Pharmacotherapy最新文献

Obesity continues to be a significant global health challenge, affecting over 800 million individuals worldwide. Traditional management strategies, including dietary, exercise, and behavioral interventions, often result in insufficient and unsustainable weight loss. Lifestyle modification remains the cornerstone of obesity management, providing the foundation for other strategies. While options such as bariatric surgery remain an effective intervention for severe obesity, it is associated with its own set of risks and is typically reserved for patients who have not achieved the desired results with pharmacotherapy and lifestyle interventions. Incretin hormone agonists represent a significant advancement in the pharmacotherapy of obesity, offering substantial weight reduction and cardiometabolic benefits. Agents like liraglutide, semaglutide, and tirzepatide supported by key clinical trials such as Satiety and Clinical Adipose Liraglutide Evidence (SCALE), Semaglutide Treatment Effect in People with Obesity (STEP) program trials, and Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1) have demonstrated remarkable efficacy in promoting weight loss and improving metabolic outcomes. Additionally, novel therapies, including dual and triple incretin agonists, are under investigation and hold the potential for further advancements in obesity treatment. These novel therapies can be categorized by their mechanisms of action and route of administration into oral glucagon-like peptide-1 (GLP-1) receptor agonists, triple agonists (targeting GLP-1, glucose-dependent insulinotropic polypeptide [GIP], and glucagon receptors), and glucagon receptor-GLP-1 receptor co-agonists. Other innovative approaches include oral GIP-GLP-1 receptor co-agonists, and the combination of long-acting amylin receptor agonists with GLP-1 receptor agonists. The ongoing development of incretin-based therapies and the expanding availability of currently available agents are expected to enhance clinical outcomes further and reduce the burden of obesity-related health complications. This review aims to discuss the mechanisms and efficacy of current and emerging incretin hormone agonists for obesity management.

Introduction: Lamotrigine (LTG) is an antiepileptic drug that has been used in pediatric epilepsy as a combination therapy or monotherapy after stabilization in recent years. However, there are significant drug-drug interactions (DDI) between LTG and combined drugs such as carbamazepine (CBZ) and valproic acid (VPA). It is particularly important to consider the risk of DDI in combination therapy for intractable epilepsy in pediatric patients. Therefore, it is necessary to adjust the dosage of LTG accordingly. The aim of this study was to establish and validate a pediatric physiologically based pharmacokinetic (PBPK) model for predicting LTG exposure. The model is designed to explore the potential for quantifying pharmacokinetic (PK) DDI of LTG when administered concurrently with CBZ or VPA in pediatric patients.

Method: Adult and pediatric PBPK models for LTG and VPA were developed using PK-Sim® software in combination with physiological information and drug-specific parameters, and a DDI model was developed in combination with the published CBZ model. The models were validated against available PK data.

Results: Predictive and observational results in adults, children, and the DDI model were in good agreement. The recommended doses of LTG for preschool children (2-6 years) and school-aged children (6-12 years) in the absence of drug interactions were 1.47 and 1.2 times higher than those for adults, respectively; 3.1 and 2.6 times higher than those for adults in combination with CBZ; and 0.67 and 0.57 times lower than those for adults in combination with VPA. In addition, plasma exposures in adolescents (12-18 years) were similar to those in adults at the same doses.

Conclusion: We have successfully developed PBPK models and DDI models for LTG in adults and children, which provide a reference for rational drug use in the pediatric population.

This article reflects on the potential value and many pitfalls of underpowered studies to help authors and readers consider whether and how they contribute meaningfully to the published literature. A basic introduction to power and sample size calculations is provided. Several problems that can arise in analysis and publication of underpowered studies are described. In addition, features of underpowered studies that may provide value are proposed, including when the hypothesis test of interest is a limited part of the story, the data is rich enough to showcase interesting features of the population of interest, when the rarity or ubiquity of events is an important finding, and when the study is preregistered to reduce the impact of publication bias. Several reporting guidelines for underpowered studies are also suggested.

Background: Kidney transplant recipients are at higher risk of infections due to immunosuppression, especially in the perioperative period after receiving induction therapy. Administration of iron has been linked to bacterial infections. This study investigated if receipt of intravenous iron at the time of kidney transplant increased bacterial infections post-transplant.

Methods: This single-center, retrospective study compared patients who received intravenous iron at the time of kidney transplant to those who did not. Patients were followed for 12 weeks after transplant. The primary outcome was incidence of bacterial infections following transplant; hemoglobin and transfusion needs were also examined.

