The proton-pump inhibitors: similarities and differences

OBJECTIVE: This paper examines the clinical pharmacology of the proton-pump inhibitors (PPIs) and briefly reviews some comparative studies of these agents. BACKGROUND: PPIs have emerged as the treatment of choice for acid-related diseases, including gastroesophageal reflux disease (GERD) and peptic ulcer disease. Although these drugs-omeprazole, lansoprazole, pantoprazole, and rabeprazole-share a common structure (all are substituted benzimidazoles) and mode of action (inhibition of H+,K+-adenosine triphosphatase [ATPase]), each differs somewhat in its clinical pharmacology. RESULTS: In comparative clinical trials found in MEDLINE, PPIs administered once daily produced endoscopic evidence of healing in >90% of patients with duodenal ulcer after 4 weeks of treatment, in >90% of those with gastric ulcer after 6 weeks of treatment, and in >90% of those with ulcerative or erosive GERD after 8 weeks of treatment. Maintenance therapy with daily doses of a PPI has been shown to be an effective means of preventing GERD relapse. PPIs also inhibit the growth of Helicobacter pylori, now recognized as an important factor in peptic ulcer disease, and, when administered in combination with antibiotics, provide the best treatment for eradication of the bacterium. Rabeprazole has a more rapid onset of H+,K+-ATPase inhibition than the other PPIs and, compared with omeprazole, a greater effect on intragastric pH after the first dose. Omeprazole and lansoprazole have a greater potential for drug-drug interactions than do pantoprazole and rabeprazole. CONCLUSION: Although the individual PPIs have similar efficacy in many cases, differences between them should be considered when choosing a treatment regimen.     

Diagnosis and treatment of gastrinoma in the era of proton pump inhibitors

The Zollinger-Ellison syndrome is characterized pathophysiologically by a significant hypergastrinemia derived from a gastrin-secreting neuroendocrine tumor with a primary location in the pancreas or duodenum. Chronic hypergastrinemia in turn triggers gastric acid hypersecretion yielding in chronic or recurrent or refractory peptic ulcer disease and/or chronic diarrhea. One half of patients with ZES will have distant metastases in the liver by the time the diagnosis is established and one half of all patients with ZES will experience chronic diarrhea as chief complaint rather than peptic ulcer-related symptoms and signs. Gastrinomas have been reported to either manifest sporadically or to occur in conjunction with the genetic background of the MEN-I syndrome. Diagnosis is based on the patients history which is typically characterized by recurrent episodes of peptic ulcer disease or by severe reflux esophagitis and/or diarrhea or by acid-related symptoms which fail to respond to standard treatment regimens. Upper gastrointestinal tract endoscopy will provide evidence for peptic ulcer disease in anatomical regions located aborally the duodenal bulb within the descending part of the duodenum or even farther distally within the jejunum. Peptic ulcers frequently occur in groups indicating some substantial acid hypersecretion. A gastric pH > 2 is mutually exclusive for ZES. Increased serum gastrin levels confirm the diagnosis biochemically. Gastrin secretion can be determined in the basal state or following stimulation with secretin or calcium. High sensitivity and specificity for the diagnosis of ZES is provided by determining the ratio of basal versus pentagastrin-stimulated gastric acid secretion: The ratio of BAO / MAO > 0.6 is highly specific for gastrinoma. To localize the gastrin-secreting tumor computer-assisted tomography, endoscopic ultrasound, and somatostatin receptor scintigraphy provide useful help but most recently, endoscopic ultrasound with high resolution transducers appear to improve preoperative site localization. If modern imaging techniques fail to elucidate the site of the tumor, intraoperative diaphany may help to detect gastrinomas within the duodenal wall. Definitive treatment will only be achieved by total surgical resection of the gastrin-producing tumor in the pancreas or duodenum including dissection of the regional lymph nodes. Control of symptoms will have to be achieved by administration of highly potent proton pump inhibitors in up to 2-3-fold increased standard doses to inhibit gastric acid hypersecretion. Elevation of gastric pH > 4 will be the therapeutic target to protect the mucosa of the upper gastrointestinal tract. Basal acid output should be reduced to less than 10 mEq H(+) per hour which requires administration of highly potent proton pump inhibitors with a recommended starting dose of 60 mg omeprazole equivalents per day.     

