大鼠出生前接触苯妥英和(或)褪黑素对学习记忆的影响

目的　探讨褪黑素对苯妥英诱发的仔代学习记忆功能发育异常的影响。方法　Wistar孕大鼠于妊娠d 11～ 14ig苯妥英 10 0 ,2 0 0mg·kg- 1·d- 1或合并ig褪黑素 4 0mg·kg- 1(每日 3次 ) ,观察F1代仔鼠的味觉回避反射、穿梭反射和Morris水迷宫空间识别能力。结果　出生前染毒仔鼠成年后味觉回避反射、主动回避反射及空间识别等学习和记忆能力下降。褪黑素和苯妥英合并用药组仔鼠上述 3种学习和记忆能力均有不同程度的改善。结论　褪黑素对苯妥英诱发的大鼠仔代学习记忆功能发育异常具有拮抗作用 ,该效应可能与其拮抗胚胎脑组织中氧化应激反应有关。     

褪黑素对苯妥英诱发胚胎脑组织氧化性损伤的拮抗作用

目的　研究褪黑素 (MT)对苯妥英 (Phe)诱发的胚胎脑组织氧化性损伤有无保护作用。方法　妊娠Wistar母鼠于妊娠 (GD11～ 14 )ig 0和 10 0mg·kg- 1Phe ,4 0mg·kg- 1MT及 4 0mg·kg- 1MT +10 0mg·kg- 1Phe ;GD15脱颈椎处死动物 ,测定胎鼠脑组织各种与氧化性损伤有关的指标。结果　妊娠期染毒Phe导致胚胎脑组织H2 O2 水平升高 ,脂质过氧化和蛋白质氧化产物增加 ,超氧化物岐化酶、过氧化氢酶和谷胱甘肽过氧化物酶活性下降 ,总还原型谷胱甘肽(GSH)含量及总抗氧化力降低。妊娠期MT处理减少正常胎鼠脑中H2 O2 及产率 ;同时MT和Phe共同处理可阻断Phe诱发的氧化性损伤 ,GSH耗竭和抗氧化酶活性的下降。结论　MT对Phe诱发的胎鼠脑组织氧化性损伤有一定的拮抗作用。     

苯系混合物对小鼠仔代形态结构,行为发育及骨髓细胞DNA合成影响的研究

雌性小鼠孕6到15天时给予苯(100mg/m~3)、甲苯(1000mg/m~3)及二甲苯1000mg/m~3)混合吸入染毒,胎鼠生长发育、形态结构及骨骼发育未见明显异常;出生仔鼠生后3周体重增长明显低于对照组,雄住仔鼠四肢肌力及协调运动发育较对照组显著延迟,雌性仔鼠兴奋性显著高于对照组。提示孕鼠器官发生期给予苯系混合物染毒,其仔代末见结构异常,但出现一定程度的行为改变。     

雷公藤提取物对大鼠致畸敏感期毒性试验研究

目的:研究雷公藤提取物(LLZ)对受孕SD大鼠在致畸敏感期的致畸作用.方法:孕鼠随机分为0,10,30和90mg·kg-1体重4个剂量组,于妊娠d6～15(胎鼠器官形成期)每日灌胃染毒1 次,妊娠d20处死母鼠,剖宫观察对胚胎的影响.结果:雷公藤提取物在90 mg·kg-1剂量时出现明显的母体毒性和胚胎毒性,表现为母鼠体重增加值比对照组小;死胎率及吸收胎率增高,活胎率降低; 30 mg·kg-1剂量时出现胎儿毒性,表现为胎儿体重、身长较小、胸骨缺失和骨化迟缓;未观察到胎儿畸形.结论:LLZ对SD大鼠在有母体毒性(90 mg·kg-1)时有胚胎毒性,在无明显的母体毒性(30 mg·kg-1)时也有一定的胎儿毒性,但均无致畸作用.     

