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European Journal of Drug Metabolism and... Jan 2024Although polypharmacy is a particular challenge in daily rheumatological practice, clinical research on the effects of hydroxychloroquine (HCQ), a commonly used drug for... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVE
Although polypharmacy is a particular challenge in daily rheumatological practice, clinical research on the effects of hydroxychloroquine (HCQ), a commonly used drug for patients with rheumatic diseases, is sparse on cytochrome P450 (CYP)-mediated metabolism. We have shown that pre-treatment with pantoprazole does not alter HCQ absorption in healthy volunteers. In this paper, we report the effects of a single 400 mg dose of HCQ on specific CYP3A and CYP2D6 substrates in healthy volunteers.
METHODS
In the trial, participants were randomized into two groups (HCQ plus a 9-day course of pantoprazole, or HCQ only). As a secondary endpoint, the effects of a single oral dose of HCQ on the exposure of the oral microdosed CYP3A probe drug midazolam (30 μg) and the oral microdosed CYP2D6 probe drug yohimbine (50 μg) were studied in 23 healthy volunteers (EudraCT no. 2020-001470-30, registered 31 March 2020).
RESULTS
The exposure of the probe drugs after intake of HCQ compared with baseline values was quantified by the partial area under the plasma concentration-time curve 0-6 h after administration (AUC) for yohimbine and the partial AUC for midazolam. Under HCQ, yohimbine AUC was unchanged, independent of CYP2D6 genotypes and pantoprazole exposure. Midazolam AUC was 25% higher on the day of HCQ administration than at baseline (p = 0.0007). This significant increase was driven by the pantoprazole subgroup, which showed a 46% elevation of midazolam AUC as compared with baseline (p < 0.0001). The ratio of midazolam to 1-OH-midazolam partial AUC significantly increased from 3.03 ± 1.59 (baseline) to 3.60 ± 1.56 (HCQ) in the pantoprazole group (p = 0.0026).
CONCLUSION
In conclusion, we observed an increased midazolam exposure most likely related to pantoprazole.
Topics: Humans; Area Under Curve; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Interactions; Healthy Volunteers; Hydroxychloroquine; Midazolam; Pantoprazole; Pharmaceutical Preparations; Yohimbine
PubMed: 38114885
DOI: 10.1007/s13318-023-00872-2 -
Journal of Investigative Medicine High... 2023Acute esophageal necrosis (AEN) or black esophagus is a rare cause of mortality in patients with gastrointestinal bleeding. We present a case of a 54-year-old female who...
Acute esophageal necrosis (AEN) or black esophagus is a rare cause of mortality in patients with gastrointestinal bleeding. We present a case of a 54-year-old female who presented with diabetic ketoacidosis (DKA) and developed melena eventually attributed to AEN. The esophagogastroduodenoscopy (EGD) identified severe inflammation with black discoloration consistent with acute esophageal necrosis in the middle and lower esophagus. The patient was managed with intravenous pantoprazole and total parenteral nutrition (TPN) until she was able to tolerate an adequate diet. Black esophagus should be added to the differential diagnosis of patients with DKA who develop gastrointestinal bleeding. This need is stressed by the fact that early treatment is essential to reducing complications and mortality associated with the condition.
Topics: Female; Humans; Middle Aged; Diabetic Ketoacidosis; Acute Disease; Necrosis; Esophageal Diseases; Gastrointestinal Hemorrhage; Diabetes Mellitus
PubMed: 38097376
DOI: 10.1177/23247096231217852 -
Nature Communications Dec 2023Target trial emulation is the process of mimicking target randomized trials using real-world data, where effective confounding control for unbiased treatment effect...
Target trial emulation is the process of mimicking target randomized trials using real-world data, where effective confounding control for unbiased treatment effect estimation remains a main challenge. Although various approaches have been proposed for this challenge, a systematic evaluation is still lacking. Here we emulated trials for thousands of medications from two large-scale real-world data warehouses, covering over 10 years of clinical records for over 170 million patients, aiming to identify new indications of approved drugs for Alzheimer's disease. We assessed different propensity score models under the inverse probability of treatment weighting framework and suggested a model selection strategy for improved baseline covariate balancing. We also found that the deep learning-based propensity score model did not necessarily outperform logistic regression-based methods in covariate balancing. Finally, we highlighted five top-ranked drugs (pantoprazole, gabapentin, atorvastatin, fluticasone, and omeprazole) originally intended for other indications with potential benefits for Alzheimer's patients.
