质子泵抑制剂对结肠炎相关性结肠癌的发生发展是否有影响?

质子泵抑制剂(proton pump inhibitors,PPIs)是H+-K+-ATP酶抑制剂,常用于胃食管反流病、消化性溃疡等酸相关性疾病的治疗。长期使用PPIs所致高胃泌素血症可能增加了胃肠道肿瘤发生的风险,但临床研究及荟萃分析并未得到长期使用PPIs导致结肠癌风险增加的结论。前期研究表明,PPIs不仅有很好的抑酸效果,尚具有抗炎、抗氧化的作用,同时也能调节肿瘤酸性微环境、改善耐药机制和抑制相关的信号通路。本文对长期使用PPIs对结肠炎相关性结肠癌(colitis associated colon cancer,CACC)的影响作一概述,供临床参考。     

酸相关疾病治疗药物的研究进展

酸相关疾病是指与酸分泌或对胃酸敏感有关的一组疾病，一般是指消化性溃疡（PUD）、胃食管反流病（GERD）和功能性消化不良（FD）。当前治疗GERD、PUD及其它酸相关疾病常选用H2受体拮抗剂（H2RAs）和质子泵抑制剂（PPIs），随着对胃酸分泌的生理和酸相关疾病的病理生理更深入的了解，酸相关疾病治疗药物的研究也取得了很大进展。     

新型抑酸制剂治疗研究进展

随着人们生活节奏的加快、生活方式的改变以及饮食结构的调整．酸相关性疾病的发病率在全球呈逐年上升趋势，在酸相关性疾病的治疗中，目前应用的药物主要有H2受体拮抗剂和质子泵抑制剂（PPIs）等．而现在应用最为广泛的是PPIs。目前使用的PPIs存在的局限性主要有：①药物达到作用最强时间较长。常用的PPIs在治疗剂量下需要3～5天才能达到最大抑酸作用．有屿患者酸抑制作用不完全，还需使用抗酸剂和H2受体拮抗剂。②夜间酸突破。夜间酸突破在许多使用PPIs治疗的患者中十分常见，     

钾离子竞争性酸阻滞剂的研究进展

胃酸分泌过多可引起消化性溃疡、反流性食管炎及其他胃酸分泌相关疾病.抑制胃酸分泌是该类疾病的主要治疗方法.临床上常用的抑酸药物有组胺H2受体拮抗剂(H2-Ras)和质子泵抑制剂(proton pump inhibitors,PPI).H2-Ras治疗反流性食管炎和胃肠出血的疗效不如治疗消化性溃疡的疗效好,且机体会对其快速产生耐受,这一点也限制此类药物在长期治疗及大量静脉注射中的应用[1].     

长期使用质子泵抑制剂可能导致的副作用分析

质子泵抑制剂(proton pump inhibitors, PPIs)在酸相关疾病患者中被广泛应用,特别是对于胃食管反流病患者,更有大剂量长期使用的趋势,然而这些使用PPIs的患者中部分并不符合临床用药指征,对PPIs副作用认识的不足是目前全球PPIs过度应用的重要原因之一.本文将从PPIs对药物代谢途径的影响和对消化道内环境的影响等方面阐述与PPIs使用相关的副作用,以利于重新认识PPIs的副作用,为今后合理使用此类药物,避免严重不良反应的发生及合理使用医疗资源提供参考.     

伏诺拉生的临床应用及不良反应

富马酸伏诺拉生(Vonoprazan, TAK-438)是临床应用中引入的第二种P-CABs药物，于2020年12月28日纳入我国医保，作为第二代P-CABs药物，伏诺拉生具有独特的吡咯衍类结构，其碱性pKa为9.06的特性，促使其能在酸性环境(如胃壁细胞的细胞内小管)中高水平积累，显示出了更强的抑酸作用。除此之外，起效快、抑酸效果持续时间长、结合可逆等方面优势较传统质子泵抑制剂(proton pump inhibitors, PPIs)药物展示了更广阔的应用前景。目前伏诺拉生已被证实可以用于临床治疗胃食管反流病、消化性溃疡、H.pylori的根除以及ESD术后延迟出血等疾病。本文拟对伏诺拉生的临床应用以及不良反应进行综述。     

