Pharmacotherapy最新文献

This systematic review and meta-analysis aimed to assess the efficacy and safety of risdiplam on motor and respiratory function in spinal muscular atrophy (SMA). We systematically searched Medline, Scopus, Web of Science, and the Cochrane Library from inception to March 2023. We included pre-post studies that determined the effect of risdiplam on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), the 32-item Motor Function Measure (MFM32), the Revised Upper Limb Module (RULM), the Hammersmith Functional Motor Scale - Expanded (HFMSE), respiratory function, and the proportion of risdiplam-related adverse events in a population with SMA (phenotypes 1 and 2/3). Meta-analyses were also performed where possible. Eleven studies were included. After 12 months of treatment, 57% of participants with SMA1 achieved a CHOP-INTEND score ≥ 40 points, and more than half were able to feed orally and had head control. In SMA2/3, MFM32, RULM, and HFMSE increased by 2.09 (1.17, 3.01), 1.73 (1.25, 2.20), and 1.00 (0.40, 1.59) points, respectively. Efficacy on respiratory function in SMA2/3 was inconsistent. Finally, 16% of participants experienced adverse events, but serious adverse events could not be quantified due to a lack of cases. The limited available evidence suggests that risdiplam is an effective and safe drug for the treatment of SMA. In addition, long-term clinical benefit may be partly determined by the stage of disease at which treatment is initiated.

Study objective: To compare guideline-based fluid resuscitation and need for respiratory support escalation in septic patients with pulmonary hypertension (PH) to those without PH.

Design: Single-center, retrospective cohort study.

Setting: Tertiary care academic medical center in Detroit, Michigan.

Patients: Adult patients with or without PH hospitalized and diagnosed with sepsis from November 1, 2013 through December 31, 2019. Patients with sepsis were assigned to one of two groups based on a previous PH diagnosis or no PH diagnosis.

Intervention: None.

Measurements and main results: The primary outcome was incidence of respiratory support escalation within 72 h from sepsis time zero. Respiratory support escalation included high-flow nasal cannula, bilevel positive airway pressure, or intubation. One-hundred and four patients were included with 52 patients in each study group. Patients with PH were more likely to require escalation of respiratory support compared to non-PH patients (32.7% vs. 11.5%; p = 0.009). Fewer patients with PH received 30 mL/kg of crystalloid within 6 h of time zero compared with non-PH patients (3.8% vs. 42.3%; p < 0.001). Vasopressor initiation was more common in patients with PH compared with the non-PH group (40.4% vs. 19.2%; p = 0.018). PH diagnosis was the only independent predictor of respiratory support escalation.

Conclusions: During initial sepsis management when compared with patients without PH, patients with PH had increased instances of respiratory support escalation within 72 h of sepsis time zero despite lower fluid resuscitation volumes.

Study objective: To assess the efficacy of single-dose sodium zirconium cyclosilicate (SZC) compared to the FDA approved three times daily (TID) dosing and to single-dose sodium polystyrene sulfonate (SPS) for the management of asymptomatic hyperkalemia in hospitalized patients.

Design: Single-center retrospective chart review.

Setting: University of Florida Health Jacksonville, a 695-bed academic medical center in Jacksonville, FL, between June 15, 2018 and August 15, 2021.

Patients: Three hundred fifty-one adult patients who were admitted to any hospital unit in the specified timeframe and received one of three interventions for asymptomatic hyperkalemia (serum potassium ≥4.7 mmol/L) were included in this study.

Intervention: The interventions compared were single-dose SZC 10 g, SZC 10 g × 3 doses (30 g total) within 24 h, or SPS 15-30 g once.

Measurements and main results: The primary outcome was the proportion of patients achieving normokalemia (K⁺ 3.3-4.6 mmol/L) within 12-30 h of the first study dose. Secondary outcomes included average change in potassium within 12-30 h and 3-54 h from the first dose. The primary outcome was met in 68 patients (58.1%) in the SZC 10 g group, 51 (43.6%) in the SZC 10 g × 3 doses group, and 81 (69.2%) in the SPS 15-30 g group (p < 0.01). The average reduction in potassium in 12-30 h was 0.70 mmol/L, 0.78 mmol/L, and 0.99 mmol/L in the SZC 10 g, SZC 10 g × 3 doses, and SPS 15-30 g groups, respectively (p < 0.01).

