-
Frontiers in Pharmacology 2018Complete eradication of is important for preventing the development of gastric cancer. The outcome of eradication therapy is mainly dependent on bacterial... (Review)
Review
Complete eradication of is important for preventing the development of gastric cancer. The outcome of eradication therapy is mainly dependent on bacterial susceptibility to antimicrobial agents and potent neutralization of intragastric pH across 24 h, especially when using acid-sensitive antimicrobial agents such as clarithromycin (CLR), amoxicillin and sitafloxacin. However, conventional regimens comprising twice-daily doses (bid) of proton pump inhibitors (PPIs) are generally insufficient for maintaining the required gastric acid secretion for 24 h for successful eradication in all -positive patients. Further, the increasing prevalence of CLR-resistant strains with each year has led to a decrease in eradication rates of first-line PPI- and CLR-containing therapies in developed countries, including Japan. In 2015, the potassium-competitive acid blocker vonoprazan (VPZ) became clinically available in Japan. VPZ competitively inhibits H/K-ATPase activity more potently than PPIs (e.g., omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole). Therefore, a VPZ-containing eradication regimen is expected to increase the eradication rate compared with conventional regimens containing a standard dose of PPI. In fact, a recent meta-analysis that investigated the efficacy of first-line eradication therapy showed that a VPZ-containing regimen achieved a higher eradication rate than a PPI-containing regimen. While the Maastricht V/Florence Consensus Report recommends selecting a bismuth or non-bismuth quadruple therapy and concomitant therapy for patients living in areas with high prevalence of CLR resistance, a VPZ-containing regimen demonstrates effectiveness for patients infected with CLR-resistant strains and patients living in areas where the prevalence of CLR-resistant strains is >15%. As a next step, studies are needed to determine the factors affecting the clinical outcome of VPZ-containing therapy and optimal VPZ-containing alternative regimens for tailored treatments. In this review, we summarize the advantages and disadvantages of VPZ in eradication therapy.
PubMed: 30697158
DOI: 10.3389/fphar.2018.01560 -
BMC Chemistry Feb 2021Imidazole is a five-membered heterocyclic moiety that possesses three carbon, two nitrogen, four hydrogen atoms, and two double bonds. It is also known as 1, 3-diazole.... (Review)
Review
Imidazole is a five-membered heterocyclic moiety that possesses three carbon, two nitrogen, four hydrogen atoms, and two double bonds. It is also known as 1, 3-diazole. It contains two nitrogen atoms, in which one nitrogen bear a hydrogen atom, and the other is called pyrrole type nitrogen. The imidazole name was reported by Arthur Rudolf Hantzsch (1857-1935) in 1887. 1, 3-diazole is an amphoteric in nature i.e. it shows both acidic and basic properties. It is a white or colorless solid that is highly soluble in water and other polar solvents. Due to the presence of a positive charge on either of two nitrogen atom, it shows two equivalent tautomeric forms. Imidazole was first named glyoxaline because the first synthesis has been made by glyoxal and ammonia. It is the basic core of some natural products such as histidine, purine, histamine and DNA based structures, etc. Among the different heterocyclic compounds, imidazole is better known due to its broad range of chemical and biological properties. Imidazole has become an important synthon in the development of new drugs. The derivatives of 1, 3-diazole show different biological activities such as antibacterial, antimycobacterial, anti-inflammatory, antitumor, antidiabetic, anti-allergic, antipyretic, antiviral, antioxidant, anti-amoebic, antihelmintic, antifungal and ulcerogenic activities, etc. as reported in the literature. There are different examples of commercially available drugs in the market which contains 1, 3-diazole ring such as clemizole (antihistaminic agent), etonitazene (analgesic), enviroxime (antiviral), astemizole (antihistaminic agent), omeprazole, pantoprazole (antiulcer), thiabendazole (antihelmintic), nocodazole (antinematodal), metronidazole, nitroso-imidazole (bactericidal), megazol (trypanocidal), azathioprine (anti rheumatoid arthritis), dacarbazine (Hodgkin's disease), tinidazole, ornidazole (antiprotozoal and antibacterial), etc. This present review summarized some pharmacological activities and various kinds of synthetic routes for imidazole and their derived products.
PubMed: 33602331
DOI: 10.1186/s13065-020-00730-1 -
Acta Gastro-enterologica Belgica 2022A 63-year-old caucasian male with history of tonsil cancer, under induction chemotherapy, reported food intolerance and vomiting with duration of one month. Symptoms had...
