Potential Anti-inflammatory Effects of Proton Pump Inhibitors: A Review and Discussion of the Clinical Implications

Proton pump inhibitors (PPIs) are potent blockers of gastric acid secretion, and are widely regarded as the agents of choice for the treatment of acid-peptic disorders. For patients with upper gastrointestinal symptoms of uncertain etiology, improvement with PPI therapy is considered prima facie evidence of a pathogenetic role for acid-peptic disease. In addition to anti-secretory effects, however, PPIs have been found to have anti-oxidant properties and direct effects on neutrophils, monocytes, endothelial, and epithelial cells that might prevent inflammation. Those anti-inflammatory effects of the PPIs might influence a variety of inflammatory disorders, both peptic and non-peptic, within and outside of the gastrointestinal tract. The purpose of this report is to review the mechanisms whereby PPIs might exert anti-inflammatory effects exclusive of gastric acid inhibition, to discuss the clinical implications of those effects, and to emphasize that a clinical response to PPIs should not be construed as proof for an underlying acid-peptic disorder.     

Review Article: Efficacy and safety of rabeprazole in treating gastroesophageal reflux disease

Abstract   Proton pump inhibitors (PPI) are the mainstay of gastroesophageal reflux disease (GERD) treatment. They have a good efficacy and short- and long-term safety profile. Rabeprazole is a second generation PPI with rapid onset of action that quickly relieves symptoms of GERD. Rabeprazole consistently and profoundly inhibits gastric acid secretion. Its metabolism is less dependent on CYP4502C19 system and therefore is the least affected among all PPIs by CYP4502C19 genetic polymorphism. Recent studies have also indicated that rabeprazole on-demand is cost effective in preventing non-erosive reflux disease (NERD) symptom relapse.     

Review article: efficacy and safety of rabeprazole in treating gastroesophageal reflux disease

Proton pump inhibitors (PPI) are the mainstay of gastroesophageal reflux disease (GERD) treatment. They have a good efficacy and short- and long-term safety profile. Rabeprazole is a second generation PPI with rapid onset of action that quickly relieves symptoms of GERD. Rabeprazole consistently and profoundly inhibits gastric acid secretion. Its metabolism is less dependent on CYP4502C19 system and therefore is the least affected among all PPIs by CYP4502C19 genetic polymorphism. Recent studies have also indicated that rabeprazole on-demand is cost effective in preventing non-erosive reflux disease (NERD) symptom relapse.     

New perspectives in gastric acid suppression: genetic polymorphisms predict the efficacy of proton pump inhibitors

Proton pump inhibitors are highly effective in the management of acid-peptic diseases. These drugs potently inhibit acid secretion from gastric parietal cells by irreversibly inhibiting activity of the H(+), K(+) ATPase (proton pump). Early studies of the pharmacokinetics of proton pump inhibitors demonstrated considerable variation in drug clearance rates among patients and healthy volunteers. This variation was also reflected in a wide range of the efficacy of acid suppression by standard doses of proton pump inhibitors among study subjects; those with slower clearance and higher drug concentrations experienced superior acid suppression. Proton pump inhibitors are predominantly inactivated by the 2C19 isoform of the hepatic cytochrome P450 mixed function oxidase system. The cytochrome P450 2C19 gene is polymorphic, with three known inactivating mutations. Individuals with one or two mutant cytochrome P450 2C19 alleles metabolize proton pump inhibitors more slowly than those with two wild-type alleles and experience higher drug levels. An individual's cytochrome P450 2C19 genotype predicts the degree of acid suppression in response to a standard dose of a proton pump inhibitor. Emerging data suggests that the clinical effectiveness of proton pump inhibitors in the treatment of acid-peptic diseases may also be dependent on cytochrome P450 2C19 genotype.     

钾离子竞争性酸阻滞剂在酸相关疾病中的应用

酸相关疾病是一类消化系统中的常见慢性疾病.质子泵抑制剂现已成为治疗酸相关疾病的一线用药,然而临床应用中逐渐显现出一些局限性,如半衰期短、起效较慢、抑酸不充分、药理作用受CYP2C19基因多态性影响、夜间酸突破等,导致分酸相关疾病患者的症状不能获得充分缓解,以及难治、复发、直接的健康相关生活质量下降和经济负担增大.钾离子...     

