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Leukemia Dec 2023Dasatinib monohydrate indicated for the treatment of chronic myeloid leukemia displays pH-dependent solubility. The aim of reported development program of novel...
Dasatinib monohydrate indicated for the treatment of chronic myeloid leukemia displays pH-dependent solubility. The aim of reported development program of novel dasatinib anhydrate containing formulation was to demonstrate improved absorption and lower pharmacokinetic variability compared to dasatinib monohydrate. In a bioavailability study comparing formulations containing 110.6 mg and 140 mg of dasatinib as anhydrate and monohydrate, respectively, both C and AUC of dasatinib were within standard 80.00-125.00% range, while the intra- and inter-subject variability for AUC after the test product was approximately 3-fold and 1.5-fold less than after the reference, respectively.In a drug-drug interaction study, omeprazole 40 mg reduced the mean AUC of dasatinib by 19%, when the test was ingested 2 h before the 5th omeprazole dose. This decrease of exposure is clinically irrelevant and substantially less than after the reference. Co-prescription analysis supports the importance of pH-dependent solubility of dasatinib, as >21% of patients were treated concomitantly with a PPI and dasatinib despite warnings against this co-medication in the SmPC.The novel dasatinib anhydrate containing formulation demonstrated improved absorption and less pharmacokinetic variability compared to dasatinib monohydrate product, which may translate into improved clinical outcomes, although this needs to be proven by an appropriate trial.
Topics: Humans; Dasatinib; Biological Availability; Omeprazole; Cross-Over Studies; Area Under Curve; Administration, Oral
PubMed: 37789147
DOI: 10.1038/s41375-023-02045-1 -
Ultrasound in Obstetrics & Gynecology :... Nov 2023To assess whether coexisting fetal growth restriction (FGR) influences pregnancy latency among women with preterm pre-eclampsia undergoing expectant management....
OBJECTIVES
To assess whether coexisting fetal growth restriction (FGR) influences pregnancy latency among women with preterm pre-eclampsia undergoing expectant management. Secondary outcomes assessed were indication for delivery, mode of delivery and rate of serious adverse maternal and perinatal outcomes.
METHODS
We conducted a secondary analysis of the Pre-eclampsia Intervention (PIE) and the Pre-eclampsia Intervention 2 (PI2) trial data. These randomized controlled trials evaluated whether esomeprazole and metformin could prolong gestation of women diagnosed with pre-eclampsia between 26 and 32 weeks of gestation undergoing expectant management. Delivery indications were deteriorating maternal or fetal status, or reaching 34 weeks' gestation. FGR (defined by Delphi consensus) at the time of pre-eclampsia diagnosis was examined as a predictor of outcome. Only placebo data from PI2 were included, as the trial showed that metformin use was associated with prolonged gestation. All outcome data were collected prospectively from diagnosis of pre-eclampsia to 6 weeks after the expected due date.
RESULTS
Of the 202 women included, 92 (45.5%) had FGR at the time of pre-eclampsia diagnosis. Median pregnancy latency was 6.8 days in the FGR group and 15.3 days in the control group (difference 8.5 days; adjusted 0.49-fold change (95% CI, 0.33-0.74); P < 0.001). FGR pregnancies were less likely to reach 34 weeks' gestation (12.0% vs 30.9%; adjusted relative risk (aRR), 0.44 (95% CI, 0.23-0.83)) and more likely to be delivered for suspected fetal compromise (64.1% vs 36.4%; aRR, 1.84 (95% CI, 1.36-2.47)). More women with FGR underwent a prelabor emergency Cesarean section (66.3% vs 43.6%; aRR, 1.56 (95% CI, 1.20-2.03)) and were less likely to have a successful induction of labor (4.3% vs 14.5%; aRR, 0.32 (95% CI, 0.10-1.00)), compared to those without FGR. The rate of maternal complications did not differ significantly between the two groups. FGR was associated with a higher rate of infant death (14.1% vs 4.5%; aRR, 3.26 (95% CI, 1.08-9.81)) and need for intubation and mechanical ventilation (15.2% vs 5.5%; aRR, 2.97 (95% CI, 1.11-7.90)).
