丙戊酸在癫痫大鼠额叶的神经药代动力学特征

目的 研究丙戊酸在癫痫大鼠的额叶神经药代动力学特征。方法 健康雄性SD大鼠12只，随机分成对照组与癫痫组，每组各6只。癫痫组大鼠用印防己碱（PTX）腹腔注射点燃，腹腔注射丙戊酸钠400mg/kg后不同时间点收集两组大鼠额叶细胞外液透析液及血标本。结果 丙戊酸迅速吸收入额叶中，在额叶中浓度显低于血中浓度；癫痫大鼠与正常大鼠额叶的神经药代动力学参数之间的差异无显性；给药1h后额叶丙戊酸浓度与血清丙戊酸浓度均呈下降趋势。结论 癫痫大鼠与正常大鼠额叶丙戊酸神经药代动力学特征相似；丙戊酸在癫痫大鼠额叶的分布可能与额以局部脑血管流量变化，血脑屏蔽功能障碍，丙戊契穿过血脑屏蔽需单羧酸（MCA）载体转运等因素有关；监测给药一段时间后血清丙戊酸 度有助于了解脑卒中后晚发性癫痫患的额叶丙戊酸浓度，指导临床合理用药。     

冰片对丙戊酸钠透过血脑屏障的影响

目的探讨冰片对丙戊酸钠在家兔体内透过血脑屏障的影响。方法12只家兔随机分为对照组和冰片组，每组6只。两组动物均静脉滴注丙戊酸钠达稳态，之后冰片组予冰片灌胃给药。采用荧光偏振免疫分析法检测家兔血浆和脑脊液丙戊酸钠的浓度，计算药代动力学参数。结果与对照组相比，冰片组家兔脑脊液平均药物浓度升高，曲线下面积增加（P〈0．05），稳态脑脊液药物浓度出现峰值时间为6h，脑血浓度比亦升高（P〈0．05），但血药浓度并未升高。结论冰片可提高血脑屏障对丙戊酸钠的通透性，但对血药浓度影响较小。     

高压氧联合中药冰片对大鼠血脑屏障丙戊酸钠透过率的影响

目的观察高压氧（HBO）联合中药冰片对大鼠血脑屏障（BBB）丙戊酸钠透过率的影响。 方法选取56只健康SD大鼠,按照随机数字表法将其分为对照组（腹腔注射丙戊酸钠0.1g/kg）、HBO-1组（HBO治疗结束后0.5h注射丙戊酸钠0.1g/kg）、HBO-2组（HBO治疗同时注射丙戊酸钠0.1g/kg）、HBO-3组（HBO治疗前0.5h注射丙戊酸钠0.1g/kg）、低剂量冰片组（灌服0.125g/kg冰片0.5h后注射丙戊酸钠0.1g/kg）、高剂量冰片组（灌服0.25g/kg冰片0.5h后注射丙戊酸钠0.1g/kg）、联合应用组（灌服0.125g/kg冰片0.5h后注射丙戊酸钠0.1g/kg,0.5h后进行HBO治疗）,每组8只。注射丙戊酸钠1.5h后,取大鼠的血液及脑脊液,采用高效液相色谱法测定丙戊酸钠的浓度。 结果与对照组比较,HBO-2组［（97.43±12.09）mg/L］、HBO-3组［（100.10±13.54）mg/L］大鼠脑脊液丙戊酸钠浓度均显著增加,差异有统计学意义（P<0.05）,脑脊液血浆浓度比也明显增高（P<0.05）;与对照组比较,高剂量冰片组大鼠脑脊液丙戊酸钠浓度［（91.09±9.45）mg/L］及脑脊液血浆浓度比值（0.577±0.051）较高,差异有统计学意义（P<0.05）。与低剂量冰片组比较,HBO-3组、联合应用组大鼠脑脊液丙戊酸钠浓度较高,差异有统计学意义（P<0.05）。与HBO-3组比较,联合应用组大鼠脑脊液丙戊酸钠浓度［（112.43±11.52）mg/L］及脑脊液血浆浓度比（0.698±0.058）均显著增加（P<0.05）。各组间血液丙戊酸钠浓度比较,差异均无统计学意义（P&rt;0.05）。 结论HBO疗法可提高大鼠BBB对丙戊酸钠的通透性,与低剂量冰片联用后效果更佳。     

