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

项目总结/摘要 与多种药物和不适当的药物使用相关的负担是死亡的第三大原因， 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以下风险： 合并症和最大的疾病负担。需要有适当的方法， 创新工具，不仅用于确定药物，而且用于确定与药物相关疾病最高风险相关的药物治疗方案 不良事件（ADE）。文献中经常引用具有抗胆碱能特性的药物 是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（如细胞色素P450超家族）的相互作用 具有抗胆碱能特性因此，为应对这些情况而开发的创新办法和工具 不仅应考虑单个药物的药理学特性，还应考虑与 多种药物摄入和相互作用的影响。我们试图利用赫斯珀罗斯专利的多器官功能 系统来研究药物诱导的痴呆和阿尔茨海默病（AD）的基础缺陷， 与Tabula Rasa HealthCare合作，在抗胆碱能药物存在下进行信息处理 （TRHC）和我们的广告顾问，博士戴夫摩根在密歇根州立大学。TRHC创建了基本和临床算法， 有助于对ADE的风险进行定量评分，包括评估药物抗胆碱能特性和多种 药物相互作用，特别关注竞争性抑制。通过以下方式增加对这些因素的了解： 利用赫斯珀罗斯的实验系统进行拟议的研究，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，减少住院治疗， 降低整体医疗成本。TRHC的CDSS和危险分层策略的价值已经得到证实 通过在同行评审期刊上发表文章和申请三项专利。很少有体外模型可以检测 CNS中的抗胆碱能药物特性，同时评估其与抗胆碱能负荷和 痴呆症的风险，包括AD。因此，基于功能测定的临床前筛选模型由以下组成： 正常和AD突变的人细胞，以评估抗胆碱能药物在模拟 AD的各个方面为理解倍增效应提供了一个平台， 药代动力学/药效学临床模型。没有其他评估抗胆碱能负荷的模型 药物应考虑其剂量、治疗持续时间和导致变化的伴随药物给药 在他们的处置。长时程增强的变化将被用作认知读数，因为它是一种功能性的 已知与记忆和学习变化相关的测量。这个神经元模块的整合 一个包括血脑屏障和具有功能酶系统的肝脏的系统将允许测试 由于预期的多药物相互作用， 影响药物代谢系统，如在多药患者中观察到的。

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.