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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 -
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 -
African Journal of Paediatric Surgery :... 2022Previous studies demonstrated faster correction of metabolic derangement associated with hypertrophic pyloric stenosis with pre-operative intravenous (IV) histamine-2...
CONTEXT
Previous studies demonstrated faster correction of metabolic derangement associated with hypertrophic pyloric stenosis with pre-operative intravenous (IV) histamine-2 receptor antagonists.
AIMS
We investigated if similar outcomes are achieved with IV pantoprazole, a proton-pump inhibitor (PPI), including the subgroup of delayed presenters in the South African setting.
SETTINGS AND DESIGN
A 5-year retrospective record review (January 2014-December 2018) compared the rate of metabolic correction in patients with hypertrophic pyloric stenosis at two tertiary centres.
SUBJECTS AND METHODS
One centre routinely administers IV pantoprazole (1 mg/kg daily) preoperatively (PPI group) and the other does not (non-PPI group). Fluid administration, chloride supplementation and post-operative emesis were evaluated.
STATISTICAL ANALYSIS
Spearman's rank correlation coefficient was used to calculate statistical significance for discrete dependent variables. Continuous variables were compared between the groups using the Student t-test. Fisher's exact contingency tables were used to classify categorical data and to assess the significance of outcome between two treatment options. P < 0.05 was considered statistically significant.
RESULTS
Forty-two patients received IV pantoprazole and 24 did not. The mean time of metabolic correction was 8 h shorter in the PPI group (P = 0.067). Total pre-operative chloride administration correlated to the rate of metabolic correction in both cohorts (P < 0.0001). Profound hypochloraemia (chloride <85 mmol/l) was corrected 23 h faster in the PPI group (P < 0.004). Post-operative emesis was noted: 0.45 episodes/patient in the PPI group and 0.75 episodes/patient in the non-PPI group (P = 0.01).
CONCLUSIONS
Pre-operative IV pantoprazole administration showed a faster correction of metabolic derangements, and in profound hypochloraemia, the correction occurred substantially faster in the PPI group. Post-operative emesis was significantly less frequent in the PPI group.
Topics: Humans; Pantoprazole; Pyloric Stenosis, Hypertrophic; Retrospective Studies
PubMed: 34916353
DOI: 10.4103/ajps.AJPS_9_21 -
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 -
Frontiers in Medicine 2022Proton pump inhibitors (PPIs) are acid suppressants that are frequently prescribed in many countries to reduce heartburn. A potassium-competitive acid blocker (P-CAB;...
BACKGROUND
Proton pump inhibitors (PPIs) are acid suppressants that are frequently prescribed in many countries to reduce heartburn. A potassium-competitive acid blocker (P-CAB; tegoprazan) was launched relatively recently that also inhibits gastric acid secretion. This study aimed to compare the hepatotoxicity of the six existing PPIs with P-CAB.
METHODS
This retrospective cohort study was conducted between January 2019 and December 2020 and included data from the total population of 50 million inhabitants in Korea. Propensity score (PS) matching was performed using 10 variables, and the differences in hepatotoxicity between P-CAB and the six PPIs were compared in a similar distribution. The primary endpoint was hepatotoxicity which included toxic liver disease, hepatitis, hepatic failure, liver transplantation, and other liver diseases.
RESULTS
The risk ratios (RR) of tegoprazan vs. the six PPIs (dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole) were all significant [RR: 0.70 (95% CI: 0.69-0.72), 0.81 (95% CI: 0.79-0.83), 0.61 (95% CI: 0.59-0.63), 1.17 (95% CI: 1.13-1.20), 0.61 (95% CI: 0.59-0.62), and 0.73 (95% CI: 0.71-0.75), respectively]. The risk ratio of tegoprazan vs. the six existing PPIs was 0.73 (95% CI: 0.72-0.75). The hazard ratios (HRs) of hepatotoxicity of the six PPIs to tegoprazan showed significantly higher values apart from omeprazole (HR: dexlansoprazole, 1.13; esomeprazole, 1.04; lansoprazole, 1.25; omeprazole, 0.77; pantoprazole, 1.26; rabeprazole, 1.15, respectively, and the six existing PPIs, 1.10).
CONCLUSION
Using a large-scale data cohort analysis consisting of 50 million Koreans, tegoprazan did not induce higher hepatotoxicity compared with the six conventional PPIs.
PubMed: 36714137
DOI: 10.3389/fmed.2022.1076356 -
Expert Review of Gastroenterology &... May 2023Proton pump inhibitors (PPI) may impact the absorption of vitamin B12. We performed a systematic review to ascertain if PPI use increases risk of vitamin B12 deficiency. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Proton pump inhibitors (PPI) may impact the absorption of vitamin B12. We performed a systematic review to ascertain if PPI use increases risk of vitamin B12 deficiency.