H2受体拮抗剂在应激性溃疡防治中的应用

应激性溃疡(SU)是各种严重应激状态下发生的并发症,而H2受体拮抗剂(H2RA)是防治SU最常用的药物.SU发病最重要的高危因素为机械通气超过48 h及凝血机制障碍.胃酸在SU发病中起重要作用,不同应激状态下胃酸分泌不同,但SU严重程度取决于实际反流入胃粘膜内的H+总量.H2RA除抑酸外尚可通过免疫调节及胃粘膜保护作用达到防治SU效果,对H2RA防治SU效果、与其他药物比较以及剂量和用法尚存在不同的观点.H2RA可通过骨髓抑制及产生血小板抗体导致血小板减少;H2RA抑酸后可导致胃内酸度下降,胃腔内革兰阴性菌可大量生长,从而可能引起医源性肺炎发病率升高.     

促动力药物在胃食管反流病治疗中的研究进展

胃食管反流病(gastroesophageal reflux disease,GERD)是由胃内容物反流引起不适症状和(或)并发症的一种疾病.GERD的发病机制包括食管下括约肌(lower esophageal sphincter,LES)功能失调,食管对反流物廓清能力下降,胃排空延迟以及食管黏膜对胃酸的抵抗力异常.因此,恢复胃动力、增强LES收缩以及食管运动的促动力药物常被用于治疗GERD,包括甲氧氯普胺、多潘立酮、西沙必利及莫沙必利等药物.目前认为,对于治疗轻度GERD促动力药物与H2受体阻滞剂具有相同的疗效,而在治疗重症GERD时促动力药物和抑酸药物联合治疗比单药治疗更有效.本文就将促动力药物在GERD治疗方案中作用和地位的研究进展作一综述.     

酸相关性疾病的抑酸标准及抑酸药物选择

酸相关性疾病(ARD)是一类与胃酸分泌相关的疾病。抑酸治疗能够显著改善ARD患者的临床疗效, 但治疗不同ARD的抑酸标准有所不同。质子泵抑制剂(PPI)和钾离子竞争性酸阻滞剂(P-CAB)作为临床常用的抑酸药物, 已获国内外指南一致推荐用于治疗ARD。本文就抑酸对ARD治疗的重要性, 常见ARD的抑酸标准, 以及PPI和P-CAB的抑酸效果及其在ARD治疗中的临床应用进行论述, 旨在为临床治疗ARD时选用抑酸药物提供参考。     

肝硬化合并上消化道出血临床治疗

肝硬化最严重且最危急的并发症是上消化道出血,一经确诊须抢救治疗：首先禁食,吸氧,保持呼吸道通畅。其次,补充血容量,必要时输血。第三应用降低门静脉压药物如生长抑素及其类似物和其他止血药。其他包括应用抑酸药物如质子泵抑制剂(PPIs)和H2受体拮抗剂(H2RA)。预防性使用抗生素。在药物治疗的基础上可联合内镜下治疗,三腔二囊管压迫止血法。绝大多数肝硬化急性上消化道出血患者经内科保守治疗和内镜下的积极治疗可止血,仍未能止血者,应考虑介入治疗(经颈静脉肝内门体分流术,TIPS)或紧急手术治疗。     

Oral pantoprazole for acid suppression in the treatment of patients with Zollinger-Ellison syndrome.

