A comparison of linaclotide and lubiprostone dosing regimens on ion transport responses in human colonic mucosa
A comparison of linaclotide and lubiprostone dosing regimens on ion transport responses in human colonic mucosa
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DOI：
10.1002/prp2.128
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发表时间：
2015-03-01
影响因子：
2.6
通讯作者：
McCole, Declan F.
中科院分区：
文献类型：
--
作者：
Kang, Sang Bum;Marchelletta, Ronald R.;McCole, Declan F.
利那洛肽是一种合成的鸟苷酸环化酶C（GC - C）激动剂，鲁比前列酮是一种前列腺素类似物，它们被批准用于治疗慢性特发性便秘和便秘型肠易激综合征。鲁比前列酮还能在缺血情况下保护肠黏膜屏障功能。GC - C信号传导调节局部液体平衡以及肠黏膜内稳态的其他组成部分，包括上皮屏障功能。本研究的目的是比较特定的给药方案是否对利那洛肽和鲁比前列酮调节正常人结肠黏膜的离子转运和屏障特性产生不同的影响。将来自健康受试者的正常乙状结肠活检组织置于尤斯灌流室中。用利那洛肽、鲁比前列酮或赋形剂处理组织，以确定对短路电流（Isc）的影响。还测量了随后对环磷腺苷（cAMP）激动剂毛喉素和钙激动剂卡巴胆碱的Isc反应，以评估这两种药物是否引起脱敏。通过测量跨上皮电阻来评估屏障特性。当双侧给药或仅在黏膜侧给药时，利那洛肽和鲁比前列酮的Isc反应显著高于赋形剂对照组。利那洛肽的单次浓度与累积浓度在疗效上存在差异，累积给药而非单次给药会导致对毛喉素脱敏。在所有条件下，鲁比前列酮都会降低对毛喉素的反应。利那洛肽和鲁比前列酮对跨上皮电阻（TER）有积极影响，这取决于给药方案。利那洛肽和鲁比前列酮增加了正常人结肠的离子转运反应，但利那洛肽对所用给药方案表现出更高的敏感性。这些发现可能对便秘患者使用这些药物的给药方案有影响。
Linaclotide, a synthetic guanylyl cyclase C (GC-C) agonist, and the prostone analog, Lubiprostone, are approved to manage chronic idiopathic constipation and constipation-predominant irritable bowel syndrome. Lubiprostone also protects intestinal mucosal barrier function in ischemia. GC-C signaling regulates local fluid balance and other components of intestinal mucosal homeostasis including epithelial barrier function. The aim of this study was to compare if select dosing regimens differentially affect linaclotide and lubiprostone modulation of ion transport and barrier properties of normal human colonic mucosa. Normal sigmoid colon biopsies from healthy subjects were mounted in Ussing chambers. Tissues were treated with linaclotide, lubiprostone, or vehicle to determine effects on short-circuit current (Isc). Subsequent Isc responses to the cAMP agonist, forskolin, and the calcium agonist, carbachol, were also measured to assess if either drug caused desensitization. Barrier properties were assessed by measuring transepithelial electrical resistance. Isc responses to linaclotide and lubiprostone were significantly higher than vehicle control when administered bilaterally or to the mucosal side only. Single versus cumulative concentrations of linaclotide showed differences in efficacy while cumulative but not single dosing caused desensitization to forskolin. Lubiprostone reduced forskolin responses under all conditions. Linaclotide and lubiprostone exerted a positive effect on TER that was dependent on the dosing regimen. Linaclotide and lubiprostone increase ion transport responses across normal human colon but linaclotide displays increased sensitivity to the dosing regimen used. These findings may have implications for dosing protocols of these agents in patients with constipation.