大气悬浮微粒提取物对小鼠子代发育的影响

在电厂下风侧居民区内收集大气悬浮微粒，经二氯甲烷提取，浓缩制成受试物，给孕鼠腹腔注射不同剂量，观察对小鼠胚胎及胎仔发育的影响。结果表明：所给剂量对孕鼠无明显毒作用，但有明显胚胎毒性，并引起胎仔骨骼发育异常，神经反射发育缓慢，提示电厂周围大气悬浮微粒有机提取物具有一定的发育毒效应。     

阿司匹林建立大鼠胚胎畸形模型研究

目的：研究阿司匹林灌胃建立大鼠的生殖毒性和胚胎畸形模型。方法：SPF级Wistar大鼠随机分成空白对照组、维生素A组（阳性对照组）和阿司匹林组,阳性组的剂量为12800μg·kg-1BW视黄醇当量,阿司匹林的剂量为280mg·kg-1,BW。灌胃量按10．0ml·kg-1BW计算,对照组灌胃给予同体积的注射用水。孕鼠于7～16d每d灌胃给药,妊娠20d处死,分析其胚胎发育指标与胎仔发育指标,检查有无外观畸形和骨肋畸形。结果：阿司匹林对孕鼠生殖能力有影响（子宫重量和卵巢重量降低,平均活胎数减少,活胎率降低,死胎率升高）（P〈0．05）;阿司匹林对胎仔生长发育有影响（活胎体重降低、活胎身长缩短、胎盘重量降低）（P〈0．05）,胎鼠外观出现异常,如全身皮肤潮红,易皮下出血（P〈0．05）;阿司匹林引起胎仔骨骼发育异常（胸骨异常,脊椎骨异常,肋骨异常）（P〈0．05）。结论：在规定剂量阿司匹林产生的胚胎毒性作用大,致畸作用明显。     

孕大鼠在胚泡着床前给醋氨酚对移植仔鼠发育及行为的影响

目的:探讨药源性大鼠着床前胚泡异常对移植胚胎发育及行为的影响.方法:采用胚胎移植生物技术,评价亲代孕d 3给醋氨酚(0.25,0.5,1.0 g·kg-1),对胚泡的细胞毒性和遗传毒性及对移植后仔鼠生理功能和行为发育的影响,探索仔鼠发育与胚泡异常间的相关性.结果:醋氨酚1.0 g·kg-1对胚泡细胞产生细胞毒性及剂量依赖性遗传毒作用.孕大鼠胚泡着床前给予醋氨酚0.5,1.0 g·kg-1可引起仔鼠某些生理功能发育延缓,导致仔鼠行为畸形.结论:醋氨酚对着床前胚泡遗传毒作用与仔鼠某些生理功能发育延缓及行为畸形相关.     

超顺磁性纳米四氧化三铁对孕前期和孕中期小鼠生殖及胚胎发育的影响

目的探讨超顺磁性纳米四氧化三铁对孕前期和孕中期小鼠生殖及胚胎发育的影响。方法选取48只健康成年雌性ICR小鼠,按体重随机分为4组(孕前期对照组、孕前期染毒组、孕中期对照组和孕中期染毒组),分别在孕前期、孕中期经尾静脉注射方式染毒,均于孕18 d处死孕鼠剖取卵巢和胎鼠,测定胎鼠发育指标(胎鼠体重、体长、尾长、外观畸形率、内脏畸形率、骨骼畸形率、胎盘重及HE切片)和孕鼠生育力指标(孕鼠体重、子宫重、卵巢重及HE切片、活胎率、死胎率、吸收胎率)。结果孕前期建模组:孕鼠生育指标两组对比差异无统计学意义(P0.05)。与对照组相比,染毒组胎仔体长显著降低(P0.05),胎盘重及吸收胎率显著增加(P0.05),其余发育指标差异无统计学意义(P0.05);孕中期建模组:孕鼠生育指标两组对比差异无统计学意义(P0.05)。与对照组相比,染毒组胎盘重量显著降低(P0.05),其余发育指标差异无统计学意义(P0.05)。结论超顺磁性纳米四氧化三铁对孕前期和孕中期染毒小鼠的生育力无显著影响,对胚胎发育有一定的毒性作用。     

