Paterson B M, Lammers K M, Arrieta M C, Fasano A, Meddings J B
Alba Therapeutics Corporation, Baltimore, MD 21201, USA.
Aliment Pharmacol Ther. 2007 Sep 1;26(5):757-66. doi: 10.1111/j.1365-2036.2007.03413.x.
Lifelong adherence to a strict gluten-free diet is the cornerstone of coeliac disease treatment. Elucidation of disease pathogenesis has created opportunities for novel therapeutic approaches to coeliac disease. AT-1001 is an inhibitor of paracellular permeability whose structure is derived from a protein secreted by Vibrio cholerae.
To determine the safety and tolerability of 12 mg doses of AT-1001 in coeliac disease subjects challenged with gluten.
An in-patient, double-blind, randomized placebo-controlled safety study utilizing intestinal permeability, measured via fractional excretions of lactulose and mannitol, as an exploratory measure of drug efficacy.
Compared to placebo, no increase in adverse events occurred in patients exposed to AT-1001. Following acute gluten exposure, a 70% increase in intestinal permeability was detected in the placebo group, while none was seen in the AT-1001 group. Interferon-gamma levels increased in four of seven patients (57%) of the placebo group, but only in four of 14 patients (29%) of the AT-1001 group. Gastrointestinal symptoms were more frequently detected in the placebo group when compared to the AT-1001 group (P = 0.018).
AT-1001 is well tolerated and appears to reduce intestinal barrier dysfunction, proinflammatory cytokine production, and gastrointestinal symptoms in coeliacs after gluten exposure.
终身坚持严格的无麸质饮食是乳糜泻治疗的基石。对疾病发病机制的阐明为乳糜泻的新型治疗方法创造了机会。AT-1001是一种细胞旁通透性抑制剂，其结构源自霍乱弧菌分泌的一种蛋白质。
确定12毫克剂量的AT-1001在接受麸质激发试验的乳糜泻患者中的安全性和耐受性。
一项住院、双盲、随机安慰剂对照的安全性研究，利用乳果糖和甘露醇的分数排泄量来测量肠道通透性，作为药物疗效的探索性指标。
与安慰剂相比，接受AT-1001的患者不良事件未增加。急性麸质暴露后，安慰剂组肠道通透性增加70%，而AT-1001组未观察到增加。安慰剂组7名患者中有4名（57%）的干扰素-γ水平升高，而AT-1001组14名患者中只有4名（29%）升高。与AT-1001组相比，安慰剂组更频繁地检测到胃肠道症状（P = 0.018）。
AT-1001耐受性良好，似乎能减轻麸质暴露后乳糜泻患者的肠道屏障功能障碍、促炎细胞因子产生和胃肠道症状。
