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Scientific Reports Jan 2024Most proton pump inhibitors (PPIs) inhibit the bioactivation of clopidogrel to its active metabolite. There is controversy concerning whether PPIs alter the...
Most proton pump inhibitors (PPIs) inhibit the bioactivation of clopidogrel to its active metabolite. There is controversy concerning whether PPIs alter the effectiveness of clopidogrel in reducing the risk of ischemic stroke (IS). We therefore aimed to examine the risk of IS associated with concomitant use of clopidogrel and omeprazole, a PPI commonly used in clinical settings. We conducted a retrospective cohort study using the National Health Insurance Research Database of Taiwan dated from 2000 to 2013. The study cohorts comprised 407 patients diagnosed with acute coronary syndrome (ACS) and with concomitant use of clopidogrel and omeprazole (the exposed cohort), 814 ACS patients with single use of clopidogrel (the comparison cohort), and 230 ACS patients with concurrent use of clopidogrel and pantoprazole (the reference cohort). The primary outcome was incident IS. The hazard ratios (HRs) and 95% confidence intervals (CIs) derived from the time-dependent Cox regression model were used to assess the association between concomitant use of clopidogrel and omeprazole and the risk of IS. The incidence rate of IS was significantly higher in the exposed cohort (81.67 per 1000 person-years) than in the comparison cohort (57.45 per 1000 person-years), resulting in an adjusted HR of 1.39 (95% CI 1.03-1.74). By contrast, there was no significant difference in the risk of IS between the exposed and reference cohorts (adjusted HR 1.11; 95% CI 0.81-1.52). The present study revealed that patients taking both clopidogrel and omeprazole was associated with an increased risk of IS.
Topics: Humans; Clopidogrel; Proton Pump Inhibitors; Cohort Studies; Omeprazole; Platelet Aggregation Inhibitors; Ticlopidine; Retrospective Studies; Ischemic Stroke; Acute Coronary Syndrome; Drug Interactions
PubMed: 38242975
DOI: 10.1038/s41598-024-51682-8 -
Frontiers in Pediatrics 2024Gastrointestinal bleeding (GI) is a prevalent condition among pediatric patients, with a reported incidence of 6.4%, often severe enough to require admission to the...
INTRODUCTION
Gastrointestinal bleeding (GI) is a prevalent condition among pediatric patients, with a reported incidence of 6.4%, often severe enough to require admission to the pediatric intensive care unit (PICU). There are multiple therapies utilized in the management of GI bleeding in pediatrics, among which continuous intravenous (IV) infusion of omeprazole is used off-label without standard pediatric dosing recommendations. Reviewing the current literature reveals a lack of studies assessing the efficacy, safety, and appropriate dosing regimen of continuous omeprazole infusion in children with GI bleeding. This study aimed to evaluate the efficacy and safety of continuous IV omeprazole infusion in comparison to other therapeutic modalities in children.
METHODS
This study is a single-center, retrospective chart review of children admitted to the PICU at King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. The treatment group included pediatric patients with GI bleeding and receiving omeprazole IV continuous infusion over ≥24 h while the control group included pediatric patients with GI bleeding managed using other therapies. Primary outcomes were the efficacy of omeprazole continuous infusion in stopping GI bleeding, and PICU length of stay (LOS). Secondary outcomes included instances of rebleeding post- therapy discontinuation, transfusion requirements, and the safety of omeprazole continuous infusion.
RESULTS
The study included 81 critically ill pediatric patients, 22 of whom received continuous infusion omeprazole while 59 received other therapies. The results indicated that patients in the control group had a significantly shorter PICU LOS (8 vs. 18.5 days, < 0.001) and bleeding episode (4 vs. 10.5 days, < 0.001) than those in the treatment group. However, no significant differences were observed between the two groups regarding secondary outcomes. The treatment group had a significantly lower all-cause mortality rate during hospitalization compared to the control group (16 patients [72.7%] vs. 56 patients [94.9%], respectively, = 0.005).