Conclusions: SZC 10 g once resulted in more patients achieving normokalemia compared to SZC 10 g × 3 doses but less than SPS (p < 0.01). Single-dose SZC may be a reasonable option to manage asymptomatic hyperkalemia in the hospital setting, but achieving normokalemia with one dose may be less likely in patients with higher baseline potassium concentrations and impaired renal function.

Study objective: The objectives of this study were to (i) quantify the incidence of three concerning fluoroquinolone adverse events of interest (FQAEI, i.e., adverse tendon event (TE), clostridioides difficile infection (CDI), and aortic aneurysm/dissection (AAD)), (ii) identify the patient-level factors that predict these events, and (iii) develop clinical risk scores to estimate the predicted probabilities of each FQAEI based on patient-level covariates available on clinical presentation.

Design: Retrospective cohort study.

Setting: Upstate New York Veterans' Healthcare Administration from 2011 to 2016.

Patients: Hospitalized patients with community-acquired pneumonia receiving care in the Upstate New York Veterans' Healthcare Administration from 2011 to 2016.

Intervention: N/A.

Measurements: The outcomes of interest for this study were the occurrence of TE, CDI, and AAD. We also evaluated a composite of these three outcomes, FQAEI.

Main results: The study population consisted of 1071 patients. The overall incidence of FQAEI, TE, AAD, and CDI was 6.5%, 1.8%, 4.5%, and 0.3%, respectively. For each outcome evaluated, the probability of the event of interest was predicted by the presence of certain comorbidities, previous healthcare exposure, choice of specific FQ antibiotic, or therapy duration. Concomitant steroids, pneumonia in preceding 180 days, and creatinine clearance <30 mL/min predicted FQAEI.

Conclusions: Individual frequencies of three important FQAEIs were quantified, and risk scores were developed to estimate the probabilities of experiencing these events to help clinicians individualize treatment decisions for patients and reduce the potential risks of select FQAEIs.

Introduction: Vancomycin pharmacokinetics are affected by renal replacement therapy and physiologic changes in critically ill patients. Literature regarding vancomycin removal and pharmacokinetics during accelerated venovenous hemofiltration (AVVH), a form of prolonged intermittent renal replacement therapy, is limited.

Objective: To describe the removal and pharmacokinetics of vancomycin during AVVH.

Methods: Eighteen critically ill adults receiving vancomycin and AVVH were included. Vancomycin serum concentrations were obtained within 4 h before and 2-6 h after the AVVH session. Patients' serum concentrations were plotted against time, and individual pharmacokinetic parameters were determined by a one-compartmental analysis. Continuous data are reported as a median (interquartile range [IQR]) and categorical data as a percentage.

Results: The median AVVH effluent rate was 39.3 mL/kg/h (IQR 35.5-48 mL/kg/h) for a duration of 9 h (IQR 8-9.75 h). AVVH decreased vancomycin concentrations by 29.8% (IQR 24.9%-35.9%), at a rate of 3.4% per hour (IQR 3.1%-4.3% per hour) of AVVH. The vancomycin elimination rate constant and half-life were 0.039 h^-1 (IQR 0.036-0.053 h^-1 ) and 17.6 h (IQR 13.1-18.8 h), respectively. The area under the curve during AVVH was 171.7 mg*h/L (IQR 149.1-190 mg*h/L). The volume of distribution in 10 patients was 1 L/kg (IQR 0.73-1.1 L/kg). After AVVH, vancomycin 1000 mg (IQR 750-1000 mg) was needed to maintain a serum trough concentration ≥15 mg/L.

Conclusion: Vancomycin is significantly removed by AVVH, which requires supplemental dosing after completion of the AVVH session to maintain desired serum concentrations. Therapeutic drug monitoring of vancomycin serum concentrations is recommended for patients undergoing AVVH.

Study objective: To develop and validate a model for predicting acute kidney injury (AKI) after high-dose methotrexate (HDMTX) exposure.

Design: Retrospective analysis.

Setting: Multisite integrated health system throughout Minnesota and Wisconsin.

Patients: Adult patients with lymphoma who received HDMTX as a 4-h infusion.