Appropriate choice of proton pump inhibitor therapy in the prevention and management of NSAID-related gastrointestinal damage

Non-steroidal anti-inflammatory drugs (NSAIDs) are associated with gastrointestinal adverse effects, ranging from dyspepsia and peptic ulcer disease to more serious complications such as haemorrhage or perforation. NSAID-induced gastrointestinal toxicity is a significant medical problem worldwide. Misoprostol is effective in reducing NSAID-induced mucosal damage, but patient compliance is limited by poor tolerance. Histamine receptor antagonists are relatively effective against duodenal ulcers but offer no significant protection against gastric ulcers. Proton pump inhibitors (PPIs), such as pantoprazole, omeprazole and lansoprazole, have been shown to be effective in preventing the development of gastric and duodenal ulcers in high-risk patients taking NSAIDs. PPI therapy is also beneficial in healing NSAID-induced ulcers and preventing their recurrence in patients requiring ongoing NSAID therapy. PPIs have an excellent safety profile, and pantoprazole--with its low potential for drug-drug interactions--is particularly suitable for administration to elderly patients who often require concomitant treatment with other medications.     

An overview of proton pump inhibitors.

SUMMARY: Proton pump inhibitors are the standard of treatment for acid-related disorders. These disorders include gastroesophageal reflux disease and its complications (i.e., erosive esophagitis and Barrett's esophagus), peptic ulcer disease, Zollinger-Ellison syndrome, and idiopathic hypersecretion. Proton pump inhibitors are also successfully used for the treatment of Helicobacter pylori infection and upper gastrointestinal bleeding.There are currently five proton pump inhibitors approved by the Food and Drug Administration and available in the United States. These are omeprazole (Prilosec), lansoprazole (Prevacid), rabeprazole (Aciphex), pantoprazole (Protonix), and esomeprazole (Nexium). This review discusses the history of proton pump inhibitors and compares and evaluates the pharmacology including mechanism of action, pharmacokinetics, pharmacodynamics, administration, dosage, and drug interactions. Information regarding therapeutic indications, clinical efficacy, short- and long-term side effects, and cost is also presented. A case presentation offers an analysis of the use of proton pump inhibitors in individualized patient care.     

老年人复合性溃疡102例胃镜与临床疗效分析

目的：探讨老年人复合性溃疡主要临床表现,溃疡好发部位和治疗效果评价。方法：分析研究102例老年人复合性溃疡与对照组的临床表现,溃疡好发部位,治疗效果等临床资料。结果：老年人复合性溃疡具有临床表现不典型,上消化道出血等并发多的特点,滥用NSAIDS或／和H—pylori感染是其发病主要原因,其高位胃溃疡、球后溃疡较对照组高。结论：对老年人有不典型溃疡症状应尽早做胃镜检查,胃镜检查时要注意少见部位的观察,减少漏诊。祛除内因、合理用药。选用高效PPI三联或四联抗HP治疗是提高老年人复合性溃疡治愈的关键。     

Proton-pump inhibition for acid-related disease.

Omeprazole and lansoprazole are the forerunners of a group of substituted benzimidazole compounds that block the gastric proton pump. These drugs exert a potent antisecretory effect by blocking the final common pathway of acid secretion. Prolonged, potent reduction of acid secretion using omeprazole has resulted in significant therapeutic advantage over existing antisecretory medication, such as H2 receptor antagonists (H2RAs). Research experience with lansoprazole indicates that it has treatment properties for acid-related disease that are similar to those of omeprazole. Omeprazole has been used successfully in the treatment of reflux esophagitis and the Zollinger-Ellison syndrome in the United States over the past year and has received approval recently as first-line therapy for duodenal ulcer disease. Research involving more than 20,000 individuals, postmarketing surveillance studies, and thorough safety studies in man and animals have shown omeprazole to be well tolerated, with an incidence and spectrum of adverse events in clinical trials similar to those observed with H2RAs.     

