞留时间延长MRT(0-6.5)[(0.824±0.203)vs(0.69±0.13)h,P<0.05]、血浆消除半衰期增大[(0.88±0.44)vs(0.53±0.28)h,P<0.05]、血浆清除率显著减小[(2.74±1.70)vs(6.23±2.21)L.h-1,P<0.05]、最大血药浓度增大[(1091.31±348.94)vs(682.20±234.56)μ...     

氟诺哌齐对新西兰家兔胚胎-胎仔发育毒性及毒代动力学

目的 研究氟诺哌齐(fronopezil)对新西兰家兔胚胎-胎仔发育的影响及其伴随毒代动力学,为临床用药提供参考。方法 按妊娠顺序将孕兔分为溶媒(1%羟丙基甲基纤维素+1.5%聚乙二醇400水溶液)对照组、环磷酰胺(18 mg·kg^-1,阳性对照)组及氟诺哌齐3.6,9.0和22.5 mg·kg^-1组。溶媒对照组和氟诺哌齐组于妊娠第6～18天(GD_6-18)ig给药,环磷酰胺组于GD_6-20ig给药。GD₂₈处死孕兔,检测胚胎-胎仔发育,ELISA检测GD₅,GD₁₈和GD₂₈孕兔血清中性激素水平,首末次给药前后采血进行伴随毒代动力学研究,采用高效液相色谱串联质谱法检测血浆、胎仔、胎盘和羊水中的药物浓度。结果 氟诺哌齐3.6,9.0和22.5 mg·kg^-1对孕兔的体重、增重、摄食量和妊娠结局及胎仔的外观、内脏、骨骼和体格生长发育均未见明显影响;仅在GD₁₈或GD     

HPLC法测定右旋兰索拉唑缓释胶囊的光学纯度

目的:建立一种右旋兰索拉唑缓释胶囊光学纯度测定的新方法。方法:在手性柱上拆分兰索拉唑,用高效液相色谱仪进行测定,色谱柱为Chiralcel OZ-H,流动相为正己烷-异丙醇(3∶1),流速为0.7 ml/min,柱温为40℃,检测波长为284 nm,进样量为20μl。结果:在测定条件下,右旋兰索拉唑检测质量浓度线性范围为0.096 64⁰.302 mg/ml(r=0.999 9),低、中、高3种质量浓度的回收率为99.75%0.302 mg/ml(r=0.999 9),低、中、高3种质量浓度的回收率为99.75%¹00.02%,RSD<0.15%(n=3)。结论 :该方法操作简单,回收率、精密度均较好,可作为右旋兰索拉唑缓释胶囊的光学纯度测定方法。     

国产兰索拉唑药代动力学研究

目的研究国产兰索拉唑人体内药代动力学参数,寻求测定兰索拉唑血药浓度的更加简便的高效液相色谱法。方法采用乙醚-二氯甲烷萃取样品,应用HypersilBDS C18色谱柱,流动相为水-乙腈-三乙胺。结果兰索拉唑血药浓度的线性范围为0.05～2.0μg/mL,最低检测浓度为0.05μg/mL,日内精密度RSD为1.4%～5.4%,日间精密度RSD为1.5%～7.8%,相对回收率为94%～96%,符合生物样品分析要求。6名健康受试者单剂量口服受试制剂后,测得受试制剂中的AUC0→t、AUC0→∞分别为(3.387±1.225)、(3.533±1.237)h.μg/mL,Cmax为(0.918±0.252)μg/mL,Tmax、T1/2分别为(1.917±0.583)、(2.081±0.771)h。结论受试制剂国产兰索拉唑的药代动力学参数与文献报道一致,方法简便可行。     

妇科再造胶囊兔胚胎-胎仔发育毒性伴随毒代动力学研究

目的:观察妇科再造胶囊对兔胚胎-胎仔发育及其伴随毒代动力学的影响,为临床用药提供参考.方法:孕兔在着床至硬腭闭合期间(GD6-18),灌胃(ig)给予不同剂量的妇科再造胶囊(0.88,2.63和5.25 g·kg-1),溶媒对照组给予纯水;GD28处死孕兔,取胎仔,检查黄体数、胎重(连子宫)、胎仔重量、胎盘重量、活胎数...     