CONCLUSION
Empirical use of omeprazole continuous intravenous infusion in children with GI bleeding was not favorable in terms of shortening PICU LOS and duration of GI bleeding. Our study results provide evidence supporting the safety and tolerability of omeprazole continuous infusion. Additional larger studies are necessary to determine the implication of such results.
PubMed: 38650990
DOI: 10.3389/fped.2024.1270911 -
Biological & Pharmaceutical Bulletin 2024Unknown interactions between drugs remain the limiting factor for clinical application of drugs, and the induction and inhibition of drug-metabolizing CYP enzymes are...
Unknown interactions between drugs remain the limiting factor for clinical application of drugs, and the induction and inhibition of drug-metabolizing CYP enzymes are considered the key to examining the drug-drug interaction (DDI). In this study, using human HepaRG cells as an in vitro model system, we analyzed the potential DDI based on the expression levels of CYP3A4 and CYP1A2. Rifampicin and omeprazole, the potent inducers for CYP3A4 and CYP1A2, respectively, induce expression of the corresponding CYP enzymes at both the mRNA and protein levels. We noticed that, in addition to inducing CYP1A2, omeprazole induced CYP3A4 mRNA expression in HepaRG cells. However, unexpectedly, CYP3A4 protein expression levels were not increased after omeprazole treatment. Concurrent administration of rifampicin and omeprazole showed an inhibitory effect of omeprazole on the CYP3A4 protein expression induced by rifampicin, while its mRNA induction remained intact. Cycloheximide chase assay revealed increased CYP3A4 protein degradation in the cells exposed to omeprazole. The data presented here suggest the potential importance of broadening the current DDI examination beyond conventional transcriptional induction and enzyme-activity inhibition tests to include post-translational regulation analysis of CYP enzyme expression.
Topics: Omeprazole; Humans; Cytochrome P-450 CYP3A; Rifampin; RNA, Messenger; Drug Interactions; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP1A2; Cell Line
PubMed: 38925922
DOI: 10.1248/bpb.b24-00161 -
Cureus Oct 2023Gastric ulcer (GU) is among the peak prevalent syndromes. This study investigates the defensive properties of (Forssk.) Sch.Bip. extract (AFE) against ethanol-induced...
Gastric ulcer (GU) is among the peak prevalent syndromes. This study investigates the defensive properties of (Forssk.) Sch.Bip. extract (AFE) against ethanol-induced stomach lesions. Twenty-eight rats were allocated into negative control, positive control, AFE + ethanol, and omeprazole ethanol. In serum and gastric homogenates, oxidative stress displays (e.g., malondialdehyde (MDA), decreased glutathione (GSH), superoxide dismutase enzyme (SOD), and catalase enzyme (CAT)) and inflammatory parameters (e.g., tumor necrosis factor-alpha (TNF-α)) were estimated. GU markers (gastric lesions, ulcer index (UI), pH) were evaluated, and gastric histopathological examinations were performed. The positive control cluster exhibited severe gastric mucosal injuries, reduced stomach mucus secretion, and pH of gastric content. Furthermore, AFE-pretreated rats displayed meaningfully increased periodic acid-Schiff (PAS) countenance in their stomach epithelial layers. Pretreatment with AFE reduced stomach lesions, UI, MDA, and TNF-α levels, while mucus, pH, CAT, GSH, and SOD levels increased. Stomach examination showed significant improvement in gastric mucosa reduced edema and leukocyte infiltration of the submucosal level in pretreatment with the AFE and omeprazole groups versus the ethanol group. Additionally, AFE extracts increase the intensity of the stomach epithelium's PAS. The acute toxicity experiment with an advanced dosage of 5 g/kg AFE did not exhibit any signs of toxicity in the rats. In conclusion, the AFE reduced the effect of ethanol on the gastric mucosa, which may be due to its antioxidants and anti-inflammatory properties.
