Pharmacotherapy最新文献

Objective: To evaluate patterns in disease-modifying antirheumatic drugs (DMARDs) initiations between 2001 and 2021 among adults with Rheumatoid Arthritis (RA) in the United States METHODS: This retrospective cohort study used a US commercial claims database (2001-2021) to identify patients (≥ 18 years) with RA newly initiating a DMARD. We calculated the annual proportion of initiations for 22 DMARDs, categorized as conventional synthetic (csDMARDs), biologic (bDMARDs), and targeted synthetic (tsDMARDs). Secondary analyses examined trends in first-line non-csDMARD initiation and biosimilar uptake.

Results: We identified 407,728 DMARD initiation episodes among 229,365 unique patients with RA (median age: 50 years [IQR], 44-58 years; 79.4% female). There were shifts in DMARD initiations, with csDMARD initiation declining from 79.9% of initiations in 2001 to 54.7% by 2021 (p < 0.001 for trend). Meanwhile, bDMARDs and tsDMARDs initiations increased from 20.3% in 2001 to 33.1% in 2021 (p < 0.001) and from 0.1% in 2012 to 12.2% in 2021 (p = 0.171), respectively. Methotrexate remained the most initiated DMARD over the 21-year study period, albeit declining from 28.7% to 15.0% of initiations over the study period (p < 0.001). Adalimumab was the most frequently initiated bDMARD (13.3% in 2003 and 12.2% in 2021; p = 0.05). Among tsDMARDs, tofacitinib initiation peaked at 8.9% in 2019 and declined to 4.4% in 2021, while upadacitinib initiation increased from 1.2% to 7.6% during the same period (p < 0.001). For secondary analyses, adalimumab was the predominant first-line b/tsDMARD initiated (> 40%). Biosimilar uptake stayed below 1%.

Conclusion: Expanded DMARD options over the last two decades have led to decreased csDMARD initiations and increased b/tsDMARD initiations, reflecting patient- and system-level factors.

First-line therapeutic approaches for Crohn's disease include immunosuppressants, aminosalicylates, and corticosteroids. However, more than one-third of patients are resistant to these treatments and require second-line therapies. Our goal was to synthesize the evidence on the efficacy and safety of biologics and small molecules for inducing remission in patients with moderate-to-severe Crohn's disease. A systematic review was conducted by searching for randomized controlled trials on the target population in PubMed, Scopus, and Web of Science (March 2025). Data synthesis for the outcomes of remission, health-related quality of life (HRQoL), and safety was performed using network meta-analyses and surface under the cumulative rating curve (SUCRA) analyses. The results were presented as risk ratios with 95% credible intervals. We included 55 trials (n = 16,113 patients) evaluating 26 biological drugs across 83 doses and six small molecules across 15 doses. Similar results were obtained in the sensitivity analyses conducted across different measurement time points. Alongside infliximab 5 mg/kg (SUCRA 98.6%), 10 mg/kg (92%), and 20 mg/kg intravenous (91.8%), the recently approved drugs guselkumab 1200 mg (83.2%), 600 mg (89.2%), and 200 mg intravenous (90.1%), as well as mirikizumab 600 mg (91.5%) and 1000 mg intravenous (82.4%) presented higher probabilities of disease remission and were associated with increased HRQoL. Drugs such as certolizumab, andecaliximab, fontolizumab, abatacept, and etanercept ranked low for remission (SUCRA < 40%) and presented high probabilities of serious adverse events (over 60%). Small molecules presented an intermediate profile. Inhibitors of interleukin-23 appear to be promising alternatives for the treatment of moderate-to-severe Crohn's disease. Given their safety profile, some anti-TNF drugs should be avoided in practice. Trial Registration: PROSPERO: CRD42024519150.

Introduction: Attention-deficit/Hyperactivity Disorder (ADHD) is increasingly recognized in adult women. However, clinical guidance on prescribing ADHD medications during breastfeeding remains limited. Despite the effectiveness of ADHD medications, concerns about drug transfer into breastmilk often lead to conservative prescribing or discontinuation of therapy during the perinatal period, compromising maternal well-being.