Topics: Humans; Alzheimer Disease; Drug Repositioning; Propensity Score; Atorvastatin
PubMed: 38081829
DOI: 10.1038/s41467-023-43929-1 -
Trials Dec 2023The REVISE (Re-Evaluating the Inhibition of Stress Erosions in the ICU) trial will evaluate the impact of the proton pump inhibitor pantoprazole compared to placebo in... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The REVISE (Re-Evaluating the Inhibition of Stress Erosions in the ICU) trial will evaluate the impact of the proton pump inhibitor pantoprazole compared to placebo in invasively ventilated critically ill patients.
OBJECTIVE
To outline the statistical analysis plan for the REVISE trial.
METHODS
REVISE is a randomized clinical trial ongoing in intensive care units (ICUs) internationally. Patients ≥ 18 years old, receiving invasive mechanical ventilation, and expected to remain ventilated beyond the calendar day after randomization are allocated to either 40 mg pantoprazole intravenously or placebo while mechanically ventilated.
RESULTS
The primary efficacy outcome is clinically important upper GI bleeding; the primary safety outcome is 90-day mortality. Secondary outcomes are ventilator-associated pneumonia, Clostridioides difficile infection, new renal replacement therapy, ICU and hospital mortality, and patient-important GI bleeding. Tertiary outcomes are total red blood cells transfused, peak serum creatinine concentration, and duration of mechanical ventilation, ICU, and hospital length of stay. Following an interim analysis of results from 2400 patients (50% of 4800 target sample size), the data monitoring committee recommended continuing enrolment.
CONCLUSIONS
This statistical analysis plan outlines the statistical analyses of all outcomes, sensitivity analyses, and subgroup analyses. REVISE will inform clinical practice and guidelines worldwide.
TRIAL REGISTRATION
www.
CLINICALTRIALS
gov NCT03374800. November 21, 2017.
Topics: Adolescent; Humans; Critical Illness; Gastrointestinal Hemorrhage; Intensive Care Units; Pantoprazole; Pneumonia, Ventilator-Associated; Proton Pump Inhibitors; Respiration, Artificial; Adult
PubMed: 38057875
DOI: 10.1186/s13063-023-07794-z -
Cureus Oct 2023Current practice for patients with suspected or confirmed upper gastrointestinal bleeding (GIB) is to utilize a proton pump inhibitor (PPI) bolus followed by a...
Comparison Between Pantoprazole Intermittent Dosing and Continuous Infusion in Suspected Upper Gastrointestinal Bleeding Prior to Endoscopy: Impact of a Pharmacist-Driven Protocol to Reduce Utilization of Pantoprazole Continuous Infusion.
BACKGROUND
Current practice for patients with suspected or confirmed upper gastrointestinal bleeding (GIB) is to utilize a proton pump inhibitor (PPI) bolus followed by a continuous infusion for 72 hours. Literature has shown similar outcomes with intermittent bolus dosing compared to continuous infusion. Substitution would lead to reduced costs and utilization of resources.
METHODS
This was a retrospective case-control study conducted via chart review. Utilizing electronic healthcare record reports, patients in the control arm were screened for inclusion if they received a pantoprazole continuous infusion from December 1, 2020, to March 31, 2021. A total of 38 patients were included in the control arm. Patients in the experimental arm were screened for inclusion with pantoprazole intermittent therapy from January 1, 2022, to June 30, 2022. A total of 60 patients were included in the experimental arm. The primary outcome was a 30-day GIB recurrence. Secondary outcomes included 30-day hospital readmission, 30-day (), hospital length of stay (LOS), and number of pantoprazole vials utilized.
RESULTS
There was a 65% reduction in the 30-day GIB recurrence in the intermittent bolus arm compared to the continuous infusion arm. Thirty-day hospital readmission was 57% lower in the intermittent bolus arm compared to the continuous infusion arm. The LOS between the two arms was almost identical with the median being five days for the intermittent bolus arm and the median being four days for the continuous infusion arm. The 30-day infection rate had 5% of patients acquiring in the intermittent bolus arm and 2.5% in the continuous infusion arm. The intermittent bolus arm used 55% fewer pantoprazole vials than the continuous infusion arm.
CONCLUSION
In hospitalized patients, the utilization of pantoprazole intermittent bolus is not only comparably efficacious but potentially represents a safer and economically advantageous alternative compared to the current guideline recommendation of a 72-hour pantoprazole continuous infusion. Further studies could provide more robust data to support our findings and challenge the current recommendation for patients who meet the indication criteria.