利奈唑胺在大鼠血、脑组织和脑脊液中的药代动力学研究

目的 探讨利奈唑胺在大鼠血、脑组织和脑脊液中药代动力学特性,为临床治疗中枢神经系统感染提供参考.方法 78只清洁型SD大鼠,尾静脉单次注射利奈唑胺54 mg/kg后,采用高效液相色谱法测定大鼠不同时间点的血、脑组织和脑脊液中利奈唑胺的药物浓度,计算其药代动力学参数.结果 注射后0～19h,利奈唑胺在大鼠的血、脑组织和脑脊液的峰浓度（Cmax）分别为31.39、5.11、23.97 μg/ml;消除半衰期（t1/2）分别为2.67、2.42、1.99 h;药物浓度-时间曲线下面积（AUC 0～∞）分别为134.55、28.23、136.43 h·μg/ml,血脑屏障穿透率为76.36％.结论 利奈唑胺能很好地进入脑脊液达到有效的抑菌浓度,具有良好的药代动力学特征和组织穿透性.     

脂多糖对孤独症大鼠行为学发育的影响及病理机制

目的：探讨发育早期感染对孤独症症状的影响,建立丙戊酸钠SD大鼠孤独症样模型,分析发育早期脂多糖暴露对其孤独症样行为的影响及病理机制。方法：随机选取9只SD孕鼠中的6只于孕12.5天给予丙戊酸钠600mg/kg腹腔注射建立孤独症模型,另外3只孕鼠作为对照组,给予生理盐水腹腔注射。模型组孕鼠产仔后,第20天随机挑选一半仔鼠作为丙戊酸钠加脂多糖组,给予脂多糖2mg/kg腹腔注射,另一半生理盐水腹腔注射作为丙戊酸钠组,注射生理盐水的孕鼠的子代为对照组。采用随机数字法在3组中随机选取仔鼠各8只,在生后43天进行旷场实验、埋珠实验、Y型迷宫实验和三箱社交实验。生后50天3组仔鼠额叶脑组织进行HE染色和透射电镜病理检测,海马组织进行HE染色。结果：旷场实验、埋珠实验、Y型迷宫实验、三箱实验结果显示,丙戊酸钠组较对照组的活动总距离长、跨格子数多、埋珠个数多、关闭臂进入次数少、关闭臂探索路程少、关闭臂探索时间少、社交性和社交偏好性降低（P<0.05）;丙戊酸钠加脂多糖组较丙戊酸钠组的活动总距离长、跨格子数多、埋珠个数多、关闭臂进入次数少、关闭臂探索路程少、社交性和社交偏好性降低（P<0.05...     

小分子化合物丙戊酸促进大鼠坐骨神经的再生

目的:观察小分子化合物丙戊酸对周围神经再生的作用。方法:实验于2005-07/10在吉林大学中日联谊医院动物实验室完成。选用成年雄性Wistar大鼠15只,随机分为假手术组、模型组和丙戊酸组3组(n=5)。模型组和丙戊酸组大鼠切断右侧坐骨神经制备单纯坐骨神经轴突切断模型,然后即刻行神经吻合术,假手术组不切断坐骨神经。丙戊酸组大鼠在神经修复术后喂食含丙戊酸水(300mg/(kg·d))16周,使血浆浓度达到50mg/L。16周后,各组大鼠取坐骨神经及双侧胫骨前肌进行组织形态学检查,观察再生的有髓神经纤维和神经再支配的肌纤维数量及大小。结果:15只大鼠全部进入结果分析。①模型组和丙戊酸组再生的单个有髓神经纤维的大小明显小于假手术组(P<0.001);模型组和丙戊酸组中再生神经有髓纤维数量是假手术组的3倍(P<0.001);丙戊酸组大鼠中有髓神经纤维数量明显高于模型组(P<0.05)。②模型组和丙戊酸组大鼠神经再支配胫骨前肌中单个肌纤维大小明显小于假手术组(P<0.05),丙戊酸组再支配胫骨前肌肌纤维数量明显高于模型组(P<0.05)。结论:丙戊酸并不能影响神经再支配肌肉组织中肌纤维的大小,但可使神经再支配肌肉中肌纤维数量显著增加,进而增强大鼠坐骨神经再生能力,提示丙戊酸对人体周围神经损伤具有潜在的临床应用价值。     