CONCLUSION
FGR is commonly present in women with early preterm pre-eclampsia and outcome is poorer. FGR is associated with shorter pregnancy latency, more emergency Cesarean deliveries, fewer successful inductions and increased rates of neonatal morbidity and mortality. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
Topics: Infant, Newborn; Infant; Pregnancy; Female; Humans; Pregnancy Outcome; Cesarean Section; Pre-Eclampsia; Fetal Growth Retardation; Watchful Waiting; Metformin
PubMed: 37289938
DOI: 10.1002/uog.26282 -
Cureus Aug 2023Peptic ulcer disease (PUD) refers to the occurrence of an open erosion in the inner lining of the stomach, duodenum, or sometimes lower esophagus. Treatments like proton... (Review)
Review
Comparing the Safety and Efficacy of Proton Pump Inhibitors and Histamine-2 Receptor Antagonists in the Management of Patients With Peptic Ulcer Disease: A Systematic Review.
Peptic ulcer disease (PUD) refers to the occurrence of an open erosion in the inner lining of the stomach, duodenum, or sometimes lower esophagus. Treatments like proton pump inhibitors (PPIs) or histamine 2 receptor antagonists (H2RAs) are available on the market to efficiently treat the break in the mucosal lining. However, there is little evidence about the effects of the medication on the type and location of the ulcer and the epigastric pain caused by disintegration and increased acidity in the stomach. Given the above, we conducted a systematic review comparing the safety and efficacy of PPIs and H2RAs in various ulcer locations (gastric, duodenal, and pre-pyloric) and the effect of prolonging the treatment with the same medication or changing into a drug from another class in treatment-resistant ulcers. We employed major research literature databases and search engines such as PubMed, Medical Literature Analysis and Retrieval System Online (MEDLINE), Science Direct, and Google Scholar to find relevant articles. After a thorough screening, a quality check using various tools, and applying filters that suited our eligibility criteria, we identified eight articles, of which five were random clinical trials (RCTs), two review articles, and one meta-analysis. This study compares the different side effects of PPIs and H2RAs. Most studies concluded that omeprazole is superior in healing ulcers and bringing pain relief and that patients resistant to H2RAs can be treated better when switched to a PPI. This study also discusses the adverse effects of chronic use, such as diarrhea, constipation, headaches, and gastrointestinal infections. Patients on long-term PPI therapy are required to take calcium supplements to prevent the risk of fractures in older adults. Regarding long-term outcomes, PPIs remain the mainstay of treatment for peptic ulcer disease, based on the papers we reviewed.
PubMed: 37779765
DOI: 10.7759/cureus.44341 -
Biomedicine & Pharmacotherapy =... Oct 2023Tacrolimus is a calcineurin inhibitor used to prevent rejection in allogenic solid organ transplant recipients, which is metabolized in the liver with cytochrome P450... (Review)
Review
Tacrolimus is a calcineurin inhibitor used to prevent rejection in allogenic solid organ transplant recipients, which is metabolized in the liver with cytochrome P450 isoforms 3A4 and 3A5 (CYP3A4, CYP3A5). In turn, proton pump inhibitors (PPIs), such as Omeprazole - a substrate and inhibitor of CYP2C19 and CYP3A4 enzymes - are administered to kidney transplant patients in order to prevent duodenal and gastric ulcer disease, associated with the glucocorticoid treatment. Simultaneous administration of both drugs in renal patients has the potential to trigger drug interactions. In fact, there are several mechanisms which may impact the pharmacokinetics of tacrolimus. Inhibition of the CYP2C19 isoform may suppress the metabolism of omeprazole, subsequently altering its metabolic pathway to be metabolized by the CYP3A4 enzyme in order to maintain adequate biotransformation. Therefore, the competition for CYP3A4 may affect the metabolism of tacrolimus and result in its increased plasma concentrations, as well as in adverse reactions. Another mechanism has been related to the genetic polymorphism of the CYP2C19 isoform. Since all these interactions may lead to dysfunctions of the transplanted kidney, it seems significant to eliminate their consequences, for instance via the administration of drugs which are neither substrates, nor inhibitors of the CYP3A4 enzyme. Finally, the nephrotoxic effect of omeprazole should also be accounted for. Bearing in mind the aforementioned observations, the aim of the presented paper was to review the available studies addressing the effect of omeprazole on the pharmacokinetics of tacrolimus.
