Pharmacotherapy最新文献

Objective: To use machine learning methods to identify factors associated with corticosteroid (CS) discontinuation 1 year after adult heart transplantation (HT).

Design: Retrospective, observational, cohort study.

Data source: This study used data from the United Network for Organ Sharing (UNOS) database.

Patients: We included adults (age ≥ 18 years) who underwent their first HT between January 2000 and December 2023 in the UNOS database with follow-up through December 2024, who were discharged on a CS.

Measurements: We divided the cohort into those with or without CS at 1-year post-transplant follow-up. We used the eXtreme Gradient Boosting (XGBoost) algorithm to build a model predicting CS discontinuation at 1 year. Relevant recipient, donor, and transplant variables were included to train the model, with Shapley Additive Explanations (SHAP) used to identify and interpret the most important and predictive features.

Results: We identified 72,730 HT recipients; 13,017 (17.9%) had CS discontinued within the first year. Compared with the CS cessation group, those who continued CS were more likely to have had a lower BMI, lower ischemic etiology of cardiomyopathy, lower intra-aortic balloon pump (IABP) and left ventricular assist device (LVAD) use before HT, better renal function, and sustained longer donor ischemic time. Model performance was strong, with an area under the curve of 0.854 (95% confidence interval: 0.848-0.861). Lower average transplant center volume (number of transplants per year), shorter donor ischemic time, and LVAD use at transplant predicted CS discontinuation.

Conclusions: In a large national database, utilizing novel ML modeling techniques, we identified annual transplant center volume, donor ischemia time, and LVAD use at the time of HT as the best predictors of CS discontinuation 1 year after HT.

Background: Abrupt cessation of alcohol consumption after prolonged periods of use leaves patients at risk for experiencing withdrawal symptoms. Alcohol is a central nervous system depressant that increases the activity of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and suppresses the activity of the excitatory neurotransmitter glutamate. Stopping consumption of alcohol reduces this inhibitory response and leads to a net excitatory state and symptoms of withdrawal, including anxiety, tremors, and even seizures. Benzodiazepines have traditionally been the treatment of choice for patients with alcohol withdrawal. Gabapentin has recently been studied as an adjunctive agent for the treatment and prevention of alcohol withdrawal, given its structural similarity to GABA and lower risk for dependence compared with benzodiazepines.

Objective: The primary objective of this study was to determine if a gabapentin-based regimen is benzodiazepine-sparing in patients experiencing alcohol withdrawal.

Methods: This was a retrospective, single center, pre- and post-implementation analysis of a gabapentin taper-based alcohol withdrawal protocol in place of a traditional benzodiazepine-based protocol used in patients admitted to a large, urban academic medical center in the Midwest for alcohol withdrawal between January 1, 2017, and January 1, 2023. The primary outcome was a comparison of cumulative benzodiazepine dose (in lorazepam equivalents) received throughout admission between groups.

Results: This study included 200 patients with 100 patients in each of the pre- and post-implementation groups. Baseline characteristics were similar between groups except for baseline serum alcohol level, which was higher in the pre-implementation group. Patients in the post-implementation group on average were exposed to 9.7-mg lorazepam equivalents during admission compared with 22.8-mg lorazepam equivalents in the pre-implementation group (p = 0.001). Patients between groups had similar symptom progression as characterized by average daily alcohol withdrawal assessment scale (AWAS) scores and length of stay.

Conclusion: Utilization of a gabapentin taper resulted in significantly lower cumulative exposure to benzodiazepines and similar clinical outcomes in patients admitted for acute alcohol withdrawal.

Objective: Angiotensin-II Receptor Blockers (ARBs) are commonly prescribed; however, their adverse events may prompt new drug prescriptions, known as prescribing cascade (PC). We aimed to identify potential ARB-induced PCs using high-throughput sequence symmetry analysis.