Case summaries: In this report, we present a case of a 25-year-old woman at 3 weeks postpartum and exclusively breastfeeding, who presented with ADHD combined type, with inadequate symptom control on extended-release bupropion 300 mg daily. Given poor tolerance at higher doses of bupropion, she was initiated on immediate-release methylphenidate and switched later to the extended-release formulation to minimize the risk of activation previously experienced with antidepressant use.

Discussion: Both mother and infant were monitored for 6 months after medication initiation, during which the mother reported improvements in hyperactive and impulsive symptoms as reflected by scoring of the Adult ADHD Self-Report Scale. She also reported improvements in concentration, mood, and functioning. There were no adverse effects on milk supply, and the infant demonstrated normal growth and development.

Conclusions: This case underscores the feasibility of cautiously escalating stimulant therapy in a breastfeeding mother with ADHD, showing improved functioning in the mother without immediate effects on development in the infant. Significant gaps persist in guidance for postpartum ADHD care, underscoring the need for more research to inform safe and effective treatment.

Background: Parathyroid hormone (PTH) analogs, denosumab, and bisphosphonates are used to treat osteoporosis but have been associated with infections in the general population. Osteoporosis is a common comorbidity following lung transplantation. However, infections increase the risk of developing chronic lung allograft dysfunction, which reduces survival. Evidence for safe and effective use of PTH analogs, denosumab, or bisphosphonates in lung transplant recipients is lacking.

Methods: This single-center retrospective study evaluated lung transplant patients treated with the PTH analogs teriparatide or abaloparatide, RANKL inhibitor denosumab, or bisphosphonates. The primary outcome of interest was the incidence of infection while on the osteoporosis medication, and a multivariable logistic regression was employed to control for infection confounders. Secondary endpoints were treated allograft rejection episodes, the incidence of new donor-specific antibodies, the incidence of fracture while on medication, and the change in bone mineral density (BMD) from the start to the end of osteoporosis medication use.

Results: Forty-four PTH analog courses and 48 denosumab courses were compared with 92 bisphosphonate courses. Infection incidence was significantly lower in the PTH analog group than the denosumab or bisphosphonate group, but this did not retain significance on multivariable modeling. Treated allograft rejection episodes were higher in those with bisphosphonate use, significantly so when compared to PTH analog patients, but patients treated with bisphosphonates were also started on therapy earlier after their transplant when rejection risk is higher. All agents were effective at increasing BMD of the lumbar spine, none improved BMD of the femoral neck, and only PTH analogs significantly improved hip BMD.

Conclusion: In this retrospective study of lung transplant patients treated for osteoporosis post-transplant, there was no difference in risk of infections in patients treated with PTH analogs, denosumab, or bisphosphonate therapies when examined with multivariable modeling. PTH analogs were the most effective since they significantly improved BMD at both the hip and lumbar spine, whereas denosumab and bisphosphonates only improved lumbar spine BMD. This study supports that PTH analogs and denosumab, despite their association with infection in the general population, may be safely utilized compared to bisphosphonates in the post-lung transplant population for the treatment of osteoporosis, but larger studies are needed to confirm these findings.

Objectives: Second-generation antipsychotic (SGA) medications are frequently prescribed for mental health conditions; however, they are associated with an increased risk of metabolic syndrome (MetS). We aimed to identify genetic associations of SGA-associated MetS (SGA-MetS) using genome-wide approaches within the UK Biobank. We also set out to evaluate if genetically predicted obesity is associated with an increased risk of SGA-MetS.

Methods: We defined SGA-MetS based on the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) criteria using cross-sectional data from 1318 UK Biobank participants who reported being on an SGA medication. An SGA-MetS case was defined as meeting three or more of the five NCEP-ATP III criteria. We performed a genome-wide association study (GWAS) and gene-based analysis to identify significant variants and gene associations. We computed the polygenic risk score (PGS) for body mass index (BMI) using 2,100,302 variants validated for obesity and metabolic traits from imputed single-nucleotide polymorphism (SNP) data. We tested the association of PGS-BMI with SGA-MetS using logistic regression.