长期使用质子泵抑制剂对肠道菌群的影响

目的观察胃食管反流病和消化性溃疡患者长期使用质子泵抑制剂治疗后肠道菌群变化。方法选取胃食管反流病及消化性溃疡患者60例（观察组）,口服奥美拉唑,20mg,每日2次,疗程8周;选取健康志愿者20例（对照组）;利用实时荧光定量聚合酶链反应（PCR）检测观察组患者服药前、服药后4周、8周及对照组健康者清晨粪便中大肠杆菌、肠球菌属、双歧杆菌属及乳酸杆菌属数量,并对各目标菌群数量进行比较分析。结果与对照组相比,观察组患者服药前及服药后4周粪便中4种目标菌群无明显变化（P〉0.05）,服药后8周,粪便中大肠杆菌（4.81±0.77）lonN/g及肠球菌属（5.24±0.63）lonN/g仍无显著变化（P〉0.05）,但双歧杆菌属（8.82±0.91）lonN/g及乳酸杆菌属（6.99±0.69）lonN/g明显减少（P〈0.05）。结论长期服用质子泵抑制剂后可致肠道双歧杆菌属及乳酸杆菌属数量明显下降,使肠道生物屏障受损,增加了肠源性感染风险。     

A Review of the Novel Application and Potential Adverse Effects of Proton Pump Inhibitors

Proton pump inhibitors (PPIs) are known as a class of pharmaceutical agents that target H⁺/K⁺-ATPase, which is located in gastric parietal cells. PPIs are widely used in the treatment of gastric acid-related diseases including peptic ulcer disease, erosive esophagitis and gastroesophageal reflux disease, and so on. These drugs present an excellent safety profile and have become one of the most commonly prescribed drugs in primary and specialty care. Except for gastric acid-related diseases, PPIs can also be used in the treatment of Helicobacter pylori infection, viral infections, respiratory system diseases, cancer and so on. Although PPIs are mainly used short term in patients with peptic ulcer disease, nowadays these drugs are increasingly used long term, and frequently for a lifetime, for instance in patients with typical or atypical symptoms of gastroesophageal reflux disease and in NSAID or aspirin users at risk of gastrotoxicity and related complications including hemorrhage, perforation and gastric outlet obstruction. Long-term use of PPIs may lead to potential adverse effects, such as osteoporotic fracture, renal damage, infection (pneumonia and clostridium difficile infection), rhabdomyolysis, nutritional deficiencies (vitamin B12, magnesium and iron), anemia and thrombocytopenia. In this article, we will review some novel uses of PPIs in other fields and summarize the underlying adverse reactions.     

Helicobacter pylori infection and eradication

H. pylori infection is associated with various gastroduodenal diseases such as gastritis, peptic ulcer, gastric cancer, gastric MALT lymphoma. H. pylori infection is suggested that it plays a role as protective factor not promoting factor for reflux esophagitis and GERD. Epidemiological studies showed lower prevalence of H. pylori infection in reflux esophagitis and Barrett's esophagus comparing the control. Increased occurrence of reflux esophagitis after curing of H. pylori infection was reported. However, the relationship between H. pylori infection and reflux esophagitis has not been actually made clear. Also the mechanism of reflux esophagitis occurrence after H. pylori eradication is not obscure.     

奥美拉唑和枸橼酸铋钾治疗消化性溃疡患者的临床疗效观察

目的观察和探讨奥美拉唑加枸橼酸铋钾胶囊治疗消化性溃疡的临床疗效。方法将2008年8月至2010年8月经胃镜确诊的幽门螺杆菌(HP)阳性消化性溃疡患者164例随机分为治疗组和对照组,其中治疗组88例,口服奥美拉唑和枸橼酸铋钾胶囊;对照组76例口服奥美拉唑、阿莫西林和甲硝唑。结果两组患者在症状消失、溃疡愈合和HP根除率方面差异无统计学意义(P>0.05);但在消化道不良反应方面,治疗组出现口干、便秘9例,占1.02%;对照组有32例出现不同程度的恶心、呕吐、厌食、纳差等消化道不良症状,占42.2%,两组患者比较差异有统计学意义(P<0.05)。结论奥美拉唑加枸橼酸铋钾胶囊组合的疗效好,消化道不良反应小,是治疗消化性溃疡比较理想的药物组合选择。     

H2-receptor antagonists in perspective.

