Department of Medicine, Taipei Veterans General Hospital, Taiwan.
Gut. 2010 Nov;59(11):1545-53. doi: 10.1136/gut.2010.210732. Epub 2010 Sep 9.
Clonidine is an α(2)-adrenoceptor agonist which, by coupling with G-protein, has been proposed as an alternative treatment for refractory ascites of patients with cirrhosis for several years. Genetic polymorphisms of β-adrenoceptor and angiotensin II type 1 receptor blockers have been reported to affect drug response in patients with cirrhosis. This study evaluated the clonidine-diuretic response rate, favourable predictors and genetic components of the clonidine-diuretic response in patients with cirrhosis with refractory ascites.
270 patients with cirrhosis with refractory ascites were randomised equally into two treatment groups to receive diuretics alone or the clonidine-diuretics association. The primary end point was clonidine-diuretic response rate. Secondary end points were mean daily dose of diuretics, times of paracentesis, ascites-related readmission and 1-year survival rate.
Good clonidine responders had better natriuresis and diuresis as well as a significant decrease in abdominal circumference, plasma renin, aldosterone and norepinephrine levels. The overall clonidine-diuretics response rate was 55-60%. In patients with cirrhosis, the prevalence of ARDA(2)C WD/DD and GNB3 CT/TT genotypes was 71% and 77%, respectively. Among the responders, 71% of patients with cirrhosis had the ARDA(2)C WD/DD genotype and 67% has the GNB3 CT/TT genotype. Besides higher baseline norepinephrine levels, the presence of both ARDA(2)C WD/DD and GNB3 CT/TT genotypes showed a positive predictive value of 82% and a negative predictive value of 79% for good clonidine response.
These results suggest that neurohormonal and genetic testing may be used as predictive factors for the additive effects of clonidine on the diuresis and natriuresis effects of diuretics in patients with cirrhosis with refractory ascites.
可乐定是一种α（2）-肾上腺素能受体激动剂，通过与 G 蛋白偶联，多年来一直被提议作为治疗肝硬化难治性腹水的替代方法。已有报道称，β-肾上腺素能受体和血管紧张素 II 型 1 受体阻滞剂的遗传多态性会影响肝硬化患者的药物反应。本研究评估了肝硬化难治性腹水患者可乐定-利尿剂反应率、有利预测因素和可乐定-利尿剂反应的遗传成分。
270 例肝硬化难治性腹水患者随机均分为两组，分别接受单独利尿剂或可乐定-利尿剂联合治疗。主要终点是可乐定-利尿剂反应率。次要终点是利尿剂的平均日剂量、放腹水次数、腹水相关再入院率和 1 年生存率。
良好的可乐定反应者具有更好的排钠和利尿作用，以及腹围、血浆肾素、醛固酮和去甲肾上腺素水平显著降低。总的可乐定-利尿剂反应率为 55-60%。在肝硬化患者中，ARDA(2)C WD/DD 和 GNB3 CT/TT 基因型的患病率分别为 71%和 77%。在反应者中，71%的肝硬化患者具有 ARDA(2)C WD/DD 基因型，67%具有 GNB3 CT/TT 基因型。除了较高的基线去甲肾上腺素水平外，同时存在 ARDA(2)C WD/DD 和 GNB3 CT/TT 基因型对良好的可乐定反应具有阳性预测值 82%和阴性预测值 79%。
这些结果表明，神经激素和基因检测可作为预测因子，用于预测可乐定对肝硬化难治性腹水患者利尿剂的利尿和排钠作用的附加效应。
