乳酸卡德沙星对大鼠生育力与早期胚胎发育毒性的实验研究

目的研究乳酸卡德沙星对大鼠生育力与早期胚胎发育的毒性。方法采用SPF级SD大鼠对乳酸卡德沙星进行生育力与早期胚胎发育毒性实验。雄鼠从交配前9周至交配成功,雌鼠从交配前2周到妊娠后第7 d,连续灌胃给药,每天1次。交配结束后处死雄鼠,进行精子活力检查和精子畸形检查及睾丸组织病理学检查。交配成功的雌鼠2组,1组于妊娠第14 d解剖,记录胎盘总质量、黄体数、着床数、活胎数、吸收胎数、死胎数等指标。计算雌雄大鼠交配率及妊娠率。另1组雌鼠自然分娩和哺乳,计算仔鼠第35 d哺乳存活率。结果各剂量组雄鼠精子计数、精子活动度、睾丸质量系数、附睾质量系数、精子畸形率与空白对照组比较差异无显著性。高剂量组(158 mg.kg-1)雌鼠的平均黄体数、平均着床数、平均活胎数明显低于空白对照组(P<0.05),中、低剂量组(79和39.5 mg.kg-1)雌鼠的受孕率、平均黄体数、平均着床数、平均活胎数、死胎率和吸收胎率与空白对照组比较差异无显著性。高剂量组仔鼠体质量显著低于空白对照组(P<0.05),乳酸卡德沙星中、低剂量组仔鼠体质量与空白对照组相比,差异无显著性。各剂量组仔鼠存活率、死亡率、性别比、仔鼠脏器系数以及第35 d哺乳存活率与空白对照组比较差异无显著性,未观察到仔鼠畸形。结论79 mg.kg-1剂量乳酸卡德沙星对雌、雄性大鼠生育力与早期胚胎发育无毒性作用。     

乳酸卡德沙星注射液连续静脉滴注的安全性和耐受性研究

目的:评价中国健康成年志愿者连续静脉滴注乳酸卡德沙星注射液的安全性和耐受性.方法:2009年4至7月选出12名健康成年志愿者纳入试验,其中男、女各6名,年龄25～35岁,平均(31.8±2.8)岁,体重指教(BMI)为19.8～24.1(22.2±1.3)kg/m2.给予乳酸卡德沙星氯化钠注射液400 mg,2 h内恒速静脉滴注,1次/d,共用药7 d.观察记录受试者的生命体征和出现的不良反应,测定血、尿常规和血生化指标,重点监测每天给药前1 h和给药开始后3、6 h的QT间期、校正QT(QTc)间期的变化以及给药开始后第3、5、8天葡萄糖耐量试验变化.结果:除1名受试者给药第3天因月经期停药外,11名受试者完成7 d连续给药.受试者的体温、脉搏、呼吸频率和血压等生命体征给药后均在正常值范围.出现的7例次不良反应中,其中5例次甘油三酯(TG)水平和1例次总蛋白(TP)水平轻度升高,1例次短暂血糖降低(2.96 mmoL/L);7例次的不良反应经分析可能与药物无关.有1名受试者给药开始后第2、5、8天白细胞(WBC)计数分别为2.75×109/L、3.07×109/L和2.95×109/L,中性粒细胞(N)分别为0.39、0.33、0.39,均低于正常值,停药后2 d恢复正常,可能与药物相关.受试者的天冬氨酸氨基转移酶(AST)、总胆红素(TB)和尿素(Urea)连续给药的7 d中个别日间值差异有统计学意义(均P<0.05),但无临床意义.给药第2、3、4、7天,给药后QT间期较给药前有所延长,但QTc间期绝对值<450 ms,未见有临床意义的异常改变.给药开始后第5天11名受试者空腹血糖为(4.21±0.35)mmol/L,低于给药前1 d[(4.74±0.59)mmol/L],给药开始后第3、5天餐后1 h血糖为(6.20±1.58)、(6.07±1.19)mmol/L,均低于给药前1 d[(8.47±2.51)mmol/L],虽然差异有统计学意义(P<0.05),但均无临床意义.其他血、尿常规及血生化指标给药前后均无明显变化.结论:乳酸卡德沙星注射液连续静脉滴注,有良好的耐受性及安全性.     

