Pharmacotherapy最新文献

Introduction: Thiopurine drugs are metabolized by thiopurine methyltransferase (TPMT) and low TPMT activity can result in severe adverse drug reactions. Therefore, TPMT testing is recommended for individuals receiving thiopurines to reduce the risk of toxicity.

Objectives: The objectives of this study were to assess the rate of TPMT testing among individuals receiving thiopurines and explore factors associated with undergoing TPMT testing in Australia.

Methods: This retrospective cohort study utilized administrative data from the Pharmaceutical Benefits Scheme (PBS), Medicare Benefits Schedule (MBS), and the 2021 Census, accessed via the Person Level Integrated Data Asset (PLIDA) at the Australian Bureau of Statistics (ABS) DataLab. Individuals receiving thiopurines aged 18 years or above were identified using PBS data and exposure to TPMT testing was determined using MBS data. Multivariate logistic regression was performed to identify factors associated with TPMT testing.

Results: A total of 62,574 prevalent thiopurine users were identified between 2020 and 2022. Of these, 20,327 (32.5%) underwent TPMT testing (2011-2022). The most significant factor associated with TPMT testing was having at least one thiopurine medication prescribed by a medical specialist (adjusted odds ratio [aOR] 2.12, 95% confidence interval [CI] 2.02-2.22), compared to having medication solely prescribed by primary care physicians (PCPs). Other significant factors associated with TPMT testing included speaking a non-English language at home (aOR 1.29, 95% CI 1.22-1.36), having no chronic health conditions (aOR 1.18, 95% CI 1.13-1.24), not requiring assistance with core activities (aOR 1.16, 95% CI 1.08-1.23), and having a higher educational attainment (aOR 1.11, 95% CI 1.06-1.11). Compared to living in major cities, individuals living in remote areas were significantly less likely to undergo testing (aOR 0.49, 95% CI 0.39-0.60).

Conclusion: Our study highlights the low utilization of TPMT testing in Australia and suggests the need for targeted interventions to address disparities and improve TPMT testing.

Conflicting data have been reported on the association between mineralocorticoid receptor antagonists (MRAs) and acute kidney injury (AKI). This systematic review and meta-analysis aimed to evaluate whether MRAs affect the risk of AKI. MEDLINE via PubMed, the Cochrane Central Register of Controlled Trials, and the ClinicalTrials.gov website were comprehensively searched to extract all relevant studies. Randomized controlled trials (RCTs) were selected that compared MRA versus placebo or no treatment and had study populations consisting of patients with heart or kidney disease. The primary outcome was AKI. The secondary outcome was kidney injury, including AKI and non-AKI. Thirty-three studies were included in the meta-analysis. MRAs were not associated with an increased risk of AKI (risk ratio [RR] 1.13, 95% confidence interval [CI] 0.88-1.46, p = 0.29, I² = 15%, 18,065 patients, 13 RCTs, moderate certainty). For the secondary outcome, MRAs were associated with an increased risk of kidney injury (RR 1.52, 95% CI 1.24-1.87, p < 0.01, I² = 48%, 27,492 patients, 33 RCTs, low certainty). In particular, only canrenone (RR 5.39, 95% CI 2.17-13.37, p < 0.01) and spironolactone (RR 1.78, 95% CI 1.48-2.14, p < 0.01) were associated with an increased risk of kidney injury. However, eplerenone and finerenone seem not to increase the risk of kidney injury in patients with heart or kidney disease. The selection of MRAs might influence the risk of kidney-associated events. Further studies focusing on individual MRAs may be needed to clarify these differences.

