Protective effects of tranilast on experimental colitis in rats
Protective effects of tranilast on experimental colitis in rats
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DOI：
10.1016/j.biopha.2017.04.035
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发表时间：
2017-06-01
影响因子：
7.5
通讯作者：
Onoue, Satomi
中科院分区：
文献类型：
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作者：
Seto, Yoshiki;Kato, Kouki;Onoue, Satomi
本研究旨在通过实验性结肠炎模型验证曲尼司特（TL）治疗炎症性肠病（IBD）的疗效。通过直肠内滴注溶于含25%乙醇的水中的2，4，6-三硝基苯磺酸（TNBS; 40 mg/kg）制备实验性结肠炎模型。通过生物标志物和组织学分析评价TL重复口服给药后的药理作用，并考察TL单次口服给药后的药代动力学行为。直肠内滴注TNBS溶液引起结肠炎，如通过ca.髓过氧化物酶（MPO）活性、浸润细胞数量和结肠粘膜下层厚度分别增加2.2倍、5倍和3倍。然而，口服TL（10 mg/kg，每天两次，持续9天）导致TNBS灌肠引起的MPO水平升高降低92%，并且实验性结肠炎模型中的细胞浸润和粘膜下层增厚也倾向于被TL的重复口服给药抑制。TL在TNBS处理的大鼠中的口服生物利用度被计算为低至约100 mg/kg。TL口服吸收不良可能是其治疗IBD的一个限制因素。TL可减轻TNBS诱导的结肠炎，抗炎作用与TL治疗IBD患者的疗效具有临床相关性。尽管TL的口服生物利用度可能需要进一步改善以获得更好的药理学结果，但TL将是治疗IBD的有效药物。(C)2017 Elsevier Masson SAS。All rights reserved.
The present study aimed to verify the efficacy of tranilast (TL) for treating inflammatory bowel disease (IBD) with the use of an experimental colitis model. The experimental colitis model was prepared by intrarectal instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS; 40 mg/kg) dissolved in water containing 25% ethanol. The pharmacological effects of TL after repeated oral administration were evaluated by biomarker and histological analyses, and the pharmacokinetic behavior of TL was also examined after single oral administration. The intrarectal instillation of TNBS solution caused colitis, as evidenced by ca. 2.2-, 5-, and 3-fold increases in myeloperoxidase (MPO) activity, infiltrated cell numbers, and the thickness of the submucosa in the colon, respectively. However, orally-taken TL (10 mg/kg, twice a day for 9 days) led to a 92% reduction in the increase of the MPO level by TNBS enema, and cellular infiltration and thickened submucosa in the experimental colitis model tended to also be suppressed by repeated oral administration of TL. The oral bioavailability of TL in TNBS-treated rats was calculated to be as low as ca. 6.5%, and the poor oral absorption of TL may be a limitation of the treatment for IBD. TL could attenuate TNBS-induced colitis on the basis of the obtained results, and the anti-inflammatory effects would have clinical relevance to the therapeutic outcomes of TL in IBD patients. Although further improvement in the oral bioavailability of TL might be required for better pharmacological outcomes, TL would be an efficacious agent for treating IBD. (C) 2017 Elsevier Masson SAS. All rights reserved.