Clinical therapeutics最新文献

Background: Cardiovascular diseases (CVD) affect about 6% of the global population and are a leading cause of death. Gout impacts approximately 3% of the population, and many do not receive adequate urate-lowering therapy to prevent disease progression. Gout is frequent in patients with CVD, and poorly managed gout is associated with cardiovascular complications, warranting proper gout treatment. This study assessed adherence to recommended gout treatment in patients with CVD.

Methods: From a prospective cohort of gout patients confirmed by microscopy-identified urate crystals, we identified those with concomitant CVD (ischemic heart disease, atrial fibrillation, or heart failure). Patients were treated in real-life healthcare settings. The primary outcome was achieving recommended target serum urate levels 2 years postdiagnosis: <0.36 mmol/L for general gout management and <0.30 mmol/L for patients with tophi.

Results: Of 286 gout patients, 117 (41%) had CVD. The median age was 71 years, 76% were male, and most had multiple comorbidities. Recommended urate levels to prevent disease progression were achieved by 59%. However, 45% had tophi at diagnosis, and only 33% of these achieved levels sufficient to dissolve tophi. The mean prescribed dose of allopurinol was 253 mg/day, which was often insufficient to achieve target urate levels.

Conclusion: Gout in patients with CVD is often inadequately managed, potentially increasing the risk of serious cardiovascular events. These findings reflect typical treatment settings. Optimizing allopurinol dosing and adherence to gout treatment guidelines may improve gout-related outcomes and could potentially have implications for cardiovascular risk. These findings highlight gout as a relevant comorbidity in patients with CVD and suggest that greater attention to gout management in cardiovascular care pathways may be warranted.

Purpose: This randomized, double-blind, multicenter, phase III clinical trial aimed to evaluate the efficacy and safety of telmisartan 20 mg and s-amlodipine 1.25 mg, a fixed-dose combination (Tel/S-Amlo) versus telmisartan 20 mg single therapy or s-amlodipine 1.25 mg single therapy for initial treatment in patients with hypertension.

Methods: After a wash-out/therapeutic lifestyle change period of ≥4 weeks, a total of 235 eligible patients were randomized and received 1 of 3 treatments for 8 weeks: (1) telmisartan 20 mg/s-amlodipine 1.25 mg (Tel/S-Amlo), (2) telmisartan 20 mg (Tel), or (3) S-amlodipine 1.25 mg (S-Amlo). The primary endpoint was the efficacy evaluation of Tel/S-Amlo by comparing changes in mean sitting systolic blood pressure (msSBP) from baseline after 8 weeks of treatment.

Findings: At 8 weeks, the least square (LS) mean (SE) change in msSBP was -20.04 (1.46) mm Hg in the Tel/S-Amlo group, compared with -16.44 (1.46) mm Hg in the Tel group (between-group difference -3.60 (1.78) mm Hg, P-value = 0.0451). Similarly, the Tel/S-Amlo group showed a change of -21.12 (1.33) mm Hg versus -15.58 (1.32) mm Hg in the S-Amlo group (between-group difference -5.53 (1.61) mm Hg, P-value = 0.0008). There were no statistically significant differences in the incidence of overall AEs and adverse drug reactions among the 3 groups, and no serious adverse events occurred during the study.

Implications: Combination therapy with a low-dose of telmisartan and s-amlodipine may be a promising initial treatment for patients with hypertension.

Clinical trial registration: This study was registered in ClinicalTrials.gov (NCT06121518).

Purpose: Pembrolizumab and nivolumab, programmed death-1 (PD-1) antibodies, are currently approved for treating head and neck squamous cell carcinoma (HNSCC). This study aimed to identify and characterize adverse events (AEs) associated with these agents and to compare their safety profiles in order to provide clinical guidance.

Methods: AEs reports were extracted from the US Food and Drug Administration Adverse Event Reporting System (FAERS). Data for pembrolizumab spanned from Q3 2016 to Q4 2024, while nivolumab data covered Q4 2016 to Q4 2024. We employed the reporting odds ratio (ROR) and proportional reporting ratio (PRR) to evaluate AEs signals associated with pembrolizumab and nivolumab in HNSCC treatment. A signal was defined as meeting the following criteria: a ≥3, ROR 95% confidence interval lower limit >1.0, PRR ≥ 2, χ² value ≥4.

Findings: A total of 1562 AE reports were retrieved from FAERS, with 428 for pembrolizumab and 1134 for nivolumab. Reports for males were more than four times as common as reports for females. As for pembrolizumab and nivolumab, patients aged 65 to 85 and 18 to 64.9 years reported the highest number of AEs. Interestingly, pembrolizumab was associated with 11 unexpected AEs, including pulmonary mass, cirrhosis, and Pneumocystis jirovecii pneumonia, whereas nivolumab was linked to 16 unexpected AEs, such as cardiac failure, device-related infection, and falls. Additionally, sex-based differences and similarities were observed in AE profiles between the two treatments.

