Campbell Colin A, Gaskin Pamela J, Darton Jill, Chiu Peter, Lee Kevin, McLean Peter G
GI Research, Neurology & GI Centre of Excellence of Drug Discovery, GlaxoSmithKline, Harlow, Essex, UK.
Eur J Pharmacol. 2008 Jul 28;589(1-3):260-3. doi: 10.1016/j.ejphar.2008.05.026. Epub 2008 May 27.
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.
新型药物分子的鉴定需要在体外和体内进行广泛评估。在体外评估之后,有必要使用相对简单的方法在体内高效筛选众多新型分子,该方法需要的动物数量少、操作快速,并且能够提供明确区分潜在候选药物以供进一步研究的结果。在此,我们描述了三种标准化合物(奥美拉唑,一种质子泵抑制剂;西咪替丁,一种组胺H₂受体拮抗剂;以及AR-H047108,一种钾竞争性酸阻滞剂)在大鼠吸入模型(基础和刺激条件下)中的结果,并将其与幽门结扎模型中的效果进行比较,以期在方法的敏感性、稳健性和简便性方面比较结果。在吸入模型中,在给予五肽胃泌素或二甲双胍前1小时口服给药或赋形剂。10分钟后口服0.9%氯化钠并立即通过抽吸回收。在幽门结扎模型中,在结扎前2小时以10 ml/kg的体积口服给药或赋形剂。对于每个模型,测量每个样品的体积并测定酸度。在基础胃酸分泌或用五肽胃泌素刺激后的吸入模型中,奥美拉唑、西咪替丁和AR-H047108产生了剂量相关的酸度抑制。奥美拉唑和西咪替丁在二甲双胍刺激后抑制胃酸分泌。在幽门结扎模型中,奥美拉唑、西咪替丁和AR-H047108抑制胃酸分泌。无论刺激程度(二甲双胍、五肽胃泌素或幽门结扎)如何,三种胃酸分泌抑制剂中的每一种的作用模式都表现出相似的效果。因此,基于这些强大的作用和简便的方法,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胃酸分泌抑制剂的主要体内方法。