Hesperos Diversity Supplement forgrant number 1 R44AG071386

Hesperos 多样性补充补助金编号 1 R44AG071386

• 批准号: 10577655
• 负责人: James J Hickman
• 金额: $ 16.27万
• 依托单位: HESPEROS, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10577655
• 关键词: Address; Adverse drug event; Adverse event; Algorithms; Alzheimer' s Disease; Anti-Cholinergics; Biological Assay; Blood - brain barrier anatomy; Caring; Cause of Death; Cells; Clinical; Cognitive; Collaborations; Cytochrome P450; Dementia; Dose; Drug Interactions; Drug Kinetics; Drug usage; Elderly; Frail Elderly; Healthcare; Hospitalization; Human; Individual; Intake; Journals; Knowledge; Learning; Legal patent; Literature; Liver; Long-Term Potentiation; Measurement; Medical; Medical Care Costs; Memory; Metabolic; Modeling; Neurons; Patients; Peer Review; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Polypharmacy; Production; Property; Publications; Regimen; Risk; System; Testing; Therapeutic; adverse event risk; base; burden of illness; comorbidity; dementia risk; drug metabolism; health care model; high risk; improved; in vitro Model; information processing; innovation; mutant; older patient; pre-clinical; risk stratification; screening; tool; treatment duration

Project Summary/Abstract The burden associated with polypharmacy and inappropriate drug use is the third leading cause of death in the USA. With advanced age, providing medical care can present challenges as these patients are at risk for comorbidities and have the largest burden of illness. There is the unmet need of having proper approaches and innovative tools to identify not only drugs but also drug regimens associated with the highest risk of drug-related adverse events (ADEs). Medications with anticholinergic properties have frequently been cited in the literature as a major cause for an increase in ADEs. The resulting prescription cascade increases the risk of multi-drug interactions on enzymatic systems (such as the Cytochrome P450 superfamily) used to metabolize many drugs with anticholinergic properties. Hence, innovative approaches and tools developed to address these situations should consider not only individual drug pharmacological properties but account for conditions associated with the impact of multi-drug intake and interactions. We seek to use Hesperos’ patented multi-organ functional systems to investigate drug-induced dementia and Alzheimer’s disease (AD) in terms of deficits in basic information processing in the presence of anticholinergic drugs in collaboration with Tabula Rasa HealthCare (TRHC) and our AD consultant, Dr. Dave Morgan at MSU. TRHC has created basic and clinical algorithms that help quantitatively score the risk of ADEs, including an assessment of drug anticholinergic properties and multi- drug interactions, with a special look at competitive inhibition. Increased knowledge on these factors through the conduct of proposed studies with Hesperos’s experimental systems shall improve the predictivity of risk stratification possibilities, help decrease the risk of ADEs in elderly patients, decrease hospitalizations, and reduce overall medical costs. The value of TRHC’s CDSS and risk stratification strategy has been demonstrated by publications in peer-review journals and filing of three patents. There are few in vitro models that examine anticholinergic drug properties in the CNS while assessing their association between anticholinergic burden and risk of dementia, including AD. Thus, a preclinical screening model based on functional assays composed of normal and AD mutant human cells to evaluate the effects of anticholinergic drugs in conditions mimicking aspects of AD enables a platform for understanding multiplicative effects and to inform TRHC’s pharmacokinetic/pharmacodynamic clinical models. No other models assessing the anti-cholinergic burden of drugs take into account their dose, duration of treatment and concomitant drug administration leading to a change in their disposition. Changes in Long-term Potentiation will be used as the cognitive readout as it is a functional measurement known to correlate with changes in memory and learning. The integration of this neuronal module with a system that includes a blood-brain-barrier and a liver with functional enzymatic systems would allow testing of combinational therapeutics and variability in their metabolic disposition due to expected multi-drug interactions impacting drug metabolism systems as observed in patients with polypharmacy.

项目概要/摘要 与多重用药和不当用药相关的负担是第三大死亡原因 在美国，随着年龄的增长，提供医疗护理可能会带来挑战，因为这些患者面临着患病的风险。 并存疾病是最大的疾病负担，而采取适当的方法和方法的需求尚未得到满足。 创新工具不仅可以识别药物，还可以识别与药物相关最高风险相关的药物治疗方案 具有抗胆碱能特性的药物经常在文献中被引用。 作为 ADE 增加的主要原因，由此产生的处方级联增加了多种药物的风险。 用于代谢许多药物的酶系统（例如细胞色素 P450 超家族）的相互作用 因此，开发了创新的方法和工具来解决这些情况。 不仅应考虑个体药物的药理学特性，还应考虑与药物相关的条件 我们寻求利用 Hesperos 的专利多器官功能。 研究药物引起的痴呆和阿尔茨海默病 (AD) 基础缺陷的系统 与 Tabula Rasa HealthCare 合作进行抗胆碱能药物存在下的信息处理 （TRHC）和我们的 AD 顾问，TRHC 的 Dave Morgan 博士创建了基本和临床算法。 帮助对 ADE 风险进行定量评分，包括评估药物抗胆碱能特性和多因素 药物相互作用，特别是通过竞争性抑制增加对这些因素的了解。 使用 Hesperos 实验系统进行拟议研究将提高风险的预测能力 分层的可能性，有助于降低老年患者发生 ADE 的风险，减少住院率，以及 降低总体医疗成本 TRHC 的 CDSS 和风险分层策略的价值已得到证明。 通过在同行评审期刊上发表文章并申请三项专利，很少有体外模型可以进行检查。 中枢神经系统中的抗胆碱能药物特性，同时评估抗胆碱能负荷与抗胆碱能药物之间的关联 因此，基于功能测定的临床前筛查模型包括： 正常和 AD 突变人类细胞，用于评估抗胆碱能药物在模拟条件下的作用 AD 的各个方面为理解乘法效应并为 TRHC 提供信息提供了一个平台 没有其他模型评估抗胆碱能负担。 考虑其剂量、药物治疗持续时间以及导致变化的伴随药物给药 长时程增强的变化将用作认知读数，因为它是功能性的。 已知与记忆和学习变化相关的测量结果。 包含血脑屏障和具有功能酶系统的肝脏的系统将允许进行测试 由于预期的多药物相互作用，组合疗法及其代谢分布的变异性 在多重用药患者中观察到影响药物代谢系统。