CYP2C19 polymorphism influences Helicobacter pylori eradication

The known factors that have contributed to the decline of Helicobacter pylori(H.pylori)eradication rate include antibiotic resistance,poor compliance,high gastric acidity,high bacterial load,and cytochrome P450 2C19(CYP2C19)polymorphism.Proton pump inhibitor(PPI)is important in the eradication regimen.The principal enzyme implicated in the metabolism of PPIs is CYP2C19.The effects of PPI depend on metabolic enzyme,cytochrome P450 enzymes,and CYP2C19 with genetic differences in the activity of this enzyme(the homozygous EM,heterozygous EM(Het EM),and poor metabolizer).The frequency of the CYP2C19 polymorphism is highly varied among different ethnic populations.The CYP2C19genotype is a cardinal factor of H.pylori eradication in patients taking omeprazole-based or lansoprazolebased triple therapies.In contrast,the CYP2C19 polymorphism has no significant effect on the rabeprazolebased or esomeprazole-based triple therapies.The efficacy of levofloxacin-based rescue triple therapy might be also affected by the CYP2C19 polymorphism,but CYP2C19 genotypes did not show obvious impact on other levofloxacin-based rescue therapies.Choice of different PPIs and/or increasing doses of PPIs should be individualized based on the pharmacogenetics background of each patient and pharmacological profile of each drug.Other possible factors influencing gastric acid secretion(e.g.,IL-1β-511 polymorphism)would be also under consideration.     

Proton Pump Inhibitor-Related Gastric Mucosal Changes

Proton pump inhibitors (PPIs) are used worldwide to treat of acid-related disorders such as peptic ulcer and gastroesophageal reflux disease and to prevent gastroduodenal injuries due to nonsteroidal anti-inflammatory drugs. PPIs are the most potent inhibitors of gastric acid secretion currently available, and they are one of the most commonly prescribed classes of drugs because of their high efficacy and low toxicity. However, long-term PPI use causes histopathological changes such as parietal cell protrusion into the gland lumen, cystic dilation of gastric fundic glands, and foveolar epithelial hyperplasia. These changes can manifest on endoscopic examination as fundic gland polyps, hyperplastic polyps, multiple white and flat elevated lesions, cobblestone-like mucosa, or black spots. Clinicians must be aware of PPI-induced endoscopic features in patients with chronic long-term PPI use. Conversely, identifying patients with long-term PPI use based on their endoscopic findings is important. Recently, potassium-competitive acid blockers (P-CABs), a new class of acid suppressants that inhibit gastric acid secretion more strongly than PPIs, have recently been introduced clinically. Further long-term prospective studies on these gastric mucosal lesions in patients with either PPI or P-CAB use are required to investigate their association with histopathological changes and to establish the clinical significance of these findings. (Gut Liver 2021;15:-652)     

Proton pump inhibitors in rheumatic diseases: clinical practice, drug interactions, bone fractures and risk of infections

Platelet activation and aggregation are key elements of the pathogenesis of acute coronary syndromes, of endothelial damage in chronic inflammatory and connective tissue disease (i.e. systemic sclerosis-SSc). Patients affected by chronic inflammatory diseases as well as by connective tissue diseases such as systemic sclerosis, often have the need to take anti-platelet therapy (e.g. ASA or clopidogrel). Current consensus recommendations state that patients prescribed clopidogrel plus aspirin should receive a proton pump inhibitor (PPI) to reduce gastrointestinal bleeding. Although each single PPI has similar efficacy in many cases, differences between them should be considered when choosing a treatment regimen. Many studies show PPI and clopidogrel drug interaction, with clopidogrel non-responsiveness in about 25% of the population. Only pantoprazole, which does not inhibit CYP P450 2C19, doesn't seem to have interaction with clopidogrel or other drugs. Patients affected by systemic sclerosis have high frequency of oesophageal mucosal abnormalities and should take long-term PPI therapy. When addressing long-term therapy safety data are clearly needed. Two recent studies have reported increased hip fracture rates with long-term PPI use, raising concerns about adverse effects of this class of drugs on mineral metabolism. The use of PPIs is also associated with an increase in the risk of development of Clostridium difficile infection (CDI) and the use of PPIs during CDI treatment is associated with an increased risk of recurrence. In order to achieve the desired results and, as with all medications, PPIs should always be used appropriately taking care never to exceed correct dosage and duration. When necessary use of pantoprazole arises as one of the best possible choices.     

