May 25, 2007（华盛顿讯）－一种全新的、第一个鸟粪嘌呤环化酶（GC-C）致效剂，linaclotide acetate （Microbia公司，麻州剑桥），在一项针对便秘型大肠急躁症（IBS-C）病患的研究中，有显著正面的效果；IBS-C占IBS病患的四成。
Linaclotide活化GC-C的作用，GC-C是一种位于大肠上皮细胞的横跨细胞膜蛋白质，使得肠液分泌增加，且抑制大肠液体吸收；使用这些药物的病患表现出强烈的药物剂量与反应之间的关系，显著地缩短食物于大肠停留时间，使排便次数增加、同时粪便较软。
明尼苏达州罗彻斯特梅约诊所生物统计部门健康科学研究科Viola Andresen医师与其同事进行这项研究，研究结果发表于2007年肠胃疾病周。
该研究将36位IBS-C妇女随机分派接受每天100或1000 μg的linaclotide或是安慰剂，为期五天；治疗阶段前有五天的试验前观察期。
以闪烁记数计评估大肠运输时间，而肠功能以布里斯通粪便外型分数每天纪录。
以linaclotide治疗48小时内对于大肠运输时间有明显剂量反应效应。高剂量下，排便频率、硬度、与距离第一次大肠运动的时间、以及排便顺利都显著改善（P<0.001），是部份疼痛改善的指标。Andresen医师评论，排便顺利代表疼痛缓解，这对IBS-C病患而言，是非常重要的。
高剂量的linaclotide相较于安慰剂，升结肠运输时间显著加快（P=0.004），且整体大肠运输时间显著地加快（P=0.020）。
Linaclotide并没有相关安全性上的顾虑。Andresen医师指出，linaclotide的作用是局部的，局限于肠上皮细胞，并不是全身性的。这个药物对于上消化道系统没有影响。
Andresen医师向听众表示，IBS确实需要新的治疗，这些结果是令人兴奋的，我们现在需要更多的
临床研究，更多的试验终点。
Linaclotide目前也正发展研究作为慢性便秘的治疗。
Microbia公司表示，根据这些第2a期临床试验的正面结果，一项第2b期的临床试验，主要是设计来评估该药物的安全性，将收纳300位慢性便秘病患。
纽约市Mount Sinai医学院发炎性肠疾病中心主任与医学副教授Maria Abreu医师在Andresen医师发表其结果的发表会中担任引言人，他回应Andresen医师的话表示，IBS好的治疗方式不多，且病患有相当的疼痛，这项研究有许多有潜力的进展。
Andresen医师表示无相关资金上的关系。Abreu医师是Procter & Gamble、Abbott、UCB、 Schering与Berlex公司的顾问，这些公司都与这项研究无关。
DDW是四个协会赞助，分别是美国肝脏疾病研究协会（AASLD）、美国肠胃道医学会（AGA）、美国肠胃道内视镜协会（ASGE）、与肠胃道外科学会（SSAT）。
Novel Drug Shows Strongly Positive Results in Irritable Bowel Syndrome With Constipation
By Martha Kerr
Medscape Medical News
May 25, 2007 (Washington) — A novel, first-in-class guanylate cyclase-C (GC-C) agonist, linaclotide acetate (Microbia Inc, Cambridge, MA), exhibited markedly positive results in a phase 2a study of patients with irritable bowel syndrome with constipation (IBS-C). IBS-C accounts for 40% of cases of IBS.
Linaclotide's activation of GC-C, a transmembrane protein located in the gut epithelium, causes an increase in intestinal fluid secretion and inhibits colonic fluid absorption. Patients receiving the drug showed a strong dose-response, with a significant acceleration in gut transit time, resulting in more frequent stools with a softer consistency.
The study was conducted by Viola Andresen, MD, of the Department of Health Sciences Research in the Division of Biostatistics, and colleagues at the Mayo Clinic in Rochester, Minnesota. Results were reported here at Digestive Disease Week 2007.
The study involved 36 women with IBS-C randomized to linaclotide 100 or 1000 μg daily or placebo for 5 days. The treatment period was preceded by a 5-day baseline observation period.
Gastrointestinal transit time was measured by scintigraphy, and bowel function was recorded daily using the Bristol Stool Form Scale.
There was a strong dose-response effect on colonic transit time within 48 hours with linaclotide. Stool frequency, consistency, time to first bowel movement, and ease of passage all improved significantly with the higher dose (P < .001), an indication of some pain relief. Dr. Andresen commented that ease of passage implies a decrease in pain, which is one of the most significant issues in IBS-C.
Ascending colon transit time was significantly accelerated (P = .004) and overall colonic transit time increased significantly (P = .020), with the higher dose of linaclotide compared with placebo (P = .010).
There were no safety issues with linaclotide. Dr. Andresen pointed out that linaclotide's effects are local, confined to the intestinal epithelium, and are not systemic. There were no effects on the upper gastrointestinal system.
"There is definitely a need for new treatments for IBS," Dr. Andresen told meeting attendees. "These results were quite exciting. We now need more clinical trials with more end points."
Linaclotide is also under development as a treatment for chronic constipation.
Microbia announced that based on these positive phase 2a results, designed primarily to assess the safety of linaclotide, a phase 2b study is now underway, involving 300 patients with chronic constipation.
Maria Abreu, MD, director of the Inflammatory Bowel Disease Center and associate professor of medicine at Mount Sinai School of Medicine in New York City, moderated the panel at which Dr. Andresen announced her results. She echoed Dr. Andresen's words, saying "IBS has few good therapies and patients have a lot of pain.... This study shows promising progress."
Dr. Andresen reports no relevant financial relationships. Dr. Abreu serves as an advisor to Procter & Gamble, Abbott, UCB, Schering, and Berlex, none of which were relevant to this study.
DDW is jointly sponsored by 4 societies: the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE), and the Society for Surgery of the Alimentary Tract (SSAT).
DDW 2007: Abstract 532. Presented May 21, 2007.
作者：
Martha Kerr 2007-6-16