单次静滴乳酸卡德沙星注射液在中国健康人体的安全耐受性研究

目的：在中国健康成年志愿者中评价单次静滴乳酸卡德沙星注射液的安全性与耐受性。方法：用区组随机化设计,选择18～40岁健康成人24名,每组12人,男女各半,进行单次3h和2h恒速静脉滴注乳酸卡德沙星氯化钠注射液400mg的2种滴注速度的安全性评价。观察试验期间发生的药物不良事件及临床症状、体征、实验室指标变化,用方差分析进行数据统计处理。结果：各组入选受试者给药前各项指标测定值均在正常范围。给药后尿常规、血常规、血生化、心电图等亦未见有临床意义的异常改变。仅1例出现轻度的腹痛、腹泻等可能与药物相关的轻度一过性药物不良反应。试验中未见严重的药物不良反应。结论：2h恒速静脉滴注乳酸卡德沙星氯化钠注射液400mg比较安全,耐受性较好。     

西那沙星对幼龄大鼠的软骨毒性

目的:观察西那沙星(sinafloxacin)静脉注射对幼龄大鼠关节软骨的影响。方法:40只大鼠,雌雄各半,按照体重随机分为西那沙星低、高剂量组(iv,10和60 mg·kg~(-1))、加替沙星阳性对照组(iv,60 mg·kg~(-1))和空白对照组(iv生理氯化钠溶液10 mL·kg~(-1))。各组连续给药7 d。d7给药后24 h处死动物取完整膝、髋关节进行病理组织学检查。结果:西那沙星可使幼龄大鼠膝、髋关节软骨表层幼稚软骨细胞数量减少,骨骺软骨细胞变性坏死,且存在量效关系。结论:西那沙星10～60 mg·kg~(-1)连续iv 7 d对幼龄大鼠关节软骨有破坏作用。     

五氧化二钒对雌性大鼠生殖毒性

五氧化二钒对雌性大鼠生殖毒性张天宝杨在昌１孙棉龄１吴忠舜１李宏霞１（第二军医大学卫生毒理学教研室，上海２００４３３；１华西医科大学公共卫生学院，成都６１００４１）选用连续两个动情周期正常的雌性Ｗｉｓｔａｒ雌性大鼠，分别经灌胃给予０，０．３３，１．０和...     

紫杉醇对大鼠的一般生殖毒性作用

紫杉醇是一种抗肿瘤新药，对大鼠的一般生殖毒性实验结果表明，给药剂量在１．０ｍｇ／ｋｇ时雄鼠和雌鼠摄食量减少，体重增长下降，雌鼠肾上腺及卵巢重量减轻，雄鼠的生育率和雌鼠受孕率下降，但对交配率无明显影响；母鼠剖检时发现黄体数、着床数及活胎数减少，着床痕数增加。未见致畸胎作用。对活胎体重、身长和尾长无明显影响。     

一类新药尖吻蝮蛇凝血酶对SD大鼠围产期生殖毒性试验

目的观察一类新药尖吻蝮蛇凝血酶对大鼠生殖功能的毒性或干扰作用,为临床用药提供依据。方法对一类新药尖吻蝮蛇凝血酶进行大鼠围产期生殖毒性试验:雌鼠从妊娠第15日至F1代大鼠离乳(出生后第21日)经静脉注射给予不同剂量的尖吻蝮蛇凝血酶(0.1、0.2、0.4 U·kg~(-1))。结果未发现尖吻蝮蛇凝血酶对雌鼠妊娠、哺乳以及胚胎和F1代大鼠生长发育有明显毒性和干扰作用。结论尖吻蝮蛇凝血酶对围产期大鼠无生殖毒性,其大鼠围产期生殖毒性试验的安全剂量为0.4 U·kg~(-1)。     

卡德沙星主要相关杂质的分析和鉴定卡德沙星主要相关杂质的分析和鉴定

目的卡德沙星原料药中相关杂质的分离及结构鉴定。方法用液相色谱-质谱联用技术分离并鉴定卡德沙星原料药中的主要相关杂质,并合成了化合物:1-环丙基-8-二氟甲氧基-6-氟-1,4-二氢-7-(1-哌嗪基)-4-氧代-3-喹啉羧酸(简称DMCA)。比较合成的化合物与原料药中相关杂质的液相色谱、紫外吸收光谱及质谱。结果相关杂质的分子量比卡德沙星少14,即一个亚甲基,推测该杂质可能为卡德沙星中3-甲基哌嗪的去甲基化合物,合成的DMCA的液相色谱、紫外吸收光谱及质谱分析结果与原料药中相关杂质一致。结论确证了该相关杂质的结构为1-环丙基-8-二氟甲氧基-6-氟-1,4-二氢-7-(1-哌嗪基)-4-氧代-3-喹啉羧酸。     