CYP2D6-, CYP2C9- und CYP2C19-basierte Arzneimitteldosisanpassungen

The efficacy of a drug therapy is influenced by many different factors such as age, weight, comorbidity and co-medication, which vary between patients, as well as fixed parameters such as gender and pharmacogenetic characteristics. Many enzymes involved in drug metabolism are genetically polymorphic, which means that their activity differs depending on a certain genotype. Drugs will be metabolized slowly in individuals who are carriers of a genetic polymorphism, leading to absent or decreased enzyme activity, and these individuals are at particular risk for adverse drug reactions or therapeutic failure. On the other hand, drug therapy could be ineffective if the drug is metabolized too fast because of a genetic polymorphism. The knowledge of these polymorphisms before beginning a drug therapy could help in choosing the right drug in a safe dosage. In particular, three polymorphic drug metabolizing enzymes are responsible for the metabolism of many commonly used drugs. These enzymes, belonging to the cytochrome P450 (CYP) family, are CYP2D6, CYP2C9 and CYP2C19. Besides beta-blockers and antidepressants, several drugs used in cancer therapy, as well as PPIs, NSAIDs, vitamin K-antagonists and oral antidiabetics are metabolized via these enzymes. Especially for drugs with a narrow therapeutic index and a high risk for the development of adverse drug effects, genotyping could be helpful when choosing the right drug in the optimal dosage for individual patients.     

Proton pump inhibitors and their drug interactions: an evidence-based approach

The proton pump inhibitors (PPIs) are the most effective antisecretory agents used to treat acid-related disorders. As such, they are frequently prescribed for patients who are concurrently using other medications. PPIs may interact with other drugs through numerous mechanisms. The most important include competitive inhibition of hepatic cytochrome P (CYP) 450 enzymes involved in drug metabolism, and alteration of the absorption of other drugs via changes in gastric pH levels. Poor metabolizers, who lack CYP2C19, may be particularly predisposed to drug interactions. Although the potential for drug interactions is high, few clinically significant interactions have been reported for the PPIs. Nevertheless, caution is indicated when certain drugs are co-prescribed with these agents. The incidence of clinically significant drug interactions increases proportionately with the number of drugs taken and with the age of the patient. The drug interaction with the greatest clinical importance is the reduction in benzodiazepine clearance by omeprazole.     

Efficacy of tailored Helicobacter pylori eradication therapy based on antibiotic susceptibility and CYP2C19 genotype

The cure rates of Helicobacter pylori(H.pylori)eradication therapy using a proton pump inhibitor(PPI)and antimicrobial agents such as amoxicillin,clarithromycin,and metronidazole are mainly influenced by bacterial susceptibility to antimicrobial agents and the magnitude of the inhibition of acid secretion.Annual cure rates have gradually decreased because of the increased prevalence of H.pylori strains resistant to antimicrobial agents,especially to clarithromycin.Alternative regimens have therefore been developed incorporating different antimicrobial agents.Further,standard PPI therapy(twice-daily dosing)often fails to induce a long-term increase in intragastric pH>4.0.Increasing the eradication rate requires more frequent and higher doses of PPIs.Therapeutic efficacy related to acid secretion is influenced by genetic factors such as variants of the genes encoding drug-metabolizing enzymes(e.g.,cytochrome P450 2C19,CYP2C19),drug transporters(e.g.,multidrug resistance protein-1;ABCB1),and inflammatory cytokines(e.g.,interleukin-1β).For example,quadruple daily administration of PPI therapy potently inhibits acid secretion within 24 h,irrespective of CYP2C19 genotype.Therefore,tailored H.pylori eradication regimens that address acid secretion and employ optimal antimicrobial agents based on results of antimicrobial agent-susceptibility testing may prove effective in attaining higher eradication rates.     

Appropriateness in prescribing PPIs: A position paper of the Italian Society of Gastroenterology (SIGE) — Study section “Digestive Diseases in Primary Care”

The introduction of proton pump inhibitors (PPIs) into clinical practice about thirty years ago has greatly improved our therapeutic approach to acid-related diseases for their well-recognized efficacy and safety.Despite the well-defined indications, however, the use of PPIs continues to grow every year in both western and eastern countries and this phenomenon poses serious queries that include the onset of potential adverse effects and the increase in health care costs. The major reason explaining this worrying market expansion is the inappropriate use of PPIs. In order to re-establish a correct use of these effective drugs in daily clinical practice, the Italian Society of Gastroenterology (SIGE), nominated a panel of experts who reviewed the available clinical literature and produced a series of updated position statements on the use of PPIs in clinical practice.     

Short and long-term PPI treatment for GERD. Do we need more-potent anti-secretory drugs?

