注射用伏立康唑前药在雌雄大鼠中代谢及毒性差异研究

目的：研究注射用伏立康唑前药（FLKZQY）在雌、雄大鼠中代谢及毒性差异,并观察SD大鼠体内性激素水平的变化对伏立康唑前药在大鼠体内代谢的影响,为其进一步临床应用提供依据。方法：选取5~6周龄SD大鼠,随机分成去势与伪手术组,雌、雄分开分组（雌、雄各半,每组8只）,手术后恢复3 d,然后连续7 d静脉注射120 mg·kg^-1·d^-1伏立康唑前药,于第7天进行眼眶采血。采用毒代动力学试验、酶联免疫吸附试验（ELISA）法,检测其代谢及毒性差异。结果：毒代动力学结果显示,伪手术雌鼠药时曲线下面积（AUC）、最大血药浓度（C_max）、半衰期（t_1/2）均高于伪手术雄鼠;去势雌鼠最大血药浓度（C_max）、半衰期（t_1/2）均较伪手术雌鼠显著性降低（P<0.05）,药时曲线下面积（AUC）极其显著性降低（P<0.01）;去势雄鼠受试物组与伪手术雄鼠受试物组相比药时曲线下面积（AUC）、半衰期（t_1/2）、最大血药浓度（C_max）则升高,其中AUC与C_max差异显著（P<0.05）;ELISA结果显示中,与伪手术雌鼠相比,去势雌鼠的肝脏细胞色素P450同工酶CYP2C19、CYP2C9以及CYP3A4含量均明显增加（P<0.05）,去势雄鼠与伪手术雄鼠相比P450同工酶含量降低,但未达到统计学差异。结论：在本试验条件下,注射用伏立康唑前药在雌、雄大鼠体内的代谢存在性别差异。而性激素水平可能通过调节伏立康唑相关代谢酶水平从而对伏立康唑代谢产生影响。     

Bayesian反馈法估算静脉输注伏立康唑的群体药动学参数

目的 用Bayesian反馈法估算临床患者静脉输注伏立康唑的群体药动学(PPK)参数.方法　收集静脉输注给药不同时间后的血样,采用HPLC法测定伏立康唑血药浓度,用Bayesian反馈法估算PPK参数.结果 以二室模型拟合伏立康唑的药动学过程,得PPK参数为Vss为(46.58±19.35)L,CL为(4.76±2.6...     

注射用伏立康唑致过敏性休克1例

1 病例介绍 患者,男,84岁,体质量60 kg.因"咳嗽咯痰、意识丧失30 min"于 2019 年 8 月 1 日入院.入院前30 min患者咳嗽、咯痰,进食呛咳后出现一过性意识丧失,双眼上吊,伴大小便失禁,为黑色稀便,无发热,无四肢抽搐,送急诊.入院体检:体温 37. 1 ℃,脉搏110次·min-1 ,呼 吸 ...     

1例注射用伏立康唑结晶的原因分析

目的 探讨注射用伏立康唑的配制方法,减少药物不良事件的发生.HT5"H方法 通过对我院发生的1例注射用伏立康唑结晶的原因进行分析,思考该药的正确配制方法.HT5"H结果 部分国产注射用伏立康唑对如何配制提示不足,使用时有发生药物不良事件的可能.HT5"H结论 为确保伏立康唑的安全使用,建议配置以丙二醇和乙醇的混合溶液作为专用溶媒的伏立康唑时,先用专用溶媒溶解并震荡摇匀,确认溶液完全澄清后,再转至5%葡萄糖注射液稀释至2mg·mL-1,立即使用并避免长时间放置.     