PubMed: 38046478
DOI: 10.7759/cureus.48056 -
Critical Care and Resuscitation :... Jun 2022Medications prescribed for indications or at doses, frequencies or durations not approved by the Australian Therapeutic Goods Administration are considered "off- label"....
Medications prescribed for indications or at doses, frequencies or durations not approved by the Australian Therapeutic Goods Administration are considered "off- label". Critical illness makes seeking consent for off-label medication use impractical. We aimed to characterise the extent of off-label medication use in a tertiary medical- surgical intensive care unit (ICU) by auditing the electronic health records of all patients admitted over a one-month period. We found 25.4% of 2292 prescriptions made for 142 patients were off-label. Eighty-one (37.2%) of the total of 218 different prescribed medications were used at least once for an off-label indication. Medications commonly prescribed off-label included antacids (pantoprazole, esomeprazole), analgesics (fentanyl, morphine, ketamine, pregabalin), anticonvulsants (levetiracetam), antibiotics (cefazolin, erythromycin), antipsychotics (quetiapine, haloperidol), and cardiovascular agents (metoprolol, clonidine). Nearly all patients (88.0%) received at least one off-label medication during their ICU stay. Most off- label medications were used for conventional (albeit not licensed) reasons, but nine out of 81 (11.1%) were not; for example, acetazolamide for hypertension, aminophylline for oliguria, and dexmedetomidine for seizures. Recognising the challenges of formally registering an indication with the Therapeutic Goods Administration, but also the value of reducing the incidence of medications used for potentially incorrect purposes, we suggest guideline endorsement of what constitutes standard critical care practice as an alternative to regulatory control.
PubMed: 38045597
DOI: 10.51893/2022.2.OA8 -
Qatar Medical Journal 2023Methotrexate (MTX) is a folic acid antagonist used to treat different immunological or proliferative illnesses because of its anti-proliferative and anti-inflammatory...
INTRODUCTION
Methotrexate (MTX) is a folic acid antagonist used to treat different immunological or proliferative illnesses because of its anti-proliferative and anti-inflammatory effects. MTX Toxicity is considered a severe problem. Although acute toxicity related to high-dose administration (doses ≥500 mg/m) can be predicted based on the given dose, chronic toxicity still has no specific factors to predict it, so treatment depends on the history and symptoms of toxicity. MTX was initially used for oncology indications with high cyclic doses, then expanded to non-oncology indications with different low doses and frequencies. This significant change in doses resulted in dosing errors that contributed to MTX toxicity reports. Measures to prevent the toxicity of MTX should be implemented.
CASE
A 66-year-old female patient ingested 10 mg of MTX daily for one month instead of the once-toxicity symptoms. The serum level of MTX was requested, and treatment with folinic acid was initiated until the patient improved with the discontinuation of MTX.
DISCUSSION
There is limited literature about the lack the total cumulative dose, duration of intake, or serum level of MTX. All this information was provided in this case report, but drug-drug interactions were not reviewed, although aspirin and pantoprazole were identified as having interactions with methotrexate in this patient. Minimum total cumulative dose identification may help assess the toxicity risk in such patients.
CONCLUSION
Low-dose MTX chronic toxicity still needs further information to guide the patient's risk of toxicity and when to initiate treatment. Safety-practical measures should be implemented to prevent such administration errors.
PubMed: 38026729
DOI: 10.5339/qmj.2023.31 -
Caspian Journal of Internal Medicine 2023() infection is strongly related to peptic ulcer disease, chronic gastritis, and gastric malignancies. Therefore, eradication is necessary in these cases. This study...
BACKGROUND
() infection is strongly related to peptic ulcer disease, chronic gastritis, and gastric malignancies. Therefore, eradication is necessary in these cases. This study was aimed to compare the efficacy of 14-day reverse hybrid therapy with standard 14-day concomitant regimen for eradication in Iran.
METHODS
Of the 317 patients with dyspepsia and infection enrolled in the study, 153 and 164 patients were randomly assigned to reverse hybrid and concomitant groups, respectively. The reverse hybrid regimen containing pantoprazole, amoxicillin, clarithromycin, and metronidazole was taken every 12 hours in the first 7 days, however, Clarithromycin and Metronidazole were discontinued within the next 7 days. Patients in the concomitant group also received the same drugs for 14-day. Eradication confirmation tests were used 8 weeks after the end of treatments.
