Modulatory Role of Blood-Brain-Barrier and Enzymatic Activity in an Innovative Human Model of Cholinergic Drug Induced Dementia

血脑屏障和酶活性在胆碱能药物诱发痴呆的创新人类模型中的调节作用

• 批准号: 10467040
• 负责人: James J Hickman
• 金额: $ 90.23万
• 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/10467040
• 关键词: Acetylcholinesterase Inhibitors; Acute; Address; Adverse drug event; Adverse event; Algorithms; Alzheimer' s Disease; Alzheimer' s disease model; Anti-Cholinergics; Applications Grants; Astrocytes; Biological Assay; Biotechnology; Blood - brain barrier anatomy; Burn injury; Caring; Cause of Death; Cells; Characteristics; Cholinergic Agents; Cholinergic Receptors; Chronic; Clinical; Cognitive; Collaborations; Constipation; Consumption; Cytochrome P450; Cytochromes; Data; Databases; Delirium; Dementia; Disease; Disease model; Dose; Drug Combinations; Drug Evaluation; Drug Interactions; Drug Kinetics; Drug usage; Elderly; Evaluation Research; Event; Expenditure; Frail Elderly; Government; Healthcare; Hospitalization; Human; Impaired cognition; Impulsive Behavior; In Vitro; Individual; Institutes; Intake; Journals; Knowledge; Learning; Legal patent; Life; Literature; Liver; Long-Term Potentiation; Measurement; Measures; Medical; Medical Care Costs; Memory; Metabolic; Microelectrodes; Modeling; Neuraxis; Neurons; Organ; Organ Model; Outcome; Paper; Patient-Focused Outcomes; Patients; Peer Review; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Pharmacotherapy; Physiology; Pneumonia; Polypharmacy; Population; Production; Property; Publications; Regimen; Research Contracts; Risk; Role; Services; System; Technology; Testing; Therapeutic; Translating; Xerostomia; abeta oligomer; adverse event risk; antagonist; base; burden of illness; cholinergic; clinically relevant; comorbidity; dementia risk; donepezil; drug metabolism; eye dryness; falls; health care model; high risk; human model; improved; in vitro Model; induced pluripotent stem cell; information processing; innovation; liver metabolism; mutant; older patient; organizational structure; pharmacokinetics and pharmacodynamics; pre-clinical; presenilin-1; risk stratification; screening; simulation; 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.

项目摘要/摘要 与多药和不适当使用相关的伯宁是死亡的第三大主要原因 美国。随着年龄的增长，提供医疗服务可能会带来挑战，因为这些患者有可能 合并症，疾病的烧伤最大。有未满足的方法需要适当的方法和 创新的工具不仅可以识别药物，还可以识别与药物相关风险最高风险相关的药物方案 不良事件（ADE）。文献中经常引用具有抗胆碱能特性的药物 作为增加ADE的主要原因。由此产生的处方级联增加了多药的风险 用于代谢许多药物的酶促系统的相互作用（例如细胞色素P450超家族） 具有抗胆碱能特性。因此，为解决这些情况而开发的创新方法和工具 不仅应该考虑单个药物药物特性，还应考虑与 多药摄入量和相互作用的影响。我们寻求使用Hesperos专利的多器官功能 研究药物诱导的痴呆症和阿尔茨海默氏病（AD）的系统 与Tabula Rasa Healthcare合作的抗胆碱能药物的信息处理 （TRHC）和我们的广告顾问，MSU的Dave Morgan博士。 TRHC创建了基本和临床算法 有助于定量评分AD的风险，包括评估药物抗胆碱能特性和多数 药物相互作用，特别了解竞争性抑制。通过通过 使用Hesperos的实验系统进行拟议的研究应提高风险的预测性 分层的可能性，有助于降低老患者的ADS风险，减少住院和 降低总体医疗费用。已经证明了TRHC的CDSS和风险分层策略的价值 由同行评审期刊的出版物和三项专利提交。很少有体外模型检查 中枢神经系统中的抗胆碱能药物特性，同时评估其抗胆碱能伯嫩和 痴呆症的风险，包括广告。这是一个基于功能测定的临床前筛选模型 正常和AD突变的人类细胞评估模仿抗胆碱能药物的影响 广告的各个方面启用了一个平台，以理解乘法效果并告知TRHC 药代动力学/药效学临床模型。没有其他评估抗胆碱能燃烧的模型 药物考虑了他们的剂量，治疗持续时间和伴随药物管理，导致了变化 在他们的性格中。长期增强的变化将用作认知读数，因为它是一种功能 已知与记忆和学习变化相关的测量。该神经元模块的整合 使用包括血脑屏障和具有功能性酶促系统的肝脏的系统，将允许测试 由于预期的多药相互作用而导致的组合疗法和变异性的变异性 在多药患者中观察到的影响药物代谢系统。