Methods: Using claims data from a national sample of Medicare beneficiaries (2011-2020), we identified new ARB users aged ≥ 66 years with continuous enrollment ≥ 360 days before and ≥ 180 days after ARB initiation. We screened for initiation of 446 other (non-antihypertensive) "marker" drug classes within ±90 days of ARB initiation. Sequence ratios (SRs) with 95% confidence intervals (CIs) were calculated as the ratio of the number of ARB users initiating the marker class after versus before ARB initiation. Adjusted SRs (aSRs) accounted for prescribing trends over time, and for significant aSRs, we calculated the naturalistic number needed to harm (NNTH); significant signals were reviewed by clinical experts for plausibility.

Results: We identified 320,663 ARB initiators, age (mean ± standard deviation) 76.0 ± 7.2 years; 62.5% female; and 91.5% with hypertension. Of the 446 marker classes evaluated, 17 signals were significant, and three (18%) were classified as potential PCs after clinical review. The strongest signals ranked by the lowest NNTH included benzodiazepine derivatives (NNTH 2130, 95% CI 1437-4525), adrenergics in combination with anticholinergics, including triple combinations with corticosteroids (NNTH 2656, 95% CI 1585-10,074), and other antianemic preparations (NNTH 9416, 95% CI 6606-23,784). The strongest signals ranked by highest aSR included other antianemic preparations (aSR 1.7, 95% CI 1.19-2.41), benzodiazepine derivatives (aSR 1.18, 95% CI 1.08-1.3), and adrenergics in combination with anticholinergics, including triple combinations with corticosteroids (aSR 1.12, 95% CI 1.03-1.22).

Conclusion: The identified PC signals reflected known and possibly under-recognized ARB adverse events in this Medicare cohort. These hypothesis-generating findings require further investigation to determine the extent and impact of these PCs on patient outcomes.

Background: Levodopa decreases blood pressure (BP) in persons with Parkinson's disease (PwP), but no pharmacodynamic studies integrating systemic levodopa concentration measurements have characterized its hypotensive effects. Understanding this relationship is clinically relevant for guiding therapeutic decisions, such as how aggressively to treat hypotension before initiating or increasing levodopa. In this pilot study, we aimed to determine the acute pharmacodynamic effects of oral immediate-release carbidopa/levodopa on BP in PwP.

Methods: PwP taking chronic oral carbidopa/levodopa with baseline BP ≥ 90/60 mmHg were recruited. Participants withheld antiparkinsonian medications overnight prior to the study visit and received carbidopa/levodopa immediate-release tablets at time 0. Capillary blood levodopa levels, seated BP measurements, and motor symptom assessments were performed at baseline and repeated every 10 min for 70-100 min. Non-compartmental pharmacokinetic parameters of levodopa were determined, including the area under the curve up to the last time point (AUC_{0 → last}), maximum concentration (C_max), and time to maximum concentration (T_max).

Results: Fourteen PwP were enrolled (mean age 69.5 ± 7.6 years, six females). Two participants had orthostatic hypotension at baseline (defined as a sustained drop in systolic BP ≥ 20 mmHg or diastolic BP ≥ 10 mmHg within 3 min of standing), and six were taking antihypertensive medications. Mean arterial pressure (MAP) declined during the study from an average of 105 ± 13.1 mmHg at baseline to a nadir of 84 ± 15.8 mmHg. The maximum MAP drop occurred at 100 min post-dose. Cumulative levodopa AUC negatively correlated with MAP (Pearson's r = -0.30; p = 0.00036).

Conclusions: Oral levodopa is associated with acute hypotension in PwP, and levodopa exposure is inversely correlated with MAP. These effects should be considered when adjusting levodopa dosing, particularly in patients with hypotension, to improve safety outcomes.

Introduction: Patients with burns are at an increased risk of multidrug-resistant pathogens including Pseudomonas aeruginosa and may need specialized dosing regimens due to alterations in physiology due to their injuries.

