Pharmacotherapy最新文献

Background: There are sparse data to guide resumption of direct oral anticoagulants (DOACs) versus warfarin in patients with atrial fibrillation (AF) who survive a major gastrointestinal bleeding (GIB) event.

Objective: To compare the risk-benefit profile of restarting DOACs versus warfarin among patients with AF following hospitalization for major GIB.

Methods: Using claims submitted to a commercial health insurance database from January 2010 to December 2017, we identified adult patients with AF hospitalized for a major GIB while receiving oral anticoagulants. Eligible patients were required to have survived and restarted oral anticoagulation with DOACs or warfarin within 90 days following hospital discharge for major GIB. The outcomes of interest were subsequent hospitalization for major bleeding, hospitalization for ischemic stroke/systemic embolism (SE), all-cause mortality, and net adverse clinical effect (NACE), which was a composite of all-cause mortality, hospitalization for ischemic stroke/SE, and hospitalization for major bleeding. Stabilized inverse probability of treatment weighting was used to balance measured covariates.

Results: Overall, 4,389 patients resumed oral anticoagulation, with 3016 (68.7%) on warfarin and 1373 (31.3%) on DOACs, within 90 days of hospital discharge for major GIB. The median (interquartile range) time from hospital discharge for major GIB to resumption of oral anticoagulant was 24 (10, 47) days. The weighted hazards ratio (HR) among individuals that resumed DOACs versus warfarin after major GIB was 0.76 (95% confidence interval, CI: 0.60, 0.96) for subsequent hospitalization for major bleeding, 0.91 (95% CI: 0.53, 1.55) for subsequent hospitalization for ischemic stroke/SE, and 0.83 (95% CI: 0.72, 0.97) for NACE.

Conclusions: Among patients with AF who survived and resumed oral anticoagulation within the first 90 days after hospitalization for a major GIB event, restarting oral anticoagulation treatment with DOACs was associated with a lower risk of subsequent hospitalization for major bleeding and the composite outcome of ischemic stroke, SE, all-cause mortality, and recurrent or incident major bleeding.

We describe a case of a 56-year-old male who developed severe, refractory hypotension after an intentional ingestion of clozapine and who became hemodynamically stable after one session of therapeutic plasma exchange (TPE). The patient, who presented after an ingestion of clozapine, was found to have altered mental status and hypotension in the emergency department. Escalating catecholamine vasoactive agents were necessary to maintain adequate hemodynamics. Angiotensin II was added and rapidly up titrated in efforts to maintain adequate blood pressure. Due to persistent hemodynamic instability despite four vasoactive agents, TPE was attempted to enhance the elimination of the highly protein bound medication. Within 2 h of completing TPE, the catecholamines and vasopressin were stopped, and angiotensin II dosing was significantly decreased. This is the first report of utilizing TPE as a method of enhanced elimination of a toxic clozapine ingestion resulting in severe hemodynamic compromise. Further study is necessary to determine if TPE should be incorporated into the care of patients experiencing clozapine toxicity.

Depression is the leading cause of disability worldwide, affecting people of all ages. Both pharmacological and non-pharmacological therapies are available for its treatment. However, some patients do not respond to first-line pharmacological interventions, referred to as treatment-resistant depression (TRD). Individuals with TRD face a significantly higher risk of mortality, including an increased risk of suicide. Additionally, TRD poses a substantial economic burden on health care systems. Various treatment options have been explored for TRD, including augmentation of an antidepressant through the use of an additional agent. Lithium salts have shown promising benefits in the TRD. Lithium requires close therapeutic monitoring due to its narrow therapeutic range, with well-defined thresholds for efficacy and toxicity, in addition to its pharmacokinetic characteristics. Furthermore, lithium has been associated with a reduced risk of mortality by lowering aggression, impulsivity, and suicide rates. Compared with other agents used in the management of TRD-such as atypical antidepressants, second-generation antipsychotics (SGAs), ketamine, and thyroid hormones-lithium is considered a cost-effective augmentation option, alongside other evidence-based strategies, and has a well-established efficacy profile. This literature review examines the role of lithium as an augmentation agent in TRD, with a focus on its pharmacological and clinical properties, as well as the current evidence supporting its use.

