Nagata Sayaka, Yamasaki Motoo, Kitamura Kazuo
Circulatory and Body Fluid Regulation, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki, 889-1692, Japan.
Drug Dev Res. 2017 Jun;78(3-4):129-134. doi: 10.1002/ddr.21383. Epub 2017 Apr 27.
Preclinical Research Human adrenomedullin (hAM), a hypotensive peptide, also has anti-inflammatory effects. hAM can reduce the severity of the dextran sulphate sodium (DSS)- and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in animal models. Furthermore, in a clinical study, hAM treatment reduced the Disease Activity Index in ulcerative colitis. However, these therapeutic effects required continuous administration of hAM as the half-life of native hAM is quite short in blood. To resolve this problem, hAM N-terminal was conjugated with two kinds of polyethylene glycol (PEG); 5 kDa PEG or 60 kDa PEG (5 kDa PEG-hAM and 60 kDa PEG-hAM respectively). In a previous study, 5 kDa PEG-hAM stimulated cAMP production and prolonged the plasma half-life compared with native hAM. Herein we examine the effect of PEG-hAM in the DSS colitis model. Treatment with both PEG-hAM preparations reduced the total inflammation score. In addition, the plasma half-life of 60 kDa PEG-hAM was much longer than 5 kDa PEG-hAM. In summary, a single subcutaneous administration of 60 kDa PEG-hAM reduced the total inflammation score in mice with DSS-induced colitis. Therefore, these results suggest that 60 kDa PEG-hAM is a possible therapeutic agent for the treatment of inflammatory bowel disease. Drug Dev Res 78 : 129-134, 2017. © 2017 Wiley Periodicals, Inc.
临床前研究 人肾上腺髓质素（hAM）是一种降压肽，也具有抗炎作用。hAM可减轻硫酸葡聚糖钠（DSS）和2,4,6-三硝基苯磺酸（TNBS）诱导的动物模型结肠炎的严重程度。此外，在一项临床研究中，hAM治疗降低了溃疡性结肠炎的疾病活动指数。然而，由于天然hAM在血液中的半衰期很短，这些治疗效果需要持续给予hAM。为了解决这个问题，将hAM的N端与两种聚乙二醇（PEG）偶联；5 kDa PEG或60 kDa PEG（分别为5 kDa PEG-hAM和60 kDa PEG-hAM）。在先前的研究中，与天然hAM相比，5 kDa PEG-hAM刺激了cAMP的产生并延长了血浆半衰期。在此我们研究PEG-hAM在DSS结肠炎模型中的作用。两种PEG-hAM制剂治疗均降低了总炎症评分。此外，60 kDa PEG-hAM的血浆半衰期比5 kDa PEG-hAM长得多。总之，单次皮下注射60 kDa PEG-hAM可降低DSS诱导的结肠炎小鼠的总炎症评分。因此，这些结果表明60 kDa PEG-hAM可能是治疗炎症性肠病的一种治疗剂。《药物研发研究》78: 129 - 134, 2017。© 2017威利期刊公司。
