Pharmacotherapy最新文献

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.

Background: Compared to soybean-oil and fish-oil formulations, the use of mixed-oil lipid injectable emulsion is associated with reduced catheter-related bloodstream infection rates in pediatric patients receiving parenteral nutrition. The objective of this study was to compare clinical outcomes of fungal catheter-related bloodstream infections in pediatric patients following receipt of parenteral nutrition with mixed-oil (SMOFlipid) lipid injectable emulsion or other formulations (soybean-oil [Intralipid] or fish-oil [Omegaven]).

Methods: A retrospective cohort study of pediatric patients with fungal catheter-related bloodstream infections following administration of parenteral nutrition and injectable lipid emulsion from five pediatric hospitals in the United States during a 5-year period was conducted. Differences in a composite outcome of 30-day mortality from first positive blood culture and/or infection persistence based on type of lipid injectable emulsion received prior to infection were assessed through generalized linear mixed models with binomial distribution.

Results: One-hundred twelve fungal catheter-related bloodstream infections were assessed from 104 patients who received mixed-oil lipid injectable emulsion (n = 43) or other formulations (n = 69) prior to infection. Thirty-nine infections met the composite outcome (32 with persistent infection, three with 30-day mortality, and four with both). On multivariable analysis, receipt of mixed-oil lipid injectable emulsion demonstrated a non-statistically significant increase in the composite outcome (odds ratio [OR] [95% confidence interval {CI}]: 1.80 [0.75-4.34]; p = 0.19). Factors independently associated with the composite outcome include receipt of systemic antifungal prophylaxis (OR [95% CI]: 5.72 [1.33-24.7]; p = 0.019) and delay in central venous catheter removal (OR [95% CI]: 1.09 [1.01-1.19]; p = 0.03). Notable factors not associated with the composite outcome included continued receipt of lipid injectable emulsion, empiric antifungal choice, time to antifungal administration, and gastrointestinal surgery within 90 days prior to infection.

Conclusion: Use of mixed-oil lipid injectable emulsion compared to other formulations (soybean-oil or fish-oil) demonstrated a non-statistically significant increase in 30-day mortality and/or infection persistence from fungal catheter-related bloodstream infections in pediatric patients receiving parenteral nutrition.

Background: Proton pump inhibitors (PPIs) have been commonly used for gastroesophageal reflux disease (GERD) and peptic ulcers (PU), which are even more prevalent in patients with chronic kidney disease (CKD). Although PPI-related adverse outcomes are well documented in the general population, evidence in patients with CKD remains limited. This study investigated the associations of PPI use and adverse outcomes in patients with CKD who had GERD or PU.

Methods: In this nationwide, retrospective cohort study, patients with CKD and also PU or GERD from 2006 to 2015 were enrolled and sorted into no-, short-term, and long-term PPI groups. Incidence and risks of outcome events between these three groups were analyzed with the Cochran-Armitage test and Cox proportional hazard analyses. Events-free probability was estimated with the Kaplan-Meier method during follow-up.

Results: In the study, 384,411 patients with CKD with PU or GERD were enrolled. The numbers of no-, short-term, and long-term PPI treatments were 147,976, 14,153, and 3459, respectively. Relative to the no-PPI group, the adjusted hazard ratios (aHRs) of admission for pneumonia and fracture, new diagnosis of type 2 diabetes mellitus (DM), and progression to end-stage kidney disease (ESKD) in the short-term (1.089, 1.083, 1.175, 1.22) and long-term PPI groups (1.882, 2.601, 1.951, 1.714) remained statistically significant, respectively, even after adjustment for significant baseline variables; the aHR of dialysis was significant only in the long-term PPI group. Kaplan-Meier analysis revealed significant outcome events in the long-term PPI group during follow-up.

Conclusion: PPI use is associated with an increased risk of pneumonia, fracture, incidence of type 2 DM, and progression to ESKD in patients with CKD, and the risk increases substantially with increased duration of PPI use.

Background: Clinically relevant drug-drug interactions (DDIs) are a common cause of adverse drug reactions (ADRs). Hepatic organic anion transporting polypeptides (OATPs) have recently been studied for their role in DDIs. The commonly prescribed antihypertensive angiotensin receptor blockers (ARBs) are known to be eliminated by hepatic OATPs. ARBs are commonly prescribed to patients with reduced kidney function, and kidney disease can result in profound changes to nonrenal drug elimination through reduced hepatic drug transport-mediated excretion. The antibiotic clarithromycin inhibits OATP activity whereas azithromycin does not, making them useful comparators to study DDIs with OATP substrate drugs.

Objective: To investigate whether co-prescription of ARBs and clarithromycin results in increased adverse events compared to azithromycin and whether kidney function modifies this risk.

Methods: We conducted a retrospective population-based cohort study in Ontario, Canada (2010-2021) using linked health care data for 106,322 older individuals (≥66 years) receiving an OATP substrate ARB (candesartan, olmesartan, telmisartan, valsartan) and newly co-prescribed clarithromycin (n = 32,693) or azithromycin (n = 73,629). Primary outcomes were hospital admissions or emergency department visits for hyperkalemia or acute kidney injury (AKI) within 14 days of antibiotic prescription. Adjusted risk ratios (aRR) were obtained using modified Poisson regression after controlling for eight potential confounders. Pre-specified effect measure modification analysis evaluated whether kidney function influenced these outcomes.

Results: Compared to those co-prescribed azithromycin, patients receiving clarithromycin had a significantly higher risk of hyperkalemia (aRR 2.05, 95% confidence interval (CI) 1.32-3.18) and AKI (aRR 1.75, 95% CI 1.41-2.17). The risk of hyperkalemia increased as kidney function declined (multiplicative interaction; p = 0.01).

Conclusions: This population-based retrospective cohort study provides evidence of OATP-mediated drug interactions between ARBs and clarithromycin that warrants further investigation to guide clinical practice, especially for patients with reduced kidney function.