小分子化合物丙戊酸促进大鼠坐骨神经的再生

目的：观察小分子化合物丙戊酸对周围神经再生的作用。 方法：实验于2005—07／10在吉林大学中日联谊医院动物实验室完成。选用成年雄性Wistar大鼠15只，随机分为假手术组、模型组和丙戊酸组3组（n=5）。模型组和丙戊酸组大鼠切断右侧坐骨神经制备单纯坐骨神经轴突切断模型，然后即刻行神经吻合术，假手术组不切断坐骨神经。丙戊酸组大鼠在神经修复术后喂食含丙戊酸水（300mg／（kg&;#183;d））16周，使血浆浓度达到50mg／L。16周后，各组大鼠取坐骨神经及双侧胫骨前肌进行组织形态学检查，观察再生的有髓神经纤维和神经再支配的肌纤维数量及大小。 结果：15只大鼠全部进入结果分析。（1）模型组和丙戊酸组再生的单个有髓神经纤维的大小明显小于假手术组（P〈0．001）；模型组和丙戊酸组中再生神经有髓纤维数量是假手术组的3倍（P〈0．001）；丙戊酸组夫鼠中有髓神经纤维数量明显高于模型组（P〈0．05）。（2）模型组和丙戊酸组大鼠神经再支配胫骨前肌中单个肌纤维大小明显小于假手术组（P〈0．05），丙戊酸组再支配胫骨前肌肌纤维数晕明显高于模型组（P〈0．05）。 结论：丙戊酸并不能影响神经再支配肌肉组织中肌纤维的大小，但可使神经再支配肌肉中肌纤维数量显著增加，进而增强大鼠坐骨神经再生能力，提示丙戊酸对人体周围神经损伤具有潜在的临床应用价值。     

血必净注射液对急性肺损伤大鼠氧自由基变化的影响

目的:探讨血必净注射液对急性肺损伤大鼠氧自由基变化的影响.方法:SD大鼠72只随机分为正常对照组、内毒素组(LPS组)和内毒素联合血必净组(LPS+XBJ组),后两组又分别分为给药后1、2、4、12 h 4个亚组,每个亚组8只.采用静脉注射LPS(5 mg/kg)建立急性肺损伤模型.LPS+XBJ组予静脉注射LPS后同时腹腔注射血必净(10 mL/kg),LPS组腹腔注射等量生理盐水(10 mL/kg),正常对照组给予等量生理盐水.观察各组肺组织病理学变化,检测各组肺湿干质量比(W/D)、血清丙二醛(MDA)浓度、超氧化物歧化酶(SOD)活力等的变化.结果:血必净注射液干预可显著降低急性肺损伤大鼠升高的W/D(P<0.05)和血清肺MDA浓度(P<0.01或P<0.05).显著升高急性肺损伤大鼠降低的SOD浓度(P<0.01或P<0.05),减轻肺组织形态学损伤.结论:血必净注射液可抑制氧自由基产生.对LPS所致急性肺损伤大鼠具有肺保护作用.     