甲基汞对大鼠的行为致畸效应研究

目的探讨妊娠期甲基汞暴露对Wistar大鼠的母体毒性及仔代的行为致畸效应.方法 Wistar孕鼠80只于妊娠第6～9天采用甲基汞0.00、0.01、0.05和2.00mg·kg-1@d-1连续灌胃染毒.分别进行母体毒性、胚胎毒性、仔鼠早期生理发育和神经行为发育指标、仔鼠迷宫和程序控制行为测试、亲仔两代大鼠脑组织形态学观察和单胺类神经递质(去甲肾上腺素、多巴胺、5-羟色胺)的测定.整个实验采用双盲法.结果未观察到明显的母体毒性;3个剂量组胎仔的体重、尾长均低于对照组(P＜0.01);各剂量组仔鼠的体重增长、早期生理及神经行为发育滞后于对照组(P＜0.05);各剂量组仔鼠迷宫错误次数均比对照组多(P＜0.05),具有剂量-效应关系(rs=0.257,P＜0.05);程序控制行为学习成绩比对照组降低(P＜0.05),有剂量-效应关系(rs=-0.727 3,P＜0.01);各剂量组母鼠和仔鼠脑组织均未见形态学改变,但脑组织单胺类神经递质含量均比对照组明显增高(P＜0.05),有剂量-效应关系(s=0.712 4～0.925 7,P＜0.01).结论甲基汞在不引起可观察到母体毒性剂量下,就可产生胚胎毒性,影响仔鼠神经系统的发育,导致神经行为功能的改变.     

多效唑原药SD大鼠两代繁殖毒性研究

目的 探讨多效唑原药对大鼠亲代生殖与子代早期发育影响.方法 动物经口喂饲多效唑原药,剂量为0、41.4、128.0和421.2mg/(kg·d),亲代和子一代各接触八周.每阶段试验结束时进行主要脏器系数、繁殖指数测定以及病理检查并测定子代仔鼠体重、身长、尾长.结果 128.0和421.2 mg/(kg·d)剂量组孕鼠体重下降,部分繁殖指数(受孕率、出生存活率、哺乳成活率)改变,睾丸体比降低和明显病理改变.结论 多效唑原药对大鼠具有繁殖毒性,其大鼠的两代繁殖毒性最大无作用剂量为41.4 mg/(kg·d).     

成骨细胞的功能与损伤和骨质疏松的防治

骨质疏松是一种全身性骨骼疾病,导致骨折风险增加。成人的骨量通过破骨细胞的骨吸收和成骨细胞的骨形成作用来维持动态平衡,治疗骨质疏松症的理想策略是抑制破骨细胞的骨吸收和/或增强成骨细胞的骨形成功能。目前针对保护成骨细胞及增强其功能的骨质疏松疗法相对较少。因此,本文针对成骨细胞相关功能蛋白、各种细胞损伤机制（内质网应激、氧化应激、机械过载、微小RNA和长链非编码RNA的影响等）及骨质疏松的治疗与预防作一综述,以期为针对增强成骨细胞功能的骨质疏松治疗策略提供新思路。     

Comparison of formation of thiolactones and active metabolites of prasugrel and clopidogrel in rats and dogs

1. Prasugrel and clopidogrel are antiplatelet prodrugs that are converted to their respective active metabolites through thiolactone intermediates. Prasugrel is rapidly hydrolysed by esterases to its thiolactone intermediate, while clopidogrel is oxidized by cytochrome P450 (CYP) isoforms to its thiolactone. The conversion of both thiolactones to the active metabolites is CYP mediated. This study compared the efficiency, in vivo, of the formation of prasugrel and clopidogrel thiolactones and their active metabolites.

2. The areas under the plasma concentration versus time curve (AUC) of the thiolactone intermediates in the portal vein plasma after an oral dose of prasugrel (1 mg kg^?1) and clopidogrel (0.77 mg kg^?1) were 15.8 ± 15.9 ng h ml^?1 and 0.113 ± 0.226 ng h ml^?1, respectively, in rats, and 454 ± 104 ng h ml^?1 and 23.3 ± 4.3 ng h ml^?1, respectively, in dogs, indicating efficient hydrolysis of prasugrel and little metabolism of clopidogrel to their thiolactones in the intestine.

3. The relative bioavailability of the active metabolites of prasugrel and clopidogrel calculated by the ratio of active metabolite AUC (prodrug oral administration/active metabolite intravenous administration) were 25% and 7%, respectively, in rats, and 25% and 10%, respectively, in dogs.

4. Single intraduodenal administration of prasugrel showed complete conversion of prasugrel, resulting in high concentrations of the thiolactone and active metabolite of prasugrel in rat portal vein plasma, which demonstrates that these products are generated in the intestine during the absorption process.

5. In conclusion, the extent of in vivo formation of the thiolactone and the active metabolite of prasugrel was greater than for clopidogrel’s thiolactone and active metabolite.