Cimetidine, like its predecessors burinamide and metiamide, has been shown in vitro to be a specific competitive histamine H2-receptor antagonist. In vivo, it is a potent inhibitor of histamine-stimulated gastric acid secretion in animals and man after both intravenous and oral administration. Doses sufficient to inhibit gastric secretions are without measureable effects on other physiologic systems. The main indication for cimetidine is in the treatment of duodenal ulcer and of the Zollinger-Ellison syndrome. Useful indications are treatment of gastric ulcer and pnacreatic insufficiency. Possible indications are prevention of gastrointestinal bleeding and treatment of peptic esophagitis. The neutrophil toxicity seen with metiamide has so far not been demonstrated with cimetidine; side effects with cimetidine have generally been trivial. In the future, H2-receptor antagonists are likely to become key therapeutic agents in diseases in which gastric acid-pepsin secretion plays a pathogenetic role.     

Recurrent peptic ulcer after gastric surgery]

Recurrent peptic ulcer after gastric surgery differs from duodenal ulcer in that they usually occur with low acid output, which is sufficient to cause ulceration in predisposed stomach or anastomosis. The proton pump inhibitor (PPI), significantly more potent and long-acting than H2-blocker, is expected to be more effective for postoperative recurrent ulcers. We evaluated the efficacy of omeprazole (OPZ) on recurrent ulcers in 12 patients following either gastrectomy or vagotomy. The healing rate after 4 week treatment with OPZ was 58% and increased to 100% after 8 week. Evaluation of quick symptom relief also supported the efficacy of OPZ treatment. These findings showed that OPZ treatment resulted in a more rapid healing of recurrent ulcers compared with H2-blocker. It remains to be clarified whether quit of treatment with PPI would induce high ulcer relapse rates, and whether maintenance therapy with PPI would be the only alternative therapy for surgical intervention.     

Anti-ulcer therapy after eradication of Helicobacter pylori

Helicobacter pylori (H. pylori) infection is the cause of the frequent relapse of peptic ulcer disease. Successful eradication therapy of H. pylori is associated with a decline in the recurrence of peptic ulcer. In this paper, we discussed the significance of anti-ulcer therapy after H. pylori eradication therapy. In patients with duodenal ulcer, maintenance therapy for preventing ulcer recurrence is not necessary because the rate of ulcer recurrence after eradication therapy is very low. However, in patients with gastric ulcer, the rate of ulcer relapse and reflux esophagitis ranges between 5-10% in the Japanese population even after successful eradication therapy; therefore, maintenance therapy for 1 year may be permissible in patients with gastric ulcer even after successful eradication therapy.     

Proton pump inhibitor for maintenance therapy of peptic ulcer]

The strategy for peptic ulcer therapy has been changing with the clinical application of the gastric proton pump inhibitor (PPI). In Japan, Miyoshi et al and Takemoto et al reported an earlier reepithelialization of peptic ulcer with omeprazole (OME) or lansoprazole (LAN) than famotidine (FAM). Miyoshi et al also reported that there was no significant difference between OME and FAM in ulcer relapse rate during a one year follow-up period. Therefore, there were two problems. One is application of PPI for prevention of ulcer relapse, and the other is the more accurate diagnosis of ulcer healing. Application of PPI for maintenance therapy is not yet realized in Japan, but, Lauritsen et al had already reported on the efficacy and safety of OME, 20 mg, three days a week and 10 mg, daily in prevention of duodenal ulcer relapse. Reepithelialization (red scar) is already established as a starting point of maintenance therapy, and from Miyake's report, a white scar is believed a favorable (non relapsing) end point.     