Topics: Humans; Omeprazole; Tacrolimus; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP2C19; Kidney Transplantation; Kidney
PubMed: 37619481
DOI: 10.1016/j.biopha.2023.115149 -
Revista Espanola de Enfermedades... Dec 2023A 72-year-old woman was referred from primary care to the gastroenterology clinic because of heartburn and occasional dysphagia for the last 8 years, with some isolated...
A 72-year-old woman was referred from primary care to the gastroenterology clinic because of heartburn and occasional dysphagia for the last 8 years, with some isolated food regurgitation events and no other warning signs; she is currently asymptomatic on omeprazole. Gastroscopy revealed a dilated esophagus and food remnants with inability to reach the gastric lumen, which led to the suspicion of achalasia. The study was completed with pH-metry, which found no pathological reflux; esophageal manometry, with absence of esophageal motor abnormalities; and barium swallow, which revealed a large diverticulum on the posterior wall of the lower third of the esophagus, which had food remnants but no other changes or evidence of achalasia. Given these findings, a repeat gastroscopy was carried out that revealed a large diverticulum in the distal third of the esophagus that occluded 50 % of the esophageal lumen, with a length of 4-5 cm and abundant semi-liquid food remnants; upon aspiration of the latter a whitish mucosa with erythematous areas was revealed, as well as a 1.5-cm sliding hiatal hernia. No changes were found on advancing to the second duodenal portion. In view of the above findings and symptoms, the patient was referred to the surgery department to be evaluated for diverticulectomy.
Topics: Female; Humans; Aged; Esophageal Achalasia; Diverticulum, Esophageal; Gastroesophageal Reflux; Manometry; Diverticulum
PubMed: 36896915
DOI: 10.17235/reed.2023.9518/2023 -
Clinical and Translational... Nov 2023Potassium-competitive acid blockers and proton pump inhibitors/sodium bicarbonate can rapidly increase intragastric pH. In this study, we aimed to compare the clinical...
INTRODUCTION
Potassium-competitive acid blockers and proton pump inhibitors/sodium bicarbonate can rapidly increase intragastric pH. In this study, we aimed to compare the clinical outcomes of tegoprazan-based and esomeprazole/sodium bicarbonate-based triple therapies in the treatment of Helicobacter pylori infection.
METHODS
We retrospectively reviewed the data of patients with H. pylori infection treated with a 14-day tegoprazan-based triple therapy or 14-day esomeprazole/sodium bicarbonate-based triple therapy. The primary end point was the H. pylori eradication rate with first-line treatment in an intention-to-treat analysis. Secondary end points included the eradication rate with first-line therapy in the per-protocol analysis and adverse events associated with eradication therapy.
RESULTS
Of the 854 included patients, 435 were treated with tegoprazan-based therapy, and 419 received esomeprazole/sodium bicarbonate-based therapy. In the intention-to-treat population, no significant difference in eradication rate was detected between the tegoprazan-treated and esomeprazole/sodium bicarbonate-treated groups (78.6% [95% confidence interval (CI), 74.6-82.3%] vs 81.4% [95% CI, 77.4-84.9%], P = 0.313). The per-protocol analysis also revealed a similar eradication rate between groups (tegoprazan vs esomeprazole/sodium bicarbonate: 85.5% [95% CI, 81.8-87.5%] vs 87.8% [95% CI, 84.1-90.7%], P = 0.339). However, abdominal discomfort and diarrhea were more common in the esomeprazole/sodium bicarbonate-treated group than in the tegoprazan-treated group (abdominal discomfort: 1.1% vs 3.8%, P = 0.012; diarrhea: 9.9% vs 21.2%, P < 0.001).
DISCUSSION
The efficacy of the esomeprazole/sodium bicarbonate-based triple therapy for H. pylori eradication was comparable with that of the tegoprazan-based triple therapy. However, esomeprazole/sodium bicarbonate-based therapy exhibited a higher risk of abdominal discomfort and diarrhea than tegoprazan-based therapy.