BACKGROUND: The management of patients with gastric acid hypersecretion due to gastrinoma, usually recognized as Zollinger-Ellison syndrome (ZES), was radically changed 10 years ago by the use of proton pump inhibitors. Surgical treatment now concentrates on tumour excision, and in the majority of patients, gastrectomy is no longer required to prevent complications of acid hypersecretion that can be managed pharmacologically. AIMS: To verify the ability of pantoprazole to control gastric acid hypersecretion and the clinical effects of acid hypersecretion in seven patients with documented ZES. METHODS: Pantoprazole was administered at an initial dose of 80 mg daily for seven days before basal acid output (BAO) was measured at 08:00, ie, 1 h before the next dose of pantoprazole was normally ingested. A lower (40 mg) or higher (120 mg or more) dose of pantoprazole was then used to keep the BAO in the therapeutic range (between 0.1 and 10 mmol/h) and to control clinical symptoms such as acid-related pain or diarrhea. RESULTS: BAO and clinical symptoms were controlled with pantoprazole 40 mg daily in one patient, 80 mg daily in two patients, 120 mg daily in three patients and 160 mg daily in one patient. CONCLUSIONS: Pantoprazole was able to control acid hypersecretion in ZES patients when administered in doses between 40 and 160 mg daily. An initial dose of 120 mg given before further titration of the drug regimen appears to be a reasonable therapeutic strategy.     

Pharmacological and pharmacodynamic essentials of H(2)-receptor antagonists and proton pump inhibitors for the practising physician

The suppression of gastric acid secretion with anti-secretory agents has been the mainstay of medical treatment for patients with acid-related disorders. Although the majority of Helicobacter pylori -related peptic ulcers can be healed with antibiotics, ulcer healing and symptom control can be significantly improved when antibiotics are given with anti-secretory agents, especially with a proton pump inhibitor. There is a dynamic relationship between the suppression of intragastric acidity and the healing of peptic ulcer and erosive oesophagitis and control of acid-related symptoms. The suppression of gastric acid secretion achieved with H(2)-receptor antagonists has, however, proved to be suboptimal for effectively controlling acid-related disorders, especially for healing erosive oesophagitis and for the relief of reflux symptoms. H(2)-receptor antagonists are also not effective in inhibiting meal-stimulated acid secretion, which is required for managing patients with erosive oesophagitis. Furthermore, the rapid development of tolerance to H(2)-receptor antagonists and the rebound acid hypersecretion after the withdrawal of an H(2)-receptor antagonist further limit their clinical use. Although low-dose H(2)-receptor antagonists are currently available as over-the-counter medications for self-controlling acid-related symptoms, their pharmacology and pharmacodynamics have not been well studied, especially in the self-medicating population. Proton pump inhibitors have been proved to be very effective for suppressing intragastric acidity to all known stimuli, although variations exist in the rapidity of onset of action and the potency of acid inhibition after oral administration at the approved therapeutic doses, which may have important clinical implications for the treatment of gastro-oesophageal reflux disease and perhaps for eradicating H. pylori infection when a proton pump inhibitor is given with antibiotics. Once-daily dosing in the morning is more effective than dosing in the evening for all proton pump inhibitors with respect to the suppression of intragastric acidity and daytime gastric acid secretion in particular, which may result from a better bio-availability being achieved with the morning dose. When higher doses are needed, these drugs must be given twice daily to achieve the optimal suppression of 24 hour intragastric acidity. Preliminary results have shown that esomeprazole, the optical isomer of omeprazole, given at 40 mg, is significantly more effective than omeprazole 40 mg, lansoprazole 30 mg or pantoprazole 40 mg for suppressing gastric acid secretion. However, more studies in different patient populations are needed to compare esomeprazole with the existing proton pump inhibitors with regard to their efficacy, cost-effectiveness and long-term safety for the management of acid-related disorders.     