Results: A total of 416 patients who received intravenous iron were compared to 416 patients who did not. Bacterial infections were similar between groups (14.4% iron group vs. 15.9% non-iron group). Intravenous iron did not influence bacterial infections on univariable or multivariable analyses when other infection confounders were accounted for. Patients who did not receive intravenous iron required more packed red blood cell transfusions in the 3 months following transplantation, but this was driven by factors other than intravenous iron as demonstrated by a post-hoc analysis.

Conclusions: Intravenous iron did not increase the risk of bacterial infections in the immediate post-kidney transplant setting. Bacterial infections after transplant were associated with female sex, increasing age at transplant, receipt of transfusions, and increased duration of urinary catheters.

Background: Heterozygous familial hypercholesterolemia (HeFH) is a genetic condition that is associated with a high risk of atherosclerotic cardiovascular disease (ASCVD) due to elevated lipid levels. Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody inhibitors have been shown to reduce low-density lipoprotein cholesterol (LDL-C) substantially. This study aimed to assess the real-world effectiveness of PCSK9 inhibitor therapy among patients with HeFH.

Methods: Retrospective cohort study of patients with probable or definite HeFH on a PCSK9 inhibitor at a specialized lipid clinic between 2015 and 2022. The primary objective was the proportion of patients who attained a ≥50% reduction in LDL-C after 12 months of treatment.

Results: In total, 141 patients were screened and 95 were included. Mean age was 63 years, 51% were female, and mean baseline LDL-C level was 4.0 mmol/L (155 mg/dL). A majority of patients (60%) had statin intolerance, and 73% were on ezetimibe. The most common PCSK9 inhibitor was evolocumab (94%). Overall, 74% of patients achieved a ≥50% reduction in LDL-C after 12 months of therapy. Mean LDL-C concentration decreased to 1.7 mmol/L (66 mg/dL) (approximately 59% reduction from baseline) after 12 months of follow-up but increased to 1.9 mmol/L (73 mg/dL) after ≥24 months of follow-up. Similar trends were observed in non-high-density lipoprotein cholesterol and apolipoprotein B. Lipoprotein(a) was significantly reduced by 45% over 12 months. Twelve percent of patients permanently discontinued therapy. Barriers to PCSK9i use were mostly related to cost.

Conclusions: In a real-world cohort of HeFH patients, most of which were intolerant to statins, a high majority were able to achieve a ≥50% reduction in LDL-C after 12 months of PCSK9 inhibitor therapy (mean reduction of approximately 59%), which is similar to clinical trial data of patients with ASCVD. A significant reduction in non-high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) were also observed.

Background: One of the goals established by the United States National Action Plan to Combat Antibiotic-Resistant Bacteria is to reduce inappropriate outpatient antibiotic prescriptions by 50% by 2020. Recent data on the achievement of this goal is lacking. The objective of our study was to examine recent trends in the appropriateness of oral antibiotic prescriptions dispensed to a commercially insured population in outpatient settings in the United States to quantify the relative trend in inappropriate antibiotic prescribing from 2010 to 2018.

Methods: Our cross-sectional analysis examined oral antibiotic prescriptions dispensed in outpatient settings using the IBM MarketScan Commercial Data from January 2010 to December 2018. Trends in the annual proportion of antibiotic prescriptions classified as appropriate, potentially appropriate, inappropriate, or without any medical visit during a 7 days look-back period were estimated using multivariable generalized linear models with Poisson distribution adjusting for beneficiaries' demographic and infectious conditions.

Results: Approximately 170 million oral antibiotic prescriptions were dispensed to 86 million beneficiaries during 2010 to 2018. The mean age of the study population was 34.5 (±19.1) years, with 58.4% females and 24.6% children. We observed a 12.9% (95% Confidence Interval [CI] = 12.6%-13.2%; p < 0.01) decline in rates of antibiotic use, from 832 to 727 prescriptions per 1000 beneficiaries, from 2010 to 2018. The proportion of prescriptions classified as appropriate increased by 36.7% (95% CI = 36.4%-36.9%; p < 0.01); potentially appropriate prescriptions increased by 9.3% (95% CI = 9.1%-9.4%; p < 0.01); whereas inappropriate prescriptions and those without a medical visit declined by 11.3% (95% CI = 11.2%-11.4%; p < 0.01) and 14.0% (95% CI = 13.9%-14.2%; p < 0.01), respectively. Similar declining trends were observed in use and proportion of inappropriate prescriptions for broad-spectrum antibiotics. In 2018, amoxicillin and azithromycin were the most common appropriate and inappropriate prescription fills, respectively.

Conclusion: Although antibiotic use and inappropriate prescribing declined steadily from 2010 to 2018 in the United States, this study demonstrates that we have not achieved the national goal of reducing inappropriate antibiotic prescribing by 50%.