抗癫癎药妥泰对幼鼠肝毒性的实验研究

An experimental study on hepatotoxicity of topiramate in young rats

摘要:

目的：目的妥泰（TPM）以其多重的药理作用，在儿童癫癎治疗中表现出明显的治疗效果，然而上市后少数病例报道出现肝功能衰竭、肝炎等不良反应，引起医学界的关注。该研究从血清生化、氧化应激指标和肝脏形态学方面探讨TPM单药高、低剂量及与丙戊酸钠（VPA）合用对幼鼠肝脏的毒性作用，为临床合理用药提供实验室依据。方法：将3周龄雄性Wistar大鼠60只，随机分为5组，每组12只。实验组（分别为A，B，C 3组），每日1次经口灌胃给予TPM 40 mg/kg，TPM 80 mg/kg和TPM 40 mg/kg＋VPA 300 mg/kg；阴性对照组（D组）给予等量的蒸馏水；阳性对照组（E组）经皮下注射10％四氯化碳橄榄油溶液5 mL/kg，每周2次。连续用药3个月后观察体重改变及肝脏形态学变化，检测与肝脏毒性有关的血清生化指标、氧化应激指标。结果：①实验组的3组大鼠，体重均显著低于阴性对照组。②实验组血清丙氨酸氨基转移酶、碱性磷酸酶和肝组织丙二醛含量、超氧化物歧化酶活性与阴性对照组相比没有显著变化，TPM高剂量组和合用药组肝组织谷胱甘肽含量较阴性对照组、TPM低剂量组明显降低，分别为29.85±1.62 mg/g蛋白和29.63±4.47 mg/g蛋白，差异有显著性(均P＜0.05)。③病理组织学检查，光镜下阳性对照组可见广泛的肝细胞脂肪变性和弥漫性点状坏死灶；TPM低剂量组可见少数肝细胞浊肿变性；TPM高剂量组可见少数肝细胞点状坏死；TPM＋VPA组可见部分肝细胞浊肿变性和脂肪变性，视野内还可见少数肝细胞点状坏死。结论：长期服用TPM可引起机体抗氧化能力降低，肝脏病理组织学检查可见轻微病理改变，TPM高剂量及合用药组影响大于TPM低剂量组。［中国当代儿科杂志，2007，9（1）：54-58］

Abstract:

OBJECTIVE: Topiramate (TPM) has an evident efficacy in the treatment of childhood epilepsy for multiple pharmacologic properties. However it was reported that it may cause adverse effects such as liver failure and hepatitis, which arouses the attention of the medical field. This study aimed to investigate the hepatotoxicity of low-dosage, high-dosage TPM or TPM along with valproate sodium (VPA) in aspects of biochemistry indexes, oxidative stress indexes and liver pathomorphology in young rats. METHODS: Sixty 3-week-old male Wistar rats were randomly assigned into five groups of 12 rats (Groups A-E). The rats in the experimental groups (Groups A-C) were administered intragastrically with TPM 40 mg/(kg?d) , 80 mg/(kg?d) and TPM 40 mg/(kg?d) plus VPA 300 mg/(kg?d) respectively. The rats in the negative control group (Group D) were administered with the same volume of distilled water. The ones in the positive control group (Group E) were treated by injection of 10% carbon tetrachloride dissolved in olive oil subcutaneously at a dose of 5 mL/kg twice a week. After 3-month administration, the changes of body weight and liver pathomorphology were observed; biochemical markers in serum and indexes of oxidative stress in liver homogenate associated with hepatotoxicity were examined. RESULTS: The body weight of rats in the experimental groups were significantly lower than that of rats in the negative control group. The levels of serum alanine aminotransferase, alkaline phosphatase and the content of malondialdehyde, and the activity of superoxide dismutase in liver tissues did not change significantly in the experimental groups. The contents of glutathion in the high dosage of TPM group (29.85±1.62 mg/g prot ) or in the TPM plus VPA group (29.63±4.47 mg/g prot) were significantly reduced compared with those of the negative control group (33.09±1.69 mg/g prot) and that of the low dosage of TPM group (32.43±2.11 mg/g prot) (both P＜0.05). In the histopathological examination, extensive steatosis and diffuse punctate necrosis of hepatocytes distributed in the portal area were found by microscopy in the positive control group. There were granular degeneration of some hepatocytes near the central veins of hepatic lobules in the low dosage of TPM group and punctate necrosis of some hepatocytes in the high dosage of TPM group. In the TPM plus VPA group, histological examination showed granular degeneration and fatty degeneration of partial liver cells and punctate necrosis of some hepatocytes. CONCLUSIONS: Long-term use of TPM can decrease antioxidant capacity of organism, resulting in slight pathological changes of liver tissues. High dosage of TPM or TPM along with VPA administration enhances the risk of the side effects.［Chin J Contemp Pediatr, 2007, 9 (1):54-58］