     

PTEN和DNA含量与非小细胞肺癌侵袭转移的关系探讨

目的 研究非小细胞肺癌(NSCLC)组织中抑癌基因PTEN的表达和DNA含量与NSCLC侵袭、转移的关系.方法 采用免疫组织化学SP方法检测PTEN在78例肺癌标本中的表达,并用流式细胞术检测30例肺癌标本中DNA含量.结果:肺癌标本中PTEN蛋白总缺失率为42.3%,有淋巴结转移组和无淋巴结转移组肺癌表达缺失率分别为52.1%和26.7%(P＜0.05),其表达缺失率随TNM分期增加而上升,分期越晚表达缺失率越高.PTEN缺失率高者生存时间短.DNA指数(DI)的分布范围在1.04～1.93.异倍体肿瘤24例,DI值随TNM分期增加而增加(P＜0.05),与淋巴结转移呈正相关.结论 肺癌组织中PTEN的表达与肺癌淋巴结转移有显著相关性,肺癌细胞DNA含量与肺癌TNM分期及淋巴结转移密切相关.检测PTEN蛋白表达和DNA含量将有助于判断肺癌的转移及预后.     

阿立哌唑与利培酮治疗自闭症谱系障碍与注意缺陷多动障碍共病患儿的疗效与安全性评价

目的：评价阿立哌唑与利培酮治疗自闭症谱系障碍（ASD）与注意缺陷多动障碍（ADHD）共病患儿的疗效与安全性。方法：选取在某院精神科治疗的ASD和ADHD共病患儿68例,根据随机数字表法将患儿分为阿立哌唑组（n=34）和利培酮组（n=34）。阿立哌唑组患儿接受起始剂量为5 mg·d^-1的阿立哌唑片口服治疗,最终剂量增加至15 mg·d^-1。利培酮组患儿接受起始剂量为1 mg·d^-1的利培酮片口服治疗,最终剂量增加至2 mg·d^-1;2组患儿均治疗12周。在基线（T₀）、治疗6周（T₁）与12周（T₂）时,采用注意缺陷/多动评定量表（ADHD-RS）评价患儿总体ADHD症状变化情况;采用康纳斯行为评定量表（CRSR）教师用量表多动因子（CRSR-I）评价患儿多动症的改善情况;采用CRSR不注意缺陷-冲动因子（CRSR-H）评价患儿注意力缺陷的改善情况;采用临床整体印象-严重程度量表（CGI-S）及儿童总体评估量表（C-GAS）评分评价患儿整体功能。对患儿的相关临床指标进行常规监测,比较2组患儿药物不良事件与安全性。结果：与T₀时比较,阿立哌唑组患儿T₁与T₂时,ADHD-RS、CRSR-I、CRSR-H与CGI-S评分均显著降低（均P<0.05）,C-GAS评分显著提高（P<0.05）。利培酮组患儿T₂时,ADHD-RS、CRSR-I、CRSR-H与CGI-S评分均显著降低（均P<0.05）,C-GAS评分显著提高（P<0.05）。2组患儿的ADHD症状显著改善,多动症状与不注意缺陷-冲动症状显著改善,患儿的整体功能也显著改善。2组患儿主要的不良事件是食欲增加、体质量增加与嗜睡,但均没有发生严重的不良事件。T₂时,利培酮组患儿催乳素水平显著提高（t=9.619,P<0.001）,其他临床指标没有显著性差异（均P>0.05）。结论：阿立哌唑和利培酮能够通过减少ASD和ADHD共病患儿的注意力涣散和多动症症状来改善患儿整体功能,具有较高的疗效、安全性,值得临床推广应用。     

Whole-body retention of mercury and selenium and histopathological and morphological studies of kidneys and liver of rats exposed repeatedly to mercuric chloride and sodium selenite

Distribution and retention of mercury and selenium was studied in rats exposed repeatedly to HgCl₂ injections (0.5 mg Hg/kg to the tail vein every other day) and intragastrically to Na₂SeO₃ (0.5 mg Se/kg every day), applying combined and separate administration of these metals for 2 weeks. Whole-body retention of mercury in the presence of selenium was augmented by 20% and that of selenium in the presence of mercury by 4% with respect to the administered dose. Combined administration of mercuric chloride and sodium selenite brought about damage to the epithelial cells of renal proximal convolutions and formation of protein casts in their lumen. These changes had the same pattern as those induced by administration of mercuric chloride alone, but the intensity was lower. Submicroscopic studies revealed that repeated combined administration of sodium selenite and mercuric chloride did not completely abolish the mercury-induced mitochondrial swelling and contributed to chromatin destruction in the hepatocyte nuclei.This work was supported by the Section of Medical Sciences of the Polish Academy of Sciences (Agreement 537/VI)     

