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酸相关性疾病(ARDs)是一类由于胃酸分泌过多,或对胃酸特别敏感而引起的一类消化道疾病的总称,包括胃食管反流病(GERD)、消化性溃疡(PU)、幽门螺杆菌(Hp)感染、功能性消化不良(FD)、卓-艾综合征(ZES)与应激性溃疡(SU)等,其中Hp感染、阿司匹林及其他非甾体抗炎药(NSAIDs)的使用是导致PU的重要病因,GERD与PU也是最常见的ARDs[1-3]。胃酸的生理功能是激活胃蛋白酶原并将其转变为胃蛋白酶,参与蛋白质的消化、减少细菌在胃和十二指肠的定植[4]。然而,胃酸是把双刃剑,其同样介导了胃黏膜损伤的病理过程并且是导致ARDs的潜在原因[5]。因此,抑制胃酸分泌是治疗ARDs的基石[6]。早在1910年,外科医生Schwarz就提出“无酸,无溃疡”的概念,奠定了胃酸在PU发病机制中的基础,使人们对溃疡的认识大幅提高,这种观点盛行了70年,直到20世纪80年代初Hp被发现,由此诞生了“无Hp,无溃疡”的第二次飞跃[7, 8]。然而,抑酸依然是治疗ARDs不可或缺的重要部分。
1915年,自Schwarz提出“无酸,无溃疡”后,美国医生Bertram Sippy开始了抗酸剂治疗PU的工作。在接下来的50年里,抗酸剂被广泛应用,并且在1952年Pickering证明中和酸性胃内容物可减缓PU患者疼痛后得到进一步普及[9]。20世纪70年代末,第一个H2受体拮抗剂(H2RA)西咪替丁的临床应用显著改善了PU的药物治疗并革新了ARDs的疾病管理,使PU择期手术几乎被废除。然而,PU的复发与GERD有限的治疗效果使H2RA依然不能满足临床需求。1988年,第一个质子泵抑制剂(PPI)奥美拉唑批准上市,PPI不仅对PU有效,而且对反流性食管炎(RE)具有显著优于H2RA的治疗效果;PPI在治疗GERD方面取得了显著进步,并将抗反流手术降级到药物治疗无法充分控制的GERD患者,因此成为治疗ARDs的一线方案[6, 10]。尽管PPI在临床中大放异彩,但随着使用数据和经验的积累,PPI的局限性逐渐显露出来:①对酸敏感,因此需制备为肠溶制剂;②本身为前药,在酸性条件下才能活化,因此活性依赖于进食,需餐前30 min服药;③起效慢,需3~5 d才能达到最大抑酸效果;④主要经CYP2C19代谢(奥美拉唑、艾司奥美拉唑、兰索拉唑、泮托拉唑与雷贝拉唑不同程度抑制其活性),药效学及药动学均受其遗传多态性影响并可能导致药物相互作用;⑤半衰期短,难以维持24 h抑酸作用;⑥难以有效改善夜间酸突破(NAB),可能与其只能抑制活化的质子泵有关[6, 10, 11]。为克服上述缺点,临床亟需可替代传统PPI、更快速有效的新型抑酸药,在此背景下诞生了钾离子竞争性酸阻滞剂(P-CAB)。本文主要就国内已上市3款P-CAB的药学特征展开综述。
Progress on pharmaceutical characteristics of potassium-competitive acid blocker
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摘要: 钾离子竞争性酸阻滞剂(P-CAB)是一类新型抑酸药,通过与H+, K+-ATP酶的K+结合位点附近可逆结合,抑制其构象转变而无法完成H+、K+交换,以K+竞争性的方式抑制胃酸分泌。P-CAB独特的结构与新颖的作用机制赋予其优于其他质子泵抑制剂(PPI)的药学特征,使其成为了酸相关性疾病(ARDs)的新选择。就P-CAB的药学特征展开综述。
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关键词:
- 钾离子竞争性酸阻滞剂 /
- 酸相关性疾病 /
- 研究进展
Abstract: As a new class of acid inhibitors, potassium-competitive acid blocker(P-CAB) inhibits the conformational transition of H+, K+-ATPase with subsequent suppression of H+, K+ exchanging by binding reversibly near the K+ binding site of H+, K+-ATPase, which results in the inhibition of gastric acid secretion in a K+-competitive manner. The unique structure and novel mechanism of P-CAB contribute to the pharmaceutical characteristics superior to other PPIs, making it a new alternative for acid-related diseases(ARDs). Progress on pharmaceutical characteristics of P-CAB were reviewed in this paper.-
Key words:
- potassium-competitive acid blocker /
- acid-related diseases /
- progress
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