Comparing the Intestinotrophic Effects of 2 Glucagon-Like Peptide-2 Analogues in the Treatment of Short-Bowel Syndrome in Neonatal Piglets
Comparing the Intestinotrophic Effects of 2 Glucagon-Like Peptide-2 Analogues in the Treatment of Short-Bowel Syndrome in Neonatal Piglets
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DOI：
10.1002/jpen.1853
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发表时间：
2020-05-21
影响因子：
3.4
通讯作者：
Wales, Paul W.
中科院分区：
文献类型：
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作者：
Pauline, Mirielle L.;Nation, Patrick N.;Wales, Paul W.
背景：在治疗短肠综合征（SBS）时，肠外营养（PN）的自主性依赖于肠道适应，这可以通过胰高血糖素样肽-2 （GLP-2）类似物来增强。方法在切除75%远端小肠后，将仔猪分为生理盐水（CON: n = 8）、每周一次APRA （5 mg/kg/剂量，n = 8）、TED （TED， 0.05 mg/kg/剂量，n = 8）、TED （TED， 0.05 mg/kg/剂量，n = 8）和TED (TEDBID， 0.05 mg/kg/剂量，n = 7) 4个治疗组。进行药代动力学（PK）研究，第7天测量小肠长度和重量，收集空肠组织进行组织学检查。结果两种类似物的PK谱不同。为了达到与APRA相当的暴露量，TED需要每天注射两次（TEDBID）。与CON相比，APRA和TEDBID增加了小肠长度（cm） （CON: 141, APRA: 166, TED: 153, TEDBID: 165, P = 0.004），而APRA增加了小肠重量(g) （CON: 26, APRA: 33, TED: 28, TEDBID: 31, P = 0.007）和绒毛高度（mm） （CON: 0.59, APRA: 0.90, TED: 0.58, TEDBID: 0.74, P < 0.001）。结论APRA连续7天注射两次比TED每天注射一次有更好的肠营养作用。即使在更相似的药物暴露下，当TED每天注射两次时，APRA在粘膜水平显示出优越的营养活性。这与儿童SBS的治疗高度相关，因为皮下注射APRA的剂量频率明显较低。
Background In treating short-bowel syndrome (SBS), autonomy from parenteral nutrition (PN) relies upon intestinal adaptation, which can be augmented by glucagon-like peptide-2 (GLP-2) analogues. In neonatal piglets with SBS, we compared intestinal adaptation following treatment with 2 GLP-2 analogues: teduglutide (TED) and apraglutide (APRA)Methods Following 75% distal small-intestinal resection, piglets were allocated to 4 treatment groups: saline (CON: n = 8), twice weekly APRA (5 mg/kg/dose; n = 8), and TED once daily (TED, 0.05 mg/kg/dose; n = 8) or twice daily (TEDBID, 0.05 mg/kg/dose; n = 7). Pharmacokinetic (PK) studies were undertaken, and on day 7, small-intestinal length and weight were measured and jejunal tissue collected for histology.Results PK profiles were different between the 2 analogues. To achieve a comparable exposure to APRA, TED requires twice daily injection (TEDBID). Compared with CON, APRA and TEDBID increased small-bowel length (cm) (CON: 141, APRA: 166, TED: 153, TEDBID: 165; P = .004), whereas APRA increased small-bowel weight (g) (CON: 26, APRA: 33, TED: 28, TEDBID: 31; P = .007) and villus height (mm) (CON: 0.59, APRA: 0.90, TED: 0.58, TEDBID: 0.74; P < .001).Conclusion APRA injected only twice during the 7 consecutive days demonstrated a superior intestinotrophic effect compared with TED injected once daily. Even at more comparable drug exposure, when TED was injected twice a day, APRA showed superior trophic activity at the mucosal level. This is highly relevant for the treatment of pediatric SBS, given the markedly lower dose frequency by subcutaneous injection of APRA.