LC-MS/MS法测定大鼠血浆伏立康唑、伏立康唑氮-氧化物浓度及药动学应用研究

摘要：目的:建立液相色谱-串联质谱（LC-MS/MS）法测定大鼠血浆中伏立康唑及伏立康唑氮-氧化物浓度,并探索灌胃给予伏立康唑后两者在大鼠体内的药动学过程。方法:样品预处理选用甲基叔丁基醚作萃取剂,通过液-液萃取法消除基质效应。采用Welch Ultimate UHPLC XB-C18（50 mm×2.1 mm; 1.8μm）色谱柱;以乙腈-水(含2 mmol·L-1甲酸铵,0.1%甲酸)为流动相进行梯度洗脱;柱温：35℃;流速：0.35 ml·min-1;分析时长：4 min;质谱方法应用电喷雾离子源,多反应监测模式进行正离子检测。利用该方法分别测定大鼠灌胃给予66.7 mg·kg-1伏立康唑后各时间点伏立康唑及伏立康唑氮-氧化物的血药浓度,分析其在大鼠体内的药动学过程。结果:伏立康唑及伏立康唑氮-氧化物在0.5～500 ng·ml-1范围内线性关系良好（r＞0.999 0）,定量下限均为0.5 ng·ml-1。用建立的方法测定伏立康唑及伏立康唑氮-氧化物血药浓度,拟合得到其药动学参数：药时曲线下面积（AUC）0-t分别为（54.66±20.30）μg·ml-1·h,（10.88±5.30）μg·ml-1·h;AUC0-∞分别为（54.66±20.30）μg·ml-1·h,（13.50±2.10）μg·ml-1·h;清除率（CL）分别为（4.19±0.90）L·min-1·kg-1,（18.98±3.70）L·min-1·kg-1;药峰浓度(Cmax)分别为（19.14±11.90）μg·ml-1,（0.95±0.20）μg·ml-1;半衰期(t1/2)分别为（5.89±6.10）h,（6.11±3.20）h。结论:该方法快速、简便、准确度高且重复性好,可用于伏立康唑及伏立康唑氮-氧化代谢产物在大鼠体内的药动学研究。     

Bayesian反馈法估算静脉输注伏立康唑的群体药动学参数

目的用Bayesian反馈法估算临床患者静脉输注伏立康唑的群体药动学(PPK)参数。方法收集静脉输注给药不同时间后的血样,采用HPLC法测定伏立康唑血药浓度,用Bayesian反馈法估算PPK参数。结果以二室模型拟合伏立康唑的药动学过程,得PPK参数为Vss为(46.58±19.35)L,CL为(4.76±2.64)L/h,k10为(0.187±0.006)h-1k,12为(4.97±0.02)h-1,k21为(0.895±0.308)h-1。结论此PPK模型能够较准确地描述伏立康唑在临床患者静脉输注的药动学特征,其预测能力尚待进一步评估。     

注射用伏立康唑无菌检查法的建立

目的：确定新药伏立康唑注射用无菌粉末的无菌检查法。方法：无菌检查法的验证试验——抑细菌和抑真菌试验及冲洗量试验。通过菌悬液的制备、培养基的检查、冲洗量的选择、阳性对照菌的选择及加入顺序等全过程，说明无菌检查法的建立，必须有验证试验的保证。结果：该药的无菌检查选用薄膜过滤法，以黑曲霉为阳性对照菌，冲洗总量1500ml。结论：通过验证试验保证的无菌检查条件检查该药，方法可行，结果可靠。应在药品检验工作中，逐步完善微生物检验方法学的内容，从而提高我国药品微生物检验工作的总体水平。     

HPLC法测定注射用伏立康唑含量及有关物质

目的建立测定注射用伏立康唑含量及有关物质的HPLC法。方法采用ShimPack CLC-ODS C18色谱柱(4.6mm×150mm,5μm),流动相为0.04mol/L磷酸二氢铵溶液(用氨水调节pH值至6.0)-乙腈(50∶50),流速为1.0mL/min,检测波长为256nm,进样量为20μL。结果伏立康唑与杂质分离良好,在0.015～0.15g/L范围内伏立康唑浓度与峰面积呈良好线性关系(r=0.9999),日内和日间RSD均小于1.5%,最低检测量为0.5ng,最低定量限为1.5ng。样品中有关物质检查符合要求。结论该法简便、快速、专属性强,可用于注射用伏立康唑含量及有关物质的测定。     

95例国产注射用伏立康唑不良反应分析

目的:探讨国产注射用伏立康唑致药品不良反应(ADR)的特点,为临床合理用药提供参考。方法:对某三甲医院2014~2018年发生的国产注射用伏立康唑ADR进行监测,分析ADR的临床表现与累及器官-系统、发生时间、联合用药以及转归等。结果:发生的95例ADR以65岁以上患者为主(占69.47%),男性多于女性,发生在用药7 d内的占84.21%;患者使用伏立康唑的用法用量均符合说明书要求、发生ADR临床表现复杂多样,累及器官-系统以循环系统(31.36%)、呼吸系统(23.67%)、皮肤及其附件损害(13.02%)、神经系统(7.10%)较为多见;有2例ADR考虑为双硫仑样反应;严重ADR 9例;除1例转归不详外,其他患者均转归良好。结论:使用国产注射用伏立康唑期间应密切监测ADR,尤其对老年患者应加强关注,注意联合用药避免双硫仑样反应等的发生,以保障患者的用药安全。     