Acid inhibition and the acid rebound effect

Acid secretion from gastric parietal cells is a result of a complex interaction between different stimulatory and inhibitory mediators. One of the most important mediators is gastrin, which stimulates gastric acid secretion from parietal cells mostly indirectly, by the release of histamine from enterochromaffin-like (ECL) cells. Therapy with antisecretory agents leads to hypergastrinemia, mucosal hyperplasia and increased ECL cell mass, which results in increase of gastric acid secretion capacity. This increased secretion capacity has been shown to manifest itself after antisecretory therapy withdrawal as rebound acid hypersecretion (RAH). Various studies have quantified acid hypersecretion after the cessation of therapy with H(2) antagonists and proton-pump inhibitors (PPIs). While most of those studies had small patient numbers, the findings generally demonstrate that RAH after H(2) antagonist therapy is of low magnitude, short duration, and has questionable clinical significance. On the contrary, acid hypersecretion after PPI therapy is more pronounced, lasts longer, and could possibly be the cause of acid-related symptoms. Potential for causing symptoms has recently been confirmed in two randomized placebo-controlled studies, and while we witness the increasing use of PPIs, RAH could become a proven cause of failure to withdraw therapy in a proportion of patients with reflux or dyspeptic symptoms.     

Physiological and clinical significance of enterochromaffin-like cell activation in the regulation of gastric acid secretion

Gastric acid plays an important role in digesting food （especially protein）, iron absorption, and destroying swallowed micro-organisms. H＋ is secreted by the oxyntic parietal cells and its secretion is regulated by endocrine, neurocrine and paracrine mechanisms. Gastrin released from the antral G cell is the principal physiological stimulus of gastric acid secretion. Activation of the enterochromaffin-like （ECL） cell is accepted as the main source of histamine participating in the regulation of acid secretion and is functionally and trophically controlled by gastrin, which is mediated by gastrin/CCK-2 receptors expressed on the ECL cell. However, longterm hypergastrinemia will induce ECL cell hyperplasia and probably carcinoids. Clinically, potent inhibitors of acid secretion have been prescribed widely to patients with acid-related disorders. Long-term potent acid inhibition evokes a marked increase in plasma gastdn levels, leading to enlargement of oxyntic mucosa with ECL cell hyperplasia. Accordingly, the induction of ECL cell hyperplasia and carcinoids remains a topic of considerable concern, especially in long-term use. In addition, the activation of ECL cells also induces another clinical concem, i.e., rebound acid hypersecretion after acid inhibition. Recent experimental and clinical findings indicate that the activation of ECL cells plays a critical role both physiologically and dinically in the regulation of gastric acid secretion.     

Clinical use of proton pump inhibitors in gastrointestinal diseases]

The development and introduction into clinical practice of proton pump inhibitors (PPIs) have influenced the management of acid-peptic disorders dramatically. PPIs inhibit the gastric hydrogen/potassium adenosine triphosphatase selectively and irreversibly which is the final step in acid secretion. PPIs are currently the most effective form of therapy in acid-peptic diseases. All PPIs are potent, effective and generally safe, but little different in equivalent doses. PPIs undergo hepatic metabolism by cytochrome P450 (CYP) system. Polymorphism of CYP2C19 influences the pharmacokinetics and pharmacodynamics of PPIs. Doses and dosing schemes of PPIs based on CYP2C19 genotype status is expected to increase the efficacy in clinical outcome. The major indication of PPIs are acid-related diseases such as peptic ulcers and their complications, gastroesophageal reflux diseases, Zollinger-Ellison syndrome and eradication of Helicobacter pylori with antibiotics and dyspepsia. The potency and cost-effectiveness of PPIs have extended their clinical uses. However, their widespread and long-term use may limit the therapeutic benefit between efficacy and clinical problems such as acid rebound hypersecretion, enhanced oxyntic gastritis, problems with carcinoids in rodents and long-term concern for gastric cancer development. Further studies are needed to minimize the side effects and to maximize the therapeutic effects of PPIs.     