人参皂甙Rgl对大鼠运动过程中糖代谢的影响

目的:探讨人参皂甙Rgl对大鼠游泳过程中血糖和相关血糖调节激素以及对血浓度变化的影响,为阐明其抗疲劳作用提供实验依据。方法:实验于2003-01/06在湖南师范大学动物实验室完成。进行两个实验,①42只大鼠随机平均分为6组(n=7),其中5组连续两天以5,10,15,25或30mg/(kg·d)的剂量给大鼠腹腔注射人参皂甙Rgl,给另一组腹腔注射等容积生理盐水,测定其力竭游泳时间。②84只大鼠随机分为12组(n=7),其中6组为人参皂甙Rg1给药组,另6组为生理盐水对照组。给药组大鼠连续两天以20mg/(kg·d)的剂量注射人参皂甙Rgl,对照组注射等体积生理盐水后。分别在安静状态下和游泳0.5,1,1.5,2,3h测定血乳酸、葡萄糖浓度及糖原含量。结果:126只大鼠均进入结果分析,无脱失值。①人参皂甙Rg1对大鼠力竭游泳时间的影响:人参皂甙Rgl给药组15mg/(kg·d)以上剂量,各给药组力竭游泳时间均长于对照组[(6.11±0.52),(6.29±0.65),(6.23±0.57),(4.00±0.37)h,P<0.05,P<0.01]。在5～25mg/(kg·d)剂量范围内随剂量增加,力竭游泳时间明显延长。②人参皂甙Rg1对大鼠游泳过程中肌、肝糖原含量的影响:安静状态下,给药组和对照组的肌、肝糖原含量基本相等。在游泳过程中,给药组与对照组肌、肝糖原含量均随着游泳时间延长而下降,但给药组下降较慢。给药组在游泳3h后约下降30%,对照组在相同的游泳时间后下降70%。③人参皂甙Rg1对大鼠游泳过程中血乳酸浓度的影响:人参皂甙Rg1给药组的血乳酸浓度上升不明显;而对照组的血乳酸浓度则有较大幅度上升,在运动1h后达到峰值,约为安静状态下的4倍。给药组游泳0.5,1h和1.5h的血乳酸浓度低于各相应对照组。④人参皂甙Rg1对大鼠游泳过程中血糖浓度的影响:游泳过程中,给药组血糖浓度仅略有下降,而对照组下降较为明显。对照组在运动1,2,3h后,下降幅度依次为24%,30%,35%,下降幅度明显大于安静组或相应给药组。结论:人参皂甙Rgl对游泳大鼠具有减缓血糖下降,预防运动性低血糖发生的作用,这种作用可能是由于相关血糖调节激素的分泌或活性变化引起。     

人参皂甙Rg1对大鼠运动过程中糖代谢的影响

目的探讨人参皂甙Rg1对大鼠游泳过程中血糖和相关血糖调节激素以及对血浓度变化的影响,为阐明其抗疲劳作用提供实验依据.方法实验于2003-01/06在湖南师范大学动物实验室完成.进行两个实验,①42只大鼠随机平均分为6组(n=7),其中5组连续两天以5,10,15,25或30 mg/(kg·d)的剂量给大鼠腹腔注射人参皂甙Rgl给另一组腹腔注射等容积生理盐水,测定其力竭游泳时间.②84只大鼠随机分为12组(n=7),其中6组为人参皂甙Rg1给药组,另6组为生理盐水对照组.给药组大鼠连续两天以20mg/(kg·d)的剂量注射人参皂甙Rgl,对照组注射等体积生理盐水后.分别在安静状态下和游泳0.5,1,1.5,2,3h测定血乳酸、葡萄糖浓度及糖原含量.结果126只大鼠均进入结果分析,无脱失值.①人参皂甙Rg1对大鼠力竭游泳时间的影响人参皂甙Rgl给药组15 mg/(kg·d)以上剂量,各给药组力竭游泳时间均长于对照组[(6.11±0.52),(6.29±0.65),(6.23±0.57),(4.00±0.37)h,P＜0.05,P＜0.01].在5～25 mg/(kg·d)剂量范围内随剂量增加,力竭游泳时间明显延长.②人参皂甙Rg1对大鼠游泳过程中肌、肝糖原含量的影响安静状态下,给药组和对照组的肌、肝糖原含量基本相等.在游泳过程中,给药组与对照组肌、肝糖原含量均随着游泳时间延长而下降,但给药组下降较慢.给药组在游泳3 h后约下降30%,对照组在相同的游泳时间后下降70%.③人参皂甙Rg1对大鼠游泳过程中血乳酸浓度的影响人参皂甙Rg1给药组的血乳酸浓度上升不明显;而对照组的血乳酸浓度则有较大幅度上升,在运动1 h后达到峰值,约为安静状态下的4倍.给药组游泳0.5,1 h和1.5 h的血乳酸浓度低于各相应对照组.④人参皂甙Rg1对大鼠游泳过程中血糖浓度的影响游泳过程中,给药组血糖浓度仅略有下降,而对照组下降较为明显.对照组在运动1,2,3 h后,下降幅度依次为24%,30%,35%,下降幅度明显大于安静组或相应给药组.结论人参皂甙Rg1对游泳大鼠具有减缓血糖下降,预防运动性低血糖发生的作用,这种作用可能是由于相关血糖调节激素的分泌或活性变化引起.     