高效液相色谱法测定注射用伏立康唑的含量

目的建立HPLC测定注射用伏立康唑含量的方法。方法选用VP-ODSC18色谱柱(150mm×4.6mm,5μm),流动相为乙腈-水(40∶60),柱温为30℃,检测波长为255nm。结果伏立康唑在0.1010~0.9605g·L-1范围内质量浓度与峰面积呈良好线性关系(r=0.9995),平均回收率为99.8%,RSD为0.27%。结论本法简便、快速、可靠,可用于注射用伏立康唑的质量检验。     

龙葵素的生殖毒性研究进展

龙葵素广泛存在于马铃薯、番茄及茄子等茄科植物中。因其具有抗肿瘤和潜在的毒性作用而引起广泛关注。本文主要介绍了龙葵素在生殖毒性方面的研究进展。     

含氟吸入麻醉剂的生殖毒性研究进展

含氟吸入麻醉剂的毒性研究主要集中在肝脏损害、肾脏损害和心血管抑制方面,其在生殖毒性方面的研究相对较少.近几年的研究表明,含氟吸入麻醉剂不但在细胞水平上能够影响细胞的分化,还能在分子水平上破坏染色体DNA的结构,但其具体作用机制现在还不十分清楚,本文就吸入麻醉剂的生殖毒性研究进展作一综述.     

The rabbit as a model for reproductive and developmental toxicity studies

The rabbit has many advantages as a nonrodent and second model for assessing the effects of toxic agents on semen quality, fertility, developmental toxicity, and teratology. The male and female reproductive systems of the rabbit are described, and data on growth, sexual development and reproduction are compared with mice, rats, and humans. Techniques for semen collection and evaluation in the male, and artificial insemination, superovulation, embryo culture, and embryo transfer in the female are included as useful procedures in toxicity testing. Examples of the use of rabbits and experimental replication for toxicity testing are given. Special features of the visceral yolk sac and development of the chorioallantoic placenta of the rabbit are compared with rodents. The rabbit extraembryonic membranes more closely resemble the human than do the rodents, in some respects. The use of the rabbit in developmental toxicity and teratology studies is discussed.     

Repeated-doses and reproductive toxicity studies of the monoterpene 1,8-cineole (eucalyptol) in Wistar rats

1,8-cineole (eucalyptol) is widely used as an excipient in the pharmaceutical industry and as a food flavoring agent, thus providing significant potential for human exposure to the compound. We investigated the preclinical toxicity and reproductive toxicity of 1,8-cineole (CIN). In the repeated-doses toxicity study for 50 days, CIN (100, 500 or 1000 mg/kg) did not produce any signs of toxicity or deaths, but affected body weight gain during the first week of treatment. The hematological and biochemical profiles did not show significant differences except for increase in the MCV, platelet and urea levels or reduction in MCHC, MPV and alkaline phosphatase. Histopathological analysis showed weak changes in the lungs, liver, kidneys and uterus. In the reproductive toxicity, CIN (250, 500 or 1000 mg/kg) produced a reduction in body weight in pregnant rats treated during the pre-implantation or organogenesis periods. The highest doses induced a reduction in the mass of fetuses (pre-implantation) and dead fetuses (both periods) of pregnant rats. The results indicate that the treatment by repeated-doses showed occasional alterations in rats of both sexes. However, provide evidence that possibly 1,8-cineole presents maternal and fetal toxicity. This requires more detailed investigation to better characterize the toxic effects of this compound.     

Food and drug administration guidelines for reproductive toxicity testing

The Food and Drug Administration generally requires reproductive toxicity testing of all new drugs to be used by pregnant women or women or men of reproductive potential. These requirements may vary among the centers within the FDA. Reproductive and developmental toxicity is usually tested in one or two animal species and is divided into three segments to represent treatment throughout the reproductive process. The FDA monitors adverse drug effects on human reproduction through postmarketing surveillance.     