Measurements and main results: LASSO methodology was used to identify factors available at the outset of therapy that predicted incident AKI within 7 days following HDMTX. The model was then validated in an independent cohort. The incidence of AKI within 7 days following HDMTX was 21.6% (95% confidence interval (CI) 18.4%-24.8%) in the derivation cohort (435 unique patients who received a total of 1642 doses of HDMTX) and 15.6% (95% CI 5.3%-24.8%) in the validation cohort (55 unique patients who received a total of 247 doses of HDMTX). Factors significantly associated with AKI after HDMTX in the multivariable model included age ≥ 55 years, male sex, and lower HDMTX dose number. Other factors that were not found to be significantly associated with AKI on multivariable analysis, but were included in the final model, were body surface area, Charlson Comorbidity Index, and estimated glomerular filtration rate. The c-statistic of the model was 0.72 (95% CI 0.69-0.75) in the derivation cohort and 0.72 (95% CI 0.60-0.84) in the validation cohort.

Conclusion: This model utilizing identified sociodemographic and clinical factors is predictive of AKI following HDMTX administration in adult patients with lymphoma.

Study objective: Neonatal opioid withdrawal syndrome (NOWS) is a condition that often occurs in neonates born to mothers who received methadone treatment for opioid use disorder during pregnancy. Early identification and treatment of infants at risk of NOWS may improve clinical outcomes. The purpose of this study was to evaluate whether maternal and umbilical cord plasma concentrations of methadone and its metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), could predict the need for NOWS treatment.

Design: Single-center prospective study.

Setting: University of Michigan Neonatal Intensive Care Unit.

Patients: The study included 11 opioid-dependent mother-infant dyads, where the mothers were treated with methadone at 34 weeks' gestation or later.

Intervention: Maternal and cord blood samples were collected from the study participants.

Measurements and main results: Maternal and cord plasma concentrations of methadone and EDDP were determined. Six out of the 11 infants required treatment for NOWS. Maternal methadone plasma concentrations were comparable between infants requiring and not requiring NOWS treatment (329.1 ± 229.7 ng/mL vs. 413.2 ± 329.8 ng/mL). However, the average cord plasma methadone concentration in infants who did not require NOWS treatment was 2.9-fold higher than in those who required the treatment (120.0 ± 88.6 ng/mL vs. 40.9 ± 24.4 ng/mL), although the difference was not statistically significant. The ratios of maternal-to-cord methadone plasma concentrations were significantly higher in patients who required treatment for NOWS compared with those who did not (7.7 ± 1.9 vs. 3.5 ± 1.6, p = 0.003). Maternal and cord plasma EDDP concentrations and the maternal-to-cord plasma EDDP concentration ratios did not differ between patients who required and did not require treatment for NOWS.

Conclusions: The results suggest that methadone permeability across the blood-placental barrier may affect in utero exposure to methadone, and the maternal-to-cord methadone plasma concentration ratio could be a potential biomarker for predicting the need for NOWS treatment.

The strength of evidence for specific ambulatory care prescribing cascades, in which a marker drug is used to treat an adverse event caused by an index drug, has not been well characterized. To perform a structured, systematic, and transparent review of the evidence supporting ambulatory care prescribing cascades. Ninety-four potential prescribing cascades identified through a previously published systematic review. Systematic search of the literature to further characterize prescribing cascades. (1) Grading of evidence based on observational studies investigating associations between index and marker drugs, including: Level I-strong evidence [i.e. multiple high-quality studies]; Level II-moderate evidence [i.e. single high-quality study]; Level III-fair evidence [no high-quality studies but one or more moderate-quality studies]; and Level IV-poor evidence [other]. (2) Listing of the adverse event associated with the index drug in the product's United States Food and Drug Administration (FDA) label. (3) Synthesis of the evidence supporting mechanisms linking index drugs and associated adverse events. Of 99 potential cascades, 94 were supported by one or more confirmatory observational studies and were therefore included in this review. The 94 cascades related to 30 types of adverse drug reactions affecting 10 different anatomic/physiologic systems and were investigated by a total of 88 confirmatory studies, including prescription sequential symmetry analysis (n = 51), cohort (n = 30), and case-control (n = 7) studies. Overall, the evidence from observational studies was strong for 18 (19.1%) prescribing cascades, moderate for 61 (64.9%), fair for 13 (13.8%), and poor for 2 (2.1%). Although the evidence supporting mechanisms that link index drugs and associated adverse events was variable, FDA labels included information about the adverse event associated with the index drug for most (n = 86) but not all of the 94 prescribing cascades. Although we identified 18 of 94 prescribing cascades supported by strong clinical evidence and most adverse events associated with index drugs are included in FDA label, the evidentiary basis for prescribing cascades varies, with many requiring further evidence of clinical relevance.

