Pathogenesis and treatment of refractory gastroesophageal reflux disease in Japanese patients

Prevalence of refractory gastroesophageal reflux disease (GERD) defined as a patient who have persistent GERD symptoms during treatment with proton pump inhibitor (PPI) is rare in Japanese patinets. Pathogenesis of refractory GERD is associated with several factors including dysfunction of esophageal motility, presence of severe hiatal hernia, complication such as stricture and short esophagus, extensive metabolizer of CYP2C19 genotype, nocturnal gastric acid breakthrough, absence of H. pylori infection, or bile reflux. Examination by 24 hr pH monitoring is necessary to assess refractory GERD and if acid suppression is insufficient, treatment with double doses of PPIs or combination of PPI and H2 blocker is effective. However, most cases of refractory GERD are required surgical treatment. Endoscopic therapy might be useful for refractory GERD in future.     

Healing and relapse rates in gastroesophageal reflux disease treated with the newer proton-pump inhibitors lansoprazole, rabeprazole, and pantoprazole compared with omeprazole, ranitidine, and placebo: evidence from randomized clinical trials

BACKGROUND: The older proton pump inhibitor (PPI) omeprazole and the newer PPIs lansoprazole, rabeprazole, and pantoprazole are approved for the acute and maintenance treatment of gastroesophageal reflux disease (GERD). OBJECTIVE: On the basis of the results of randomized clinical trials, this study sought to estimate healing and relapse rates in acute and maintenance treatment of GERD with the newer PPIs compared with omeprazole, the histamine2-receptor antagonist ranitidine (the most frequent non-PPI comparator in studies of PPIs), and placebo. METHODS: A search of MEDLINE was conducted to identify randomized, controlled clinical trials that included a PPI in > or =1 treatment arm and assessed the healing of erosive esophagitis endoscopically. The primary outcome for studies of acute therapy was healing rate, and the primary outcome for studies of maintenance therapy was relapse rate. RESULTS: Fifty-three studies were identified, of which 38 involved acute therapy (12 excluded) and 15 maintenance therapy. None of the studies of pantoprazole met the inclusion criteria for maintenance therapy. The 8-week overall healing rate ratios in the comparison of newer PPIs with omeprazole 20 mg/d were as follows: lansoprazole 30 mg/d, 1.02 (95% CI, 0.98-1.06): rabeprazole 20 mg/d, 0.93 (95% CI, 0.87-1.00); and pantoprazole 40 mg/d, 0.98 (95% CI, 0.90-1.07). In the comparison of any PPI with ranitidine 300 mg/d, the ratios were as follows: lansoprazole, 1.62 (95% CI, 1.46-1.76); rabeprazole, 1.36 (95% CI, 1.20-1.54); pantoprazole, 1.60 (95% CI, 1.33-1.96); and omeprazole, 1.58 (95% CI, 1.41-1.78). Relapse rates over 1 year of treatment were similar between lansoprazole and rabeprazole. Compared with ranitidine, there were statistically significant differences in the rates of resolution of heartburn symptoms (P < 0.002), ulcer healing (P < 0.05), and relapse (P < 0.01). Similar results were seen in the comparison of PPIs with placebo in terms of rates of resolution of heartburn symptoms (P < 0.01), ulcer healing (P < 0.001), and relapse (P < 0.006). CONCLUSIONS: In this study, the newer PPIs were of similar efficacy to omeprazole in terms of heartburn control, healing rates, and relapse rates. All the PPIs were superior to ranitidine and placebo in healing erosive esophagitis and decreasing relapse rates.     

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.     

Recent advances in the treatment of GERD in the elderly: focus on proton pump inhibitors

The prevalence of gastroesophageal reflux disease (GERD) increases with age, and older people are more likely to develop severe disease. Studies of elderly patients with GERD indicate differences in presentation and diagnosis, compared with GERD in younger adults. Indeed, an older patient with GERD may present with atypical symptoms such as dysphagia, vomiting, weight loss, anaemia and anorexia, and less frequently with typical symptoms such as heartburn or acid regurgitation. These findings are attributed to pathophysiological changes in esophageal function that occur with age. Therefore, GERD in elderly patients is more likely to be poorly diagnosed or undiagnosed. Although few studies have concentrated specifically on elderly patients, the proton pump inhibitors (PPIs) have been shown to be more effective than histamine receptor antagonists for healing reflux esophagitis and for preventing its recurrence when they are given as maintenance therapy. In addition, the PPIs seem to be safe both in short- and in long-term therapy of elderly patients with GERD.     

