Novel approaches to inhibition of gastric acid secretion.
Novel approaches to inhibition of gastric acid secretion.
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DOI：
10.1007/s11894-010-0149-5
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发表时间：
2010-12-01
影响因子：
--
通讯作者：
Hunt, Richard
中科院分区：
文献类型：
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作者：
Sachs, George;Shin, Jai Moo;Hunt, Richard
胃H，K-腺苷三磷酸酶（ATP酶）是治疗酸相关疾病的主要靶点。质子泵抑制剂（PPI）是由两个部分组成的弱碱，一个是取代吡啶，其初级pK（a）约为4.0，允许在壁细胞分泌小管中选择性蓄积，另一个是苯并咪唑，其次级pK（a）约为1.0。该苯并咪唑的质子化激活这些前药，将它们转化为次磺酸和/或亚磺酰胺，其与可从ATP酶的腔表面接近的一个或多个半胱氨酸共价反应。PPI作为一个组的最大药效学效应依赖于环磷酸腺苷驱动的H，K-ATP酶从细胞质移位至壁细胞的小管膜。目前，这种效果只能通过蛋白粉刺激来实现。由于共价结合，抑制作用持续的时间比其血浆半衰期长得多。然而，药物在血液中的短停留时间和对酸活化的要求削弱了它们在酸抑制中的功效，特别是在夜间。所有PPI均使消化性溃疡愈合良好，并在反流性食管炎中产生良好但不太令人满意的结果。PPI联合抗生素根除幽门螺杆菌，但成功率已降至80%以下。更长的停留时间PPI有望改善酸抑制，从而改善临床结局。钾竞争性酸阻断剂（P-CAB）是另一类ATP酶抑制剂，至少有一种正在开发中。正在开发的P-CAB具有长的作用持续时间，即使其结合不是共价的。留置时间较长的PPI或持续时间较长的P-CAB有望解决因无法抑制夜间酸分泌而导致的未满足的临床需求，这些需求具有持续症状、延迟愈合和H生长抑制。幽门螺杆菌降低克拉霉素和阿莫西林的敏感性。因此，新的和更有效的抑制酸分泌将有利于那些患有酸相关的发病率，持续的食管损伤和疼痛，非甾体抗炎药诱导的溃疡，和H。根除幽门
The gastric H,K-adenosine triphosphatase (ATPase) is the primary target for treatment of acid-related diseases. Proton pump inhibitors (PPIs) are weak bases composed of two moieties, a substituted pyridine with a primary pK(a) of about 4.0 that allows selective accumulation in the secretory canaliculus of the parietal cell, and a benzimidazole with a second pK(a) of about 1.0. Protonation of this benzimidazole activates these prodrugs, converting them to sulfenic acids and/or sulfenamides that react covalently with one or more cysteines accessible from the luminal surface of the ATPase. The maximal pharmacodynamic effect of PPIs as a group relies on cyclic adenosine monophosphate-driven H,K-ATPase translocation from the cytoplasm to the canalicular membrane of the parietal cell. At present, this effect can only be achieved with protein meal stimulation. Because of covalent binding, inhibitory effects last much longer than their plasma half-life. However, the short dwell-time of the drug in the blood and the requirement for acid activation impair their efficacy in acid suppression, particularly at night. All PPIs give excellent healing of peptic ulcer and produce good, but less than satisfactory, results in reflux esophagitis. PPIs combined with antibiotics eradicate Helicobacter pylori, but success has fallen to less than 80%. Longer dwell-time PPIs promise to improve acid suppression and hence clinical outcome. Potassium-competitive acid blockers (P-CABs) are another class of ATPase inhibitors, and at least one is in development. The P-CAB under development has a long duration of action even though its binding is not covalent. PPIs with a longer dwell time or P-CABs with long duration promise to address unmet clinical needs arising from an inability to inhibit nighttime acid secretion, with continued symptoms, delayed healing, and growth suppression of H. pylori reducing susceptibility to clarithromycin and amoxicillin. Thus, novel and more effective suppression of acid secretion would benefit those who suffer from acid-related morbidity, continuing esophageal damage and pain, nonsteroidal anti-inflammatory drug-induced ulcers, and nonresponders to H. pylori eradication.