异甘草酸镁对SD大鼠的生殖毒性

异甘草酸镁（Magnesium Isoglyeyrrhizinate）为天然甘草酸的立体异构体镁盐。在甘草中存在甘草酸的2个立体异构体（18α-甘草酸和18β-甘草酸）均有抗肝损伤的作用，由于α体甘草酸的亲脂性大于前者，在体内易与受体蛋白及类固醇激素的靶细胞受体结合而发挥抗炎、抗过敏、抗毒等作用，且不良反应小，因此其疗效大于β体甘草酸。目前，国内外对于甘草酸的报道仅见于其药效机制方面，因此，本研究旨在研究异甘草酸镁对SD大鼠一般生殖毒性作用，以期为临床研究提供依据。     

Parathion toxicity in perinatal rats exposed in utero

Adult pregnant female rats were exposed to subchronic doses of parathion throughout gestation and lactation. Their offspring were examined for possible toxicological effects. This study found that several physiological parameters were affected. Female perinates exhibited a significant reduction in plasma cholinesterase (pseudo ChE) activity. Plasma renin activity was reduced with increased dose of parathion in both male and female perinates. Heart rate, QRS complex duration, S-T and P-R intervals were all reduced in the perinates. The results of this study indicated that physiological function can be altered by organophsophate exposure at levels lower than those required to show pseudo ChE inhibition.     

连续单剂静脉滴注乳酸卡德沙星在中国健康志愿者的耐受性及药代动力学

目的 研究乳酸卡德沙星氯化钠注射液在健康人体内连续给药的药代动力学特征.方法 12名受试者同时予以乳酸卡德沙星氯化钠注射液进行连续静滴(每次400 mg,恒速静滴2h,每天1次,给药7 d),观察给药前后临床症状、体征、实验室指标,重点观测QT间期及糖耐量.用高效液相色谱法测定给药后不同时间的血浓度,求主要药代动力学参数.结果 给药后,尿常规、血生化、心电图、糖耐量试验等亦未见有临床意义的异常的改变.出现1例与药物可能有关的轻度不良反应,停药后2日恢复正常.未见严重的药物不良反应.血药浓度约在第3天达稳态,Cmax为(7.01±1.19)mg·L-1,Cav为(2.15±0.34)mg·L-1,AUC88为(55.99±9.84) mg·L-1·h,Accumulation_Index为(1.08±0.05),DF为(310.97±9.854).结论 连续静滴乳酸卡德沙星在体内无蓄积,受试者耐受性良好.     

Long-term toxicity/carcinogenicity study of calcium lactate in F344 rats

The long-term toxicity/carcinogenicity of calcium lactate, a food additive, was examined in F344 rats. Calcium lactate was given ad lib. in the drinking-water at levels of 0, 2.5 or 5% to groups of 50 male and 50 female rats for two years. No clear toxic lesion was specifically caused by long-term administration of calcium lactate. No significant dose-related increase was found in the incidences of tumours in any organ or tissue. The results indicated that calcium lactate had neither toxic nor carcinogenic activity in F344 rats.     

Reproduction/developmental toxicity screening test in rats with orally-administered 1-hexene

This study was conducted to provide screening information concerning the potential systemic, reproductive and developmental toxicity of 1-hexene when administered orally, by gavage, to male and female rats using a modified OECD 421 protocol. 1-Hexene was administered at doses of 100, 500, and 1000 mg/kg/day in corn oil; the control group received the vehicle at an equivalent volume. The males were treated for 28 days prior to mating and until euthanasia (44 days of dosing). The females were treated for 14 days prior to mating and during mating, gestation, and lactation until euthanasia (41-55 total days of dosing). Females were allowed to deliver and rear their offspring until lactation day 4. The parental rats were subject to a gross and microscopic examination. Viability and development of the pups were followed through lactation day 4. There was no mortality, and there were no clinical signs of toxicity or differences in body weights, weight gain, feed consumption or organ weights. Copulation and fertility indices, precoital intervals, gestation lengths and pregnancy rates were comparable among the groups, and no signs of prolonged delivery or unusual nesting behaviors were noted. Pup viability, body weights, external observations and necropsy data were comparable among the groups. Pitted kidneys were observed at necropsy for two parental males in the 500 mg/kg/day group and three males in the 1000 mg/kg/day group. Microscopic changes in the kidneys of some male rats from the 100, 500, and 1000 mg/kg/day groups consisted of dose-related accumulations of hyaline droplets in the epithelial cells of the proximal convoluted tubules of the kidneys. In summary, the only treatment-related effect noted in this study was hydrocarbon nephropathy in male rats, which is not considered relevant for human health. The NOAEL for systemic and reproductive toxicity was 1000 mg/kg/day, excluding the finding of male rat hydrocarbon nephropathy.     