PubMed: 38021520
DOI: 10.7759/cureus.47696 -
Acta Cirurgica Brasileira 2024Reflux esophagitis is a condition characterized by inflammation and irritation of the esophagus, resulting from the backflow of stomach acid and other gastric contents...
PURPOSE
Reflux esophagitis is a condition characterized by inflammation and irritation of the esophagus, resulting from the backflow of stomach acid and other gastric contents into the esophagus. Columbianadin is a coumarin derivative that exhibits anti-inflammatory and antioxidant effects. In this study, we tried to scrutinize the protective effect of Columbianadin against acute reflux esophagitis in rats.
METHODS
RAW 264.7 cells were utilized to assess cell viability and measure the production of inflammatory parameters. The rats received anesthesia, and reflux esophagitis was induced via ligation of pylorus and fore stomach and corpus junction. Rats received the oral administration of Columbianadin (25, 50 and 100 mg/kg) and omeprazole (20 mg/kg). The gastric secretion volume, acidity, and pH were measured. Additionally, the levels of oxidative stress parameters, cytokines, and inflammatory markers were determined. At the end of the study, mRNA expression was assessed.
RESULTS
Columbianadin remarkably suppressed the cell viability and production of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and prostaglandin (PGE2). Columbianadin treatment remarkably suppressed the secretion of gastric volume, total acidity and enhanced the pH level in the stomach. Columbianadin remarkably altered the level of hydrogen peroxidase, free iron, calcium, and plasma scavenging activity, sulfhydryl group; oxidative stress parameters like malonaldehyde, glutathione, superoxide dismutase, catalase, glutathione peroxidase; inflammatory cytokines viz., TNF-α, IL-6, IL-1β, IL-10, IL-17, and monocyte chemoattractant protein-1; inflammatory parameters including PGE2, iNOS, COX-2, and nuclear kappa B factor (NF-κB). Columbianadin remarkably (P < 0.001) suppressed the mRNA expression TNF-α, IL-6, IL-1β and plasminogen activator inhibitor-1.
CONCLUSIONS
Columbianadin demonstrated a protective effect against acute reflux esophagitis via NF-κB pathway.
Topics: Animals; Esophagitis, Peptic; NF-kappa B; Male; Rats; Oxidative Stress; Cytokines; Disease Models, Animal; Cell Survival; Acute Disease; RAW 264.7 Cells; Mice; Rats, Wistar; Signal Transduction; Antioxidants; Anti-Inflammatory Agents
PubMed: 38716957
DOI: 10.1590/acb391824 -
Pharmaceutics Nov 2023(1) Background: In critically ill cardiac patients, parenteral and enteral food and drug administration routes may be used. However, it is not well known how drug...
(1) Background: In critically ill cardiac patients, parenteral and enteral food and drug administration routes may be used. However, it is not well known how drug absorption and metabolism are altered in this group of adult patients. Here, we analyze drug absorption and metabolism in patients after cardiogenic shock using the pharmacokinetics of therapeutically indicated esomeprazole. (2) Methods: The pharmacokinetics of esomeprazole were analyzed in a consecutive series of patients with cardiogenic shock and controls before and after elective cardiac surgery. Esomeprazole was administered orally or with a nasogastric tube and once as an intravenous infusion. (3) Results: The maximum plasma concentration and AUC of esomeprazole were, on average, only half in critically ill patients compared with controls ( < 0.005) and remained lower even seven days later. Interestingly, esomeprazole absorption was also markedly compromised on day 1 after elective surgery. The metabolites of esomeprazole showed a high variability between patients. The esomeprazole sulfone/esomeprazole ratio reflecting CYP3A4 activity was significantly lower in critically ill patients even up to day 7, and this ratio was negatively correlated with CRP values ( = 0.002). The 5'-OH-esomeprazole and 5-O-desmethyl-esomeprazol ratios reflecting CYP2C19 activity did not differ significantly between critically ill and control patients. (4) Conclusions: Gastrointestinal drug absorption can be significantly reduced in critically ill cardiac patients compared with elective patients with stable cardiovascular disease. The decrease in bioavailability indicates that, under these conditions, any vital medication should be administered intravenously to maintain high levels of medications. After shock, hepatic metabolism via the CYP3A4 enzyme may be reduced.
