TitlePharmacokinetics and Pharmacodynamics of Key Components of a Standardized Product in Cognitively Impaired Older Adults: A Phase 1, Double-Blind, Randomized Clinical Trial.
Publication TypeJournal Article
Year of Publication2022
AuthorsWright KM, Bollen M, David J, Speers AB, Brandes MS, Gray NE, Magana AAlcazar, McClure C, Stevens JF, Maier CS, Quinn JF, Soumyanath A
JournalAntioxidants (Basel)
Date Published2022 Jan 23

is reputed in Eastern medicine to improve cognitive function in humans. Preclinical studies have demonstrated that aqueous extracts of improve cognition in mouse models of aging and Alzheimer's disease (AD) through the modulation of mitochondrial biogenesis and nuclear factor-erythroid-2-related factor 2 (-dependent antioxidant response genes. This randomized, double-blind, crossover Phase I trial explored the oral bioavailability and pharmacokinetics of key compounds from two doses (2 g and 4 g) of a standardized aqueous extract product (CAP), over 10 h, in four mildly demented older adults on cholinesterase inhibitor therapy. The analysis focused on triterpenes (TTs) and caffeoylquinic acids (CQAs), which are known to contribute to 's neurological activity. The acute safety of CAP and the effects on gene expression in peripheral blood mononuclear cells were evaluated. Single administration of 2 g or 4 g of CAP was safe and well-tolerated. The TT aglycones, asiatic acid and madecassic acid, were identified in plasma and urine, while the parent glycosides, asiaticoside and madecassoside, although abundant in CAP, were absent in plasma and had limited renal excretion. Similarly, mono- and di-CQAs showed delayed absorption and limited presence in plasma or urine, while the putative metabolites of these compounds showed detectable plasma pharmacokinetic profiles and urinary excretion. CAP elicited a temporal change in gene expression, mirroring the TT aglycone's pharmacokinetic curve in a paradoxical dose-dependent manner. The oral bioavailability of active compounds or their metabolites, target engagement, and the acute safety and tolerability of CAP support the validity of using CAP in future clinical studies.

Alternate JournalAntioxidants (Basel)
PubMed ID35204098
PubMed Central IDPMC8868383
Grant ListP30 AG066518 / AG / NIA NIH HHS / United States
R61AT009628 / AT / NCCIH NIH HHS / United States
T32AT002688 / AT / NCCIH NIH HHS / United States
KL2 TR002370 / TR / NCATS NIH HHS / United States
UL1TR002369 / TR / NCATS NIH HHS / United States
S10RR027878 / RR / NCRR NIH HHS / United States
KL2TR002370-03S1 / AT / NCCIH NIH HHS / United States
UL1 TR002369 / TR / NCATS NIH HHS / United States
P30AG008017 / AG / NIA NIH HHS / United States
T32 AT002688 / AT / NCCIH NIH HHS / United States