阿立哌唑与利培酮治疗痴呆精神行为症状的疗效及安全性比较

目的观察阿立哌唑和利培酮治疗老年痴呆精神行为症状的疗效及安全性。方法采用随机对照研究,将具有精神行为症状的痴呆患者68例完全随机分为阿立哌唑组及利培酮组,各34例。阿立哌唑组患者服用阿立哌唑,起始剂量2．5mg／d,最大剂量不超过15mg／d;利培酮组患者口服利培酮,起始剂量0．5mg／d,最大剂量不超过3mg／d。疗程均为8周。治疗前和治疗第2、4、8周末采用痴呆病理分析评定量表（BEHAVE—AD）评定疗效,用副反应量表（TESS）评定不良反应,并于入组时和治疗第8周末分别检测2组患者空腹血糖、餐后2h血糖、TC、TG、LDL—C、HDL—C及体重。结果阿立哌唑组和利培酮组患者治疗2、4、8周后BEHAVE—AD评分均明显低于治疗前[阿立哌唑组：（14．8±4．2）、（10．2±3．6）、（6．8±2．8）分比（16．4±4．6）分;利培酮组：（15．2±3．9）、（11．8±3．8）、（7．2±3．0）分比（17．2±5．O）分,P〈0．05或P〈0．01]。2组患者间治疗前及治疗后BEHAVE—AD评分比较,差异均无统计学意义（P〉0．05）。2组不良反应发生率均为8．8％（3／34）,差异无统计学意义（P〉0．05）。利培酮组治疗8周末体重较治疗前增加明显[（71±6）kg比（66±6）kg,P〈0．05],TG及LDL—C升高[分别为（1．62±0．46）mmol／L比（0．96±0．29）mmol／L．（3．82±0．86）mmol／L比（3．08±0．74）mmol／L,而阿立哌唑组则改变不明显（均P〉0．05）。结论阿立哌唑治疗老年痴呆精神行为症状总体疗效、安全性与利培酮相当,但阿立哌唑对患者血糖、血脂及体重影响小于利培酮。     

Correlation of behavioral and neurochemical effects of d- and l-amphetamines

In an attempt to correlate the behavioral and neurochemical effects of d- and l-amphetamines, the time courses of the effects of the two isomers (1 mg/kg; base, i.p.) were studied on spontaneous motor activity (SMA) and stereotyped behavior (ST) as well as on the concentrations of norepinephrine (NE), dopamine (DA), and serotonin (5-HT) in discrete brain areas, such as the caudate nucleus (CN), pons-medulla (PM), and diencephalonmidbrain (DM) in rats. In addition, the dose-response relationship for d-isomer (0.5–2 mg/kg, i.p.) and l-isomer (1–4 mg/kg, i.p.) was also studied on SMA and ST. SMA increased with the dose up to 1.5 mg/kg for d-isomer and up to 3 mg/kg for l-isomer and then decreased, whereas ST increased with the dose for both the isomers. At 1 mg/kg dose, SMA reached its peak during the fourth postdrug 20–minute period for both d- and l-isomers, whereas ST reached its peak during third to fifth 20-minute periods for d-isomer and during the third period for the l-isomer. The d-isomer significantly increased the DA levels in the CN and DM at 30 minutes postdrug, which reached their maximum at 60 minutes, whereas NE levels in the PM had no significant change at 30 minutes, but were significantly reduced in the DM at 30 minutes and in both PM and DM at 60 minutes postdrug; 5-HT levels in the PM and DM showed no significant change. Compared to d-amphetamine, the l-isomer at 30 and 60 minutes postdrug caused more or less similar changes in the NE levels in the DM and PM, whereas it produced less increase in the DA levels in the CN and DM and significant decrease in 5-HT levels in the DM and PM. It appears that the difference in the behavioral effects induced by the two isomers of amphetamine may be due to the difference in their effects on dopaminergic and serotonergic systems.