注射用兰索拉唑杂质定量测定及定性研究

目的:建立注射用兰索拉唑有关物质测定方法,并对其杂质进行定性研究。方法:采用液相色谱及液相色谱-质谱联用技术,DAD检测器检测,等度洗脱方式。结果:样品中检出的单个杂质为杂质B。结论:该方法简便、快速、灵敏度高,可用于注射用兰索拉唑有关物质的检测。     

右兰索拉唑N-氧化物杂质测定及毒性分析

摘要 目的：建立液相-质谱联用法（Liquid chromatography mass spectrometry,LC-MS）测定右兰索拉唑中N-氧化物的方法并对N-氧化物的毒性进行预测。方法：使用X-Bridge C18（250×4.6mm,5μm）柱,流动相A为0.02M醋酸铵溶液,流动相B为乙腈,梯度洗脱,采用电喷雾离子源,选择性正离子检测模式。利用ADMET Predictor软件对N-氧化物的毒性进行预测。结果：右兰索拉唑N-OX亚砜、N-OX砜、N-OX硫化物各杂质之间的分离度符合要求。线性浓度范围分别为12.92～206.68 ng·mL-1、12.31～196.92 ng·mL-1和13.15～210.40ng·mL-1,检测限分别为0.23 ng·mL-1、0.14 ng·mL-1和0.14 ng·mL-1,定量限分别为2.57 ng·mL-1、1.73 ng·mL-1和1.25 ng·mL-1。各杂质回收率,精密度以及24 h内稳定性均符合要求,可以用于上述杂质的测定。软件预测表明：各N-氧化物均有不同程度的肝毒性和致癌性,N-OX硫化物毒性最高。检测结果显示：三批供试品均检出N-OX亚砜,检出量分别为12.75 ng·mg-1、8.28 ng·mg-1和9.13 ng·mg-1,均未检出N-OX砜和N-OX硫代物。结论：本文所建立的LC-MS方法方便、快捷、灵敏度高,可用于右兰索拉唑N-氧化物检查。N-氧化物作为潜在毒性杂质在生产过程及质量控制中需要加以关注。     

R-兰索拉唑的合成

目的合成R-(+)-兰索拉唑。方法 2,3-二甲基吡啶经硝化、取代、酰化、水解得兰索拉唑硫醚,再经不对称氧化制得R-兰索拉唑。结果粗品经纯化得到化学纯度99.6%、光学纯度99.5%的目标产物,总收率23.2%。结论该方法反应条件可控,操作简单。     

Establishment of an in vitro method of rabbit embryo toxicity with toxicokinetics study

This report introduces a novel method, rabbit whole embryo culture (WEC) combined with toxicokinetics (TK), for toxicity testing. Rodent WEC has been extensively used for in vitro screening of developmental toxicity. To improve the reliability of in vitro data, it is important to consider TK and species specificity. To test the utility and effectiveness of this method, we investigated the toxic effect of thalidomide on rabbit embryos and its behavior in test systems both in vitro and in vivo under the same experimental condition. The data showed that thalidomide induced embryo malformations such as embryonic brain hypoplasia, short limb buds, and declined embryonic growth both in vitro and in vivo. The toxic effect increased with the increasing exposure of the embryo to thalidomide. In addition, we observed similar toxic effects and exposure–effect relationships in vivo and in vitro. Therefore, we preliminarily conclude that this new method can effectively predict and explain thalidomide toxicity. Furthermore, we investigated the behavior of test compounds in the WEC system for the first time, and this method is expected to be an important technique for in vitro toxicity study after extensive verification.     

家兔敌敌畏代谢动力学与胆碱酯酶抑制毒效动力学的关系

用比色法测定全血中敌敌畏浓度求得其ｉｖ及ｉｇ的房室模型及系列毒代动力学参数．ｉｖ时呈三房室分布，ｔ１／２β＝１７２ｍｉｎ，Ｖｃ＝０．６１Ｌｋｇ－１；ｉｇ时呈二房室分布，ｔ１／２β＝１２６ｍｉｎ，ｋａ＝０．４９ｍｉｎ－１，Ｆ＝０．３９０．用Ｅｌｍａｎ氏法测定全血胆碱酯酶活性求得敌敌畏的毒效动力学参数．证明两种动力学的曲线型基本一致且同步变化，但毒效动力学曲线的斜率较小．敌敌畏ｉｇ中毒时ｉｖ碘解磷定，对敌敌畏毒代动力学没有影响，但对毒效动力学有明显影响，使斜率增加约３倍．离体实验敌敌畏抑制全血胆碱脂酶活性的浓度－效应关系与在体者基本一致，故离体的浓度－效应关系配合以在体的时间－效应关系，可推测出在体的时间－浓度关系．     