托吡酯、丙戊酸钠预防幼鼠慢性癫痫脑损伤的实验研究

目的研究托吡醣、丙戊酸钠单药及联合用药对幼鼠慢性癫痫脑损伤的影响。方法将3～4周龄雄性Wistar大鼠60只随机分为5组,B、C、D、E组为慢性癫痫组,C、D、E组于戊四氮(PZT)腹腔注射后给予TPM 40 mg/kg、VPA 200mg/kg、TPM 40mg/kg+VPA 200mg/kg,A、B组给予等量的蒸馏水,连续用药2个月,观察癫痫发作后幼鼠的体重改变、行为学表现及海马组织病理形态学的变化检测血清神经元特异性烯醇化酶(NSE)水平,了解脑损伤的发生情况及药物的情况保护。结果①TPM使体重增长降低,VPA使体重增长增加;②TPM、VPA均使发作持续时间缩短(P<0.05),联合用药组使发作持续的时间长(P<0.05);③TPM组、VPA组的NSE水平降低显著(P<0.05);④TPM组、VPA组神经元的退行性变和胶质细胞的反应性增生较阳性组减少。TPM+VPA组神经元变性坏,胞浆浓缩,出现红色神经元。结论TPM、VPA单药均对癫痫脑损伤有保护作用,但2者联合可能削弱其单药的神经保护作用。     

How chronically administered valproate increases chlordiazepoxide transfer through the blood-brain barrier

Sodium valproate (VPA) is a drug widely used in the treatment of epileptics often in association with benzodiazepines. Recent animal studies have shown that the addition of valproate increases diazepam levels in the cortex and the cerebellum (Hariton et al, 1985). The aim of our study was to determine the effect of VPA on the transfer of benzodiazepines through the blood-brain barrier. They were investigated using the intracarotid injection technique in rats as described by Oldendorf (1971). Our results show that the 14C-chlordiazepoxide brain extraction is significantly higher in rats on prolonged valproate treatment than in controls. With regard to plasma protein binding effects on chlordiazepoxide transport, our data indicate that a fraction of the protein-bound chlordiazepoxide could transfer from the intracapillary space to the brain tissue space because of enhanced drug dissociation from albumin in the brain microcirculation (Kd in vitro = 74.1 microM; Kd in vivo = 793.7 microM). Two distinct mechanisms can be deduced from this study: 1) chlordiazepoxide is displaced from HSA by valproate, 2) in addition, this fatty acid could increase drug permeation through the blood brain barrier (PS/F (chlordiazepoxide) = 0.60 in controls, PS/F (chlordiazepoxide) = 0.97 in treated rats). On the contrary, the washout of the benzodiazepine from the rat brain does not seem to be modified by the addition of valproate.     

联合应用托吡酯与丙戊酸钠对癫痫幼鼠海马线粒体超微结构的影响

目的 研究应用托吡酯与丙戊酸钠后慢性癫痫幼鼠海马线粒体超微结构的变化情况。方法 将3～4周龄雄性Wistar大鼠60只，随机分为5组。B-E组为慢性癫痫组，C、D、E组于戊四氮腹腔注射后给予TPM 40 mg/kg、VPA 200 mg/kg 、TPM40mg/kg +VPA 200 mg/kg；A、B组给予等量的蒸馏水。连续用药2个月。常规固定、包埋，透射电镜观察海马CA1区神经元线粒体的结构。结果 与阳性对照组比较，托吡酯、丙戊酸钠单药组线粒体的结构基本完整,但间隙肿胀(尤其是嵴部分)，TPM与VPA联合用药组海马线粒体的线粒体肿胀较明显，嵴出现断裂和脱落，部分线粒体空泡化。结论 托吡酯、丙戊酸钠对癫痫发作所致的线粒体损伤有保护作用，而TPM与VPA联合用药可削弱这种保护作用。     

