Gastric Acid-related Diseases Research Articles

Tegoprazan, a Novel Potassium-Competitive Acid Blocker to Control Gastric Acid Secretion and Motility.

Tegoprazan [(S)-4-((5,7-difluorochroman-4-yl)oxy)-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide], a potassium-competitive acid blocker (P-CAB), is a novel potent and highly selective inhibitor of gastric H+/K+-ATPase. Tegoprazan inhibited porcine, canine, and human H+/K+-ATPases in vitro with IC50 values ranging from 0.29 to 0.52 μM, while that for canine kidney Na+/K+-ATPase was more than 100 μM. A kinetic analysis revealed that tegoprazan inhibited H+/K+-ATPase in a potassium-competitive manner and the binding was reversible. Oral single administrations of tegoprazan ranging from 0.3 to 30 mg/kg in dogs were well absorbed into the blood stream and distributed in gastric tissue/fluid higher than in plasma. Tegoprazan potently inhibited histamine-induced gastric acid secretion in dogs, and a complete inhibition was observed at 1.0 mg/kg starting from 1 hour after administration. Moreover, an oral administration of tegoprazan at 1 and 3 mg/kg reversed the pentagastrin-induced acidified gastric pH to the neutral range. Interestingly, 3 mg/kg tegoprazan immediately evoked a gastric phase III contraction of the migrating motor complex in pentagastrin-treated dogs and similar effects was observed with the other P-CAB, vonoprazan. Tegoprazan is the novel P-CAB that may provide a new option for the therapy of gastric acid-related and motility-impaired diseases.

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.

Overuse of proton pump inhibitors and its consequences.

Direct inhibition of H+ ion excretion to the gastric lumen makes proton pump inhibitors (PPI) the most effective drugs against gastric acid-related diseases. Over recent years usage of proton pump inhibitors has increased dramatically. Due to the low costs, high efficacy and rarity of adverse effects, their use is prevalent and often it does not correspond with existing medical guidelines. The literature lists stress ulcer prophylaxis among patients with low risk of bleeding, routine 'gastroprotective' medication during treatment and non-specific abdominal symptoms as the most common patterns of off-label PPI use. This article summarizes the influence of PPI therapy on gastric mucosa, absorption and occurrence of adverse effects. The authors note that their low awareness among physicians contributes to wide and imprudent use of drugs of this group.

Oxidation of R- and S-omeprazole stereoselectively mediated by liver microsomal cytochrome P450 2C19 enzymes from cynomolgus monkeys and common marmosets

Racemic omeprazole has been used for clinically treating gastric acid-related diseases and also as a typical human cytochrome P450 (P450) 2C19 probe substrate in preclinical studies. S-Omeprazole has been developed as a single enantiomer medicine, which has been reported not to be associated with polymorphic human P450 2C19 phenotypes. In this study, 5-hydroxylation and sulfoxidation activities, with respect to stereoselective R- and S-omeprazole oxidations by liver microsomes from experimental animals including non-human primates and humans, were investigated in vitro. Liver microsomes from humans, cynomolgus monkeys, and mice preferentially mediated R-omeprazole 5-hydroxylations, however those from marmosets, minipigs, dogs, and rats preferentially mediated S-omeprazole 5-hydroxylations. High catalytic activities were observed for recombinant human P450 2C19 in R-omeprazole 5-hydroxlations, cynomolgus monkey P450 2C19 in both R- and S-omeprazole 5-hydroxlations, and marmoset P450 2C19 in S-omeprazole 5-hydroxlations. On the other hand, human, cynomolgus monkey, and marmoset P450 3A enzymes preferentially mediated S-omeprazole sulfoxidations. Correlation and kinetic analyses revealed a high affinity of polymorphic cynomolgus monkey and marmoset liver microsomal P450 2C19 enzymes with respect to R- and S-omeprazole 5-hydroxylations, respectively, and a high capacity of cynomolgus monkey and marmoset liver microsomal P450 3A4 for omeprazole 5-hydroxylations and sulfoxidations. R-and S-omeprazole 5-hydroxylation activities in cynomolgus monkey and marmoset liver microsomes were significantly different among wild-type, heterozygous, and homozygous animals genotyped for cynomolgus monkey P450 2C19 p.[(Phe100Asn; Ala103Val; Ile112Leu)] and for marmoset P450 2C19 p.[(Phe7Leu; Ser254Leu; Ile469Thr)], respectively. The results of this study demonstrate polymorphic cynomolgus monkey and marmoset P450 2C19-dependent omeprazole oxidation activities with individual variations similar to humans.

