Exploratory Studies With BT-11: A Proposed Orally Active Therapeutic for Crohn's Disease.
Exploratory Studies With BT-11: A Proposed Orally Active Therapeutic for Crohn's Disease.
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对BT-11的探索性研究：提议的针对克罗恩病的口服活性治疗。
DOI：
10.1177/1091581816646356
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发表时间：
2016-09
影响因子：
2.2
通讯作者：
Bassaganya-Riera J
中科院分区：
文献类型：
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作者：
Bissel P;Boes K;Hinckley J;Jortner BS;Magnin-Bissel G;Werre SR;Ehrich M;Carbo A;Philipson C;Hontecillas R;Philipson N;Gandour RD;Bassaganya-Riera J
羊毛硫氨酸合成酶环化酶样2(LANCL2)是治疗克罗恩病(CD)的新靶点。BT-11是一种结合LANCL2的小分子，具有口服活性，并已在3种有效的小鼠结肠炎模型中显示出治疗效果，剂量低至8 mg/kg/天。探索性实验评价BT-11在雄性Harlan Spraogue Dawley大鼠身上的作用，单次口服500 mg/kg和80 mg/kg/d，连续14天(n=10只/组)。观察治疗组和对照组大鼠的行为损害情况，并采集血液和组织进行临床病理和组织病理学检查。功能观察组显示，在对量化、明确和连续终点的多次观察中，治疗组和对照组之间没有差异，包括姿势、笼内活动、接近、对触摸的反应、重量、握力、体温和旋转棒上的时间。脑、肾、肝、肾上腺、睾丸、胃、小肠和大肠、十二指肠、胰腺、心、肺、脾、胸腺和肋骨的组织病理学检查，组间无显著差异。与肝功能相关的血浆酶在单次给药后2~4天出现一过性升高，8天后恢复正常，连续给药14天后各时间点均未观察到与肝功能相关的酶。单次口服80 mg/kg剂量后1小时，BT-11的最大血药浓度为21 ng/ml，半衰期为3小时。这些实验结果表明，BT-11在大鼠中耐受性良好，进一步的测试表明，BT-11有望成为CD的口服活性治疗药物。
Lanthionine Synthetase Cyclase-Like 2 (LANCL2) is a novel therapeutic target for Crohn's disease (CD). BT-11 is a small molecule that binds LANCL2, is orally active, and has demonstrated therapeutic efficacy in 3 validated mouse models of colitis at doses as low as 8 mg/kg/day. Exploratory experiments evaluated BT-11 in male Harlan Sprague Dawley rats with a single oral dose of 500 mg/kg and 80 mg/kg/day for 14 days (n=10 rats dosed/group). Treated and control rats were observed for behavioral detriments, and blood and tissues were collected for clinical pathology and histopathological examination. A functional observational battery demonstrated no differences between treated and control groups over multiple times of observation for quantal, categorical and continuous endpoints, including posture, in-cage activity, approach, response to touch, weight, grip strength, body temperature, and time on a rotarod. Histopathological examination of brain, kidney, liver, adrenal gland, testes, stomach, small and large intestines, duodenum, pancreas, heart, lungs, spleen, thymus and rib found no significant differences between the groups. Plasma enzymes associated with liver function were transiently elevated 2-4 days after the 500 mg/kg single dose but returned to normal values by 8 days and were not observed at any time in rats given 80 mg/kg/day for 14 days. One hour after oral administration of a single 80 mg/kg dose, BT-11 had a maximal concentration of 21 ng/ml; the half-life was 3 hr. These experimental results demonstrated that BT-11 is well-tolerated in rats, and, with further testing, may hold promise as an orally active therapeutic for CD.
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影响因子：
3.2
作者：
Lu, Pinyi;Hontecillas, Raquel;Bassaganya-Riera, Josep
通讯作者：
Bassaganya-Riera, Josep
影响因子：
6.1
作者：
Zhang, Yong;Huo, Meirong;Xie, Shaofei
通讯作者：
Xie, Shaofei
影响因子：
4.8
作者：
Bassaganya-Riera, Josep;Guri, Amir J.;Hontecillas, Raquel
通讯作者：
Hontecillas, Raquel
影响因子：
3.7
作者：
Lu P;Hontecillas R;Horne WT;Carbo A;Viladomiu M;Pedragosa M;Bevan DR;Lewis SN;Bassaganya-Riera J
通讯作者：
Bassaganya-Riera J
DOI：
10.1016/b978-0-12-387815-1.00005-8
发表时间：
2013-01-01
期刊：
COMPREHENSIVE GUIDE TO TOXICOLOGY IN PRECLINICAL DRUG DEVELOPMENT
影响因子：
--
作者：
Denny, Kevin H.;Stewart, Christopher W.
通讯作者：
Stewart, Christopher W.