Topics: Humans; Esomeprazole; Helicobacter Infections; Helicobacter pylori; Sodium Bicarbonate; Anti-Bacterial Agents; Bicarbonates; Retrospective Studies; Diarrhea
PubMed: 37561041
DOI: 10.14309/ctg.0000000000000632 -
European Journal of Medical Research Aug 2023To evaluate the efficacy and safety of vonoprazan-amoxicillin (VA) dual therapy for radically eradicating Helicobacter pylori (H. pylori). (Meta-Analysis)
Meta-Analysis Review
AIM
To evaluate the efficacy and safety of vonoprazan-amoxicillin (VA) dual therapy for radically eradicating Helicobacter pylori (H. pylori).
METHODS
The PubMed, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI) and Wanfang databases were searched up to July 7, 2022, to identify clinical trials comparing the efficacy of VA dual therapy and triple therapy for H. pylori eradication. After evaluating the quality of the included studies, random effects models were conducted, and risk ratios (RRs) with 95% confidence intervals (CIs) were calculated to estimate the efficacy and safety of each approach.
RESULTS
Six publications (including four randomized controlled trials) involving 2019 patients were included in this meta-analysis. Overall, the eradication rate for VA dual therapy was 89.9%, while it was 85.2% for triple therapy based on other acid inhibitors. The eradication rate of H. pylori in the VA dual regimen group was higher than that in the PPI-based (omeprazole or lansoprazole) triple therapy group (RR = 1.15, 95% CI 1.07-1.23, p < 0.0001). However, the efficacy of VA dual therapy was comparable with VA-Clarithromycin (VAC) triple therapy (RR = 0.97, 95% CI 0.93-1.02). Besides, the incidence of adverse reactions in VA dual therapy was also lower than that in triple therapy (RR = 0.80, 95% CI 0.70-0.91, p = 0.0009).
CONCLUSION
Compared with PPI-based triple therapy, VA dual therapy showed a better therapeutic effect, safety and patient compliance rate for eradicating H. pylori, which should be used as a novel curative strategy in the future.
Topics: Humans; Amoxicillin; Helicobacter pylori; Anti-Bacterial Agents; Helicobacter Infections; Proton Pump Inhibitors; Drug Therapy, Combination; Treatment Outcome; Randomized Controlled Trials as Topic
PubMed: 37550781
DOI: 10.1186/s40001-023-01249-6 -
Pharmaceutics Oct 2023Regulatory agencies worldwide expect that clinical pharmacokinetic drug-drug interactions (DDIs) between an investigational new drug and other drugs should be conducted...
Regulatory agencies worldwide expect that clinical pharmacokinetic drug-drug interactions (DDIs) between an investigational new drug and other drugs should be conducted during drug development as part of an adequate assessment of the drug's safety and efficacy. However, it is neither time nor cost efficient to test all possible DDI scenarios clinically. Phenytoin is classified by the Food and Drug Administration as a strong clinical index inducer of CYP3A4, and a moderate sensitive substrate of CYP2C9. A physiologically based pharmacokinetic (PBPK) platform model was developed using GastroPlus to assess DDIs with phenytoin acting as the victim (CYP2C9, CYP2C19) or perpetrator (CYP3A4). Pharmacokinetic data were obtained from 15 different studies in healthy subjects. The PBPK model of phenytoin explains the contribution of CYP2C9 and CYP2C19 to the formation of 5-(4'-hydroxyphenyl)-5-phenylhydantoin. Furthermore, it accurately recapitulated phenytoin exposure after single and multiple intravenous and oral doses/formulations ranging from 248 to 900 mg, the dose-dependent nonlinearity and the magnitude of the effect of food on phenytoin pharmacokinetics. Once developed and verified, the model was used to characterize and predict phenytoin DDIs with fluconazole, omeprazole and itraconazole, i.e., simulated/observed DDI AUC ratio ranging from 0.89 to 1.25. This study supports the utility of the PBPK approach in informing drug development.
