Cargando…

Pharmacokinetics and Pharmacodynamics of Key Components of a Standardized Centella asiatica Product in Cognitively Impaired Older Adults: A Phase 1, Double-Blind, Randomized Clinical Trial

Centella asiatica is reputed in Eastern medicine to improve cognitive function in humans. Preclinical studies have demonstrated that aqueous extracts of C. asiatica improve cognition in mouse models of aging and Alzheimer’s disease (AD) through the modulation of mitochondrial biogenesis and nuclear...

Descripción completa

Detalles Bibliográficos
Autores principales: Wright, Kirsten M., Bollen, Melissa, David, Jason, Speers, Alex B., Brandes, Mikah S., Gray, Nora E., Alcázar Magaña, Armando, McClure, Christine, Stevens, Jan F., Maier, Claudia S., Quinn, Joseph F., Soumyanath, Amala
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8868383/
https://www.ncbi.nlm.nih.gov/pubmed/35204098
http://dx.doi.org/10.3390/antiox11020215
_version_ 1784656256374407168
author Wright, Kirsten M.
Bollen, Melissa
David, Jason
Speers, Alex B.
Brandes, Mikah S.
Gray, Nora E.
Alcázar Magaña, Armando
McClure, Christine
Stevens, Jan F.
Maier, Claudia S.
Quinn, Joseph F.
Soumyanath, Amala
author_facet Wright, Kirsten M.
Bollen, Melissa
David, Jason
Speers, Alex B.
Brandes, Mikah S.
Gray, Nora E.
Alcázar Magaña, Armando
McClure, Christine
Stevens, Jan F.
Maier, Claudia S.
Quinn, Joseph F.
Soumyanath, Amala
author_sort Wright, Kirsten M.
collection PubMed
description Centella asiatica is reputed in Eastern medicine to improve cognitive function in humans. Preclinical studies have demonstrated that aqueous extracts of C. asiatica 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 (Nrf2)-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 C. asiatica 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 C. asiatica’s neurological activity. The acute safety of CAP and the effects on NRF2 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 NRF2 gene expression, mirroring the TT aglycone’s pharmacokinetic curve in a paradoxical dose-dependent manner. The oral bioavailability of active compounds or their metabolites, NRF2 target engagement, and the acute safety and tolerability of CAP support the validity of using CAP in future clinical studies.
format Online
Article
Text
id pubmed-8868383
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-88683832022-02-25 Pharmacokinetics and Pharmacodynamics of Key Components of a Standardized Centella asiatica Product in Cognitively Impaired Older Adults: A Phase 1, Double-Blind, Randomized Clinical Trial Wright, Kirsten M. Bollen, Melissa David, Jason Speers, Alex B. Brandes, Mikah S. Gray, Nora E. Alcázar Magaña, Armando McClure, Christine Stevens, Jan F. Maier, Claudia S. Quinn, Joseph F. Soumyanath, Amala Antioxidants (Basel) Article Centella asiatica is reputed in Eastern medicine to improve cognitive function in humans. Preclinical studies have demonstrated that aqueous extracts of C. asiatica 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 (Nrf2)-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 C. asiatica 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 C. asiatica’s neurological activity. The acute safety of CAP and the effects on NRF2 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 NRF2 gene expression, mirroring the TT aglycone’s pharmacokinetic curve in a paradoxical dose-dependent manner. The oral bioavailability of active compounds or their metabolites, NRF2 target engagement, and the acute safety and tolerability of CAP support the validity of using CAP in future clinical studies. MDPI 2022-01-23 /pmc/articles/PMC8868383/ /pubmed/35204098 http://dx.doi.org/10.3390/antiox11020215 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wright, Kirsten M.
Bollen, Melissa
David, Jason
Speers, Alex B.
Brandes, Mikah S.
