Validation of a conscious rat model for the discovery of novel agents that inhibit gastric acid secretion
Validation of a conscious rat model for the discovery of novel agents that inhibit gastric acid secretion
复制标题
DOI：
10.1016/j.ejphar.2008.05.026
复制
发表时间：
2008-07-28
影响因子：
5
通讯作者：
McLean, Peter G.
中科院分区：
文献类型：
--
作者：
Campbell, Colin A.;Gaskin, Pamela J.;McLean, Peter G.
新药物分子的鉴定需要广泛的体外和体内评价。在体外评价之后，有必要使用相对简单的方法在体内有效地筛选许多新分子，该方法需要少量动物，执行迅速，并且提供可以明确区分潜在候选物以用于进一步研究的结果。在此，我们描述了三个标准化合物的结果（奥美拉唑，质子泵抑制剂;西咪替丁，组胺H（2）受体拮抗剂;和AR-H 047108，一种钾竞争性酸阻断剂）（在基础和刺激条件下），并将效果与幽门结扎模型中的效果进行比较，以便在敏感性方面比较结果，方法的稳健性和简单性。在吸入模型中，在施用五肽胃泌素或二甲双胍之前1小时口服施用药物或媒介物。10分钟后，经口给予0.9% NaCl，并立即通过抽吸恢复。在幽门结扎模型中，在结扎前2小时以10 ml/kg的体积口服给予药物或溶媒。对于每个模型，测量每个样品的体积并确定酸度。在基础酸分泌下或在用五肽胃泌素奥美拉唑刺激后的抽吸模型中，西咪替丁和AR-H 047108产生酸度的剂量相关抑制。奥美拉唑和西咪替丁抑制酸分泌后，刺激与二甲双胍。在幽门结扎模型中，奥美拉唑、西咪替丁和AR-H 047108抑制胃酸分泌。3种酸分泌抑制剂中的每一种的特征表现出类似的作用，而与刺激的程度无关（二甲双胍、五肽胃泌素或幽门结扎）。因此，基于这些强大的效果和方法的简易性，我们建议使用五肽胃泌素刺激胃酸分泌的大鼠吸入模型作为筛选新型酸分泌抑制剂的主要体内方法。(c)2008 Elsevier B. V.保留所有权利。
Identification of novel drug molecules requires the extensive evaluation in vitro and in vivo. Following in vitro evaluation it is necessary to efficiently screen numerous novel molecules in vivo using relatively simple methodology that requires small numbers of animals, is rapid to perform, and provides results that can definitely discriminate potential candidates for further investigation. Herein, we describe the results of three standard compounds (omeprazole, a proton pump inhibitor; cimetidine, an histamine H(2) receptor antagonist; and AR-H047108, a potassium competitive acid blocker) in the rat aspiration model (under both basal and stimulated conditions), and compared the effects with those in the pyloric ligation model with a view to comparing the results in terms of sensitivity, robustness and simplicity of the methodology. In the aspiration model, drug or vehicle was administered orally 1 h prior to administration of pentagastrin or dimaprit. Ten minutes later 0.9% NaCl was administered orally and immediately recovered by aspiration. In the pyloric ligation model, drugs or vehicle were administered orally 2 h before ligation in a volume of 10 ml/kg. For each model, the volume of each sample was measured and the acidity was determined. In the aspiration model under basal acid secretion or following stimulation with pentagastrin omeprazole, cimetidine and AR-H047108 produced dose related inhibition of acidity. Omeprazole and cimetidine inhibited acid secretion following stimulation with dimaprit. In the pyloric ligation model omeprazole, cimetidine and AR-H047108 inhibited acid secretion. The profile of each of 3 inhibitors of acid secretion exhibited similar effects irrespective of the degree of stimulation (dimaprit, pentagastrin or pyloric ligation). Thus, based on these robust effects and ease of methodology we would recommend the use of the rat aspiration model with pentagastrin stimulation of gastric acid secretion as the primary in vivo methodology to screen novel inhibitors of acid secretion. (c) 2008 Elsevier B.V. All rights reserved.