Test of refractory gastroesophageal reflux disease

It should be considered that the causes of refractory gastroesophageal reflux disease (GERD) are multifactorial. Esophageal manometry study is useful when we make distinguish patients with esophageal motility disorders from those with refractory GERD. Endoscopic ultrasonography is also performed to observe the thickness of esophageal wall which represents the disturbance of esophageal motor function. Esophageal pH monitoring is useful to detect the acid clearance disturbance and phenomenon of nocturnal acid breakthrough. Both are occurred at night, and are recently considered to be responsible for refractory GERD. Catheter-free pH monitoring system, Bravo, makes it possible to measure esophageal pH under quite physiological conditions. Genotype of CYP2C19 is sometimes checked in patients with PPI resistance GERD. Intra-gastric pH with omeprazole and lansoprazole depends on patient's genotype of CYP2C19. Monitoring of 24-hour bilirubin, Bilitec, is also useful to detect duodeno-gastro-esophageal reflux.     

Maintenance therapy of mild form of GERD by H2 receptor antagonists

Because of high relapse rate after the healing by proton pump inhibitor(PPI) or H2 receptor antagonist(H2RA), GERD usually needs long time maintenance therapy. PPI is superior to H2RA in the first line as well as maintenance therapy. PPI is necessary for severe cases of GERD. However, H2RA is sufficient for milder form of GERD patients. Among the H2RA using in Japan, nizatidine has known to stimulate gastric emptying and elevate LES pressure. Nizatidine may be superior to other H2RAs in the treatment of GERD. Recently, nocturnal acid breakthrough which night time acid is secreted even PPI is administered twice daily has been documented. H2RAs are stronger than PPI to inhibit nocturnal acid breakthrough and may be better than night time acid reflux.     

Treatment of gastroesophageal reflux disease

Therapeutic modalities for gastroesophageal reflux disease (GERD) continue to evolve despite the introduction of proton pump inhibitors (PPIs), the most successful antireflux class of drugs. On-demand modalities such as antacids and alginates as well as histamine type-2 receptor antagonists continue to be popular with GERD patients who seek temporary relief of symptoms. The PPIs have revolutionized the treatment of patients with severe erosive esophagitis, complications of GERD, and atypical or extraesophageal manifestations of GERD. Antireflux surgery, commonly performed via laparoscopy, remains popular among patients who do not wish to take medications long term. In addition, the recent introduction of various endoscopic techniques offers GERD patients a long-term solution with less morbidity and lower cost than antireflux surgery.     

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。     

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.     

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.     

PPI: new strategies for GERD

Proton pump inhibitor (PPI) is the first-line drug for GERD and is far more effective than H2-receptor antagonist (H2RA). H2RA suppresses mainly nocturnal gastric acid secretion from parietal cells, while PPI blocks acid production at nighttime as well as daytime when acid refluxes often occur. PPI-test is a therapeutic diagnosis and can reliably distinguish GERD from other diseases presenting similar symptoms. Initial therapy of GERD should be started with a full dose of PPI. However, most of the GERD patients need maintenance therapy. The maintenance dose of PPI should be individualized with a titration technique ('New Step-down therapy'). A small number of GERD patients resistant to PPI therapy may be due to nocturnal acid breakthrough (NAB) or rapid metabolism of PPI (extensive metabolizer for CYP2C19).     

Comparison of an increased dosage regimen of rabeprazole versus a concomitant dosage regimen of famotidine with rabeprazole for nocturnal gastric acid inhibition in relation to cytochrome P450 2C19 genotypes

BACKGROUND AND OBJECTIVE: A concomitant dosage regimen of a histamine 2 receptor antagonist with a proton pump inhibitor (PPI) effectively decreases the incidence of nocturnal acid breakthrough, which is one of the problems encountered when acid-related diseases are treated with a PPI alone. We compared the effectiveness of an increased dosage regimen of rabeprazole with that of a concomitant dosage regimen of rabeprazole with famotidine, relative to cytochrome P450 (CYP) 2C19 genotype status, on nocturnal acid inhibition. METHODS: Fifteen Helicobacter pylori-negative volunteers, consisting of 5 homozygous extensive metabolizers (EMs), 6 heterozygous EMs, and 4 poor metabolizers (PMs) of CYP2C19, took 20 mg rabeprazole, 40 mg rabeprazole, and 20 mg rabeprazole plus 20 mg famotidine at bedtime (at 10 PM) for 8 days. The subjects then underwent 24-hour intragastric pH monitoring on day 8. RESULTS: For the 20-mg rabeprazole, 40-mg rabeprazole, and concomitant dosage regimens, the median percent times and ranges when nocturnal intragastric pH values were lower than 4.0 were 78.8% (47.5%-98.0%), 45.3% (29.0%-52.2%), and 15.5% (0.0%-40.8%), respectively, for homozygous EMs; 51.0% (7.0%-91.6%), 41.3% (33.0%-59.0%), and 18.5% (8.4%-31.9%), respectively, for heterozygous EMs; and 4.5% (2.0%-31.2%), 9.5% (0.0%-31.1%), and 9.3% (0.0%-14.7%), respectively, for PMs. Although significant differences in acid inhibition between the different CYP2C19 genotypes were observed when rabeprazole alone was given (P = .016 for 20 mg rabeprazole and P = .023 for 40 mg rabeprazole), such differences were not observed when famotidine was concomitantly given (P = .206). CONCLUSIONS: The combination regimen of famotidine plus rabeprazole is more effective for nocturnal acid inhibition in homozygous and heterozygous EMs than the increased dosage regimen of rabeprazole. This concomitant therapy could be a rescue regimen for patients with nocturnal acid breakthrough refractory to a standard PPI therapy who are likely to be CYP2C19 EMs.     

