Jeppesen P B, Sanguinetti E L, Buchman A, Howard L, Scolapio J S, Ziegler T R, Gregory J, Tappenden K A, Holst J, Mortensen P B
Department of Medicine CA-2121, Section of Gastroenterology, Rigshospitalet, University Hospital of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
Gut. 2005 Sep;54(9):1224-31. doi: 10.1136/gut.2004.061440.
Glucagon-like peptide 2 (GLP-2) may improve intestinal absorption in short bowel syndrome (SBS) patients with an end jejunostomy. Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant GLP-2 analogue, prolongs the intestinotrophic properties of GLP-2 in animal models. The safety and effect of teduglutide were investigated in SBS patients with and without a colon in continuity.
Teduglutide was given subcutaneously for 21 days once or twice daily to 16 SBS patients in the per protocol investigational group, 10 with end jejunostomy (doses of 0.03 (n = 2), 0.10 (n = 5), or 0.15 (n = 3) mg/kg/day), one with <50% colon in continuity (dose 0.03 mg/kg/day), and five with > or = 50% colon in continuity (dose 0.10 mg/kg/day). Nutrient balance studies, D-xylose tests, and intestinal mucosa biopsies were performed at baseline, on the last three days of treatment, and after three weeks of follow up. Pre-study fasting native GLP-2 levels were determined for the five patients with > or = 50% colon in continuity.
Pooled across groups and compared with baseline, teduglutide increased absolute (+743 (477) g/day; p<0.001) and relative (+22 (16)%; p<0.001) wet weight absorption, urine weight (+555 (485) g/day; p<0.001), and urine sodium excretion (+53 (40) mmol/day; p<0.001). Teduglutide decreased faecal wet weight (-711 (734) g/day; p = 0.001) and faecal energy excretion (-808 (1453) kJ/day (-193 (347) kcal/day); p = 0.040). In SBS patients with end jejunostomy, teduglutide significantly increased villus height (+38 (45)%; p = 0.030), crypt depth (+22 (18)%; p = 0.010), and mitotic index (+115 (108)%; p = 0.010). Crypt depth and mitotic index did not change in colonic biopsies from SBS patients with colon in continuity. The most common side effects were enlargement of the stoma nipple and mild lower leg oedema. The improvements in intestinal absorption and decreases in faecal excretion noted after treatment had reversed after the drug free follow up period. A controlled study with a more robust design is ongoing in order to determine the optimal dosage of teduglutide for SBS patients to achieve the maximal effect and utility of this drug in clinical practice.
Teduglutide, at three dose levels for 21 days, was safe and well tolerated, intestinotrophic, and significantly increased intestinal wet weight absorption in SBS patients with an end jejunostomy or a colon in continuity.
胰高血糖素样肽2（GLP - 2）可能改善行空肠造口术的短肠综合征（SBS）患者的肠道吸收。替度鲁肽（ALX - 0600）是一种二肽基肽酶IV抗性GLP - 2类似物，在动物模型中可延长GLP - 2的肠营养特性。我们对有或没有连续结肠的SBS患者中替度鲁肽的安全性和疗效进行了研究。
在符合方案研究组中，对16例SBS患者皮下给予替度鲁肽，每日1次或2次，共21天。其中10例为空肠造口术患者（剂量分别为0.03（n = 2）、0.10（n = 5）或0.15（n = 3）mg/kg/天），1例连续结肠长度<50%（剂量0.03 mg/kg/天），5例连续结肠长度≥50%（剂量0.10 mg/kg/天）。在基线、治疗的最后三天以及随访三周后进行营养平衡研究、D - 木糖试验和肠黏膜活检。对5例连续结肠长度≥50%的患者测定研究前空腹天然GLP - 2水平。
综合各治疗组并与基线相比，替度鲁肽增加了绝对湿重吸收（+743（477）g/天；p<0.001）和相对湿重吸收（+22（16）%；p<0.001）、尿重量（+555（485）g/天；p<0.001）以及尿钠排泄（+53（40）mmol/天；p<0.001）。替度鲁肽降低了粪便湿重（-711（734）g/天；p = 0.001）和粪便能量排泄（-808（1453）kJ/天（-193（347）kcal/天）；p = 0.040）。在有空肠造口术的SBS患者中，替度鲁肽显著增加了绒毛高度（+38（45）%；p = 0.030）、隐窝深度（+22（18）%；p = 0.010）和有丝分裂指数（+115（108）%；p = 0.010）。连续结肠的SBS患者结肠活检中的隐窝深度和有丝分裂指数未发生变化。最常见的副作用是造口乳头增大和轻度小腿水肿。治疗后观察到的肠道吸收改善和粪便排泄减少在停药随访期后恢复。正在进行一项设计更完善的对照研究，以确定替度鲁肽对SBS患者的最佳剂量，从而在临床实践中实现该药物的最大疗效和效用。
替度鲁肽在三个剂量水平下使用21天，对于有空肠造口术或有连续结肠的SBS患者是安全且耐受性良好的，具有肠营养作用，并显著增加肠道湿重吸收。