丙戊酸钠对脂多糖诱导大鼠急性肺损伤的保护作用

目的 研究丙戊酸钠(valproic acid,VPA)对脂多糖(lipopolysaccharide,LPS)诱导的大鼠急性肺损伤的影响.方法 实验地点在武汉协和医院中心实验室,通过股静脉注射LPS复制大鼠急性肺损伤模型,观察光镜下肺组织病理学改变、血清炎性因子和肺部炎性反应判定模型是否成功.依据干预药物的不同确定实验分组:股静脉给予5mL/kg生理盐水为对照组(NS组),股静脉给予LPS 10 mg/kg为模型组(LPS组),模型成功后股静脉给予VPA 300mg/kg治疗为治疗组(LPS+VPA组).注射LPS或NS后6 h处死动物,血气分析观察动脉血氧分压(PaO2)、肺泡气-动脉血氧分压差(A-aDO2)、乳酸(Lac),检测肺组织干湿重比(W/D),髓过氧化物酶(MPO)活性,肺泡灌洗液(BALF)中白蛋白质量浓度,用ELISA法检测6 h血清中TNF-α和IL-1β的含量,HE染色光镜下观察肺组织病理学变化.计量资料以均数±标准差(-x±s)表示,应用SPSS 13.0统计软件行单因素方差分析.结果 LPS组PaO2(mmHg)(81.50±3.24)较NS组(106.40±4.50)降低,A-aDO2(mmHg),Lac[(19.70±2.21),(3.63±0.22)]较NS组[(6.30±1.70),(1.21±0.19)]升高,W/D,MPO活性(μ/g),BALF中白蛋白质量浓度(pg/mL)分别为[(6.52±0.30),(7.25±0.49),(2.940±0.047)]较NS组[(4.38±0.17),(1.76±0.31),(0.099±0.077)]升高,血清中TNF-α和IL-1β的质量浓度(pg/ml)分别为(3325±284),(1950±222)较NS组(90±12),(50±11)显著升高,差异具有统计学意义(P＜0.05),LPS组肺组织出现病理学改变;与LPS组比较,LPS+VPA组上述指标除PaO2(mmHg)(94.50±4.38)上升外,其余指标均降至[(13.50±4.77),(2.13±1.02),(5.33±0.12),(4.38±0.42),(1.260±0.039),(2410±320),(1220±162)],差异具有统计学意义(P＜0.05),LPS+VPA组肺组织病理学改变明显减轻.结论 丙戊酸钠对脂多糖诱导的大鼠急性肺损伤有一定保护作用.

Abstract：

Objective To investigate the effects of valproic acid (VPA) on acute lung injury induced by Lipopolysaccharide in rats. Method The rat model of acute lung injury was made by intravenous injection of lipopolysaccharide (LPS). The pathological changes of lung were observed under light microscope and inflammatory cytokines in serum detected by using ELISA to judge whether the model was successfully done or not. All rats were divided into three groups as per the different intervention agents employed. Rats in control group were treated with intravenous injection of NS in dose of 5 ml/kg, rats in LPS group were exposed to LPS with dosage of 10 mg/kg and model rats in LPS + VPA group were treated with VPA in dose of 300 mg/kg. The rats were sacrificed 6 h after LPS or NS administration. The blood PaO2 ,A-aDO2 and blood lactic acid (Lac) were measured, the lungs were removed for observing the histopathological changes and determination of wet/dry lung weight (W/D) ratio and myeloperoxidase (MPO) activity as well as albumin concentration in broncho-alveolar lavage fluid (BALF) . Seurm was collected to determine the concentrations of tumor necrosis factor-a (TNF-α) and interleukin-1β( IL-1 β) by using LISA 6 h later. All data were presented in ((x)±s). One-way ANOVA was used for comparing differences between groups. Results Compared with acute lung injury group, the blood PaO2 (94. 50 ± 4.38 ) in rats of LPS + VPA group was higher, whereas A-aDO2 ( 13.50 ± 4.77 ) and blood lac( 2.13 ± 1. 02 ) in LPS + VPA group were lower. VPA significantly lowered W/D (5.33 ±0. 12) ratio and MPO activity (4.38 ±0. 42) in the lung. Albumin concentration ( 1. 260 ± 0. 039 ) in BALF, and the levels of TN F-α( 2 410 ±320 )and IL-1β( 1 220 ± 162 )in serum were lower in LPS + VPA group. The histological changes of lung injury were lessened by VPA. Conclusions Valproic acid has protective effects against lipopolysaccharide-induced acute lung injury in rats.     

