利福昔明针对肝性脑病的用量

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利福昔明在肝性脑病中的治疗作用
Rifaximin treatment in hepatic encephalopathy.
出处：N Engl J Med   2010  Mar  362(12) :1071-81
作者：Bass NM;Mullen KD;Sanyal A.,oordad F;Neff G;Leevy CB;Sigal S;Sheikh MY;Beavers K;Frederick T;Teperman L;Hillebrand D;Huang S;Merchant K;Shaw A;Bortey E;Forbes WP
PMID：20335583

背景：肝性脑病是肝硬化长期衰弱的并发症。利福昔明是一种吸收最少的抗生素，不少文献报道其对急性肝性脑病治疗有效，但对该病的预防效果尚未确定。
方法：在这项随机，双盲，安慰剂对照试验中，299名患者均处于由慢性肝病所致的复发性肝性脑病缓解期，我们将其随机分为两组，一组接受利福昔明，每日两次，每次550毫克(140例），另一组接受安慰剂 (159 例) ，治疗6个月。主要的疗效终点指标为治疗中肝性脑病首次发作时间，关键的次要终点指标为因肝性脑病首次住院时间。
结果：在6个月期间，与服用安慰剂比较，利福昔明显降低了肝性脑病发作的风险（应用利福昔明危险比为0.42；95％可信区间[CI]为0.28～0.64；P <0.001）。利福昔明组治疗中肝性脑病发作率为22.1％，而安慰剂组为45.9%。福昔明组患者因肝性脑病住院治疗占13.6％，而安慰剂组为22.6%，危险比为0.50（95％CI： 0.29～0.87；P=0.01）。超过90%的患者同时接受乳果糖治疗。研究期间两组报告不良事件的发生率相似，如严重不良事件的发生率。
结论：在6个月期间，利福昔明比安慰剂更有效维持肝性脑病的缓解。应用利福昔明治疗还能明显降低因肝性脑病而住院的风险。（ClinicalTrials.gov注册号：NCT00298038）

BACKGROUND: Hepatic encephalopathy is a chronically debilitating complication of hepatic cirrhosis. The efficacy of rifaximin, a minimally absorbed antibiotic, is well documented in the treatment of acute hepatic encephalopathy, but its efficacy for prevention of the disease has not been established. METHODS: In this randomized, double-blind, placebo-controlled trial, we randomly assigned 299 patients who were in remission from recurrent hepatic encephalopathy resulting from chronic liver disease to receive either rifaximin, at a dose of 550 mg twice daily (140 patients), or placebo (159 patients) for 6 months. The primary efficacy end point was the time to the first breakthrough episode of hepatic encephalopathy. The key secondary end point was the time to the first hospitalization involving hepatic encephalopathy. RESULTS: Rifaximin significantly reduced the risk of an episode of hepatic encephalopathy, as compared with placebo, over a 6-month period (hazard ratio with rifaximin, 0.42; 95% confidence interval [CI], 0.28 to 0.64; P<0.001). A breakthrough episode of hepatic encephalopathy occurred in 22.1% of patients in the rifaximin group, as compared with 45.9% of patients in the placebo group. A total of 13.6% of the patients in the rifaximin group had a hospitalization involving hepatic encephalopathy, as compared with 22.6% of patients in the placebo group, for a hazard ratio of 0.50 (95% CI, 0.29 to 0.87; P=0.01). More than 90% of patients received concomitant lactulose therapy. The incidence of adverse events reported during the study was similar in the two groups, as was the incidence of serious adverse events. CONCLUSIONS: Over a 6-month period, treatment with rifaximin maintained remission from hepatic encephalopathy more effectively than did placebo. Rifaximin treatment also significantly reduced the risk of hospitalization involving hepatic encephalopathy. (ClinicalTrials.gov number, NCT00298038.)