The perinatal and postnatal toxicity of D-methylphenidate and D,L-methylphenidate in rats

D-methylphenidate is an enantiomer of D,L-methylphenidate and was developed as an improved treatment for attention deficit hyperactivity disorder (ADHD) in children. The current study was performed to assess the potential perinatal and postnatal toxicity of both compounds in rats. About 125 presumed pregnant rats were assigned to five dose groups of 25 each. They were dosed with 2, 6, and 20 mg/kg/day D-methylphenidate and 40 mg/kg/day D,L-methylphenidate from gestation Day 7 to lactation Day 20. F1 generation rats were rebred to produce F2 fetuses. Various perinatal and postnatal measurements were made for the F0 and F1 rats. Among the significant findings were a reduction in maternal body weight gain for 20 mg/kg/day D-methylphenidate and D,L-methylphenidate and increased incidences of dilated pupil and vocalization for D,L-methylphenidate during the gestation period. Neither compound produced any other significant adverse findings in F0 and F1 generation rats at doses that were at least 25 times the maximum daily human therapeutic dose.     

The toxicity of behenyl alcohol. II. Reproduction studies in rats and rabbits

Behenyl alcohol is a saturated 22-carbon, long-chain aliphatic alcohol, which has potential for use in foods as an oil-structuring and -solidifying agent in fats. Previously completed studies with behenyl alcohol indicated an absence of mutagenic or genotoxic potential. In addition, subchronic toxicity studies in rats and dogs reported no adverse effects following gross and histopathological examinations. Compound-related effects were limited to the observation of pale feces in dogs treated with high doses of behenyl alcohol, and were attributable to unabsorbed behenyl alcohol. The reproductive effects of behenyl alcohol were investigated in a fertility and reproduction study, and an embryonic development study in rats and rabbits, respectively. No evidence of maternal or fetal toxicity was observed in either study. Behenyl alcohol demonstrated no effects on the fertility or reproduction of rats dosed up to 1000 mg/kg body weight. Similarly, behenyl alcohol had no reproductive effects on rabbits treated with doses up to 2000 mg/kg body weight. The observation of pale feces was the only compound-related effect reported, limited to rabbits treated with 2000 mg behenyl alcohol/kg body weight. Based on these findings, there is no evidence to suggest that behenyl alcohol is teratogenic or embryotoxic.     

Determination of caderofloxacin lactate in rat plasma by high-performance liquid chromatography-mass spectrometry and its application in rat pharmacokinetic studies

A sensitive liquid chromatography–electrospray ionization mass spectrometric (LC–ESI-MS) method for the quantification of a newly active quinolone carboxylic acid caderofloxacin lactate in rat plasma was developed and validated after precipitation method with methanol. Chromatographic separation was achieved on a reversed-phase Shimadzu 2.0 μm C18 column (150 mm × 2.00 mm) with the mobile phase of methanol–0.02% formic acid and step gradient elution resulted in a total run time of about 10.0 min. The analytes were detected by using an electrospray positive ionization mass spectrometry in the selected ion monitoring (SIM) mode. A good linear relationship was obtained in the concentration range studied (5–2000 ng/mL) (r = 0.9998). The lowest limit of quantification (LLOQ) was 5 ng/mL and the lowest limit of detection (LLOD) was 2 ng/mL. Average recoveries ranged from 88.80 to 93.05% in plasma at the concentrations of 10, 100 and 1000 ng/mL. Intra- and inter-day relative standard deviations were 4.01–7.30 and 4.15–7.51%, respectively. This method was successfully applied in the pharmacokinetic studies in rats.