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

项目摘要/摘要 与服用多种药物和不适当使用药物有关的负担是#年导致死亡的第三大原因。 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 并有最大的疾病负担。还有一种尚未得到满足的需求，即有适当的方法和 创新工具，不仅可以识别药物，还可以识别与药物相关风险最高的药物方案 不良事件(ADE)。具有抗胆碱能特性的药物在文献中经常被引用 作为ADE增加的一个主要原因。由此产生的处方连锁增加了多种药物的风险 代谢多种药物的酶系统(如细胞色素P450超家族)上的相互作用 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 不仅应考虑个别药物的药理特性，还应考虑与 多种药物摄取和相互作用的影响。我们寻求使用Hesperos的专利多功能器官功能 研究药物引起的痴呆症和阿尔茨海默病(AD)的系统 与Tabula Rasa Healthcare合作，在存在抗胆碱能药物的情况下进行信息处理 和我们的广告顾问，密歇根州立大学的戴夫·摩根博士。TRHC已经创建了基本和临床算法， 帮助对ADE的风险进行量化评分，包括评估药物的抗胆碱能特性和多个 药物相互作用，特别关注竞争抑制。通过以下方式增加对这些因素的了解 用Hesperos的实验系统进行拟议的研究应提高风险的可预测性 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，以及 降低总体医疗成本。TRHC的CDSS和风险分层战略的价值已经得到证明 通过在同行评议期刊上发表文章和申请三项专利。很少有体外模型可以检验 中枢神经系统中抗胆碱能药物的特性，同时评估它们与抗胆碱能负荷和 患痴呆症的风险，包括阿尔茨海默病。因此，基于功能分析的临床前筛查模型由以下组成 在模拟条件下评估抗胆碱能药物对正常和AD突变人类细胞的影响 AD的方方面面为理解乘法效应和告知TRHC 药代动力学/药效学临床模型。没有其他模型评估阿司匹林的抗胆碱能负荷。 药物考虑到它们的剂量、治疗持续时间和导致变化的伴随用药 在他们的性格中。长时程增强的变化将被用作认知读数，因为它是功能性的 已知的测量与记忆和学习的变化相关。这个神经元模块的整合 如果系统包括血脑屏障和具有功能酶系统的肝脏，将允许测试 由于预期的多药相互作用，联合疗法及其代谢处置的可变性 观察到多药联用对药物代谢系统的影响。

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.