牛蒡子苷元对大鼠和家兔的胚胎-胎仔发育毒性研究

目的 以受精大鼠和家兔为实验系统,评价牛蒡子苷元对动物胚胎-胎仔发育的影响,为其药用价值的进一步开发提供参考。方法 100只受精雌鼠分为溶媒对照组和牛蒡子苷元高、中、低剂量（64、16、4 mg/kg）组,每组25只;72只受精雌兔分为溶媒对照组和牛蒡子苷元高、中、低剂量（25、10、4 mg/kg）组,每组18只。全部动物于妊娠第6天（GD6）开始给药,每天ip给药1次,大鼠连续给药至GD15,停药至GD20解剖检查,家兔连续给药至GD18,停药至GD29解剖检查。试验期间,每天观察动物一般状态,定期检测动物体质量和摄食量,解剖时计数卵巢黄体数量、检查着床数和活胎数,测量活胎顶臀长和尾长,检查活胎外观、内脏和骨骼。结果 给药期间,动物除给药方法导致的注射部位炎症反应外,其他未见异常体征变化;与溶媒对照组比较,牛蒡子苷元未引起大鼠和家兔体质量异常增长;母本动物受孕率、平均黄体数量和受精卵着床丢失率也未见异常改变;窝均活胎率、死胎率和吸收胎率,胎仔顶臀长和尾长也未见明显改变;也未见受试物导致的胎仔外观、内脏和骨骼畸形。结论 牛蒡子苷元未见潜在的大鼠和家兔胚胎-胎仔发育毒性。在本试验条件下,牛蒡子苷元大鼠和家兔胚胎-胎仔发育毒性的无明显损害作用剂量（NOAEL）分别为64和25 mg/kg。     

Interactions of pesticides with membrane drug transporters: implications for toxicokinetics and toxicity

Introduction: Drug transporters are now recognized as major actors of pharmacokinetics. They are also likely implicated in toxicokinetics and toxicology of environmental pollutants, notably pesticides, to which humans are widely exposed and which are known to exert various deleterious effects toward health. Interactions of pesticides with drug transporters are therefore important to consider.

Areas covered: This review provides an overview of the interactions of pesticides with membrane drug transporters, i.e. inhibition of their activity, regulation of their expression, and handling of pesticides. Consequences for toxicokinetics and toxicity of pesticides are additionally summarized and discussed.

Expert opinion: Some pesticides belonging to several chemical classes, such as organochlorine, pyrethroid, and organophosphorus pesticides, have been demonstrated to interact with various uptake and efflux drug transporters, including the efflux pump P-glycoprotein (P-gp) and the uptake organic cation transporters (OCTs). This provides proof of the concept that pesticide–transporter relationships merit attention. More extensive and systematic characterization of pesticide–transporter relationships, possibly through the use of in silico methods, is however likely required. In addition, consideration of transporter polymorphisms, pesticide mixture effects, and realistic pesticide concentrations reached in humans may help better define the in vivo relevance of pesticide–transporter interactions in terms of toxicokinetics and toxicity.     

Systemic toxicity and toxicokinetics of a high dose of polyethylene glycol 400 in dogs following intravenous injection

Polyethylene glycol 400 (PEG-400) has been used in injections. However, limited data are available concerning the toxicity of a high dose of PEG-400 following intravenous (i.v.) injection. The aim of the present study was to estimate the systemic toxicity and toxicokinetics of a high dose of PEG-400 in dogs following i.v. injection. Twenty-four dogs were divided into four groups: a control group receiving normal saline and three test groups receiving 4.23, 6.34, and 8.45?g/kg of PEG-400, respectively, by i.v. injection once a day for 30 days. The repeated-dose toxicity of PEG-400 was assessed. Toxicokinetic parameters of PEG-400 in dogs were estimated on days 1 and 30. Dry mouth and dry nasal mucus membrane were observed in dogs treated with 6.34 and 8.45?g/kg of PEG-400. Cloudy swelling of kidney cell and increased glomerular volume were observed in dogs treated with 8.45?g/kg of PEG-400 when the animals were sacrificed 24 hours after the last injection. No significant histological changes were found 21 days later. Repeated dosing did not affect the toxicokinetic profile of PEG-400 in dogs. This study has shown that the toxicity of a high dose of PEG-400 following repeated intravenous injections is low, and alterations produced are reversible.     