Gray, Nora E.
Alcázar Magaña, Armando
McClure, Christine
Stevens, Jan F.
Maier, Claudia S.
Quinn, Joseph F.
Soumyanath, Amala
Pharmacokinetics and Pharmacodynamics of Key Components of a Standardized Centella asiatica Product in Cognitively Impaired Older Adults: A Phase 1, Double-Blind, Randomized Clinical Trial
title Pharmacokinetics and Pharmacodynamics of Key Components of a Standardized Centella asiatica Product in Cognitively Impaired Older Adults: A Phase 1, Double-Blind, Randomized Clinical Trial
title_full Pharmacokinetics and Pharmacodynamics of Key Components of a Standardized Centella asiatica Product in Cognitively Impaired Older Adults: A Phase 1, Double-Blind, Randomized Clinical Trial
title_fullStr Pharmacokinetics and Pharmacodynamics of Key Components of a Standardized Centella asiatica Product in Cognitively Impaired Older Adults: A Phase 1, Double-Blind, Randomized Clinical Trial
title_full_unstemmed Pharmacokinetics and Pharmacodynamics of Key Components of a Standardized Centella asiatica Product in Cognitively Impaired Older Adults: A Phase 1, Double-Blind, Randomized Clinical Trial
title_short Pharmacokinetics and Pharmacodynamics of Key Components of a Standardized Centella asiatica Product in Cognitively Impaired Older Adults: A Phase 1, Double-Blind, Randomized Clinical Trial
title_sort pharmacokinetics and pharmacodynamics of key components of a standardized centella asiatica product in cognitively impaired older adults: a phase 1, double-blind, randomized clinical trial
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8868383/
https://www.ncbi.nlm.nih.gov/pubmed/35204098
http://dx.doi.org/10.3390/antiox11020215
work_keys_str_mv AT wrightkirstenm pharmacokineticsandpharmacodynamicsofkeycomponentsofastandardizedcentellaasiaticaproductincognitivelyimpairedolderadultsaphase1doubleblindrandomizedclinicaltrial
AT bollenmelissa pharmacokineticsandpharmacodynamicsofkeycomponentsofastandardizedcentellaasiaticaproductincognitivelyimpairedolderadultsaphase1doubleblindrandomizedclinicaltrial
AT davidjason pharmacokineticsandpharmacodynamicsofkeycomponentsofastandardizedcentellaasiaticaproductincognitivelyimpairedolderadultsaphase1doubleblindrandomizedclinicaltrial
AT speersalexb pharmacokineticsandpharmacodynamicsofkeycomponentsofastandardizedcentellaasiaticaproductincognitivelyimpairedolderadultsaphase1doubleblindrandomizedclinicaltrial
AT brandesmikahs pharmacokineticsandpharmacodynamicsofkeycomponentsofastandardizedcentellaasiaticaproductincognitivelyimpairedolderadultsaphase1doubleblindrandomizedclinicaltrial
AT graynorae pharmacokineticsandpharmacodynamicsofkeycomponentsofastandardizedcentellaasiaticaproductincognitivelyimpairedolderadultsaphase1doubleblindrandomizedclinicaltrial
AT alcazarmaganaarmando pharmacokineticsandpharmacodynamicsofkeycomponentsofastandardizedcentellaasiaticaproductincognitivelyimpairedolderadultsaphase1doubleblindrandomizedclinicaltrial
AT mcclurechristine pharmacokineticsandpharmacodynamicsofkeycomponentsofastandardizedcentellaasiaticaproductincognitivelyimpairedolderadultsaphase1doubleblindrandomizedclinicaltrial
AT stevensjanf pharmacokineticsandpharmacodynamicsofkeycomponentsofastandardizedcentellaasiaticaproductincognitivelyimpairedolderadultsaphase1doubleblindrandomizedclinicaltrial
AT maierclaudias pharmacokineticsandpharmacodynamicsofkeycomponentsofastandardizedcentellaasiaticaproductincognitivelyimpairedolderadultsaphase1doubleblindrandomizedclinicaltrial
AT quinnjosephf pharmacokineticsandpharmacodynamicsofkeycomponentsofastandardizedcentellaasiaticaproductincognitivelyimpairedolderadultsaphase1doubleblindrandomizedclinicaltrial
AT soumyanathamala pharmacokineticsandpharmacodynamicsofkeycomponentsofastandardizedcentellaasiaticaproductincognitivelyimpairedolderadultsaphase1doubleblindrandomizedclinicaltrial