Idiopathic gastric acid hypersecretion presenting as a diarrheal disorder and mimicking both Zollinger-Ellison syndrome and Crohn's disease

Many gastric acid hypersecretory states (basal acid output of greater than 15.0 mEq/h) exist for which the etiology is known, such as Zollinger-Ellison syndrome, systemic mastocytosis, antral exclusion, antral predominant Helicobacter pylori gastritis (antral G cell hyperplasia), chronic gastric outlet obstruction, short gut syndrome and basophilic leukemias. However, many hypersecretory patients have no identified etiology for their acid hypersecretion and are designated as idiopathic gastric acid hypersecretors with a basal acid output of greater than 10 mEq/h and a normal serum gastrin level. Because of the gastric acid hypersecretion these patients also commonly have an increased frequency of stools. Idiopathic gastric acid hypersecretion represents a known cause of gastric acid hypersecretion that is far more common than Zollinger-Ellison syndrome and it has a markedly different treatment regimen and natural history. We report a case of a patient with idiopathic gastric acid hypersecretion previously misdiagnosed as having Crohn's disease because of a presenting complaint of diarrhea and mimicking Zollinger-Ellison syndrome because her fasting serum gastrin level was elevated when incorrectly measured in the presence of antisecretory treatment.     

Gastric acid hypersecretory states: Recent insights and advances

Gastric acid hypersecretory states are characterized by basal hypersecretion of gastric acid and historically include disorders associated with hypergastrinemia, hyperhistaminemia, and those of unknown etiology. Although gastric acid secretion is infrequently measured, it is important to recognize the role of gastric hypersecretion in the symptoms of these disorders because they share several features of pathogenesis and treatment. In this article, recent important articles reporting insights into their diagnosis, pathogenesis, and treatment are reviewed. Particular attention is paid to Zollinger-Ellison syndrome, because it has the most extreme acid hypersecretion of this group of disorders and because numerous recent articles deal with various aspects of the diagnosis, molecular pathogenesis, and treatment of the gastrinoma itself or the acid hypersecretion. Two new hypersecretory disorders are reviewed: rebound acid hypersecretion after the use of proton pump inhibitors and acid hypersecretion with cysteamine treatment in children with cystinosis.     

Vonoprazan: A Novel and Potent Alternative in the Treatment of Acid-Related Diseases

Although proton pump inhibitors (PPIs) have been used widely, acid-related diseases are still associated with a huge burden on the health care system. Recently, the efficacy and safety of a new acid suppressant named vonoprazan in the treatment of acid-related diseases have been evaluated by a series of studies. As a novel potassium-competitive acid blocker, vonoprazan may provide reversible acid suppression by preventing K⁺ from binding to gastric H⁺/K⁺-ATPase. It has been clinically used for the short-term treatment of gastroesophageal reflux disease (GERD), peptic ulcer disease and Helicobacter pylori (H. pylori) infection in Japan. The healing rate of GERD and gastric ulcers by vonoprazan is more than 95 and 90%, respectively; also, it is effective in curing PPI-resistant GERD. It increases H. pylori eradication rate to more than 88% as part of both first-line and second-line therapy. It is also effective in the eradication of clarithromycin-resistant H. pylori strains. All of these short-term studies show vonoprazan is safe and well-tolerated. As a safe and effective acid inhibitor, vonoprazan might be a novel alternative in the treatment of acid-related diseases.     

Recent advances in the management of gastric acid hypersecretion in patients with Zollinger-Ellison syndrome

Several histamine H2 receptor antagonists and the H+,K(+)-ATPase inhibitor, omeprazole, have been shown to be capable of controlling gastric acid secretion safely and effectively in patients with Zollinger-Ellison syndrome. The relative merits of these agents are discussed, and their use in the acute and long-term control of acid hypersecretion and in special circumstances that require particular care are described. The surgical approaches to the control of acid secretion are described, and the current place of surgery in the management of acid hypersecretion is discussed.     

Diagnosis and management of Zollinger-Ellison syndrome

With the recent widespread availability of gastrin radioimmunoassays, the development of increasingly effective medical therapy for gastric hypersecretion, and improved methods to localize gastrinomas in patients with Zollinger-Ellison syndrome, the diagnosis, treatment of the gastric acid hypersecretion, and approach to the tumor have changed significantly. Recent advances in each of these areas and the current management of a patient with Zollinger-Ellison syndrome are reviewed.