Proton Pump Inhibitor–Associated Hypomagnesemia: What Do FDA Data Tell Us?

Proton pump inhibitors (PPIs) are a class of medications indicated for the treatment of gastric acid-related diseases. Hypomagnesemia is a rare but serious adverse effect of PPIs. To address the association between the use of different PPIs and hypomagnesemia by examining the frequency of occurrence of hypo magnesemia among the reported adverse drug reactions from the Food and Drug Administration (FDA) Adverse Event Reporting System database. We conducted a cross-sectional study of PPI-associated adverse effect cases reported to the FDA between November 1, 1997, and April 1, 2012. Logistic regression was used to examine the association of sex, age, and different PPIs with hypomagnesemia. χ² analysis was conducted to investigate the association of PPI-associated hypomagnesemia with hypocalcemia and hypokalemia. Among 66,102 subjects identified as experiencing 1 or more adverse effects while taking a PPI, 1.0% (n = 693) were reported to have hypomagnesemia. The mean (SD) age of PPI users presenting with hypomagnesemia was 64.4 (12.9) years. Results from logistic regression indicated that, compared with esomeprazole, all other PPIs had a higher rate of hypomagnesemia, with pantoprazole having the highest rate (OR 4.3; 95% CI 3.3-5.7; p < 0.001). The risk of female subjects having hypo magnesemia (OR 0.83; 95% CI 0.71-0.97; p = 0.016) was significantly lower than that of males. Elderly subjects (age >65 years) were at increased risk of PPI-associated hypomagnesemia (OR 1.5; 95% CI 1.2-1.7; p < 0.001). χ² analysis showed strong association between hypomagnesemia and both hypocalcemia (p < 0.001) and hypokalemia (p < 0.001). All PPIs were associated with hypomagnesemia, with esomeprazole having the lowest risk and pantoprazole having the highest risk. The risk of PPI-associated hypomagnesemia was higher in males and the elderly population. Hypocalcemia and hypokalemia commonly coexisted with PPI-associated hypomagnesemia.

Systematic review: hypomagnesaemia induced by proton pump inhibition

Proton pump inhibitors (PPIs) are a mainstay therapy for all gastric acid-related diseases. Clinical concerns arise from a small but growing number of case reports presenting PPI-induced hypomagnesaemia (PPIH) as a consequence of long-term PPI use. Current opinion is that reduced intestinal magnesium absorption might be involved, but nothing is known on the molecular mechanism underlying PPIH. To investigate whether or not PPIH is a true, long-term drug-class effect of all PPIs and to scrutinise a possible role of comorbidity in its aetiology. Therefore, the primary objective in particular was to investigate serum magnesium dynamics in trials drug withdrawal and re-challenge. The secondary objective was to profile the 'patient at risk'. We reviewed systematically all currently available case reports on the subject and performed a statistical analysis on extracted data. Proton pump inhibitor-induced hypomagnesaemia PPIH is a drug-class effect and occurred after 5.5years (median) of PPI use, onset was broad and ranged from 14days to 13years. Discontinuation of PPIs resulted in fast recovery from PPIH in 4days and re-challenge led to reoccurrence within 4days. Histamine-2-receptor antagonists were the preferable replacement therapy in PPIH and prevented reoccurrence of hypomagnesaemia. In PPIH no specific risk profile was identified that was linked to the hypomagnesaemia. The cases of PPIH show severe symptoms of magnesium depletion and identification of its causation was only possible through withdrawal of the PPI. Clinical awareness of PPIH is key to avoid putting patients at risk.