Implications: Providing real-world evidence on the AE profiles of pembrolizumab and nivolumab in patients with HNSCC, our study highlights important sex-based differences and suggests that clinicians should consider potential sex-specific AEs when using these PD-1 inhibitors.

Purpose: The evolution of Severe Acute Respiratory Syndrome Coronavirus 2 challenged the effectiveness of vaccines, while monoclonal antibodies (mAbs) were discontinued due to emergent resistance. This study evaluated the safety and explored the preliminary efficacy of COR-101, a novel mAb with a silenced Fc region designed to minimize antibody-dependent enhancement in hospitalized patients with moderate-to-severe disease.

Methods: Thirty-three participants were enrolled across Germany and Ukraine in a randomized, double-blind, placebo-controlled Phase Ib/II trial. Patients received either a single dose of COR-101, or placebo, as add-on therapy to the standard of care.

Findings: COR-101 was well tolerated, with no treatment-related severe adverse events (AEs), grade ≥3 AEs, or acute infusion reactions. Four unrelated severe AEs were observed, and 2 patients died due to coronavirus disease 2019. COR-101 showed dose-proportional pharmacokinetics, long half-life, and serum concentrations above IC₅₀. Patients were treated in different dose groups, and in exploratory analysis, viral clearance was observed at day 28 in 80%, 55.6%, 16.7%, and 42.9% of patients in the 4.0, 10.0, 25.0 mg/kg, and placebo groups, respectively. The predominant virus variant changed from alpha to delta and omicron, resulting in reduced in vitro neutralization, potentially explaining the observed reduced efficacy.

Implications: COR-101 demonstrated a favorable safety profile, but exploratory data showed limited efficacy against omicron, highlighting the tolerability of Fc-silenced mAbs and the need for adaptive therapeutic strategies against rapidly evolving viral pathogens (ClinicalTrials.gov identifier: NCT04674566).

Background: Asthma and chronic obstructive pulmonary disease are common respiratory disorders with significant global health implications. Budesonide/formoterol (Symbicort) is a fixed-dose inhaler combining budesonide and formoterol fumarate dihydrate, widely used for disease management. While its clinical efficacy is well established, there is an increasing number of adverse drug event (ADE) reports, highlighting the need for thorough real-world safety evaluations.

Methods: We performed a retrospective pharmacovigilance study using three major spontaneous reporting systems: the US Food and Drug Administration Adverse Event Reporting System (FAERS), the Japanese Adverse Drug Event Report (JADER), and the Canada Vigilance Adverse Reaction Database (CVARD). We used multiple disproportionality algorithms, including reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker for signal detection. Additionally, subgroup and sensitivity, along with logistic regression, were performed. Weibull distribution and log-rank testing were used to assess event timing.

Results: A total of 30,689 ADEs were identified in FAERS, spanning 27 system organ classes. Expected signals such as cough, dysphonia, and bronchitis were confirmed. Unexpected events included dyspnea, visual and memory impairment, coronary artery embolism, and asthmatic crisis. Sex-stratified analysis revealed female-specific risks (eg, malaise, bronchitis, alopecia, weight gain) and male-specific risks (eg, dysuria, myocardial infarction). Younger patients (<18 years) were at higher risk for asthmatic crisis, whereas older patients (>65 years) showed a protective effect. The median onset of ADEs was 55 days. Distinctive signals emerged from JADER (eg, pneumonia, liver injury) and CVARD (eg, hemoptysis, hypothyroidism).

Conclusions: This multi-database analysis highlights the need for continuous pharmacovigilance for budesonide/formoterol. The identification of novel ADE signals emphasizes the importance of vigilant monitoring, especially during early treatment, to enhance safety and therapeutic outcomes.

Purpose: Hereditary anemias are a cause of nonimmune hydrops fetalis (NIHF). Our objective was to review the spectrum of hereditary anemia genes in NIHF diagnosed by exome sequencing (ES).

Methods: We performed a systematic review of ES studies in NIHF from January 1, 2000 to August 1, 2024 with emphasis on genes causing fetal anemia as a primary phenotype.

Findings: Forty-one ES studies with 207 genetically diagnosed NIHF cases met our inclusion criteria; 6 cases within 6 studies involved NIHF and hereditary anemia. Among the six cases, five had definitive diagnosis or likely diagnosis supported by pathogenic or likely pathogenic variants, while one case harbored only variants of uncertain significance and was classified as a possible diagnosis. The six different hereditary anemia genes included SEC23B, SPTA1, KLF1, RPL11, UNC13D, and RFWD3.

Implications: Overall, ES confirmed the etiology of hereditary anemia in 2.4% (5/207) of genetically diagnosed NIHF cases. Hereditary anemias, therefore, represent a distinct and clinically relevant subset of ES-diagnosed NIHF cases. ES should be considered first line in fetuses with NIHF, as common non-genetic causes such as fetomaternal hemorrhage, infectious etiologies, and alloimmunization are excluded. It is also indicated when fetal anemia is suspected, particularly in the setting of elevated MCA Dopplers with a negative evaluation for common hemoglobinopathies and nongenetic etiologies.