METHODS
Electronic databases (PubMed, Embase, Scopus) were searched on first of September 2022. We selected studies that compared the frequency of vitamin B12 deficiency in PPI users and non-users. Pooled Odds Ratio (OR) was calculated for the occurrence of vitamin B12 deficiency in PPI users compared to non-users. The risk of bias was assessed using the Newcastle Ottawa scale.
RESULTS
Twenty-five studies were included. The pooled OR of vitamin B12 deficiency among PPI users (2852 participants) was higher than non-users (28070 participants) (OR 1.42, 95% CI: 1.16-1.73; I = 54%). Overall risk of PPI use among vitamin B12 deficient individuals was higher than those without deficiency (OR 1.49, 1.20-1.85; I = 68%). Most studies found no difference between serum vitamin B12 levels among PPI users compared to non-users.
CONCLUSION
Although the pooled OR of vitamin B12 deficiency was slightly increased in PPI users, but there was significant heterogeneity, and the pooled OR was too low to imply an association clearly. Better-designed prospective studies in long-term users may clarify the issue.
REGISTRATION
This study was not registered on PROSPERO.
Topics: Humans; Proton Pump Inhibitors; Prospective Studies; Vitamin B 12 Deficiency; Vitamin B 12
PubMed: 37060552
DOI: 10.1080/17474124.2023.2204229 -
Journal of Voice : Official Journal of... Nov 2023Atraumatic laryngeal fractures are extremely rare and are most commonly provoked by sneezing or coughing. Only seven cases have been described in medical literature, and...
INTRODUCTION AND AIM
Atraumatic laryngeal fractures are extremely rare and are most commonly provoked by sneezing or coughing. Only seven cases have been described in medical literature, and only one case described a fracture after swallowing. We present two cases of atraumatic laryngeal fracture after swallowing.
CASE REPORT
A 37-year-old male presented to the outpatient ENT clinic with severe dysphonia and odynophagia. He reported feeling a crack in the throat after swallowing with a flexed head. The patient's physical examination showed diffuse swelling and tenderness over the thyroid cartilage without subcutaneous emphysema. Flexible nasolaryngoscopy showed a large right true vocal fold hematoma with normal vocal fold movement. Computed tomography (CT) showed a fracture of the thyroid. Treatment consisted of corticosteroids and pantoprazole. Two years later he presented again at the emergency department with extreme odynophagia after suffering a knee punch on the larynx. CT showed a new fracture line, slightly off midline to the left in the thyroid cartilage. A 42-year-old male presented at the emergency department with odynophagia, dysphonia, and fever after feeling a crack in the throat during forceful swallowing in an extended neck position. Physical examination demonstrated a painful thyroid cartilage with subcutaneous emphysema. Flexible nasolaryngoscopy was normal but CT scan showed a slightly displaced fracture line of the median thyroid cartilage. Complaints gradually disappeared with conservative treatment with corticosteroids and antibiotics.
CONCLUSION
Congenital anomalies by abnormal mineralization and ossification could lead to focal weakness of the thyroid cartilage and thus predispose to non-traumatic fractures. The double triad of odynophagia, dysphagia, and dysphonia after sneezing, coughing or swallowing should raise the physician's attention to the possibility of thyroid cartilage fracture, especially after feeling or hearing a crack. Further investigation is obligatory with high-resolution CT of the neck and examination by an ENT specialist.
Topics: Male; Humans; Adult; Sneezing; Dysphonia; Laryngeal Diseases; Thyroid Cartilage; Adrenal Cortex Hormones; Subcutaneous Emphysema
PubMed: 34294489
DOI: 10.1016/j.jvoice.2021.05.022 -
Cureus Jan 2024Globally, over 25% of the population suffers from acid-related disorders such as dyspepsia or gastroesophageal reflux disease (GERD), and around 7.6% of Indians report... (Review)
Review
Globally, over 25% of the population suffers from acid-related disorders such as dyspepsia or gastroesophageal reflux disease (GERD), and around 7.6% of Indians report having GERD symptoms on a frequent enough basis to warrant a diagnosis. Over the past three decades, proton-pump inhibitors (PPIs) have been the mainstay of medical therapy for acid-peptic diseases like GERD, etc. Additionally, they are frequently prescribed for prophylactic purposes and in conjunction with non-steroidal anti-inflammatory drugs. PPIs are generally prescribed for four to eight weeks. However, it may be prescribed for patients with comorbidities and multiple medications for a longer period of time. While this remains true in terms of effectiveness, concerns have been raised about the safety of long-term PPI use and the serious adverse effects that may result. Some of the observational and population-based cohort studies have shown an association between long-term use of PPIs and an increased risk of pneumonia, major cardiovascular events, dementia, vitamin B12 deficiency, bone fractures, gastric cancer, and kidney injury, among others. This review analyzes the clinical data supporting the long-term use of PPIs and takes a deep dive into whether these several emerging long-term concerns apply to the currently available PPIs in India. We have summarized a vast array of studies, including randomized trials, cohort studies, and meta-analyses, that report low or high incidences of major health risks linked with PPIs and have assessed their appropriateness over a given period.