PubMed: 38004576
DOI: 10.3390/pharmaceutics15112598 -
American Journal of Veterinary Research May 2024Develop a cytochrome P450 (CYP) phenotyping cocktail for dogs using specific substrates for hepatic P450 enzymes CYP2B11, CYP2D15, and CYP3A12 and determine whether...
OBJECTIVE
Develop a cytochrome P450 (CYP) phenotyping cocktail for dogs using specific substrates for hepatic P450 enzymes CYP2B11, CYP2D15, and CYP3A12 and determine whether alternative sampling methods (saliva and urine) or single time point samples could be used instead of multiple blood sampling.
ANIMALS
12 healthy client-owned dogs (8 females and 4 males) from February 2019 to May 2019.
METHODS
In a randomized crossover study, dogs received oral administration of the probe drug bupropion (75 mg), dextromethorphan (30 mg), or omeprazole (40 mg) alone or as a 3-drug combination (Program in Individualized Medicine [PrIMe] cocktail) to evaluate simultaneous phenotyping of CYP2B11, CYP2D15, and CYP3A12. Pharmacokinetic profiles for the probe drugs and metabolites were determined using plasma, saliva, and urine. Dogs received probe drugs alone or combined. Pharmacokinetic profiles up to 6 hours postdose for the probe drugs and metabolites were determined using plasma, saliva, and urine.
RESULTS
The PrIMe cocktail was well tolerated. There was no statistically significant interaction between the probe drugs when administered together. Single time point plasma metabolic ratios at 4 hours postdose for all probe drugs strongly correlated with the corresponding area under the plasma concentration-versus-time curve (AUC) ratios. Saliva AUC metabolic ratios for CYP3A12 and CYP2D15 and 6-hour urine for CYP2B11 and CYP2D15 were correlated with plasma AUC ratios.
CONCLUSIONS
The PrIMe cocktail can be used for simultaneous CYP phenotyping using plasma 4-hour single time point sample metabolic ratios. Saliva and urine sampling are suitable for specific CYPs.
CLINICAL RELEVANCE
The PrIMe cocktail has potential as a useful tool in dogs to detect clinically important CYP-mediated drug-drug interactions, identify novel pharmacogenes, determine the drug-metabolizing phenotype of individual dogs, aid in individualized dose selection, and evaluate the effects of various physiological states on drug metabolism.
PubMed: 38718826
DOI: 10.2460/ajvr.24.02.0049 -
Pharmaceutics Nov 2023Liquid formulations are mostly used in the paediatric population. However, with certain active pharmaceutical ingredients (APIs), it is very difficult to guarantee...
Liquid formulations are mostly used in the paediatric population. However, with certain active pharmaceutical ingredients (APIs), it is very difficult to guarantee quality and stability; this is the case, for example, with omeprazole. Omeprazole is used as a model drug due to the lack of a paediatric formulation meeting gastro-resistance requirements, which remains a challenge today. In this experimental study, the development of enteric polymer-coated pellets is proposed. It is proposed to use aqueous coating dispersions without the use of organic solvents, which are commonly used in fluidised bed coatings. To do this, the design of experiments method is used as a statistical tool for experiment creation and the subsequent analysis of the responses. In particular, this study uses a randomised full factorial design. The mean weight increases of the protective layer and the enteric coating are chosen as factors. Each factor is assigned two levels. Therefore, the design of the used experiments is a 2 + 1 central point. Overall, the obtained pellets can be an alternative to the compounding formulas of omeprazole that are currently used in the paediatric population, which do not meet the gastro-resistance specifications necessary to guarantee the therapeutic efficacy of this active ingredient.