Efficacy of esomeprazole in patients with acid-peptic disorders.

Esomeprazole (Nexium) is a new proton pump inhibitor that provides more effective acid control compared with other proton pump inhibitors. In patients with gastroesophageal reflux disease, standard doses of esomeprazole maintain intragastric pH above 4 for significantly longer periods compared with standard doses of other proton pump inhibitors after 5 days of treatment. Esomeprazole is approved for the treatment of symptomatic gastroesophageal reflux disease, the healing of erosive esophagitis, and maintenance of healing. In clinical trials, esomeprazole 40 mg once daily for up to 8 weeks provided higher rates of healing of erosive esophagitis and a greater proportion of patients with sustained resolution of heartburn, than either omeprazole 20 mg or lansoprazole 30 mg once daily. For the maintenance of healing, esomeprazole 20 mg once daily provided significantly higher rates of maintained healing of erosive esophagitis after 6 months of treatment compared with lansoprazole 15 mg once daily. Esomeprazole is also approved for use as part of a triple-drug therapy regimen in combination with amoxicillin and clarithromycin for the eradication of Helicobacter pylori in patients with duodenal ulcer disease. The side effect profile of esomeprazole is similar to that of omeprazole. Many patients with acid-related disorders may benefit from the more rapid symptom relief, higher rates of healing of erosive esophagitis, and improved maintenance of healing that can be achieved with esomeprazole.     

Primary care for GEDR

Current approach for the treatment of gastroesopageal reflux disease (GERD) was reviewed. The most effective treatment of erosive esophagitis or symptomatic GERD is to reduce gastric acid secretion with either an H2 receptor antagonists (H2RA) or a proton pump inhibitor (PPI). The PPI lead to more rapid healing and symptom relief than H2RA. Despite treatment with PPI, some patients with GERD continue to have symptoms or endoscopic evidence of esophagitis. Nocturnal acid breakthrough may be one of the mechanisms responsible for the refractory GERD. There are two approaches to the initial medical treatment of gastroesophageal reflux disease ('step down' therapy or 'step up' approach). Although there are arguments in favour of both approaches, the former is considered to be preferable these days.     

HP根治前后胃粘膜Gas、SS、SP变化及G、D、EC_1细胞图像定量研究

该研究旨在探讨HP感染的慢性胃炎和消化性溃疡患者HP根治前后胃粘膜中胃肠激素Gas、SS、SP及G、D、EC1细胞变化和其相关性。方法 :1997年 3月～ 1999年 12月对 10 2例HP感染的病人 ,HP根治前后分别用放射免疫法及免疫组化染色图像定量分析Gas、SS、SP含量和G、D、EC1细胞密度、灰度。结果 :HP阳性的三组病人经药物治疗根治后胃粘膜Gas含量均较治疗前明显降低 (P <0 .0 1) ,SS、SP含量较治疗前升高 (P<0 .0 1,P <0 .0 5 )。图像定量分析示HP根治前后胃粘膜G、D、EC1细胞密度显著降低 (P <0 .0 5 ) ,D、EC1细胞灰度增加 (P <0 .0 5 )。结论 :三组病人HP根除后胃粘膜Gas减少 ,G细胞灰度降低 ,SS、SP升高 ,D、EC1细胞灰度增加 ,细胞分泌颗粒变化与粘膜相应激素变化呈正相关。提示HP感染干扰了这些激素分泌释放的调控 ,可能是HP相关性胃炎和消化性溃疡的发病机制之一。根除HP后SS、SP升高 ,Gas降低纠正HP感染所致的这些激素分泌释放紊乱 ,可能是HP根除后溃疡复发率降低的原因之一。在HP根除前SP ,EC1细胞灰度降低 ,根除后升高 ,提示SP抑制胃泌素分泌释放 ,而对生长抑素无抑制作用 ,具有胃粘膜保护功能。     