Potassium-competitive acid blockade: a new therapeutic strategy in acid-related diseases

Current therapies to treat gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), and other acid-related diseases either prevent stimulation of the parietal cell (H2 receptor antagonists, H2RAs) or inhibit gastric H+,K+-ATPase (e.g., proton pump inhibitors, PPIs). Of the 2 approaches, the inhibition of the final step in acid production by PPIs provides more effective relief of symptoms and healing. Despite the documented efficacy of the PPIs, therapeutic doses have a gradual onset of effect and do not provide complete symptom relief in all patients. There is scope for further improvements in acid suppressive therapy to maximize healing and offer more complete symptom relief. It is unlikely that cholecystokinin2 (CCK2, gastrin) receptor antagonists, a class in clinical trials, will be superior to H2RAs or PPIs. However, a new class of acid suppressant, the potassium-competitive acid blockers (P-CABs), is undergoing clinical trials in GERD and other acid-related diseases. These drugs block gastric H+,K+-ATPase by reversible and K+-competitive ionic binding. After oral doses, P-CABs rapidly achieve high plasma concentrations and have linear, dose-dependent pharmacokinetics. The pharmacodynamic properties reflect the pharmacokinetics of this group (i.e., the effect on acid secretion is correlated with plasma concentrations). These agents dose dependently inhibit gastric acid secretion with a fast onset of action and have similar effects after single and repeated doses (i.e., full effect from the first dose). Animal studies comparing P-CABs with PPIs suggest some important pharmacodynamic differences (e.g., faster and better control of 24-hr intragastric acidity). Studies in humans comparing PPIs with P-CABs will help to define the place of this new class in the management of acid-related diseases.     

难治性胃食管反流病的反流危险因素调查

目的：收集胃食管反流病（gastroesophageaf reflux disease,GERD）患者的临床信息、胃镜表现以及24 h食管pH-阻抗监测结果,比较难治性GERD和非难治性GERD的反流特点,探讨难治性GERD的预测因素,为临床处理提供依据.方法：入选2008年10月-2012年12月因反酸、烧心、非心源性胸痛、咽痛等症状在复旦大学附属中山医院消化科疑诊为GERD的74例患者.记录患者的年龄、性别、身高、体质量、胃镜结果等.监测患者的食管下段pH和食管阻抗变化.难治性GERD诊断：符合GERD诊断标准,同时经过质子泵抑制剂（PPI）治疗4周（每天至少1次）无效或者deMeester评分下降少于50％;非难治性GERD诊断：符合GERD诊断标准,同时经过PPI治疗4周（每天至少1次）症状改善明显;非GERD诊断：内镜检查未见食管黏膜损害,且24 h食管pH-阻抗监测反流次数和deMeester评分不足以诊断GERD.计数资料正态分布者用r±s表示,菲正态分布者用中位数和百分位数（25th,75th）表示.采用SPSS 17.0软件进行统计学处理.按是否为GERD、是否为难治性GERD分组,比较患者的一般资料和反流特征性因素.结果：（1）难治性GERD患者与非难治性GERD患者的酸反流次数、总反流次数差异无统计学意义;难治性GERD患者的deMeester评分较非难活性GERD患者高,长酸反流次数较非难治GERD患者多（P=0.032,P=0.008）;（2）经Logistic多因素分析发现,难治性GERD与长酸反流次数、非糜烂性胃食管反流病（NERD）呈正相关（P值分别为0.01和0.045）.长酸反流次数增加1次,发生难治性GERD的危险增加36％;NERD患者发生难治性GERD的危险是反流性食管炎患者的4.54倍;（3）不同类型GERD的反流特征：NERD患者的近端反流次数大于反流性食管炎和Barrett食管患者,而近端反流百分比显著大于反流性食管炎患者和Barrett食管患者（P=0.006）.结论：（1）长酸反流次数多和NERD是难治性GERD的独立危险因素;（2）NERD患者比糜烂食管炎患者更容易发展为难治性GERD.NERD患者的近端反流百分比的升高可能与其对PPI的反应差有关.     

