Abdel-Salam Omar M E, Baiuomy Ayman R, Ameen Amany, Hassan Nabila S
Department of Pharmacology, National Research Centre, Tahrir Street, Dokki, Cairo, Egypt.
Pharmacol Res. 2005 Jan;51(1):59-67. doi: 10.1016/j.phrs.2004.04.009.
Forty-eight rats with biliary obstruction induced by double ligation and section of the common bile duct were randomly and blindly assigned to receive subcutaneous injection of either conventional heparin sodium (1000IU kg(-1)), three already marketed low molecular weight heparin (LMWH) preparations: nadroparin (1000 anti-Xa IU kg(-1)), tinzaparin (1000 anti-Xa IU kg(-1)), enoxaparin (180 anti-Xa IU kg(-1)) or saline. Drugs were administered once a day, starting 7 days after surgery and continued for 3 weeks. At the end of the treatment period, rats were killed and analyzed for blood biochemistry and liver pathology. Liver fibrosis was assessed by image analysis. Data indicated that treatment with nadroparin decreased plasma total bilirubin, serum alkaline phosphatase (ALP) and gamma glutamyltransferase (GGT) levels by 80.3, 70.7 and 42%, compared with bile duct ligated (BDL) control values. The reduction in plasma total protein observed in BDL controls was prevented by nadroparin. Enoxaparin-treated rats showed significant reduction in plasma total bilirubin and alanine aminotransferase levels by 32.5 and 38.4% versus BDL controls. Liver necrosis evaluated histologically was significantly reduced in the nadroparin- and enoxaparin-treated rats. Morphometric analysis showed significant reduction in fibrosis on nadroparin and enoxaparin treatment: area of fibrosis: 1.66 +/- 0.17% and 14.03 +/- 1.1% versus 18.94 +/- 2.4% (P<0.05); nadroparin and enoxaparin versus BDL control. By contrast, neither conventional heparin nor tinzaparin prevented the bile duct ligation-induced liver damage as indicated by increased plasma aminotransferases, ALP and GGT concentrations and the histological evidence of necrosis. Total serum bilirubin was increased by 27.5% in rats treated with conventional heparin, while ALP and GGT levels were 38.6 and 31.4% higher after tinzaparin treatment versus BDL controls. Significant increase in the area of fibrosis was observed after tinzaparin treatment compared to BDL control group. Results suggest a beneficial effect for nadroparin and enoxaparin in the therapy of patients with obstructive jaundice or cholestatic liver disorders. The present data from bile duct ligated rats suggest an antifibrotic effect for nadroparin and enoxaparin.
将48只通过双重结扎和切断胆总管诱导产生胆道梗阻的大鼠随机、盲法分组，分别皮下注射常规肝素钠（1000IU kg⁻¹）、三种已上市的低分子肝素（LMWH）制剂：那屈肝素（1000抗Xa IU kg⁻¹）、替扎肝素（1000抗Xa IU kg⁻¹）、依诺肝素（180抗Xa IU kg⁻¹）或生理盐水。药物每天给药一次，于术后7天开始，持续3周。在治疗期结束时，处死大鼠并进行血液生化和肝脏病理学分析。通过图像分析评估肝纤维化。数据表明，与胆管结扎（BDL）对照组相比，那屈肝素治疗使血浆总胆红素、血清碱性磷酸酶（ALP）和γ-谷氨酰转移酶（GGT）水平分别降低了80.3%、70.7%和42%。那屈肝素可防止BDL对照组中观察到的血浆总蛋白降低。与BDL对照组相比，依诺肝素治疗的大鼠血浆总胆红素和丙氨酸氨基转移酶水平分别显著降低了32.5%和38.4%。组织学评估显示，那屈肝素和依诺肝素治疗的大鼠肝坏死明显减少。形态计量分析显示，那屈肝素和依诺肝素治疗后纤维化显著减少：纤维化面积分别为1.66±0.17%和14.03±1.1%，而BDL对照组为18.94±2.4%（P<0.05）；那屈肝素和依诺肝素与BDL对照组相比。相比之下，常规肝素和替扎肝素均未预防胆管结扎诱导的肝损伤，这表现为血浆氨基转移酶、ALP和GGT浓度升高以及坏死的组织学证据。常规肝素治疗的大鼠总血清胆红素升高了27.5%，而替扎肝素治疗后ALP和GGT水平比BDL对照组分别高38.6%和31.4%。与BDL对照组相比，替扎肝素治疗后纤维化面积显著增加。结果表明，那屈肝素和依诺肝素对梗阻性黄疸或胆汁淤积性肝病患者的治疗有益。来自胆管结扎大鼠的当前数据表明，那屈肝素和依诺肝素具有抗纤维化作用。