PubMed: 37896246
DOI: 10.3390/pharmaceutics15102486 -
Journal of Thrombosis and Haemostasis :... Aug 2023Patients hospitalized with COVID-19 suffer thrombotic complications. Risk factors for poor outcomes are shared with coronary artery disease. (Randomized Controlled Trial)
Randomized Controlled Trial
A randomized controlled trial to investigate the use of acute coronary syndrome therapy in patients hospitalized with COVID-19: the COVID-19 Acute Coronary Syndrome trial.
BACKGROUND
Patients hospitalized with COVID-19 suffer thrombotic complications. Risk factors for poor outcomes are shared with coronary artery disease.
OBJECTIVES
To investigate the efficacy of an acute coronary syndrome regimen in patients hospitalized with COVID-19 and coronary disease risk factors.
METHODS
A randomized controlled, open-label trial across acute hospitals (United Kingdom and Brazil) added aspirin, clopidogrel, low-dose rivaroxaban, atorvastatin, and omeprazole to standard care for 28 days. Primary efficacy and safety outcomes were 30-day mortality and bleeding. The key secondary outcome was a daily clinical status (at home, in hospital, on intensive therapy unit admission, or death).
RESULTS
Three hundred twenty patients from 9 centers were randomized. The trial terminated early due to low recruitment. At 30 days, there was no significant difference in mortality (intervention vs control, 11.5% vs 15%; unadjusted odds ratio [OR], 0.73; 95% CI, 0.38-1.41; p = .355). Significant bleeds were infrequent and were not significantly different between the arms (intervention vs control, 1.9% vs 1.9%; p > .999). Using a Bayesian Markov longitudinal ordinal model, it was 93% probable that intervention arm participants were more likely to transition to a better clinical state each day (OR, 1.46; 95% credible interval [CrI], 0.88-2.37; Pr [beta > 0], 93%; adjusted OR, 1.50; 95% CrI, 0.91-2.45; Pr [beta > 0], 95%) and median time to discharge to home was 2 days shorter (95% CrI, -4 to 0; 2% probability that it was worse).
CONCLUSION
Acute coronary syndrome treatment regimen was associated with a reduction in the length of hospital stay without an excess in major bleeding. A larger trial is needed to evaluate mortality.
Topics: Humans; COVID-19; SARS-CoV-2; Acute Coronary Syndrome; Bayes Theorem; Aspirin; Hemorrhage; Treatment Outcome
PubMed: 37230416
DOI: 10.1016/j.jtha.2023.04.045 -
Drug Metabolism and Disposition: the... Jun 2024Arsenite is an important heavy metal. Some Chinese traditional medicines contain significant amounts of arsenite. The aim of this study was to investigate subacute...
Arsenite is an important heavy metal. Some Chinese traditional medicines contain significant amounts of arsenite. The aim of this study was to investigate subacute exposure of arsenite on activities of cytochrome P450 enzymes and pharmacokinetic behaviors of drugs in rats. Midazolam, tolbutamide, metoprolol, omeprazole, caffeine, and chlorzoxazone, the probe substrates for CYPs3A2, 2C6, 2D2, 2C11, 1A2, and 2E1, were selected as model drugs for the pharmacokinetic study. Significant decreases in AUCs of probe substrates were observed in rats after consecutive 30 day exposure at 12 mg/kg. Microsomal incubation study showed that the subacute exposure to arsenite resulted in little changes in effects on the activities of P450 enzymes examined. However, everted gut sac study demonstrated that such exposure induced significant decreases in intestinal absorption of these drugs by both passive diffusion and carrier-mediated transport. In addition, study showed that the arsenite exposure decreased the rate of peristaltic propulsion. The decreases in intestinal permeability of the probe drugs and peristaltic propulsion rate most likely resulted in the observed decreases in the internal exposure of the probe drugs. Exposure to arsenite may lead to the reduction of the efficiencies of pharmaceutical agents co-administered resulting from the observed drug-drug interactions. Exposure to arsenite may lead to the reduction of the efficiencies of pharmaceutical agents co-administered resulting from the observed drug-drug interactions. In this study, we found that P450 enzyme probe drug exposure was reduced in arsenic-exposed animals (AUCs) and the intestinal absorption of the drug was reduced in the animals. Subacute arsenic exposure tends to cause damage to intestinal function, which leads to reduced drug absorption.
PubMed: 38849209
DOI: 10.1124/dmd.124.001772