RESUMEN
The unintended modulation of nuclear receptor (NR) activity by drugs can lead to toxicities amongst the endocrine, gastrointestinal, hepatic cardiovascular, and central nervous systems. While secondary pharmacology screening assays include NRs, safety risks due to unintended interactions of small molecule drugs with NRs remain poorly understood. To identify potential nonclinical and clinical safety effects resulting from functional interactions with 44 of the 48 human-expressed NRs, we conducted a systematic narrative review of the scientific literature, tissue expression data, and used curated databases (OFF-X™) (Off-X, Clarivate) to organize reported toxicities linked to the functional modulation of NRs in a tabular and machine-readable format. The top five NRs associated with the highest number of safety alerts from peer-reviewed journals, regulatory agency communications, congresses/conferences, clinical trial registries, and company communications were the Glucocorticoid Receptor (GR, 18,328), Androgen Receptor (AR, 18,219), Estrogen Receptor (ER, 12,028), Retinoic acid receptors (RAR, 10,450), and Pregnane X receptor (PXR, 8044). Toxicities associated with NR modulation include hepatotoxicity, cardiotoxicity, endocrine disruption, carcinogenicity, metabolic disorders, and neurotoxicity. These toxicities often arise from the dysregulation of receptors like Peroxisome proliferator-activated receptors (PPARα, PPARγ), the ER, PXR, AR, and GR. This dysregulation leads to various health issues, including liver enlargement, hepatocellular carcinoma, heart-related problems, hormonal imbalances, tumor growth, metabolic syndromes, and brain function impairment. Gene expression analysis using heatmaps for human and rat tissues complemented the functional modulation of NRs associated with the reported toxicities. Interestingly, certain NRs showed ubiquitous expression in tissues not previously linked to toxicities, suggesting the potential utilization of organ-specific NR interactions for therapeutic purposes.
RESUMEN
Secondary pharmacology screening of investigational small-molecule drugs for potentially adverse off-target activities has become standard practice in pharmaceutical research and development, and regulatory agencies are increasingly requesting data on activity against targets with recognized adverse effect relationships. However, the screening strategies and target panels used by pharmaceutical companies may vary substantially. To help identify commonalities and differences, as well as to highlight opportunities for further optimization of secondary pharmacology assessment, we conducted a broad-ranging survey across 18 companies under the auspices of the DruSafe leadership group of the International Consortium for Innovation and Quality in Pharmaceutical Development. Based on our analysis of this survey and discussions and additional research within the group, we present here an overview of the current state of the art in secondary pharmacology screening. We discuss best practices, including additional safety-associated targets not covered by most current screening panels, and present approaches for interpreting and reporting off-target activities. We also provide an assessment of the safety impact of secondary pharmacology screening, and a perspective on opportunities and challenges in this rapidly developing field.
Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Animales , Industria Farmacéutica , Desarrollo de Medicamentos/métodos , Evaluación Preclínica de Medicamentos/métodos , Drogas en Investigación/farmacología , Drogas en Investigación/efectos adversosRESUMEN
Background: In the pivotal WATCHMAN trials, warfarin was used exclusively for postprocedural anticoagulation following left atrial appendage closure. We sought to investigate the safety and efficacy of direct oral anticoagulants (DOACs) in high-risk patients with atrial fibrillation who underwent left atrial appendage closure with WATCHMAN. Methods: This was a retrospective study of 318 patients who underwent the WATCHMAN procedure in a tertiary referral center (June 2016-September 2020). We compared the outcomes of patients who were discharged on DOACs versus warfarin after the WATCHMAN procedure. The primary outcome was the composite of any bleeding, thromboembolism, or cardiovascular death through 7 âdays and 45 âdays after the procedure. Results: The final analysis included 301 patients, of whom 82.4% (248/301) were discharged on DOACs and 17.6% (53/301) were discharged on warfarin. The mean CHA2DS2-VASc and HAS-BLED scores were 4.9 â± â1.6 and 2.9 â± â0.9, respectively. The primary composite outcome was similar between the DOAC and warfarin groups through 7 âdays (3.2% vs 5.6%; adjusted odds ratio [OR], 0.65; 95% confidence interval [CI], 0.13-3.17; P â= â.59) and 45 days after procedure (10.1% vs 11.3%; adjusted OR, 1.18; 95% CI, 0.41-3.45; P â= â.76). Major bleeding (5.2% vs 9.5%; P â= â.34) and all-cause readmission (12.5% vs 16.9%; P â= â.85) at 45 âdays were comparable between the DOAC and warfarin groups. The overall incidence of device-related thrombus and significant peri-device flow at 45 âdays were low (<0.5%). Conclusions: In high-risk patients with atrial fibrillation, the primary composite outcome of any bleeding, thromboembolism, or cardiovascular death through 7 âdays and 45 âdays following WATCHMAN implantation was similar in patients receiving DOACs versus warfarin.