血清PGⅠ、GS-17及TNF-α水平与幽门螺杆菌感染消化性溃疡相关性研究

目的探讨血清胃蛋白酶原Ⅰ(pepsinogenⅠ,PGⅠ)、胃泌素-17(gastrin-17,GS-17)及肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)与幽门螺杆菌(Helicobacter pylori,HP)感染消化性溃疡(peptic ulcer,PU)的相关性。方法选取PU 132例,根据有无HP感染将其分为HP感染PU组(75例)和无HP感染PU组(57例)两组。HP感染PU组中胃溃疡29例,十二指肠溃疡46例;无HP感染PU组中胃溃疡30例,十二指肠溃疡27例。另选取同期进行体检的健康体检者47例作为健康体检组。比较3组血清PGⅠ、GS-17及TNF-α水平,HP感染PU组和无HP感染PU组不同溃疡类型患者血清PGⅠ、GS-17及TNF-α水平;采用Logistic回归分析探讨血清PGⅠ、GS-17及TNF-α水平与HP感染PU的关系;采用受试者工作特征(ROC)曲线分析血清PGⅠ、GS-17、TNF-α检测及三者联合检测对HP感染PU的诊断价值。结果HP感染PU组和无HP感染PU组血清PGⅠ、GS-17和TNF-α水平均高于健康体检组,HP感染PU组血清PGⅠ、GS-17和TNF-α水平高于无HP感染PU组,差异有统计学意义(P<0.01)。HP感染PU组胃溃疡患者血清GS-17水平低于十二指肠溃疡患者,差异有统计学意义(P<0.01)。HP感染PU组胃溃疡和十二指肠溃疡患者血清PGⅠ、GS-17和TNF-α水平均高于无HP感染PU组胃溃疡和十二指肠溃疡患者,差异有统计学意义(P<0.01)。Logistic回归分析结果显示,血清PGⅠ>70 U/ml、GS-17>55 pg/ml及TNF-α>10 ng/ml是HP感染PU的危险因素(P<0.01)。ROC曲线分析结果显示,血清PGⅠ、GS-17和TNF-α三者联合检测对HP感染PU的诊断价值最佳。结论血清PGⅠ、GS-17及TNF-α水平升高与HP感染PU有一定相关性,三者联合检测对HP感染PU的诊断价值最佳。     

Esomeprazole for acid peptic disorders

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, and safety of esomeprazole, a new proton-pump inhibitor (PPI). DATA SOURCES: A MEDLINE search (1966-March 2001) was conducted for relevant literature using the terms esomeprazole, Nexium, and H199/18. Abstracts from the XXXII Nordic Meeting of Gastroenterology and journal articles provided by AstraZeneca were reviewed. STUDY SELECTION AND DATA EXTRACTION: All available studies on the pharmacology, pharmacokinetics, clinical efficacy, and safety of esomeprazole were reviewed. DATA SYNTHESIS: Esomeprazole is a new PPI and is the S-isomer of racemic omeprazole. Esomeprazole has demonstrated acid control comparable to that of the other PPIs currently available. Esomeprazole undergoes less hepatic metabolism compared with omeprazole, and thus may result in less interpatient variability among slow and fast metabolizers of CYP2C19. The oral bioavailability of esomeprazole is approximately 89% with a dose of 40 mg, and the half-life is approximately 1.5 hours. Esomeprazole is effective in the healing of erosive esophagitis, with a rate of healing at week 8 of 93.7% (p < 0.001). In maintenance therapy of healed erosive esophagitis, esomeprazole maintained healing rates >90% (6-mo trial). Esomeprazole is comparable with omeprazole (both in combination with appropriate antibiotics) in the eradication of Helicobacter pylori, with eradication rates of 89.7% and 87.8%, respectively. The drug is well tolerated. The few adverse effects associated with esomeprazole are diarrhea, headache, nausea, abdominal pain, respiratory infection, and sinusitis. CONCLUSIONS: Esomeprazole is a safe and effective PPI. It is effective in the treatment of peptic ulcer disease and gastroesophageal reflux disease.