Pediatric obesity is a growing health concern that has many secondary adverse health implications. Personalized medicine is a tool that can be used to optimize diagnosis and treatments of many diseases. In this review, we will focus on three areas related to the genetics of pediatric obesity: (i) genetic causes predisposing to pediatric obesity, (ii) pharmacogenomics that may predict weight gain associated with pharmacotherapy, and (iii) pharmacogenomics of anti-obesity pharmacotherapy. This narrative review evaluates genetic cause of pediatric obesity and how genetic findings can be used to optimize pharmacotherapy to minimize weight gain and optimize obesity treatment in pediatric patients. Pediatric obesity has many genetic causes including genomic obesity syndromes and monogenic obesity disorders. Several genetic etiologies of obesity have current or emerging targeted genetic therapies. Pharmacogenomic (PGx) targets associated with pharmacotherapy-induced weight gain have been identified for antipsychotic, antiepileptic, antidepressant therapies, and steroids, yet to date no clinical guidelines exist for application use of PGx to tailor pharmacotherapy to avoid weight gain. As legislation evolves for genetic testing coverage and technology advances, this will decrease cost and expand access to genetic testing. This will result in identification of potential genetic causes of obesity and genes that predispose to pharmacotherapy-induced weight gain. Advances in precision medicine can ultimately lead to development of clinical practice guidelines on how to apply genetic findings to optimize pharmacotherapy to treat genetic targets of obesity and avoid weight gain as an adverse event associated with pharmacotherapy.

Introduction: Guidelines for vancomycin therapeutic monitoring recommend using a Bayesian approach with a population pharmacokinetic model to estimate the 24 h area under the concentration-time curve over first-order equations. Thus, we performed an external evaluation of population pharmacokinetic models of vancomycin in neonates and compared Bayesian results with those observed in clinical practice via pharmacokinetic equations to improve therapeutic monitoring by proposing optimized initial dosing nomograms and assessing the feasibility of reduced blood sampling strategies using the most predictive models.

Methods: Models were identified from the literature and evaluated via an external neonatal population. A priori predictive performance was first assessed by prediction-based diagnostics, then by simulation-based diagnostics and a posteriori analyses only if deemed satisfactory; model-informed vancomycin exposure was also compared with reference first-order pharmacokinetic equations. The best-performing models were ultimately subjected to Monte Carlo simulations to develop new initial dosing nomograms offering the highest probability of achieving therapeutic target.

Results: A total of 28 population pharmacokinetic models were evaluated in the external dataset, which includes 72 neonates and 380 vancomycin concentrations. Eleven models had an adequate predictive performance with bias ≤ ± 15% and imprecision $\le$ 30%, while the Bayesian approach yielded over 75% agreement with reference exposure values in most cases. Nonetheless, Capparelli et al. and Mehrotra et al. models performed the best overall, showing the lowest imprecisions of 16.8% and 16.9%, respectively; both models recommended higher dosage regimens than the theoretical nomogram currently applied to favor therapeutic target attainment.

Discussion: We externally evaluated numerous neonatal population pharmacokinetic models of vancomycin and used the most predictive ones to advocate new initial dosing nomograms. Clinical implementation of the Bayesian approach could reduce the time needed to reach therapeutic target and limit the number of blood samples in newborns compared with traditional pharmacokinetic equations.

The avian influenza is a serious infection caused by influenza virus that is native to birds. Avian influenza remains a global challenge due to high transmission and mortality rates. The highly pathogenic strain of H5N1 resulted in significant outbreaks and deaths globally since the late 1800s. The most recent outbreaks in wild birds, domestic birds, and cows with some genetic variations and mutations among H5N1 strains has raised major concerns about potential transmission and public health risks. Symptoms range from asymptomatic to mild flu-like illness to severe illness that requires hospitalization. There are multiple vaccines in development for humans to protect against avian influenza, specifically the H5N1 virus. This includes a cell-based vaccine approved by the FDA for people aged 6 months and older who are at higher risk of exposure to the H5N1 virus called Audenz. Chemoprophylaxis against avian influenza following a suspected exposure should be started as soon as possible or no later than 48 h, and it is recommended to be continued for 7 days. The majority of avian influenza viruses are susceptible to neuraminidase inhibitors and cap-dependent endonuclease inhibitor. Neuraminidase inhibitors are the mainstay of the avian influenza treatment and includes oseltamivir, peramivir, and zanamivir. Baloxavir marboxil is a cap-dependent endonuclease inhibitor. This clinical review aims to highlight the background, epidemiology, clinical presentation, complications and current treatment and prevention strategies for avian influenza H5N1.

Background: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) have been shown to improve cardiovascular outcomes by reducing low-density lipoprotein cholesterol (LDL-C). However, sex differences in the efficacy of evolocumab remain unclear. This study aimed to investigate sex differences in the efficacy of evolocumab using real-world data.