溴苯腈在兔的血药浓度GC-MS法测定及其药动学研究

目的:建立兔血浆溴苯腈检测的气相色谱-质谱分析的方法,研究溴苯腈在兔体内的毒代动力学。方法:雄性日本大耳白7只,予30 mg.kg-1溴苯腈原药灌胃,分别于灌胃前及给药后72 h内多点抽取静脉血。用气相色谱-质谱联用法(GC-MS)测定血浆中溴苯腈浓度。结果用DAS软件进行分析,计算毒代动力学参数。结果:兔30 mg.kg-1溴苯腈ig后t1/2ke为11.327±3.043 h,Tmax为5.571±1.134 h,Cmax为109.943±43.486 mg.L-1,AUC0-tn为2275±959 mg.L.h-1,AUC0-∞为2315±980 mg.L.h-1,MRT0-tn为16.9±2.5 h,MRT0-∞为18.1±2.9 h。结论:溴苯腈经口吸收后的毒代过程符合一级吸收一室开放模型,吸收及消除均较慢。本研究采用的气相色谱-质谱联用法检测血浆溴苯腈浓度准确、快速、简便。     

环磷酰胺对新西兰兔胚胎-胎仔发育的毒性作用研究

目的探讨环磷酰胺用作兔胚胎一胎仔发育毒性实验阳性对照药物的可行性及最佳用药方案,为顺利开展规范化生殖毒性试验提供依据。方法实验用普通级新西兰兔,以交配成功日为妊娠第0天（GD0）,采用计算机完全随机区组法将妊娠兔分为4组,包括环磷酰胺A组（14只,GD6～20环磷酰胺18mg／kg,10：／a灌胃）、B组（11只,GD10—13环磷酰胺25mg／kg,1次／d皮下注射）、C组（12只,GD6～18环磷酰胺15mg／kg,1次／d肌内注射）和溶媒对照组（12只,GD6—18生理盐水2ml／kg,1次／d灌胃）。观察用药期间动物的一般情况,分别于GD0、3、6、10、13、15、18、20、24、28对各组妊娠兔称重并计算宫外增重,于GD5和GD28取兔血清测定睾酮、黄体酮和雌二醇水平。GD28处死各组兔,取胎仔,记录黄体数、着床数、活胎率、吸收胎率、死胎率;检查胎仔,计算外观、内脏和骨骼畸形发生率。结果环磷酰胺A组兔GD10和GD15、环磷酰胺B和C组兔GDl5体重均明显低于溶媒对照组（P〈0．05或P〈0．01）;环磷酰胺A组宫外增重明显低于溶媒对照组[（-0．013±0．163）kg比（0．208±0．194）kg,P〈0．01]。GD28与GD5的激素水平差值比较显示,环磷酰胺A组激素水平变化明显,与溶媒对照组相比,雌二醇和睾酮变化幅度差异有统计学意义（P〈0．01或P〈0．05）,黄体酮变化幅度差异无统计学意义（P〉0．05）;环磷酰胺B组及C组激素变化幅度与溶媒对照组相比,均无统计学意义（P〉0．05）。大体解剖未见母兔有明显异常。环磷酰胺A组、B组活胎率（65．1％、19．2％）均明显低于溶媒对照组（93．1％）（均P〈0．01）,吸收胎率（17．4％、53．9％）及死胎率（17．4％、26．9％）均明显高于溶媒对照组（4．2％、2．8％）（均P〈0．01）。环磷酰胺A组、B组、C组胎仔外观畸形发生率（60．6％、93．3％、16．1％）、内脏畸形发生率（62．9％、93．3％、25．9％）及骨骼畸形发生率（91．4％、100．0％、61．7％）均明显高于溶媒对照组（0、0、3．0％）（均P〈0．01）。结论环磷酰胺用作新西兰兔胚胎-胎仔发育毒性实验阳性对照药物是可行的,其最佳用药方案为18m∥kg,10c／a灌胃,GD6～20连续用药15d。     

左氧氟沙星氯替泼诺依碳酯滴眼液的毒性实验

目的观察左氧氟沙星氯替泼诺依碳酯滴眼液长期给药对家兔产生的毒性反应。方法48只日本大耳白家兔随机分为高、中、低剂量组,两单方组及空白对照组,高、中、低剂量组各8只,分别给予2%,1%和0.5%左氧氟沙星氯替泼诺依碳酯滴眼液,两单方组及空白对照组各8只,分别给予1%两单方和空白液。各组连续眼结膜囊内给药,每次2滴,每日4次,1个月后进行血液学、血液生化、脏器质量及系数、组织病理学检查及常规观察。结果给药组动物的外观行为、体质量、脏器系数、血液学和血液生化学指标,与空白对照组比较,均无明显差异;病理检查未见与药物毒性相关的明显病变,停药后也未见药物延迟性毒性反应。结论左氧氟沙星氯替泼诺依碳酯滴眼液长期用药对家兔无明显毒性,推断临床拟用剂量是安全的。