Methods: Therefore, we conducted a single-dose, open-label, pharmacokinetic study of ceftolozane (2 g)/tazobactam (1 g) infused over 60 min in six patients with partial- or full-thickness burns and central line access. Serial blood samples were obtained at the following time points: 0 (predose) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 h following the start of infusion for determination of plasma drug concentrations.

Results: Similar estimates of clearance (CL) were observed between the groups, and as a consequence the half-life (T1/2) was longer in the six patients with burns in the current study compared to previous studies of healthy volunteers on average. Although these mean comparisons suggest similarity in exposure based on area under the curve (AUC) and maximum concentration (Cmax), it is important to recognize that the interindividual variability is approximately 2- to 5-fold higher in patients with burns compared to healthy volunteers.

Conclusions: We did not find sufficient deviations in the concentrations of ceftolozane/tazobactam to recommend an empiric dose adjustment for patients with burns. However, this finding is limited by our small sample size and lack of clinical outcome data. Therefore, we also provide a conditional recommendation to conduct therapeutic drug monitoring to adjust ceftolozane/tazobactam dosing or to switch to a continuous infusion approach in cases of a suboptimal clinical response.

Background: Osteomyelitis (OM) is a complex inflammatory bone infection typically requiring prolonged antibiotic therapy. Oritavancin (ORI), a long-acting lipoglycopeptide with activity against biofilm-embedded pathogens, has emerged as a potential treatment option despite previous US Food and Drug Administration (FDA) warnings against its use in OM.

Methods: We conducted a systematic review and meta-analysis of observational studies in seven databases through August 8, 2024 (PROSPERO registration: CRD42025635473) to evaluate the available evidence on ORI's efficacy and safety in OM. Clinical success was defined as the improvement or resolution of infection without requiring additional gram-positive antibiotics, surgical debridement, or amputation. Study quality was assessed using the Newcastle-Ottawa Scale.

Results: Our systematic review included nine observational studies comprising 316 patients with OM treated with ORI. Quality assessment using the Newcastle-Ottawa Scale revealed scores ranging from 5/9 to 8/9, with most studies demonstrating adequate outcome assessment but limitations in cohort selection and comparability. Meta-analysis demonstrated a pooled clinical success rate of 81% (95% CI: 76%-85%). Comparative analysis of two studies yielded an odds ratio of 2.99 (95% CI: 0.86-10.36) favoring ORI over comparators (daptomycin and dalbavancin), though with substantial heterogeneity (I² = 80.2%, p = 0.0247).

Conclusions: Despite previous warnings, we found no evidence of ineffectiveness with ORI for OM. ORI's infrequent dosing schedule may provide convenience over daily parenteral therapy, particularly for difficult-to-treat pathogens like MRSA and VRE. Further research is needed to optimize dosing strategies based on pathogen susceptibility and establish appropriate therapeutic drug monitoring protocols.

Context: To meet the need for effective treatments during the COVID-19 Public Health Emergency, the U.S. government sought to accelerate the discovery and development of new antiviral treatments-a process that normally took 4-12 years. The government changed many features of the established system, selecting the investigational drugs, sponsoring or conducting the clinical testing, and purchasing and managing the distribution of the successful products.

Methods: We focused on novel therapeutic agents for COVID-19 that were funded, clinically tested, and/or received Emergency Use Authorization during the Public Health Emergency from January 2020 to May 2023. The primary sources were the public records of the National Institutes of Health, the U.S. Food and Drug Administration, and the Biomedical Advanced Research and Development Authority. Excluded were vaccines, devices, diagnostic tests, and new indications for approved drugs.

Results: In less than 24 months, the emergency program developed, tested, approved, and distributed eight new therapeutic products, including six monoclonal antibodies and two new oral antivirals. In addition, 11 other investigational agents were funded or tested under the emergency program but did not receive Emergency Use Authorization. More than 30 million courses of treatment were distributed at a cost of $29 billion or $881 per patient. By the end of the emergency, viral mutations and rapidly growing population immunity rendered the new products ineffective in almost all patients.

