摘要：柏林Park-Klinik Weissensee的Stefan Müller-Lissner博士及其同事声称，长期使用替加色罗能安全有效的治疗慢性便秘，且有很好的耐受性。
背景：替加色罗是一种5-羟色胺拮抗剂，能刺激胃肠动力，并在一定程度上增加肠道的水氯分泌。而5-羥色胺的信号的改变是慢性便秘的机制之一。替加色罗的治疗导致纯粹的腔内水运动，粪便更软，加强了肠腔内容物的离口流动。超过12个月的替加色罗治疗肠易激综合征相关的便秘，其疗效已经被证明。目前总样本数超过1万四千例。
对象与方法：Müller-Lissner博士他们此前已经完成了一项替加色罗治疗慢性便秘三个月的双盲随机安慰剂对照临床试验，人群覆盖欧洲，澳大利亚和南非共和国，由此确立了该药物的短期的安全性和有效性。 随后，他们在那项研究的基础上延长了13个月。原本配以6mg b.i.d 的患者（共283名）和给以安慰剂的患者（共274名），在延长的研究期给以6mg b.i.d的剂量;而原本用2mg b.i.d的患者（283名）则继续原用量。如果有超过四天以上无肠道运动则唯一可用的附加药物是比沙可啶15mg/d．受试者均不超过65岁，平均年龄是45.8，平均患慢性便秘病史为10年。
结果：
1、症状改善情况：据患者反映，相关症状，像腹痛、腹胀、便秘，在这13个月的延续期中比初始情况得到了缓解。症状的改善在前６个月最明显，后七个月中得以保持。特别是腹胀，非常常见的症状，且目前对其并没有什么特异而有效的疗法。但在本研究中这一症状得到了持续而显著的改善。
2、副作用：
——92.7％的患者并没有腹泻症状，即使在有症状的患者中发作也是暂时性的，不需要其他治疗或用药。
——不会出现低钾、脱水、晕厥、低血压、或心脏反应等需要处理，也未出现缺血性肠炎。
——最常见的副作用是头痛（11.3％到16.1％）腹痛（8.8％到16.1％）。其他还有腹泻、恶心、背痛、便秘和胃肠胀气。并且，在三组完成延长期研究的患者中，副作用的发生率随着时间的延长而下降。
——实验室检查也未发现有临床意义的生命体征或尿分析、血液学检查的改变，也没有QT间期的延长或心电图异常。有一些病例出现一过性的肝酶升高，但这没什么临床意义。
3、中断原因：所有报导的27例严重病例都是由于病人的基础健康状况导致的，与便秘或替加色罗无关。中途退出试验的人群中，总共有19.3％的患者是因为缺乏疗效，6.3％是由于副作用。
结论：对慢性便秘患者来说替加色罗是一种可长期使用、耐受性好的治疗选择。（该文发表在美国胃肠病学杂志11月刊上）
Long-Term Tegaserod Safe, Effective Treatment for Chronic Constipation
December 8, 2006 — Tegaserod (Zelnorm) used for up to 16 months is a safe, well tolerated, and effective treatment for patients with chronic constipation, according to a study conducted in Europe, Australia, and the Republic of South Africa.
Altered serotonin signaling is believed to be one mechanism involved in chronic constipation, according to Dr. Stefan Müller-Lissner, from Park-Klinik Weissensee, Berlin, and colleagues. Tegaserod is a serotonin receptor agonist that "stimulates GI motility, and to a lesser extent, increases intestinal chloride and water secretion."
As a result, they report in the November issue of the American Journal of Gastroenterology, treatment with tegaserod results in "net intraluminal water movement, softer stool, and enhanced aboral flow of luminal contents."
Tegaserod has already proved effective over 12 months in treating constipation related to irritable bowel syndrome, the authors note. Previous trials of tegaserod included more than 14,000 patients.
In their current report, the investigators explain that they already completed a 3-month, randomized, double-blind, placebo-controlled clinical trial of tegaserod for treatment of chronic constipation, which established the drug's short-term safety and efficacy. The current trial is a 13-month extension of that study.
Subjects who were originally dosed at 6 mg twice daily (n = 283), as well as participants originally assigned to placebo (n = 274), used the 6 mg b.i.d. dose during the extension trial. Those originally on tegaserod 2 mg twice daily (n = 283) continued at that dose. The only other medication they were permitted to use was bisacodyl 15 mg/day if they had gone for more than 4 days without a bowel movement.
None of the participants were older than 65 years. Mean age of the whole group was 45.8 years, and median duration of chronic constipation symptoms was 10 years.
The patients reported that symptoms, such as abdominal pain, bloating, and constipation, were less bothersome throughout the 13 month extension study compared with baseline. The improvements in symptoms were greatest during the first 6 months, then sustained for the next 7 months.
"The continued improvement in bloating is particularly noteworthy, as this symptom is difficult to treat and there is currently no specific treatment shown to be effective against this common complaint," the investigators write.
The most common adverse events included headache (11.3% to 16.1%) and abdominal pain (8.8% to 16.1%). Others included diarrhea, nausea, back pain, constipation, flatulence. The authors note that the adverse event rate decreased over time in all three treatment groups who completed the extension study.
Dr. Müller-Lissner and associates point out that 92.7% of patients did not experience episodes of diarrhea. Among those who did have a bout, diarrhea was transient and usually required no other treatment or study drug interruption. None required treatment for hypokalemia, dehydration, syncope, hypotension or cardiac effects; and no cases of ischemic colitis occurred.
Laboratory testing showed no clinically relevant changes in vital signs or urinalysis, hematology, or prolongation of the QTc interval or other ECG abnormalities. There were some cases of transiently elevated liver enzymes, but they were not considered clinically significant.
All of the 27 serious adverse events documented were attributed to conditions other than the constipation or tegaserod. Overall, 19.3% withdrew from the study because of lack of efficacy, and 6.3% because of adverse effects.
"In summary," the team writes, "these data suggest that tegaserod is a well-tolerated long-term treatment option for patients with chronic constipation."
This study was funded by Novartis Pharma AG, manufacturer of tegaserod.
Am J Gastroenterol. 2006;101:2558-2569.
http://www.medscape.com/viewarticle/549021
编辑：蓝色幻想