Interactions between carbapenems and valproic acid among the patients in the intensive care units

PurposeTo evaluate risk factors for epileptic seizures or status epilepticus (SE) in patients concomitantly receiving valproic acid (VPA) and carbapenems.Materials and methodsAdult patients in the intensive care units (ICUs) who concomitantly received VPA and carbapenems from 2007 to 2017 were included. The impacts of different carbapenems on serum concentration of VPA were compared.ResultsAmong 162 patients included, 104 (64.2%) and 45 (27.8%) developed epileptic seizures and SE, respectively. The risk factors for epileptic seizures were age (per year increase, adjusted odds ratio [aOR], 1.03), initial antiepileptic regimen (monotherapy and polytherapy, aOR, 0.43 and 0.18, respectively), and VPA serum concentration after concomitant carbapenem administration (per 1 μg/mL increase, aOR, 0.96). VPA serum concentration after concomitant carbapenem administration was an independent risk factor for SE (per μg/mL increase, aOR, 0.98). Concomitant imipenem/cilastatin administration did not significantly decrease VPA serum concentration compared to that by meropenem or ertapenem. The length of stay and number of days on ventilation after concomitant carbapenem administration in the ICUs were significantly more in those with epileptic seizures or SE.ConclusionsCarbapenems decreased VPA serum concentration and increased the risk of epileptic seizures and SE, which led to increased length of ICU stay.     

Serum protein binding and pharmacokinetics of valproate in man, dog, rat and mouse.

The serum protein binding of valproate (di-n-propylacetate) has been determined at therapeutic concentrations by equilibrium dialysis in man (94.8%), dog (78.5%), rat (63.4%) and mouse (11.9%). In dog serum, the binding was found to be independent of the valproate concentration in the range of 5 to about 70 microgram/ml, but fell with higher concentrations. In addition, the kinetics of valproate has been determined in dogs and rats. After intravenous administration, serum concentrations declined biexponentially in both species, the half-life of elimination (T 0.5 (beta)) being 1.7 hours in dogs and 4.6 hours in rats. In comparison with the pharmacokinetics of valproate in man and mouse, it can be assumed that the protein binding of valproate is rate-limiting for its clearance by the liver and may be responsible for the striking differences in the half-lives of the drug in different species. Increased drug binding was associated with a decrease in the total clearance and in all species examined, the calculated hepatic extraction ratios (0.009-0,17) were smaller that the free fraction, indicating that valproate fits into the group of drugs with restrictive and liver blood flow independent elimination, i.e., only the unbound drug can be cleared.     

The effect of carnitine on the metabolism of valproic acid in epileptic patients.

The half-life of valproic acid (VPA) was studied in 8 epileptic and severely mental retarded patients before and after one month of carnitine supplementation. Serum carnitine concentration was significantly decreased and VPA half-life was prolonged especially in adult patients before carnitine supplementation. After the treatment with carnitine, serum carnitine concentration was increased, and prolonged half-lives of VPA were corrected near to the normal range (from 12.2 +/- 4.2 hr to 9.7 +/- 2.2 hr; p < 0.05). Controlled state of epilepsy was unchanged during the short period of observation.     

全蝎醇提物与丙戊酸干预氯化锂-匹罗卡品慢性点燃模型大鼠癫痫发作的疗效比较

目的 探讨全蝎醇提物(Ethanol Extracts of Scorpion,EES)与丙戊酸(Valproic Acid,VPA)干预氯化锂一匹罗卡品(Lithium Chloride-Pilocarpine,Licl-Pilo)慢性点燃模型大鼠癫痫发作的疗效.方法 186只成年雄性大鼠除6只设为正常对照组外.其余均建立Licl-Pilo慢性点燃大鼠模型,遣模成功后分为模型组、VPA干预组、低 EES 剂量干预组(EESL干预组)、中EES剂量干预组(EESM干预组)和高EES剂量干预组(EESH干预组)各36只.正常对照组、模型组分别灌胃给予等容积的生理盐水,VPA干预组灌胃给予VPA溶液[浓度为120 ms/(kg·d)],EESL干预组、EESM干预组、EESH干预组灌胃给予EES溶液[浓度分别为290 ms/(kg·d)、580 nag/(kg·d)及1160 ms/(kg·d)],观察30天内致痫大鼠慢性癫痛自发性发作(spontaneous seizures,SRS)、发作级别、发作次数,并进行组问比较.结果 Licl-Pilo慢性点燃模型鼠的造模成功率为85.65%,各实验组SRS发生频率5～15次/周.治疗后,EESM干预组、EESH干预组和VPA干预组癫痫大鼠痫性发作级别及SRS发作次数与模型组比较差异有统计学意义(P<0.05);EESL干预组治疗效果不明显,与模型组比较差异无统计学意义(P>0.05).结论 一定剂量的EES能显著降低癫痫大鼠的自发性发作,且与疗效呈明显的量效关系,即剂量越大疗效越好,该结果 为EES的抗癫痫作用提供了行为学依据.     