A Review: Development &amp; Validation of HPLC Method for the Determination of Esomeprazole in Pharmaceuticals

Esomeprazole is chemically bis(5methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl]sulfinyl]-1Hbenzimidazole-1-yl). It is a gastric proton-pump inhibitor (PPI) used in treatment of gastric-acid related diseases. Simple, selective and accurate high performance liquid chromatographic (HPLC) methods were developed and validated for the analysis of esomeprazole magnesium. The objective of this review is to describe various analytical methods for estimation of Esomeprazole. All methods are validated as per ICH guidelines. © 2011 IGJPS. All rights reserved.

A Review of the Management of Gastric Acid-Related Diseases: Focus on Rabeprazole

Current treatment guidelines for acid-related diseases (ARDs) recommend first-line treatment with a proton pump inhibitor (PPI) to reduce gastric acid production. PPIs are indicated in the management of gastroesophageal reflux disease (reflux esophagitis, nonerosive reflux disease), peptic ulcer (gastric and duodenal ulcer, non-steroidal anti-inflammatory drug (NSAID)-associated ulcer, bleeding ulcer), functional dyspepsia, and in association with Helicobacter pylori eradication therapy when needed. Currently, PPIs (omeprazole, lansoprazole, pantoprazole, rabeprazole and esomeprazole) are widely used for the treatment of ARDs. All 5 PPIs are effective. However, there are differences in PPI pharmacokinetic and pharmacodynamic profiles that might influence their clinical utility. Rabeprazole is a useful option for the treatment of acid-related diseases due to its rapid onset of acid inhibition and few drug interactions.

Computational investigation of interactions between human H 2 receptor and its agonists

Type 2 histamine receptor (H 2R) is widely distributed in the body. Its main function is modulating the secretion of gastric acid. Most gastric acid-related diseases are closely associated with it. In this study, a combination of pharmacophore modeling, homology modeling, molecular docking and molecular dynamics methods were performed on human H 2R and its agonists to investigate interaction details between them. At first, a pharmacophore model of H 2R agonists was developed, which was then validated by QSAR and database searching. Afterwards, a model of the H 2R was built utilizing homology modeling method. Then, a reference agonist was docked into the receptor model by induced fit docking. The ‘induced’ model can dramatically improve the recovery ratio from 46.8% to 69.5% among top 10% of the ranked database in the simulated virtual screening. The pharmocophore model and the receptor model matched very well each other, which provided valuable information for future studies. Asp98, Asp186 and Tyr190 played key roles in the binding of H 2R agonists, and direct interactions were observed between the three residues and agonists. Residue Tyr250 could also form a hydrogen bond with H 2R agonists. These findings would be very useful for the discovery of novel and potent H 2R agonists.

The pharmacology of esomeprazole and its role in gastric acid related diseases

Esomeprazole (S-isomer of omeprazole) demonstrates a better pharmacokinetic/pharmacodynamic profile than the racemic product omeprazole. Esomeprazole's pharmacological activity of gastric acid secretion is through proton pump inhibition. The pharmacokinetic properties provide for an enhanced pharmacological effect. Esomeprazole is rapidly absorbed and the extent of absorption is higher resulting in higher systemic absorption of esomeprazole (bioavailability), which coupled with reduced clearance results in greater systemic exposure. This pharmacodynamic profile then provides for a prolongation of inhibition of gastric acid output and correlates well with its more beneficial therapeutic efficacy over omeprazole and some of the other proton-pump inhibitors. It has been well proven as an effective agent in the treatment of gastro-esophagitis reflux disease, (reflux esophagitis and non-erosive reflux disease), NSAID-induced gastric-intestinal symptoms and ulcers, Helicobacter pylori infection and Zollinger-Ellison syndrome. Esomeprazole has a good tolerability profile and a low potential for drug interaction.