PubMed: 38004567
DOI: 10.3390/pharmaceutics15112587 -
Pharmaceuticals (Basel, Switzerland) May 2024(1) Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are extremely severe cutaneous adverse drug reactions which are relatively rare in...
(1) Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are extremely severe cutaneous adverse drug reactions which are relatively rare in routine clinical practice. An analysis of a national pharmacovigilance database may be the most effective method of obtaining information on SJS and TEN. (2) Methods: Design-a retrospective descriptive pharmacoepidemiologic study of spontaneous reports (SRs) with data on SJS and TEN retrieved from the Russian National Pharmacovigilance database for the period from 1 April 2019 to 31 December 2023. Descriptive statistics was used to assess the demographic data of patients and the structure of suspected drugs. (3) Results: A total of 170 SRs on SJS and TEN were identified, of which 32.9% were SJS and 67.1%-TEN. In total, 30% were pediatric SRs, 21.2%-SRs of the elderly. There were 12 lethal cases, and all cases were TEN. The leading culprit drugs were anti-infectives for systemic use and nervous system agents. The top 10 involved drugs are as follows: lamotrigine (23.5%), ibuprofen (12.9%), ceftriaxone (8.8%), amoxicillin and amoxicillin with beta-lactam inhibitors (8.8%), paracetamol (7.6%), carbamazepine (5.9%), azithromycin (4.1%), valproic acid (4.1%), omeprazole (3.5%), and levetiracetam (3.5%). (4) Conclusions: Our study was the first study in Russia aimed at the assessment of the structure of the drugs involved in SJS and TEN on the national level.
PubMed: 38931343
DOI: 10.3390/ph17060675 -
Biomedicines Mar 2024Defined as systemic hypotension caused by intense vasodilation due to the loss of systemic vascular resistance, vasoplegic syndrome (VS) is associated with elevated...
Cardiotoxic Effects Produced by Omeprazole and Methylene Blue in an Animal Model of Cardiac Ischemia and Reperfusion and Potential Implications for the Pharmacological Strategy for Vasoplegic Syndrome.
Defined as systemic hypotension caused by intense vasodilation due to the loss of systemic vascular resistance, vasoplegic syndrome (VS) is associated with elevated morbidity and mortality in humans. Although vasopressors such as norepinephrine and vasopressin are the first-choice drugs for VS treatment, several other drugs such as methylene blue (MB) can be used as adjuvant therapy including rescue therapy. To develop new pharmacological strategies to reduce the risk of VS, we investigated the effects of treatments with MB (2 mg/kg/IV), omeprazole (OME, 10 mg/kg/IV), and their combination in an animal model of cardiac ischemia-reperfusion (CIR). The ventricular arrhythmia (VA), atrioventricular block (AVB), and lethality (LET) incidence rates caused by CIR (evaluated via ECG) and serum levels of the cardiac lesion biomarkers creatine kinase-MB (CK-MB) and troponin I (TnI) in adult rats pretreated with saline solution 0.9% and submitted to CIR (SS + CIR group) were compared to those pretreated with MB (MB + CIR group), OME (OME + CIR group), or the MB + OME combination (MB + OME + CIR group). The AVB and LET incidence rates in the MB + CIR (100%), OME + CIR (100%), and MB + OME + CIR (100%) groups were significantly higher compared to the SS + CIR group (60%). The serum level of CK-MB in these groups were also significantly higher compared to the SS + CIR group, demonstrating that the treatments before CIR with MB, OME, and MB + OME produced similar effects in relation to cardiac function and the occurrence of lesions. These results demonstrate that the treatment of animals subjected to the CIR protocol with OME produced the same effects promoted by the treatment with MB, which may suggest the possibility of using OME alone or in combination with MB in medical clinics in treatment of VS.
PubMed: 38540195
DOI: 10.3390/biomedicines12030582