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

项目总结/文摘

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.