Conclusions: The emergency program was dramatically effective in finding and testing new drug treatments using a variety of clinically relevant endpoints and serving varied patient populations. Planning for future pandemics should include a global network of clinical testing centers that were key to a rapid response. Research is needed to discover more durable antiviral treatments, especially in settings where mutation and population immunity are subject to rapid change.

Purpose: Filgrastim is administered to shorten the duration of chemotherapy-induced neutropenia. Filgrastim can be administered intravenously or subcutaneously, but different routes of administration may result in different pharmacokinetic properties, which may affect efficacy. The primary objective of this study was to determine if subcutaneous (SQ) filgrastim would be associated with a shorter time to neutrophil recovery in patients with myeloma undergoing autologous hematopoietic stem cell transplantation (autoHSCT) when compared to intravenous piggyback (IVPB) filgrastim.

Methods: This was a single-center, retrospective cohort study of patients undergoing autoHSCT for myeloma admitted and discharged between 2018 and 2019. The primary outcome was the mean number of days from transplant day 0 to absolute neutrophil count (ANC) greater than 500 cells/μL. Secondary outcomes were the incidence of and mean number of days of gram-negative antibiotic treatment and 30-day mortality.

Results: A total of 196 patients with myeloma met the inclusion criteria. No significant differences in time to neutrophil recovery between IVPB and SQ filgrastim were observed (11.0 ± 0.7 days vs. 10.8 ± 0.8 days, p = 0.15, respectively). No significant differences were observed in any of the secondary outcomes between IVPB and SQ filgrastim.

Conclusion: In patients with myeloma undergoing autoHSCT, no differences in time to neutrophil recovery, incidence of or duration of gram-negative antibiotic treatment, or 30-day mortality were observed between IVPB and SQ routes of filgrastim administration.

Background: Although randomized controlled trials (RCTs) have established evidence regarding thromboembolic risks of thrombopoietin receptor agonists (TPO-RAs) in immune thrombocytopenia (ITP) during short-term follow-up, the long-term risks remain uncertain. This meta-analysis integrates data from prospective studies and RCTs to provide a comprehensive evaluation of thromboembolic risks associated with TPO-RA therapy.

Methods: PubMed, Embase, Web of Science, and the Cochrane Library were searched from inception to January 23, 2025 for RCTs and prospective studies reporting thromboembolic events in patients treated with TPO-RAs. The primary outcome was the risk of any thromboembolism. Subgroup analyses separately assessed the incidence of venous and arterial thrombosis. Short-term (≤ 6 months) evidence was derived from RCTs, while long-term (6-12 months and > 12 months) evidence was supplemented by prospective studies. Data from RCTs were analyzed using the Peto odds ratio (OR) with 95% confidence intervals (CIs), and data from prospective studies were pooled to calculate the incidence of thromboembolic events.

Results: The analysis included 12 RCTs (involving 1530 patients) and 11 prospective studies (involving 1820 patients). TPO-RAs significantly increased thromboembolic risk compared to placebo in the short-term (0.72% vs. 0.23%, Peto OR = 3.25, 95% CI = 1.11-9.51, p = 0.03). Pooled results from prospective studies demonstrated thromboembolism incidence of 3.84% at 6 to 12 months and 5.59% beyond 12 months of treatment with TPO-RAs. The reported incidence of arterial thrombosis increased from 0.14% (≤ 6 months) to 1.51% (6-12 months), and further to 4.2% (> 12 months). Whereas the reported incidence of venous thrombosis increased from 0.18% (≤ 6 months) to 2.50% (6-12 months), and plateaued at 2.55% beyond 12 months.

Conclusion: This analysis demonstrates that TPO-RAs therapy increases the risk of thromboembolism, with the risk of arterial events becoming particularly pronounced during long-term use. These findings highlight the need for individualized risk assessment and vigilant monitoring in patients receiving TPO-RAs.