Results: GWAS identified suggestive associations (p < 1 × 10^-5) on chromosome 15. The variant rs12914956 in CHD2 was associated with increased risk of SGA (odds ratio (OR) = 1.73, 95% confidence interval (CI) = 1.4-2.4, p = 3.6 × 10^-7). The gene-based analysis identified significant gene associations with RBFOX1 (p = 4.85 × 10^-7), PTPRD (p = 7.6 × 10^-7), CSMD1 (p = 2.2 × 10^-6), and CHD2 (p = 1.3 × 10^-6). The PGS-BMI (β = 0.23, p = 6.8 × 10^-5), was associated with increased MetS in a model adjusted for age, sex, physical activity, alcohol consumption, antidepressant medications, schizophrenia diagnosis, and principal components of ancestry.

Conclusion: Using a gene-based analysis, we identified significant gene associations with SGA-MetS that have been previously associated with obesity and metabolic traits. The PGS-BMI was associated with MetS, suggesting that a genetic predisposition to a higher BMI may increase the risk of SGA-MetS. Future research should replicate the findings in a larger dataset with more diverse populations.

Background and objectives: The relative contribution of vancomycin exposure versus clinical factors to acute kidney injury (AKI) development in pediatric patients remains unclear. This study examined risk factors for AKI in pediatric patients receiving intravenous vancomycin therapy, with particular focus on elucidating the role of vancomycin concentrations and evaluating the safety implications of recent dosing guideline changes published in 2020.

Methods: For this retrospective cohort study, Texas Children's Hospital database was queried between 2011 and 2019 for demographics, concomitant medications, vancomycin dosing and levels, serum creatinine, and mortality. AKI was defined using modified KDIGO criteria. Empirical Bayesian forecasting with a published population pharmacokinetic (PK) model generated rich PK profiles from sparse sampling data. Multivariate logistic regression was used to identify risk factors, and simulations were performed to evaluate 2020 guideline recommendations.

Results: The final analysis dataset included 2318 vancomycin courses in 1714 unique patients. The typical dosing regimen in our dataset was 45 mg/kg/day every 8 h. AKI occurred in 18.9% of patients. Independent risk factors included lower age, ICU residence, vasopressor administration, concurrent piperacillin/tazobactam, and amphotericin B use. While vancomycin 24-h area under the curve (AUC_0-24) showed statistically significant association with AKI, the relationship was modest with minimal improvement in model performance compared to clinical factors alone. Simulations of 2020 guideline recommendations (60-80 mg/kg/day) predicted modest increases in AKI incidence from 19% to 21% when AUC was capped at 600 mg·h/L. However, given low mortality rate (1.9%) in our dataset despite only 43% of patients achieving the recommended AUC target of 400 mg·h/L, the clinical necessity for increased dosing remains questionable.

Conclusions: Clinical factors are substantially more predictive of AKI than vancomycin exposure in pediatric patients. Given the questionable clinical necessity for increased dosing based on low mortality rates, prospective studies incorporating clinical efficacy endpoints are needed to establish optimal dosing strategies that balance therapeutic benefit with nephrotoxicity risk.

Carbapenem-resistant Acinetobacter baumannii (CRAB) are difficult-to-treat pathogens that primarily cause health care-associated infections. Sulbactam/durlobactam (SUL/DUR) is a novel antibiotic combination that is uniquely formulated to target CRAB isolates. However, investigations of SUL/DUR's pharmacokinetics in obese patients are limited. Here, we report on the successful treatment of CRAB bacteremia in a patient with acute renal failure and severe obesity (weight 273 kg, body mass index 103 kg/m²) with SUL/DUR and meropenem combination therapy. The patient had a calculated creatinine clearance of 25 mL/min and received therapy with intravenous SUL/DUR 1 g/1 g every 8 h over 3 h in combination with intravenous meropenem 500 mg every 8 h to complete 14 days of therapy. Pharmacokinetic analysis revealed target attainment with prolonged half-life (T_1/2) and volume of distribution (Vd) of 35.3 h and 81.3 L for sulbactam and 30.5 h and 169.1 L for durlobactam, respectively. Susceptibility testing using the broth disk elution test did not show synergy between SUL/DUR and meropenem. No adverse effects were observed, and the patient achieved clinical cure without recurrence of A. baumannii infection.