Clinico-functional evaluation of the efficacy of treating gastroesophageal reflux disease combined with bronchial asthma with omeprazole

AIM: To investigate the prevalence of gastroesophageal reflux disease (GERD) among patients with bronchial asthma (BA) and to determine the effects of omeprazole therapy on the outcome of asthma in patients with GERD. MATERIAL AND METHODS: 117 BA patients were examined. Those who had a concomitant GERD were divided into two groups to receive outpatiently omeprazole 40 mg/day or placebo for 8 weeks. Spirometry was performed before and after the treatment. Clinical indices were calculated by daily summarizing of pulmonary (CIEI I) and gastric (CIEI II) symptoms improvement. RESULTS: The trial showed a significant correlation between CIEI I and CIEI II (r = 0.574, p < 0.001) during 8-week omeprazole therapy. The analysis of PEV and FEV1 dynamics showed a significant improvement (p < 0.05) of bronchial conduction in BA patients receiving omeprazole vs placebo. CONCLUSION: A significant correlation exists between the severity of gastroesophageal refluxes and bronchoobstructive syndrome in BA and GERD patients. Omeprazole treatment of such patients relieves BA and GERD symptoms.     

A randomised prospective study comparing the effectiveness of esomeprazole treatment strategies in clinical practice for 6 months in the management of patients with symptoms of gastroesophageal reflux disease

One option for patients with symptoms of gastroesophageal reflux disease (GERD) is treatment with proton pump inhibitors without prior endoscopy. Continuous or on-demand maintenance therapy are options for symptom-free patients. This study assessed the efficacy of three different treatment options in GERD patients in Norway. About 395 General Practitioners enrolled 2156 patients with symptoms of GERD in an open, randomised, parallel group trial. Following a 4-week symptom control phase [esomeprazole 40 mg once daily (od)], patients received either esomeprazole 20 mg od continuously or on-demand or ranitidine 150 mg twice-daily continuously for 6 months. The percentage of patients with no heartburn at the end of the study was maintained most effectively in the esomeprazole 20 mg continuous group (72.2%) and least effectively in the ranitidine group (32.5%). Significantly, more patients were completely/very satisfied with esomeprazole continuous (82.2%) and esomeprazole on-demand (75.4%) than with ranitidine continuous (33.5%) treatment (p < 0.0001). More patients were kept in remission, symptom free and were overall more satisfied with esomeprazole treatment than ranitidine.     

Acid-suppressive strategy against gastroesophageal reflux diseases and non-erosive reflux diseases: the alternative of proton- pump inhibitors or H2 receptor antagonists

Gastroesophageal reflux disease (GERD) is categorized into three distinct entities: erosive reflux diseases(ERD), non -erosive reflux diseases(NERD) and Barrett's esophagus. In ERD, early symptomatic relief as well as healing of the esophageal mucosal injury to prevent complications is the goal of the treatment, whereas in NERD, alleviation of the symptoms leading to better quality of life is the main goal. According to the results of randomized controlled trials comparing proton-pump inhibitors (PPIs) with H2-receptor antagonists (H2RAs) head-to-head, PPIs are superior to H2RAs in the treatment for ERD. However, H2RA was equally effective with PPI to the Japanese ERD patients with low-grade esophageal mucosal breaks and positive Helicobacter pylori (H. pylori) infection. PPIs are also more beneficial than H2RAs in NERD in Western literatures but overall therapeutic gains of PPIs in NERD are lower than those reported in ERD, indicating heterogeneity of NERD pathophysiology. Again, H2RA was reported to show equal effectiveness with PPI in NERD patients with positive H. pylori status in Japan. Thus, on -demand treatment with H2RA in NERD patients with positive H. pylori status could be an alternative option. In conclusion, optimal management of the Japanese GERD patients with acid suppressive therapies should be tailored to individual conditions.     

Management of gastroesophageal reflux disease (GERD) with refractory to standard dose of proton pump inhibitor

Approximately 10% of Japanese patients with reflux esophagitis (RE) are refractory to a standard dose of proton pump inhibitor(PPI) and most refractory patients have severe RE. Lack of response may be due to inadequate gastric acid suppression in conjunction with CYP2C19 genotype status and nocturnal acid reflux. Twice-daily dosing of PPI for inadequate gastric acid suppression and the administration of H2-receptor antagonist before bedtime for nocturnal acid reflux, is effective in most cases. The response to a standard dose of PPI in patients with non-erosive reflux disease (NERD) is approximately 50%. The reasons for a lower response rate, compared with RE patients, are not clear but may relate to an acid-hypersensitive esophagus, inadequate gastric acid suppression, non -acid reflux and emotional or psychological abnormality. High dose PPI therapy, endoscopic or surgical anti-reflux therapy, or/and pain modulators may be effective in some patients.