Objectives: The immunomodulators tocilizumab and baricitinib improve outcomes in severely ill patients with coronavirus disease 2019 (COVID-19); however, comparative analyses of clinical outcomes related to these agents are lacking. A tocilizumab national shortage shifted treatment to baricitinib in critically ill patients, allowing for an outcome comparison in a similar population. The purpose of this study is to compare clinical outcomes in critically ill COVID-19 patients who received tocilizumab and those who received baricitinib.

Design: Retrospective, observational cohort study using generalized estimating equation models, accounting for clustering by hospital and known confounders, to estimate the proportional odds of the ordinal World Health Organization Clinical Progression Scale (WHO-CPS) score at day 14, the primary outcome. Secondary outcomes included WHO-CPS score at day 7.

Setting: Multiple hospitals within the Cleveland Clinic Health System.

Patients: Adult patients admitted for COVID-19 between January 2021 and November 2021.

Interventions: Receipt of tocilizumab, before its shortage, or baricitinib, during shortage.

Measurements and main results: In total, 507 patients were included; 217 received tocilizumab and 290 received baricitinib. Over 96% of patients required ICU admission and 98% received concomitant dexamethasone. Tocilizumab recipients had higher (worse) baseline WHO-CPS scores. After adjustment, tocilizumab use was associated with higher odds of a worse day 14 WHO-CPS score compared with baricitinib (adjusted odds ratio [OR] 1.65 [95% confidence interval (CI) 1.10-2.48]). Similarly, after adjustment, tocilizumab use was associated with higher odds of a worse day 7 WHO-CPS score (adjusted OR 1.65 [95% CI 1.22-2.24]).

Conclusions: Baricitinib use was associated with better WHO-CPS scores at day 14 and day 7 compared with tocilizumab in a cohort of critically ill patients with COVID-19. The odds of having a one unit increase in WHO-CPS score at day 14 was 71% higher with tocilizumab than baricitinib. No difference in mortality or adverse effects was noted.

Background: Fall-related injuries are a significant health issue that occur in 25% of older adults and account for a significant number of trauma-related hospitalizations. Although medication intensification may increase the risk of hospital readmissions in non-trauma patients, data on a geriatric trauma population are lacking.

Objective: The primary objective was to evaluate the effect of medication intensification on 30-day hospital readmissions in geriatric patients hospitalized for fall-related injuries.

Methods: This multicenter, retrospective cohort study included patients with geriatric who presented to one of three trauma centers within a large, health-system between January 1, 2018 and December 31, 2020. Patients at least 65 years old admitted with a fall-related injury were eligible for inclusion. Patients were grouped according to medication changes at discharge, which included intensified and non-intensified groups. Medication intensification included increased dose(s) or initiation of new agents. The primary outcome was the 30-day hospital readmission rate.

Results: Of the 870 patients included (median [interquartile range, IQR] age, 82 [74-89] years, 522 (60%) female, and 220 (25%) with a previous fall), there were 471 (54%) and 399 (46%) patients in the intensified and non-intensified groups, respectively. The intensified group had a higher 30-day hospital readmission rate (21% intensified vs. 16% non-intensified, p = 0.043; number needed to harm 20) based on an unweighted analysis. According to a weighted propensity score logistic regression, medication intensification was associated with higher 30-day hospital readmissions (24% [95% confidence interval [CI] 19-31%] intensified vs. 15% [95% CI 11-20%] non-intensified, p = 0.018). These results were consistent within competing risk models accounting for death (cause-specific model: hazard ratio [HR] 1.63 [95% CI 1.07-2.49], p = 0.023; Fine-Gray model: HR 1.64 [95% CI 1.07-2.50], p = 0.022).

Conclusions: In a geriatric trauma population hospitalized after a fall, intensification of medications may pose an increased risk of 30-day hospital readmission.