专家评价：
Piero Portincasa
University Medical School of Bari, Italy
Gastroenterology & Hepatology

In this interesting randomized, double-blind, placebo-controlled trial, the authors assigned 299 cirrhotic patients in remission from recurrent hepatic encephalopathy to either oral rifaximin (550mg twice daily) or placebo for a long time (6 months). Both the first episode of hepatic encephalopathy and first hepatic encephalopathy-related hospitalization were evaluated. The authors show that rifaximin maintained remission from hepatic encephalopathy more effectively than did placebo (22% vs. 46%) and significantly reduced the risk of hospitalization due to hepatic encephalopathy (14% vs. 23%). This positive effect of rifaximin was evident irrespective of treatment with lactulose and did not yield an increased incidence of adverse events.

Of note, in this study high doses of rifaximin were used chronically and not acutely (21 days or less) or intermittently for the maintenance of remission from episodes of hepatic encephalopathy in outpatients with a recent history of recurrent, overt hepatic encephalopathy. The effect of rifaximin was superior to that of lactulose alone. There are multiple issues that make this article highly interesting: (1) the choice of a frequent disease (hepatic cirrhosis) and hepatic encephalopathy as one of the most debilitating, costly and disturbing complications of liver cirrhosis; (2) the potentially harmful side effects of lactulose and/or oral antibiotics (neomycin, paromomycin, vancomycin, metronidazole) in the prevention of overt hepatic encephalopathy; (3) the use of oral rifaximin -- a minimally absorbed oral antimicrobial agent -- as an effective agent to challenge Gram-positive and Gram-negative aerobic and anaerobic enteric bacteria, with negligible risk of inducing bacterial resistance; (5) the clinically significant finding of a reduced risk of hospitalization in the rifaximin-treated group. The results of this study imply that the non-absorbable rifaximin is safe, effective and yields decreased hospital costs in cirrhotic patients at risk of hepatic encephalopathy. Larger studies are urgently required to confirm the findings of this study. Trial registration: NCT00298038
Rifaximin for Maintaining Remission in Hepatic Encephalopathy
During a 6-month study, rifaximin was more effective than placebo in reducing breakthrough episodes in cirrhotic patients Hepatic encephalopathy (HE) is a common complication of cirrhosis and is associated with substantial morbidity and mortality. Previous studies have shown that rifaximin (Xifaxan, a minimally absorbed antimicrobial agent with high concentration in the gastrointestinal tract) was superior to nonabsorbable disaccharides (the mainstay of therapy) and was as good or better than other antibiotics in treating patients with acute HE.
To evaluate the efficacy of using rifaximin concomitantly with a nonabsorbable disaccharide (lactulose) to maintain remission in HE patients, investigators conducted a randomized, double-blind, placebo-controlled trial involving cirrhotic patients who had experienced≥2 episodes of documented HE in the previous 6 months, were in remission at enrollment, and had a Model for End-Stage Liver Disease (MELD) score of <25. A total of 140 received rifaximin (55 mg twice daily), and 155 received placebo. About 91% of patients in each group were taking lactulose at baseline and during the study. Patients were monitored weekly for 2 weeks and then every 2 weeks until day 168.
Adherence to therapy (at least 80% of dispensed tablets) was nearly 85% in each group. At day 186, fewer breakthrough episodes of HE had occurred in the rifaximin group than in the placebo group (22.1% vs. 45.9%; hazard ratio, 0.42; P<0.001). Also, fewer patients in the rifaximin group than in the placebo group had been hospitalized for HE (13.6% vs. 22.6%; HR, 0.50=0.01). The incidence of adverse events was similar in both groups.
Comment: These findings demonstrate that among patients with cirrhosis, most of whom were receiving lactulose, rifaximin was superior to placebo in reducing breakthrough episodes of HE. This study is different from previous smaller, randomized studies that showed that rifaximin was at least as effective as lactulose in treating patients with acute episodes of HE. These data add to the body of literature suggesting that rifaximin should be included among the therapeutic modalities for HE.
— Atif Zaman, MD, MPH
Published in Journal Watch Gastroenterology March 24, 2010

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这里面作者其一的Dr F. Poordad （认识他6年，最近在Clinical Care Options也有一个对于抗病毒新知的Flash）等在CSMC做此药研究颇有收效。

[ 本帖最后由 liver411 于 2010-6-9 04:23 编辑 ]

进口

411老师这个利福昔明好像是抗生素，可不可以长期不停的吃？或者吃一段时间停一段时间？怕不怕耐药之类的？是否需要跟乳果糖合用？