gamma-Hydroxybutyrate modulates synthesis and extracellular concentration of gamma-aminobutyric acid in discrete rat brain regions in vivo.

gamma-Hydroxybutyrate possesses most of the properties of a neurotransmitter/neuromodulator that acts via specific pathways and receptors in brain. Beside its regulatory effects on dopaminergic transmission, gamma-hydroxybutyrate was thought for many years to interfere with gamma-aminobutyric acid (GABA)ergic processes in the brain. The present study demonstrates that in the rat frontal cortex in vivo, gamma-hydroxybutyrate or its agonist NCS-356 administered systemically at a high dose (500 mg/kg) increases GABA contents in dialysates via a mechanism blocked by the peripheral administration of the gamma-hydroxybutyrate antagonist NCS-382. Under the same conditions, the extracellular concentration of this amino acid was not modified in the hippocampus. However, when administered at a low dose (250 mg/kg), gamma-hydroxybutyrate decreases GABA content of the dialysates of the frontal cortex by an NCS-382-sensitive mechanism. Spontaneous [3H]GABA release was observed in the frontal cortex of rats at 160 min after i.p. [3H]-gamma-hydroxybutyrate administration. This result indicates that gamma-hydroxybutyrate in vivo could be the precursor of an extracellular GABA pool in the frontal cortex. After i.p. [3H]-gamma-hydroxybutyrate administration in the rat, the amino acid contents of several brain regions were quantified 160 min later, and the radioactivity in each region was measured. [3H]GABA, [3H]glutamate, and [3H]glycine were detected in most, but not all, of the brain regions studied. In particular, radioactive GABA was not detected in the hippocampus. The other amino acids were not labeled. These results show that gamma-hydroxybutyrate modulates the synthesis and the extracellular concentrations of GABA in specific regions of the rat brain. Identification of these GABA pools and determination of their functional role remain to be defined.     

吗啡依赖及戒断对大鼠脑源性神经营养因子表达的影响

背景阿片类药物多次用药可引起脑内有关神经部位出现形态及功能的适应性变化,这些适应性变化是导致药物渴求和戒断后复吸的重要神经生物学基础,但其确切的分子机制目前尚不清楚.目的研究吗啡依赖形成及戒断对大鼠脑源性神经营养因子表达的影响,以期为脑源性神经营养因子参与阿片类药物依赖及戒断反应提供实验学依据.设计以实验动物为观察对象的随机设计,对照研究.单位一所医科大学医院的心理卫生中心.材料实验于2004-03/2004-07在重庆医科大学药学系药理实验室完成.选择近交清洁级Sprague-Dawley大鼠30只,均为雄性,体质量200～250 g,购自解放军第三军医大学实验动物中心.按随机数字法将其分为空白对照组、吗啡依赖组、盐酸纳洛酮处理戒断组,每组10只.方法采用剂量递增法皮下注射吗啡建立大鼠吗啡依赖模型,然后对戒断组大鼠皮下注射2 mg/kg的盐酸纳络酮激发戒断症状.空白对照组大鼠按同等剂量给予生理盐水.分别对建立模型的各组大鼠进行生物学和行为学的观察.应用免疫组化和地高辛标记寡核苷酸探针原位杂交技术检测3组大鼠不同脑区脑源性神经营养因子的表达水平.主要观察指标①各组大鼠脑内脑源性神经营养因子蛋白、脑源性神经营养因子mRNA平均光密度的比较;②各组大鼠戒断症状评定比较.结果吗啡依赖组大鼠前额叶皮层、蓝斑、海马脑源性神经营养因子蛋白的相对含量高于对照组(P＜0.05);吗啡依赖组大鼠前额叶皮层脑源性神经营养因子mRNA的相对含量高于对照组(P＜0.05).吗啡戒断组大鼠前额叶皮层、蓝斑、海马脑源性神经营养因子蛋白及其mRNA的相对含量均高于依赖组及对照组(P＜0.05).结论慢性给予吗啡可影响大鼠相关脑区BDNF蛋白及其mRNA的表达,提示脑源性神经营养因子表达的改变参与吗啡依赖及戒断反应.