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

> **NIH NIH R44** · HESPEROS, LLC · 2021 · $902,320

## Abstract

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...

## Key facts

- **NIH application ID:** 10258975
- **Project number:** 1R44AG071386-01A1
- **Recipient organization:** HESPEROS, LLC
- **Principal Investigator:** James J Hickman
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $902,320
- **Award type:** 1
- **Project period:** 2021-08-15 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10258975

## Citation

> US National Institutes of Health, RePORTER application 10258975, Modulatory Role of Blood-Brain-Barrier and Enzymatic Activity in an Innovative Human Model of Cholinergic Drug Induced Dementia (1R44AG071386-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10258975. Licensed CC0.

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