A 63-year-old caucasian male with history of tonsil cancer, under induction chemotherapy, reported food intolerance and vomiting with duration of one month. Symptoms had increased over the last days and were associated with a weight loss of 10 Kg during the past three months. The patient lived all of is life in an urban environment. General physical examination revealed cachexia and dehydration. Gastrointestinal symptoms persisted despite intravenous pantoprazole, prokinetic drugs and nasogastric tube insertion. On investigation, patient presented normocytic and normochromic anemia (9.2 g/dL), lymphocytosis (11.78 x109/L) with neutrophilia (70.7%) and eosinophilia (7.7%), hypoalbuminemia (2.8 g/dL) and elevated C-reactive protein (25.5 mg/dL). Upper endoscopy revealed deformation of bulb and second part of the duodenum with mucosal edema, superficial ulceration and friability (Figure 1a). Biopsies were taken from the bulb and second portion of the duodenum. Computer tomography demonstrated gastric distention, duodenal wall thickening and lumen narrowing in the second and third portion of the duodenum (Figure 2). These findings were indicative of a functionally relevant duodenum stenosis. Histopathologic evaluation of biopsy specimens from the duodenum revealed moderate accumulation of eosinophilic granulocytes and nematode larvae within mucosal crypts (Figure 1b). What is the diagnosis?
Topics: Biopsy; Duodenal Obstruction; Duodenum; Eosinophilia; Humans; Male; Middle Aged; Tomography, X-Ray Computed
PubMed: 35305006
DOI: 10.51821/85.1.9344 -
Gels (Basel, Switzerland) Jan 2023Bilayer/multilayer tablets have been introduced to formulate incompatible components for compound preparations, but they are now more commonly used to tailor drug...
Bilayer/multilayer tablets have been introduced to formulate incompatible components for compound preparations, but they are now more commonly used to tailor drug release. This research aimed to formulate a novel gastro-retentive tablet to deliver a combination of a fixed dose of two drugs to eliminate () in the gastrointestinal tract. The bilayer tablets were prepared by means of the direct compression technique. The controlled-release bilayer tablets were prepared using various hydrophilic swellable polymers (sodium alginate, chitosan, and HPMC-K15M) alone and in combination to investigate the percent of swelling behavior and average drug release. The weight of the controlled-release floating layer was 500 mg, whereas the weight of the floating tablets of pantoprazole was 100 mg. To develop the most-effective formulation, the effects of the experimental components on the floating lag time, the total floating time, T 50%, and the amount of drug release were investigated. The drugs' and excipients' compatibilities were evaluated using ATR-FTIR and DSC. Pre-compression and post-compression testing were carried out for the prepared tablets, and they were subjected to in vitro characterization studies. The pantoprazole layer of the prepared tablet demonstrated drug release (95%) in 2 h, whereas clarithromycin demonstrated sustained drug release (83%) for up to 24 h (F7). The present study concluded that the combination of sodium alginate, chitosan, and HPMC polymers (1:1:1) resulted in a gastro-retentive and controlled-release drug delivery system of the drug combination. Thus, the formulation of the floating bilayer tablets successfully resulted in a biphasic drug release. Moreover, the formulation (F7) offered the combination of two drugs in a single-tablet formulation containing various polymers (sodium alginate, chitosan, and HPMC polymers) as the best treatment option for local infections such as gastric ulcers.
PubMed: 36661809
DOI: 10.3390/gels9010043 -
Frontiers in Neurology 2018The purpose of this review study is to reveal a potential threat of one type of such widely used and freely distributed drugs, which are proton pump inhibitors that... (Review)
Review
The purpose of this review study is to reveal a potential threat of one type of such widely used and freely distributed drugs, which are proton pump inhibitors that might be the cause of the onset of both dementia and depression. The authors performed a literature review of available studies on the research topic describing the adverse effect of proton pum inhibitors (PPIs) (omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, pantoprazole, dexrabeprazole, ilaprazole). For a long time, PPIs were considered to be completely safe drug substances for both short and long-term use. In recent years, there have been a few contradictory studis of absolute safety, especially in patients, who have long been using PPIs. At this time when depression and dementia are rising in the population, this is a very worrying fact that needs to be highlighted, and which needs to be carefully studied and evaluated, ideally trying to prevent it. The findings of most research studies described in this review indicate that there is a direct association between the onset of dementia and depression on one side and the long-term use of PPIs on the other.
PubMed: 30671013
DOI: 10.3389/fneur.2018.01142 -
Frontiers in Pharmacology 2023Pharmacogenetics-informed drug prescribing is increasingly applied in clinical practice. Typically, drug metabolizing phenotypes are determined based on genetic test...