Rabeprazole

Rabeprazole (Aciphex, Alfence, Pariet) is a proton pump inhibitor (PPI) used for the treatment of adults with conditions requiring a reduction of gastric acid secretion such as erosive or ulcerative gastro-oesophageal reflux disease (GORD), non-erosive reflux disease (NERD), duodenal and gastric ulcers, and pathological hypersecretory conditions including Zollinger-Ellison syndrome (ZES). It is also used as part of combination therapy for the eradication of Helicobacter pylori, a pathogen frequently implicated in the development of gastric and duodenal ulcers. Rabeprazole has a well established efficacy and safety profile in the treatment of gastric acid-related diseases. Rabeprazole is a useful, well tolerated and cost-effective option for the treatment of GORD, NERD, peptic ulcer and other gastric acid-related diseases (including ZES), and provides an appropriate alternative to other currently available PPIs, with the added benefits of having a consistent efficacy profile and low drug interaction potential due to its predominantly nonenzymatic metabolism.

A new titanate/(+)-(1 R,2 S)- cis-1-amino-2-indanol system for the asymmetric synthesis of ( S)-tenatoprazole

Tenatoprazole, a substituted imidazopyridinyl derivative, is an irreversible proton pump inhibitor (PPI), which is used for the prevention and treatment of gastric acid-related diseases. A new highly efficient asymmetric oxidation using cumene hydroperoxide (CHP) as the oxidant in the presence of titanium tetraisopropoxide (Ti(O iPr) 4) and (+)-(1 R,2 S)- cis-1-amino-2-indanol, in a polar aprotic solvent at 0–20 °C, has been developed to prepare tenatoprazole with an enantiomeric excess of >99%, a chemoselectivity of >90% and a chemical yield of >90% from the corresponding sulfide. This procedure was successfully implemented on scales ranging from 100 mg to multiple kilograms. Detailed studies of the parameters controlling purity and yield for this reaction are presented.

Synthesis of Metabolites and Related Substances of Rabeprazole, an Anti-Ulcerative Drug

Rabeprazole sodium (Aciphex®) is a gastric proton pump inhibitor used for the prevention and treatment of gastric acid–related diseases. During the synthesis of bulk drug of rabeprazole sodium, we have observed metabolites rabeprazole sulfide and rabeprazole sulfone and related substances rabeprazole-N-oxide, rabeprazole sulfone-N-oxide, N-aralkyl rabeprazole, chloro rabeprazole, and methoxy rabeprazole as impurities in the drug substance. The present work describes the synthesis and characterization of these compounds.

Activation and Stabilization of Drugs by Supramolecular pKa Shifts: Drug‐Delivery Applications Tailored for Cucurbiturils

Controlling the drug supply: UV and NMR spectroscopic studies show that drugs such as omeprazole and lansoprazole, popular drugs for the treatment of gastric acid related diseases, are stable for several weeks by using cucurbit[7]uril as a macrocyclic host (see scheme). The drugs are also more rapidly converted into their active forms by an acid-promoted reaction catalyzed by a supramolecular pKa shift.

