Comparison of selective M3 and nonselective muscarinic receptor antagonists on gastrointestinal transit and bowel habits in humans
Comparison of selective M3 and nonselective muscarinic receptor antagonists on gastrointestinal transit and bowel habits in humans
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DOI：
10.1152/ajpgi.00072.2010
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发表时间：
2010-07-01
影响因子：
4.5
通讯作者：
Zinsmeister, Alan R.
中科院分区：
文献类型：
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作者：
Bharucha, Adil E.;Ravi, Karthik;Zinsmeister, Alan R.
Bharucha AE，Ravi K，Zinsmeister AR.选择性M-3和非选择性毒蕈碱受体拮抗剂对人类胃肠传输和排便习惯的比较。美国生理学杂志胃肠和肝脏生理学299：G215-G219，2010年。首次发表于2010年4月15日; doi：10.1152/ajpgi.00072.2010。尽管体外研究表明，毒蕈碱M-3受体主要介导乙酰胆碱对胃肠道收缩性的影响，但调节人体体内胃肠道运动活动和转运的毒蕈碱受体亚型尚不清楚。我们假设，毒蕈碱M-3特异性而非特异性受体拮抗剂将延迟人类胃肠道和结肠转运。在这项平行组研究中，72名健康受试者在第4-6天通过结肠造影评估胃排空、小肠传输和结肠传输（49名女性）接受安慰剂（n = 16）、M-3拮抗剂达非那新ER [每日7.5 mg（n = 20）或15 mg（n = 17）]，或非特异性拮抗剂托特罗定[4 mg/d（n = 19）]治疗6天。通过每日日记记录排便习惯。两种剂量的达非那新均显著延迟了小肠转运[与安慰剂相比P <0.01（对于两种剂量），与托特罗定相比P < 0.01（对于15 mg）]，即，6 h时的结肠充盈（安慰剂[59.6 +/-6.4%，平均值+/- SE]，7.5 mg ER [34.4 +/- 6.1%]，15 mg ER [20.4 +/- 6.3%]）。达非那新（15 mg）也延迟了（P < 0.01，与安慰剂和托特罗定相比）升结肠排空的半衰期[安慰剂（12.0 +/- 1.5 h），7.5 mg（18.6 +/- 1.9 h），15 mg（22.9 +/- 2.6 h）]和24 h时的结肠转运（几何中心）[安慰剂（2.8 +/- 0.2）、7.5 mg（2.4 +/- 0.2）、15 mg（1.9 +/- 0.2）]，但不是48 h。达非那新不影响胃排空，托特罗定不影响排便习惯或胃肠转运。使用临床批准剂量的毒蕈碱拮抗剂，这些发现表明，毒蕈碱M-3受体调节人体小肠和结肠转运;结肠效应在右结肠比左结肠更明显。在影响小肠和大肠转运的剂量下，M-3拮抗剂不影响人体胃排空。应评价达非那新治疗大肠杆菌为主型肠易激综合征的疗效。
Bharucha AE, Ravi K, Zinsmeister AR. Comparison of selective M-3 and nonselective muscarinic receptor antagonists on gastrointestinal transit and bowel habits in humans. Am J Physiol Gastrointest Liver Physiol 299: G215-G219, 2010. First published April 15, 2010; doi:10.1152/ajpgi.00072.2010.-Although in vitro studies show that muscarinic M-3 receptors primarily mediate the effects of acetylcholine on gastrointestinal contractility, the muscarinic receptor subtypes regulating gastrointestinal motor activity and transit in humans in vivo are unclear. We hypothesized that muscarinic M-3-specific but not nonspecific receptor antagonists would delay gastrointestinal and colonic transit in humans. In this parallel-group study, gastric emptying, small intestinal transit, and colonic transit were assessed by scintigraphy on days 4-6 in 72 healthy subjects (49 women) who received placebo (n = 16), the M-3 antagonist darifenacin ER [7.5 mg (n = 20) or 15 mg daily (n = 17)], or the nonspecific antagonist tolterodine [4 mg daily (n = 19)] for 6 days. Bowel habits were recorded by daily diaries. Both doses of darifenacin substantially delayed [P < 0.01 vs. placebo (for both doses), P < 0.01 vs. tolterodine (for 15 mg)] small intestinal transit, i.e., colonic filling at 6 h (placebo [59.6 +/- 6.4%, mean +/- SE], 7.5 mg ER [34.4 +/- 6.1%], 15 mg ER [20.4 +/- 6.3%)]. Darifenacin (15 mg) also delayed (P < 0.01 vs. placebo and tolterodine) half-time for ascending colonic emptying [placebo (12.0 +/- 1.5 h), 7.5 mg (18.6 +/- 1.9 h), 15 mg (22.9 +/- 2.6 h)] and colonic transit (geometric center) at 24 [placebo (2.8 +/- 0.2), 7.5 mg (2.4 +/- 0.2), 15 mg (1.9 +/- 0.2)] but not 48 h. Darifenacin did not affect gastric emptying and tolterodine did not affect bowel habits or gastrointestinal transit. With muscarinic antagonists used at clinically approved doses, these findings demonstrate that muscarinic M-3 receptors regulate small intestinal and colonic transit in humans; colonic effects are more pronounced in the right than left colon. At doses that affect small and large intestinal transit, M-3 antagonists do not affect gastric emptying in humans. The efficacy of darifenacin in diarrhea-predominant irritable bowel syndrome should be evaluated.