Subchronic,reproductive, and maternal toxicity studies with tertiary butyl acetate (TBAC)

Tertiary-butyl acetate (TBAC) was tested for subchronic toxicity in rats and mice and reproductive toxicity in rats at inhalation concentrations of 0, 100, 400 or 1600 ppm. An oral maternal toxicity study was conducted in rats at dose levels of 0, 400, 800, 1000 and 1600 mg kg⁻¹ d⁻¹. In the inhalation studies, hematology, clinical chemistry, urinalysis, gross pathology and the majority of body weight and feed consumption values were unaffected. Exposure to TBAC at concentrations of 400 ppm and higher caused transient hyperactivity in mice and some evidence of increased motor activity counts in male rats at the 1600 ppm exposure level. TBAC caused α₂u-globulin accumulation in male rat kidneys from all exposure groups and increased liver weights in 1600 ppm rats and mice. Levels of thyroxin were decreased in male mice exposed to 1600 ppm TBAC for 4 weeks but otherwise thyroid endpoints were unaffected in rats and mice at either the 4 or 13 weeks time points. There was no evidence or immunotoxicity or reproductive toxicity in rats. Pregnant rats receiving 1000 mg kg⁻¹ d⁻¹ TBAC exhibited severe signs of acute neurotoxicity and decreased feed consumption and body weight gain. Fetal viability and growth were unaffected.     

匹多莫德的生殖毒性实验研究

目的研究匹多莫德(pidotimod,PDM)对实验大鼠在致畸敏感期的生殖毒性。方法健康Wis-tar雌性受孕大鼠,于受孕后5~15d灌胃给予200、4008、00mg/kg的匹多莫德,至受孕后20d处死动物,检测各项指标,对匹多莫德的致畸敏感期生殖毒性进行评价。结果口服匹多莫德200、4008、00mg/kg后,匹多莫德对受孕大鼠的黄体数、着床率、胎儿数、胎儿体重及性别、胎儿内脏及骨骼检查等各项检测指标均无明显变化,同对照组比较差异无统计学意义。结论匹多莫德在本实验所用剂量时无致畸作用,这种用于大鼠的剂量,相当于该药的人用最大剂量的8倍、16倍、32倍,所以人用此药是安全的。     

Sensitivity of different generations and developmental stages in studies on reproductive toxicity

Numerous studies on reproductive toxicity are expected to be necessary under the EU program on Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH). Therefore, it is important to analyse existing testing strategies including also the recently implemented extended one-generation reproduction toxicity study (EOGRTS, OECD guideline 443). For this purpose the responsiveness of the different generations and developmental stages in studies on reproductive toxicity is analysed and critical targets of reproductive toxicity are identified by using the Fraunhofer FeDTex database.     

An evaluation of the male reproductive toxicity of cathinone

(−)-Cathinone is the major psychoactive component of khat plant (Catha edulis Forssk.). Khat has been shown to produce reproductive toxicity in human beings and experimental animals. However, the chemical constituents of khat leaves responsible for sexual dysfunction are not known. In the present study cathinone enantiomers have been investigated for their reproductive toxicity in rats. Cathinone produced a dose-dependent decrease in food consumption and suppressed the gain in body weight. There was a significant decrease in sperm count and motility and increase in the number of abnormal sperms in cathinone treated animals. Histopathological examination of testes revealed degeneration of interstitial tissue, cellular infiltration and atrophy of Sertoli and Leydig's cells in cathinone treated animals. Cathinone also produced a significant decrease in plasma testosterone levels of the rats. Although both enantiomers of cathinone produced deleterious effects on male reproductive system, (−)-cathinone was found to be more toxic. From this study it may be concluded that the cathinone content in khat may be partially or totally responsible for the reproductive toxicity in khat chewers.     

HPLC-MS/MS法同时测定人血浆中伏立康唑及其氮氧化代谢物浓度

目的：建立快速测定人血浆中伏立康唑及其主要代谢物伏立康唑-N-氮氧化物浓度的HPLC-MS/MS方法,用于人体药代动力学研究。方法：以伏立康唑和伏立康唑-N-氮氧化物的D3同位素为内标,血浆样品经蛋白沉淀后,用Agilent ZORBAX SB-Aq色谱柱（2.1 mm × 50 mm,1.8 μm）和API 4000质谱仪进行正离子模式电喷雾离子化分析。流速为0.6 mL·min-1,以甲醇为有机相,0.1%甲酸为水相,按一定程序进行梯度洗脱。结果：伏立康唑和伏立康唑-N-氮氧化物在10.00 ~ 8000 ng·mL-1范围内线性关系良好,该方法的特异性、批内/批间精密度、准确度、介质效应、提取回收率、稳定性和稀释可靠性符合相关要求。结论：建立了一种准确、简便、可靠的HPLC-MS/MS分析方法,成功应用于健康中国人静脉注射4 mg·kg-1伏立康唑后的药代动力学研究。