RESULTS
A crowd of 281 patients continued the trial until the end. eradication rates based on intention to treat analysis were 71.2% (109/153) and 83.5% (137/164) in reverse hybrid and concomitant groups, respectively ( = 0.007). By the per-protocol analysis, rates of eradication were 85.8% (109/127) and 89% (137/154), respectively ( = 0.428). Severe side effects were few in both groups. More side effects were observed in concomitant group ( < 0.001), however, the severity of side effects was not statistically different between the two regimens ( = 0.314). Reverse hybrid regimen was better tolerated (98% vs. 91.5%, = 0.009).
CONCLUSION
Both 14-day reverse hybrid and concomitant regimens have a fair response rate in Iran.
PubMed: 38024170
DOI: 10.22088/cjim.14.4.68 -
Caspian Journal of Internal Medicine 2023() has infected about 50% of the world's population and it is the main cause for peptic ulcer, gastric adenocarcinoma and even a major cause for gastric MALT lymphoma.
BACKGROUND
() has infected about 50% of the world's population and it is the main cause for peptic ulcer, gastric adenocarcinoma and even a major cause for gastric MALT lymphoma.
METHODS
This study was performed in Mazandaran, Sari, situated in North of Iran. Three-hundred and twenty-eight adult patients with endoscopically approved gastric or duodenal ulcers or erosions and infection were randomly divided into 2 groups to receive either 14 days PABT (Pantoprazole 40 mg, Amoxicillin 1 g, Bismuth 425 mg (all twice daily) and Tetracycline 500 mg four times a day) and PACM (Pantoprazole 40 mg, Amoxicillin 1g, Clarithromycin 500 mg, and Metronidazole 500 mg, all twice daily). To evaluate eradication, fecal antigen test was performed 8 weeks after treatment.
RESULTS
The eradication rates were 94.51% in the PABT and 91.46% in PACM group based on the intention to treat analysis. Moreover, the eradication rates were 95.58% and 92.72% according to per-protocol analysis, respectively. Also, both groups had very low rates of severe side effects.
CONCLUSION
Regarding the ideal eradication rates achieved by both treatment groups and the low rates of severe side effects, both treatment protocols can be prescribed for H. pylori eradication in North of Iran.
PubMed: 38024162
DOI: 10.22088/cjim.14.4.676 -
Medicine Nov 2023Acute generalized exanthematous pustulosis (AGEP) is a serious adverse skin reaction characterized by the rapid appearance of densely distributed, small, sterile...
RATIONALE
Acute generalized exanthematous pustulosis (AGEP) is a serious adverse skin reaction characterized by the rapid appearance of densely distributed, small, sterile pustules with erythema. However, its pathogenesis is not fully understood. Hydroxychloroquine is widely used for the treatment of autoimmune diseases. Some patients presenting with AGEP have IL36RN and CARD14 gene mutations. Our report describes a patient with rheumatoid arthritis and AGEP associated with hydroxychloroquine and a newly discovered CARD14 gene mutation.
PATIENT CONCERNS
A 28-year-old woman with rheumatoid arthritis, treated with leflunomide therapy without marked relief of joint pain, developed multiple rashes with pruritis covering the body 5 days after switching to hydroxychloroquine treatment.
DIAGNOSES
Based on the patient's history, symptoms, and histopathological findings, AGEP was diagnosed.
INTERVENTIONS
Whole-exome sequencing and Sanger validation revealed no mutations in the IL36RN gene; however, a CARD14 gene mutation was present. The patient was treated using ketotifen fumarate tablets, dexamethasone sodium phosphate, calcium gluconate injection, methylprednisolone injection, vitamins C and B12, hydrocortisone butyrate cream, Reed acne cream, potassium chloride tablets, and pantoprazole enteric-coated capsules.
OUTCOMES
The rash improved after 15 days.
LESSONS SUBSECTIONS
There has been little basic research on AGEP-related genetics, and the CARD14 mutation may underlie several pustular rashes, including AGEP and generalized pustular psoriasis. Follow-up studies and further accumulation of patient data are required.
Topics: Female; Humans; Adult; Hydroxychloroquine; Acute Generalized Exanthematous Pustulosis; Skin; Arthritis, Rheumatoid; Exanthema; Mutation; Guanylate Cyclase; Membrane Proteins; CARD Signaling Adaptor Proteins; Interleukins
PubMed: 38013380
DOI: 10.1097/MD.0000000000036168