Pharmacogenetics-informed drug prescribing is increasingly applied in clinical practice. Typically, drug metabolizing phenotypes are determined based on genetic test results, whereupon dosage or drugs are adjusted. Drug-drug-interactions (DDIs) caused by concomitant medication can however cause mismatches between predicted and observed phenotypes (phenoconversion). Here we investigated the impact of genotype on the outcome of CYP2C19-dependent DDIs in human liver microsomes. Liver samples from 40 patients were included, and genotyped for *2, *3 and *17 variants. S-mephenytoin metabolism in microsomal fractions was used as proxy for CYP2C19 activity, and concordance between genotype-predicted and observed CYP2C19 phenotype was examined. Individual microsomes were subsequently co-exposed to fluvoxamine, voriconazole, omeprazole or pantoprazole to simulate DDIs. Maximal CYP2C19 activity (V) in genotype-predicted intermediate metabolizers (IMs; *1/*2 or *2/*17), rapid metabolizers (RMs; *1/*17) and ultrarapid metabolizers (UMs; *17/*17) was not different from V of predicted normal metabolizers (NMs; *1/*1). Conversely, *2/*2 genotyped-donors exhibited V rates ∼9% of NMs, confirming the genotype-predicted poor metabolizer (PM) phenotype. Categorizing CYP2C19 activity, we found a 40% concordance between genetically-predicted CYP2C19 phenotypes and measured phenotypes, indicating substantial phenoconversion. Eight patients (20%) exhibited CYP2C19 IM/PM phenotypes that were not predicted by their CYP2C19 genotype, of which six could be linked to the presence of diabetes or liver disease. In subsequent DDI experiments, CYP2C19 activity was inhibited by omeprazole (-37% ± 8%), voriconazole (-59% ± 4%) and fluvoxamine (-85% ± 2%), but not by pantoprazole (-2 ± 4%). The strength of CYP2C19 inhibitors remained unaffected by genotype, as similar percental declines in CYP2C19 activity and comparable metabolism-dependent inhibitory constants (K/K) of omeprazole were observed between CYP2C19 genotypes. However, the consequences of CYP2C19 inhibitor-mediated phenoconversion were different between genotypes. In example, voriconazole converted 50% of *1/*1 donors to a IM/PM phenotype, but only 14% of *1/*17 donors. Fluvoxamine converted all donors to phenotypic IMs/PMs, but *1/*17 (14%) were less likely to become PMs than *1/*1 (50%) or *1/*2 and *2/*17 (57%). This study suggests that the differential outcome of CYP2C19-mediated DDIs between genotypes are primarily dictated by basal CYP2C19 activity, that may in part be predicted by genotype but likely also depends on disease-related factors.
PubMed: 37361233
DOI: 10.3389/fphar.2023.1201906 -
World Journal of Gastroenterology Nov 2014The known factors that have contributed to the decline of Helicobacter pylori (H. pylori) eradication rate include antibiotic resistance, poor compliance, high gastric... (Review)
Review
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 (HetEM), and poor metabolizer). The frequency of the CYP2C19 polymorphism is highly varied among different ethnic populations. The CYP2C19 genotype is a cardinal factor of H. pylori eradication in patients taking omeprazole- based or lansoprazole-based triple therapies. In contrast, the CYP2C19 polymorphism has no significant effect on the rabeprazole-based 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.
Topics: Anti-Bacterial Agents; Cytochrome P-450 CYP2C19; Drug Therapy, Combination; Genotype; Helicobacter Infections; Helicobacter pylori; Humans; Pharmacogenetics; Phenotype; Polymorphism, Genetic; Proton Pump Inhibitors; Treatment Outcome
PubMed: 25473155
DOI: 10.3748/wjg.v20.i43.16029 -
Journal of Clinical Medicine Mar 2024Proton pump inhibitors (PPIs) are commonly prescribed long-acting drugs used to treat acid reflux, gastroesophageal reflux disease (GERD), and peptic ulcers. Recently,... (Review)
Review
Proton pump inhibitors (PPIs) are commonly prescribed long-acting drugs used to treat acid reflux, gastroesophageal reflux disease (GERD), and peptic ulcers. Recently, concerns have been raised about their safety, particularly due to the association between long-term PPI use and cancer development. Multiple comprehensive studies have consistently suggested a noteworthy link between prolonged PPI usage and an increased risk of developing gastric, esophageal, colorectal, and pancreatic cancers, yet the precise underlying mechanism remains elusive. First, we review the extensive body of research that investigates the intricate relationship between cancer and PPIs. Then, we predict PPI toxicity using the prodrug structures with the ProTox-II webserver. Finally, we predict the relative risk of cancer for each PPI, using PubMed citation counts of each drug and keywords related to cancer. Our review indicates that prolonged PPI use (exceeding three months) is significantly associated with an elevated risk of cancer, while shorter-term usage (less than three months) appears to pose a comparatively lower risk. Our review encompasses various proposed mechanisms, such as pH and microbiome alterations, vitamin and mineral malabsorption, hypergastrinemia, and enterochromaffin-like cell proliferation, while ProTox-II also suggests aryl hydrocarbon receptor binding. Potentially, the PubMed citations count suggests that the PPIs omeprazole and lansoprazole are more associated with cancer than pantoprazole and esomeprazole. In comparison, the H2R blocker, famotidine, is potentially less associated with cancer than PPIs, and may serve as a safer alternative treatment for periods beyond 3 months. Despite the well-established cancer risk associated with PPIs, it is notable that these medications continue to be widely prescribed for periods longer than 3 months. Thus, it is of paramount importance for clinicians and patients to thoughtfully evaluate the potential risks and benefits of long-term PPI usage and explore alternative treatments before making informed decisions regarding their medical management.