Stereoselective Disposition of Proton??Pump Inhibitors

It is estimated that about half of all therapeutic agents are chiral, but most of these drugs are administered in the form of the racemic mixture, i.e. a 50/50 mixture of its enantiomers. However, chirality is one of the main features of biology, and many of the processes essential for life are stereoselective, implying that two enantiomers may work differently from each other in a physiological environment. Thus, receptors or metabolizing enzymes would recognize one of the ligand enantiomers in favour of the other. With one exception, all presently marketed proton pump inhibitors (PPIs)--omeprazole, lansoprazole, pantoprazole and rabeprazole--used for the treatment of gastric acid-related diseases are racemic mixtures. The exception is esomeprazole, the S-enantiomer of omeprazole, which is the only PPI developed as a single enantiomer drug. The development of esomeprazole (an alkaline salt thereof, e.g. magnesium or sodium) was based on unique metabolic properties that clearly differentiated esomeprazole from omeprazole, the racemate. At comparable doses, these properties led to several clinical advantages, for example higher bioavailability in the majority of patients, i.e. the extensive metabolizers (EMs; 97% in Caucasian and 80-85% in Asian populations), lower exposure in poor metabolizers (PMs; 3% in Caucasian and 15-20% in Asian populations) and lower interindividual variation. For the other, i.e. racemic, PPIs there are some data available on the characteristics of the individual enantiomers, and we have therefore undertaken to analyse the current literature with the purpose of evaluating the potential benefits of developing single enantiomer drugs from lansoprazole, pantoprazole and rabeprazole. For lansoprazole, the plasma concentrations of the S-enantiomer are lower than those of the R-enantiomer in both EMs and PMs, and, consequently, the variability in the population or between EMs and PMs is not likely to decrease with either of the lansoprazole enantiomers. Furthermore, plasma protein binding differs between the two lansoprazole enantiomers, in that the amount of the free S-enantiomer is two-fold higher than that of the R-enantiomer. This will counteract the difference seen in total plasma concentrations of the enantiomers. Also, studies using expressed human cytochrome P450 isoenzymes show that the metabolism of one enantiomer is significantly affected by the presence of the other, which is likely to result in different pharmacokinetics when administering a single enantiomer. For pantoprazole, there is a negligible difference in plasma concentrations between the two enantiomers in EMs, while the difference is substantial in PMs. The difference in AUC between PMs and EMs would decrease to some extent, but in the majority of the population the variability and efficacy would not be altered with a single enantiomer of pantoprazole. The metabolism of the enantiomers of rabeprazole displays stereoselectivity comparable to that of lansoprazole, i.e. the exposure of the R-enantiomer is higher than that of the S-enantiomer in EMs as well as in PMs, which, by analogy to lansoprazole, makes them less suitable for development of a single enantiomer drug. Furthermore, the chiral stability of the rabeprazole enantiomers may be an issue because of significant degradation of rabeprazole to its sulfide analogue, which is subject to non-stereoselective metabolic regeneration of a mixture of the two enantiomers. In conclusion, in contrast to esomeprazole, the S-enantiomer of omeprazole, minimal if any clinical advantages would be expected in developing any of the enantiomers of lansoprazole, pantoprazole, or rabeprazole as compared with their racemates.

Histamine and its receptors

This article reviews the development of our knowledge of the actions of histamine which have taken place during the course of the 20th century. Histamine has been shown to have a key physiological role in the control of gastric acid secretion and a pathophysiological role in a range of allergic disorders. The synthesis of, and pharmacological studies on, selective agonists and antagonists has established the existence of four types of histamine receptor and histamine receptor antagonists have found very important therapeutic applications. Thus, in the 1940s, H(1)-receptor antagonists ('the antihistamines') yielded and still provide valuable treatment for allergic conditions such as hay fever and rhinitis. In the late 1970s and 1980s, H(2)-receptor antagonists (in the discovery of which the two authors were personally involved) revolutionised the treatment of peptic ulcer and other gastric acid-related diseases. The H(3)-receptor antagonists, although available since 1987, have been slower to find a therapeutic role. However, the discovery of nonimidazole derivatives such as brain-penetrating H(3) antagonists has provided drugs that are in early-phase clinical trials, possibly for application in obesity, and a variety of central nervous system disorders, such as memory, learning deficits and epilepsy. Finally, the most recently (1999) discovered H(4) receptor promises the potential to provide drugs acting on the immunological system with possible applications in asthma and inflammation.

A Pharmacological Approach to Gastric Acid Inhibition

Proton pump inhibitors have changed our approach to gastric acid-related diseases. They are much more potent acid inhibitors than H2-antagonists and exhibit a sophisticated mechanism of action. The present review analyses the general pharmacology of proton pump inhibitors and differentiates the specific characteristics of the various compounds that belong to this family. Special emphasis has been placed in describing the clinical implications of such differences and the potential importance for adverse effects.