PubMed: 38389608
DOI: 10.7759/cureus.52773 -
Biochemical Pharmacology Dec 2020Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed medications for alleviating pain and inflammation but may cause gastrointestinal tract...
Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed medications for alleviating pain and inflammation but may cause gastrointestinal tract damage. Proton pump inhibitors (PPI) prevent NSAID-induced gastric damage but may aggravate intestinal damage via dysbiosis and intestinal permeability alteration. Currently, there is growing interest regarding the influence of potassium competitive acid blockers (PCAB) on NSAID-induced enteropathy. Here, we investigated the relative changes in indomethacin-induced enteropathy by combining indomethacin with pantoprazole (as PPI) or revaprazan (as PCAB). We examined intestinal permeability-related molecular changes in in vitro Caco-2 cell models and in an in vivo indomethacin-induced enteropathy rat model. Indomethacin alone or in combination with pantoprazole significantly increased relative lucifer yellow dye flux and decreased relative trans-epithelial electrical resistance and tight junction protein (TJP) expression compare to normal cells. In contrast, indomethacin combined with revaprazan significantly preserved TJPs compare to indomethacin-treated cells. MLC phosphorylation, Rho activation, and ERK activation responsible for TJP were significantly increased by indomethacin alone or a combination of indomethacin and pantoprazole but not by a combination of indomethacin and revaprazan. Intestinal damage scores significantly increased with indomethacin and pantoprazole combination but not with indomethacin and revaprazan combination. Indomethacin and pantoprazole combination significantly activated Rho-GTPase, p-MLC, and p-ERK but significantly decreased TJP expression. However, indomethacin and revaprazan combination significantly preserved TJPs and inactivated Rho-GTPase, MLC, and ERK. Hence, revaprazan rather than PPIs should be co-administered with NSAIDs to mitigate NSAID-induced intestinal damage.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Caco-2 Cells; Humans; Indomethacin; Intestinal Mucosa; Intestine, Small; Male; Proton Pump Inhibitors; Pyrimidinones; Rats; Rats, Sprague-Dawley; Tetrahydroisoquinolines; Tight Junctions
PubMed: 33075311
DOI: 10.1016/j.bcp.2020.114290 -
JGH Open : An Open Access Journal of... Feb 2024Combining proton pump inhibitors (PPIs) with prokinetics can provide synergistic action in patients with gastroesophageal reflux disease (GERD) and overlapping...
Efficacy and safety of pantoprazole and itopride in patients with overlap of gastroesophageal reflux disease and dyspepsia: A prospective, open-label, single-arm pilot study.
BACKGROUND AND AIM
Combining proton pump inhibitors (PPIs) with prokinetics can provide synergistic action in patients with gastroesophageal reflux disease (GERD) and overlapping dyspepsia, but data regarding this is lacking.
METHODS
This single-center, prospective study evaluated the efficacy and safety of 6-week treatment with fixed-drug combination (FDC) of pantoprazole (PPI) and itopride (prokinetic) in 50 patients with ≥3 month history of GERD and overlapping dyspepsia refractory to pantoprazole. Efficacy was assessed as reduction in GERD symptom assessment scale (GSAS) distress score for 15 symptoms from baseline to week 6. Adverse events (AEs) were monitored up to week 6.
RESULTS
Although heartburn was the most common symptom at week 6 (26.8%), its frequency significantly decreased from baseline (84.0%; <0.01). A similar trend was observed for other symptoms: pressure/discomfort inside chest (19.5%), belching (14.6%), regurgitation (12.2%), bloating (9.8%), flatulence (9.8%), early satiety (7.3%), acidic/sour taste in mouth (7.3%), nausea (7.3%), frequent gurgling in stomach/belly (4.9%), and pressure/lump in throat (2.4%). Mean distress scores of all symptoms markedly decreased at week 6. Three AEs ( = 2) of moderate intensity were reported.
CONCLUSION
The FDC of pantoprazole and itopride showed favorable efficacy and safety in patients with GERD and overlapping dyspepsia refractory to pantoprazole monotherapy. Nevertheless, further studies are warranted.
PubMed: 38344252
DOI: 10.1002/jgh3.12988