PubMed: 38610738
DOI: 10.3390/jcm13071970 -
World Journal of Gastrointestinal... May 2015Clopidogrel is a widely used antiplatelet agent for the secondary prevention of cardiovascular events in patients with stable coronary heart disease, acute coronary... (Review)
Review
Clopidogrel is a widely used antiplatelet agent for the secondary prevention of cardiovascular events in patients with stable coronary heart disease, acute coronary syndromes and ischemic stroke. Even though clopidogrel is safer than aspirin in terms of risk for gastrointestinal (GI) bleeding, the elderly, and patients with a history of prior GI bleeding, with Helicobacter pylori infection or those who are also treated with aspirin, anticoagulants, corticosteroids or nonsteroidal anti-inflammatory drugs are at high risk for GI complications when treated with clopidogrel. Accordingly, proton pump inhibitors are frequently administered in combination with clopidogrel to reduce the risk for GI bleeding. Nevertheless, pharmacodynamic studies suggest that omeprazole might attenuate the antiplatelet effect of clopidogrel. However, in observational studies, this interaction does not appear to translate into increased cardiovascular risk in patients treated with this combination. Moreover, in the only randomized, double-blind study that assessed the cardiovascular implications of combining clopidogrel and omeprazole, patients treated with clopidogrel/omeprazole combination had reduced risk for GI events and similar risk for cardiovascular events than patients treated with clopidogrel and placebo. However, the premature interruption of the study and the lack of power analysis in terms of the cardiovascular endpoint do not allow definite conclusions regarding the cardiovascular safety of clopidogrel/omeprazole combination. Other proton pump inhibitors do not appear to interact with clopidogrel. Nevertheless, given the limitations of existing observational and interventional studies, the decision to administer proton pump inhibitors to patients treated with clopidogrel should be individualized based on the patient's bleeding and cardiovascular risk.
PubMed: 25949846
DOI: 10.4292/wjgpt.v6.i2.17 -
Clinical Pharmacology and Therapeutics Feb 2018Only limited data are available regarding the treatment of critically ill patients with clopidogrel. This trial investigated the effects and the drug concentrations of... (Clinical Trial)
Clinical Trial Comparative Study
Only limited data are available regarding the treatment of critically ill patients with clopidogrel. This trial investigated the effects and the drug concentrations of the cytochrome P450 (CYP450) activated prodrug clopidogrel (n = 43) and the half-life of the similarly metabolized pantoprazole (n = 16) in critically ill patients. ADP-induced aggregometry in whole blood classified 74% (95% confidence intervals 59-87%) of critically ill patients as poor responders (n = 43), and 65% (49-79%) responded poorly according to the vasodilator-stimulated phosphoprotein phosphorylation (VASP-P) assay. Although the plasma levels of clopidogrel active metabolite normally exceed the inactive prodrug ∼30-fold, the parent drug levels even exceeded those of the metabolite 2-fold in critically ill patients. The half-life of pantoprazole was several-fold longer in these patients compared with reference populations. The inverse ratio of prodrug/active metabolite indicates insufficient metabolization of clopidogrel, which is independently confirmed by the ∼5-fold increase in half-life of pantoprazole. Thus, high-risk patients may benefit from treatment with alternative platelet inhibitors.
Topics: Activation, Metabolic; Aged; Austria; Biomarkers; Blood Platelets; Cell Adhesion Molecules; Clopidogrel; Critical Illness; Cytochrome P-450 CYP2C19; Down-Regulation; Drug Monitoring; Drug Resistance; Female; Half-Life; Humans; Male; Microfilament Proteins; Middle Aged; Pantoprazole; Phosphoproteins; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Proton Pump Inhibitors
PubMed: 28913918
DOI: 10.1002/cpt.878