Background: Drug safety has historically been understudied in pediatric populations, rendering them "therapeutic orphans." Pediatric drug indications and dosages are often inferred by extrapolating safety, efficacy, and dosing data from adult studies, leading to widespread off-label use. However, this approach fails to account for age-specific differences in disease pathophysiology and developmental pharmacokinetics (PK). Despite evidence that adverse drug events (ADEs) manifest with greater severity in pediatric populations than in adults, fewer than 50% of drugs have been systematically studied for pediatric use. The lack of robust drug safety data may result in suboptimal or harmful treatment strategies.

Methods: We used a data-driven approach that integrated three databases -including Merative MarketScan claims, the Maternal and Pediatric Precision in Therapeutics (MPRINT) Knowledgebase (including 670,185 pediatric pharmacoepidemiology, PK, and clinical trial publications on 5062 drugs), the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS, a postmarketing safety surveillance database), and FDA drug label data- to identify high-impact target. High-impact targets were defined as drugs that have a high prescription volume, limited safety evidence and high risk of serious ADEs.

Results: With 229,550 prescriptions in MarketScan, only 9 studies, and almost 50 high risk serious ADEs benzonatate was identified as a high-impact drug of concern. Serious ADEs included seizure, death, and arrhythmia with proportional reportion ratios (PRRs) ranging from 4.3 to 477.8.

Conclusion: Approved in 1958, Benzonatate, a nonnarcotic antitussive agent has a limited safety evidence with only nine PE/PK publications in six decades. Moreover, it is frequently prescribed off-label for cough relief despite questionable effectiveness, and high-risk of serious ADEs. Our findings reveal a disconnect between clinical practice and suppporting safety evidence. As such, there is critical need to study the safety of this drug using emerging real-world data for real-world evidence. In summary, this study presents an approach that is systematic, objective, reproducible, and data driven to identify and prioritize drug-ADE combinations with limited evidence.

Introduction: Pediatric plastic bronchitis (PB) is a rare complication of surgically palliated congenital heart disease (CHD). Fibrin casts obstruct airways and can cause respiratory distress. There are no therapeutics approved by the United States Food and Drug Administration to treat PB, but inhaled tissue plasminogen activator (tPA) has been anecdotally used to relieve symptoms. We conducted a phase II open-label clinical trial to test the safety of inhaled tPA in pediatric PB.

Methods: Patients with an acute exacerbation of PB requiring hospitalization were enrolled to test the safety of an inhaled tPA regimen (5 mg every 6 h). The primary end point was to assess the safety and tolerability of repeated doses of nebulized, inhaled tPA in pediatric patients with acute PB. Safety parameters consisted of clinical laboratories to assess bleeding, which were measured prior to, during, and after tPA treatment. To benchmark efficacy using spirometry and oxygen saturation, children with Fontan-palliated CHD without a history of PB, with and without protein losing enteropathy (PLE), and healthy children were enrolled in a control arm that did not receive tPA.

Results: Of the 10 patients with PB screened for enrollment, eight qualified for immediate treatment with inhaled tPA. A total of 29 non-PB participants (PLE, n = 8 [10-18 yo]; CHD, n = 9 [8-17 yo]; and healthy, n = 12 [7-16 yo]) were enrolled. There were no differences in pretreatment clinical blood laboratory values of hemostasis and those during and after treatment with the study drug (primary safety outcome). However, there were four episodes of self-limiting epistaxis related to the study drug. Inhaled tPA statistically improved oxygen saturation although this was moderate and likely not clinically significant; inhaled tPA did not alter spirometry values.

Conclusion: In this small, phase II study, repeated doses of inhaled tPA in patients with an acute exacerbation of PB did not result in disrupted systemic coagulation or hematological homeostasis or serious bleeding. However, patients should be monitored for localized bleeding. Larger, randomized trials are needed to provide more comprehensive assessments of bleeding risk and to further assess efficacy.

Trial registration: ClinicalTrials.gov identifier: NCT02315898.