Because the reflux of the acidic gastric content into the esophagus plays a major role in the pathogenesis of symptoms of GERD and lesions of erosive esophagitis, acid suppression with a proton pump inhibitor (PPI) is currently the mainstay of anti-reflux therapy. There is a strong correlation between the degree of acid suppression provided by a given drug and its efficacy. The superiority of PPIs over other drugs (antacids, prokinetics and H(2)-receptor antagonists) has now been established beyond doubt, both for short- and long-term treatment. However, there are still some unmet therapeutic needs in GERD; hence, patients with non-erosive reflux disease (NERD) are less responsive to PPIs than those with erosive esophagitis. Moreover, the efficacy of PPIs in patients with atypical symptoms is frequently limited to the relief of associated heartburn or regurgitation. With respect to safety, although most studies on short- and long-term PPI use have provided reassuring data, recent reports have drawn attention to potential side effects or drug-drug interference. Better healing rates in the most severe forms of esophagitis, or a faster onset of symptom relief, may require optimization of acid suppressive therapy with regard to the daily course of acid secretion, especially during the night. Different pharmacological approaches can be considered, with the ultimate goals of achieving faster, stronger and more-sustained acid inhibition. How a better pharmacological profile may translate into clinical benefit should now be tested in appropriate, controlled studies.     

Pharmacology of proton pump inhibitors

The gastric H,K-ATPase is the primary target for the 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, which allows selective accumulation in the secretory canaliculus of the parietal cell, and a benzimidazole with a second pK_a of about 1.0. PPIs are acid-activated prodrugs that convert to sulfenic acids or sulfenamides that react covalently with one or more cysteines accessible from the luminal surface of the ATPase. Because of covalent binding, their inhibitory effects last much longer than their plasma half-life. However, the short half-life of the drug in the blood and the requirement for acid activation impair their efficacy in acid suppression, particularly at night. PPIs with longer half-life promise to improve acid suppression. All PPIs give excellent healing of peptic ulcers and produce good results in reflux esophagitis. PPIs combined with antibiotics eradicate Helicobacter pylori.     

Novel Approaches to Inhibition of Gastric Acid Secretion

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.     

Intravenous proton pump inhibitors for peptic ulcer bleeding: Clinical benefits and limits

Peptic ulcer bleeding is a common disease and recurrent bleeding is an independent risk factor of mortality.Infusion with proton pump inhibitors(PPIs) prevents recurrent bleeding after successful endoscopic therapy.A gastric acidic environment of less than pH 5.4 alters coagulation function and activates pepsin to disaggregate platelet plugs.Gastric acid is secreted by H+,K+-ATPase,naming the proton pump.This update review focuses on the mechanism and the role of PPIs in the clinical management of patients with peptic ulcer bleeding.An intravenous omeprazole bolus followed by high-dose continuous infusion for 72 h after successful endoscopic therapy can prevent the recurrent bleeding.In the Asian,however,the infusion dosage can possibly be diminished whilst preserving favorable control of the intragastric pH and thereby still decreasing rates of recurrent bleeding.Irrespective of the infusion dosage of PPIs,rates of recurrent bleeding remain high in patients with co-morbidities.Because recurrent peptic ulcer bleeding may be prolonged in those with co-morbidities,a lowdose infusion of IV PPIs for up to 7-day may result in better control of recurrent bleeding of peptic ulcers.Due to the inter-patient variability in CYP2C19 genotypes,the infusion form of new generation PPIs,such as esomeprazole,should be promising for the prevention of recurrent bleeding.This article offers a comprehensive review of clinical practice,highlighting the indication,the optimal dosage,the duration,and the potential limitation of PPIs infusion for peptic ulcer bleeding.     

Role of acid suppressants in prophylaxis of NSAID damage

Gastric acid contributes to the pathogenesis of non-steroidal anti-inflammatory drug (NSAID)-induced ulceration via several mechanisms, including conversion of superficial to deeper injury, impairment of haemostasis, and interference with ulcer healing. The suppression of acid secretion has been shown to reduce the severity of NSAID-induced mucosal damage in experimental models and clinical studies. Current evidence indicates that proton pump inhibitors (PPIs) are the preferred treatment for the healing of gastric ulcers when NSAIDs cannot be discontinued. PPIs are superior to standard-dose H(2)-receptor antagonists and equivalent to low-dose misoprostol in preventing NSAID-induced gastric ulcers. Whether there is any significant advantage of PPIs over higher doses of H(2)-receptor antagonists or misoprostol is unknown. The efficacy of PPIs is enhanced in the presence of H. Pylori infection. Omeprazole has been shown to be effective for the secondary prevention of ulcer bleeding in H. pylori -infected NSAID users. The efficacy of PPIs for the prevention of ulcer complications in H. pylori-negative NSAID users remains uncertain.