Review article: the pharmacodynamics and pharmacokinetics of proton pump inhibitors – overview and clinical implications

During the past two decades, enormous changes occurred in the management of gastric acid-related diseases. First, the histamine2-receptor antagonists were introduced, offering patients the first single-agent therapy that effectively reduced gastric acid secretion. Proton pump inhibitors became widely available in the early 1990s, and they generally appeared to be superior to the histamine2-receptor antagonists in acid-suppressing activity, symptom control and healing. Most physicians now use proton pump inhibitors as first-line treatment for many patients with acid-peptic disorders, including erosive gastro-oesophageal reflux disease (GERD), nonerosive reflux disease (NERD) and duodenal and gastric ulcers. Although proton pump inhibitors are often thought to be interchangeable, some differences have emerged in their pharmacological properties, which may be reflected in some aspects of clinical efficacy. Such differences include potency, speed of onset and duration of pH 'holding times'. Helicobacter pylori has now been recognized as an important factor in the pathogenesis of acid-peptic disorders. It is clear that H. pylori eradication can dramatically reduce the chronicity of gastric and duodenal ulcers, and accepted therapeutic regimens for H. pylori eradication now include proton pump inhibitors and two or more antibiotics. Although all accepted proton pump inhibitor-based 'triple therapies' are roughly equivalent in efficacy, there is now a shortened regimen available that will potentially enhance compliance and decrease cost. This review examines the relative advantages of proton pump inhibitors vs. histamine2-receptor antagonists in the context of acid suppression and in various gastric acid-related diseases. A brief overview presents the pharmacodynamics and pharmacokinetics of the proton pump inhibitors with particular attention paid to rabeprazole, one of the newer drugs in its class.

An Improved and Single-Pot Process for the Production of Pantoprazole Substantially Free from Sulfone Impurity

Pantoprazole (1), a substituted benzimidazole derivative, is an irreversible proton pump inhibitor, essentially used for the prevention and treatment of gastric acid-related diseases. The process for its preparation generally suffers from the drawback of producing a potential sulfone impurity (5). The present work details a report of the journey towards the development of a simple, single-pot process for the production of pantoprazole, substantially free from sulfone impurity (5). The detailed study of the different parameters affecting the purity and yield of the compound has been presented.

Single-isomer drugs: true therapeutic advances.

Chirality is one of the main features of biology, and many of the processes essential for life are stereospecific, meaning that one out of two or more isomers may work best in a particular physiological situation. Could this be used in drug development and result in any clinical relevance and true therapeutic advance? There are occasions when the development of one of the isomers might be expected to be advantageous: for example, only one of the isomers may be active, only one of the isomers may cause adverse effects, or one of the isomers may have more advantageous pharmacological properties. As an example of the last, the successful development of esomeprazole will be described. Before the introduction of esomeprazole, the proton pump inhibitor omeprazole was the standard treatment for gastric acid-related diseases, such as gastro-oesophageal reflux disease. A serious type of gastro-oesophageal reflux disease is erosive oesophagitis, an increasingly common condition that may lead to life-threatening complications. Doubling the standard dose of omeprazole from 20 to 40 mg did not improve healing rates (74% versus 75%), and thus a substantial proportion of patients remained unhealed with standard treatment. The (S)-isomer of omeprazole, esomeprazole, was shown to heal more patients than omeprazole as a result of unique metabolic properties that clearly differentiates esomeprazole from omeprazole, the racemate. At comparable doses, these properties lead to several clinical advantages: higher bioavailability in extensive metabolisers (the majority of patients), lower exposure in poor metabolisers, less interindividual variation and a steeper dose-response curve at steady state resulting in a more pronounced inhibition of gastric acid secretion. Esomeprazole has been studied clinically for a variety of acid-related conditions, showing that the compound is as well tolerated and more effective with regard to healing and symptom relief than the recommended treatment with omeprazole. Thus, from this example it is clear that the exploration and development of single-isomer drugs may bring significant advances in treatment options.