Novel Approaches to Inhibition of Gastric Acid Secretion

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• 作者：George Sachs (1)
  Jai Moo Shin (1)
  Richard Hunt (2)
  
• 关键词：Proton pump inhibitor ; Gastric H ; K ; ATPase ; Ulcer ; Gastroesophageal reflux disease
• 刊名：Current Gastroenterology Reports
• 出版年：2010
• 出版时间：December 2010
• 年：2010
• 卷：12
• 期：6
• 页码：437-447
• 全文大小：4153KB
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• 作者单位：George Sachs (1)
  Jai Moo Shin (1)
  Richard Hunt (2)
  
  1. Department of Physiology and Medicine, David Geffen School of Medicine, University of California at Los Angeles, and VA Greater Los Angeles Healthcare System, Room 324, Building 113, 11301 Wilshire Boulevard, Los Angeles, CA, 90073, USA
  2. Farncombe Family Digestive Disease Research Institute, Division of Gastroenterology, McMaster University Health Sciences Centre, 1200 Main Street West, Room 4W8A, Hamilton, ON, L8N 3Z5, Canada
  

文摘

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 pKa of about 4.0 that allows selective accumulation in the secretory canaliculus of the parietal cell, and a benzimidazole with a second pKa 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.