Method: Data were collected from the First Affiliated Hospital of Guangxi Medical University. A total of 416 eligible patients were selected from 1463 patients treated with evolocumab for secondary prevention. Clinical data, including individual characteristics and lipids profiles, were recorded. Propensity score matching (PSM) was used to control for potential confounders, with covariates including age, body mass index, smoking status, and diabetes. All eligible participants were propensity-matched 1:1 for female versus male with a match tolerance of 0.02. The efficacy of evolocumab in females and males was compared by PSM-adjusted analysis.

Results: In the PSM analysis, a significant difference was found in the relative percentage reduction of LDL-C between females and males (-42.7% vs. -54.4%, p < 0.001). In addition, the absolute LDL-C reduction was lower in females compared to males (interquartile range: -1.5 [-2.2, -0.8] mmol/L vs. -1.9 [-2.5, -1.0] mmol/L, p = 0.018). The rate of target LDL-C attainment was lower in females than in males after treatment with evolocumab (21.6% vs. 39.8%, p = 0.009).

Conclusion: These results suggest that males have a better response to evolocumab in term of LDL-C reduction compared to females.

Cannabinoids have emerged as a potential treatment for obstructive sleep apnea (OSA). This systematic review aimed to summarize the efficacy and safety of cannabinoids to treat OSA. Databases including Ovid MEDLINE, EMBASE, Scopus, PsycINFO, and International Pharmaceutical Abstracts were searched; experimental and observational studies were eligible for inclusion. One-hundred seventy unique records were screened, and nine studies included: five full-text studies and four published abstracts. The five full-text studies were judged for quality appraisal: two studies deemed at low risk for bias, one study deemed to have some concerns for bias, and two studies deemed to have high risk for bias. Seven of nine total studies were experimental designs and evaluated dronabinol, and the other two studies were observational designs evaluating cannabis. The range of cannabinoid therapy duration spanned from 1 to 6 weeks, and the median duration was 3 weeks. Eight of nine total studies reported statistically significant, positive OSA outcomes due to cannabinoid therapy including reductions in the apnea hypopnea index and improvements in patient-reported daytime sleepiness scales. Between 70% and 80% of study participants reported neuropsychiatric and gastrointestinal adverse events attributable to cannabinoids. The American Academy of Sleep Medicine does not recommend using cannabinoids to treat OSA due to a lack of long-term safety and efficacy data. This systematic review found similar limitations, with the median cannabinoid treatment duration being only 3 weeks. Adequately powered experimental trials over longer time frames are necessary to more completely assess the long-term efficacy and safety of cannabinoids in the treatment of OSA and its effects on common comorbid conditions, such as obesity and cardiovascular disease.

Introduction: There is a paucity of data evaluating early initiation of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with diabetes following acute coronary syndrome (ACS) and coronary artery bypass graft surgery (CABG).

Objectives: To describe the efficacy and safety of SGLT2i initiated early after CABG in patients with type 2 diabetes who experienced ACS.

Methods: This is a retrospective cohort study of patients with type 2 diabetes (T2DM) who experienced ACS and subsequent CABG with follow up at 3 and 12 months. Patients who filled a SGLT2i prescription within 14 days of discharge were allocated to the SGLT2i group and those who did not were included in the no SGLT2i group. The primary efficacy end point was first occurrence of a 4-point Major Adverse Cardiovascular Event (MACE), and the primary safety end point was a composite of hypoglycemia, hypotension, diabetic ketoacidosis, acute kidney injury, and urinary tract infection. Secondary end points included a comparative analysis of the primary outcome, 30-day readmission rates, and subgroup analyses of key populations.

Results: A total of 1629 patients were included: 226 received a SGLT2i within 14 days of discharge and 1403 did not. At 12 months, 8.9% and 15.3% of patients experienced MACE in the SGLT2i and no SGLT2i groups, respectively (adjusted Hazard Ratio [aHR] 0.65, 95% confidence interval [CI] 0.41-1.04). The primary safety outcome occurred in 12.0% of the SGLT2i group and 19.1% of the no SGLT2i group at 12 months (aHR 0.68, 95% CI 0.45-1.01).