Background: Omeprazole, a widely used proton pump inhibitor, has been associated with rare but serious adverse events such as myopathy. Previous research suggests that concurrent use of omeprazole with fluconazole, a potent cytochrome P450 (CYP) 2C19/3A4 inhibitor, may increase the risk of myopathy. However, the contribution of genetic polymorphisms in CYP enzymes remains unclear.

Aims: This study leveraged electronic health record (EHR) and biobank data to validate an interaction between omeprazole and fluconazole and to explore drug-gene interactions (DGIs) between omeprazole and polymorphisms in CYP enzymes.

Materials and methods: A nested case-control design with incidence-density matching was used. Cases were defined as patients who developed myopathy during ongoing omeprazole therapy. For each case, up to four controls were selected from patients who had not developed myopathy by the time the case was diagnosed. Conditional logistic regression models, adjusting for relevant covariates, evaluated (i) the association between concomitant fluconazole use and myopathy and (ii) genotype-stratified myopathy risk.

Results: Among 902 cases and 3608 controls, the combined use of omeprazole and fluconazole was linked to an increased risk of myopathy (adjusted odds ratio [AOR] = 1.75, 95% confidence interval [CI]: 1.17-2.63, p = 0.007). In the DGI analysis, which included 862 cases and 3448 controls, individuals classified as CYP2C19 poor metabolizers paired with CYP3A4 extensive metabolizers showed a significantly higher myopathy risk (AOR = 1.62, 95% CI: 1.03-2.55, p = 0.036); those with CYP2C19 poor metabolizer/CYP3A4 intermediate metabolizer had an even greater risk (AOR = 4.77, 95% CI: 1.74-13.1, p = 0.002).

Discussion: These findings not only confirm previously reported drug-drug interactions (DDIs) between omeprazole and fluconazole but also reveal the emerging clinical implications of DGIs.

Conclusion: By integrating EHR and genetic data, the study showcases how informatics tools can translate DDI findings into DGI hypotheses, effectively bridging genetic insights and clinical outcomes.

Lecanemab is an amyloid-targeted antibody indicated for treating patients with amyloid-confirmed early Alzheimer's Disease in mild dementia or mild cognitive impairment stages. We report here a case of a subject with early stage of Alzheimer's Disease dementia, amyloid positive, who developed severe acute urinary retention following his first dose of intravenous lecanemab. His urinary retention resolved after a week but recurred following the second intravenous dose 2 weeks later. Lecanemab was discontinued, but the urinary retention has persisted for 8 months indicating possible permanent adverse impact on the bladder. The Naranjo causality probability score was 6. The incidence of urinary retention with intravenous lecanemab is not known but given that elderly patients with dementia may have multiple risks for bladder dysfunction, clinicians should remain vigilant. It is hoped that newer formulations, such as subcutaneous lecanemab, may prove safer in such patients.

Introduction: Vancomycin is a critical antibiotic for treating methicillin-resistant Staphylococcus aureus and other gram-positive bacterial infections, but achieving and maintaining therapeutic trough concentrations is challenging.

Objectives: We hypothesized that a deep learning model could accurately predict vancomycin trough concentrations 2 days in advance in critically ill patients and provide recommendations for optimal dosing adjustments to achieve target drug concentrations.

Methods: We trained and validated the model using electronic health record (EHR) data from adults admitted to the University of California San Diego Health system intensive care units (ICUs) from January 1, 2016, to June 30, 2024. Features included patient demographics, comorbidities, vital signs, laboratory measurements, medications, and vancomycin dosing information. The model architecture combined Long Short-Term Memory and Multi-Head Attention layers, supplemented with skip connections to incorporate past dosage information at the final layer of the deep learning model. Model performance was evaluated using mean absolute error (MAE) and root mean square error (RMSE) metrics.

Results: A total of 2205 encounters met the eligibility criteria. The median age was 57 years, and the median ICU length of stay was 4.9 days. The model achieved an MAE of 3.15 mg/L and an RMSE of 4.17 mg/L, comparable to that of a critical care pharmacist aided by a Bayesian dosing software. Additionally, deviations from patient-specific model-based dose recommendations were generally associated with nontherapeutic vancomycin levels.

Conclusion: This study demonstrates the potential to leverage deep learning to individualize and support vancomycin therapeutic drug monitoring in critically ill patients.