Conclusion: Early initiation of SGLT2i use was not associated with a reduction in MACE in patients with T2DM who experienced ACS and underwent subsequent CABG surgery. However, no apparent safety concerns were identified. Adequately powered trials are required to confirm this finding.

Introduction: The concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) and proton pump inhibitors (PPIs) potentially increases the risk of acute kidney injury (AKI). However, the risk of AKI has not been comprehensively assessed for the concomitant use of NSAIDs with gastroprotective agents such as misoprostol and PPIs. The objective of this study was to evaluate whether the use of various gastroprotective agents affects the risk of AKI in patients receiving NSAIDs.

Methods: The data analyzed were obtained from the JMDC hospital-based administrative claims database between April 2014 and August 2022. Histamine-2 receptor antagonists (H2RAs) were compared with PPIs or misoprostol in patients receiving NSAIDs. The primary outcome was the incidence of AKI. The covariates considered were age and sex, admission to intensive care unit, presence of comorbidities based on the modified Charlson Comorbidity Index, and use of renin-angiotensin system inhibitors, loop diuretics, other diuretics, and lithium. AKI was identified by changes in serum creatinine. The distribution of AKI was analyzed using the log-rank test, and estimates of the incidence of AKI were compared among the groups using a Cox proportional hazards model with time-varying variables. Models were adjusted using a doubly robust method that accounts for the inverse probability of treatment weighting at baseline while adjusting for covariates.

Results: After screening, 11,688 patients were eligible for inclusion (1729 for H2RAs, 368 for misoprostol, and 9591 for PPIs). AKI occurred in 0.5% of H2RA recipients and 1.1% of PPI recipients; no AKI was observed in the misoprostol group. Compared with H2RAs, the risk of AKI tended to be higher with PPIs (adjusted hazard ratio 1.83, 95% confidence interval 0.92-3.63, p = 0.08).

Conclusion: Compared with H2RAs, PPIs may increase the risk of AKI in patients receiving NSAIDs, although no statistically significant difference was observed. Further research is required to assess the risk trade-off with consideration of both peptic ulcer prevention and the increased risk of AKI in patients concurrently treated with NSAIDs and H2RAs, misoprostol, or PPIs.

Background: Clinical trials have shown the kidney-protective benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i). However, their real-world impact, particularly across varying levels of albuminuria, remains less well understood. This study aimed to evaluate the association of SGLT2i, compared with other oral glucose-lowering drugs, with end-stage kidney disease (ESKD) progression in patients with type 2 diabetes and chronic kidney disease (CKD) stratified by urine albumin-to-creatinine ratio (UACR) levels.

Methods: Using data from a national database spanning from 2016 to 2021, the study included patients with type 2 diabetes and CKD with estimated glomerular filtration rates (eGFRs) below 60 mL/min/1.73 m² and who started on SGLT2i or other oral glucose-lowering drugs. Patients were stratified into groups by UACR ≥300 mg/g and <300 mg/g. Propensity score matching was used to minimize confounding, and progression to ESKD was evaluated using competing risks and Cox proportional-hazards models. All-cause mortality was also analyzed.

Results: Following propensity score matching, 18,514 patients in the severely increased albuminuria group (UACR ≥300 mg/g) were tracked, with 2.6% progressing to ESKD over 3 years. In contrast, only 0.3% of the 26,946 patients with UACR <300 mg/g progressed to ESKD. SGLT2i use was associated with a 30% reduction in risk of ESKD progression, compared with the use of other oral glucose-lowering drugs, in the severely increased albuminuria group (hazard ratio[HR]: 0.70, 95% confidence interval [CI]: 0.61-0.80). In the lower albuminuria group, no significant association was evident, though there was a nonsignificant trend toward protection over time. A consistent reduction in mortality risk was observed across all albuminuria levels.

Conclusions: SGLT2i are associated with a reduction in the progression to ESKD among patients with severely increased albuminuria, with less pronounced effects observed in those with lower albuminuria levels, suggesting variability in renal outcomes based on albuminuria severity. The consistent survival benefit across all albuminuria levels supports the potential utility of SGLT2i in diabetes and CKD treatment strategies, emphasizing the need for more targeted research.