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Donepezil in Alzheimer's disease: From conventional trials to pharmacogenetics.

Cacabelos R - Neuropsychiatr Dis Treat (2007)

Bottom Line: Although donepezil represents a non cost-effective treatment, most studies convey that this drug can provide a modest benefit on cognition, behavior, and activities of the daily living in both moderate and severe AD, contributing to slow down disease progression and, to a lesser exetnt, to delay institutionalization.Patients with vascular dementia might also benefit from donepezil in a similar fashion to AD patients.Some potential effects of donepezil on the AD brain, leading to reduced cortico-hippocampal atrophy, include the following: AChE inhibition, enhancement of cholinergic neurotransmission and putative modulation of other neurotransmitter systems, protection against glutamate-induced excitotoxicity, activation of neurotrophic mechanisms, promotion of non-amyloidodgenic pathways for APP processing, and indirect effects on cerebrovascular function improving brain perfusion.

View Article: PubMed Central - PubMed

Affiliation: EuroEspes Biomedical Research Center, Institute for CNS Disorders, Coruña, Spain; EuroEspes Chair of Biotechnology and Genomics, Camilo José Cela University, Madrid, Spain. rcacabelos@euroespes.com

ABSTRACT
Donepezil is the leading compound for the treatment of Alzheimer's disease (AD) in more than 50 countries. As compared with other conventional acetylcholinesterase inhibitors (AChEIs), donepezil is a highly selective and reversible piperidine derivative with AChEI activity that exhibits the best pharmacological profile in terms of cognitive improvement, responders rate (40%-58%), dropout cases (5%-13%), and side-effects (6%-13%) in AD. Although donepezil represents a non cost-effective treatment, most studies convey that this drug can provide a modest benefit on cognition, behavior, and activities of the daily living in both moderate and severe AD, contributing to slow down disease progression and, to a lesser exetnt, to delay institutionalization. Patients with vascular dementia might also benefit from donepezil in a similar fashion to AD patients. Some potential effects of donepezil on the AD brain, leading to reduced cortico-hippocampal atrophy, include the following: AChE inhibition, enhancement of cholinergic neurotransmission and putative modulation of other neurotransmitter systems, protection against glutamate-induced excitotoxicity, activation of neurotrophic mechanisms, promotion of non-amyloidodgenic pathways for APP processing, and indirect effects on cerebrovascular function improving brain perfusion. Recent studies demonstrate that the therapeutic response in AD is genotype-specific. Donepezil is metabolized via CYP-related enzymes, especially CYP2D6, CYP3A4, and CYP1A2. Approximately, 15%-20% of the AD population may exhibit an abnormal metabolism of AChEIs; about 50% of this population cluster would show an ultrarapid metabolism, requiring higher doses of AChEIs to reach a therapeutic threshold, whereas the other 50% of the cluster would exhibit a poor metabolism, displaying potential adverse events at low doses. In AD patients treated with a multifactorial therapy, including donepezil, the best responders are the CYP2D6-related extensive (EM)(*1/*1, *1/*10) (57.47%) and intermediate metabolizers (IM)(*1/*3, *1/*5, *1/*6, *7/*10) (25.29%), and the worst responders are the poor (PM) (*4/*4)(9.20%) and ultra-rapid metabolizers (UM) (*1xN/*1) (8.04%). Pharmacogenetic and pharmacogenomic factors may account for 75%-85% of the therapeutic response in AD patients treated with donepezil and other AChEIs metabolized via enzymes of the CYP family. The implementation of pharmacogenetic protocols can optimize AD therapeutics.

No MeSH data available.


Related in: MedlinePlus

CYP2D6-related therapeutic response in Alzheimer’s disease. Influence of CYP2D6 genotypes on cognitive performance during treatment with a multifactorial therapy (CDP-choline, 500 mg/day; piracetam, 1600 mg/day; nicergoline, 5 mg/day; donepezil, 5 mg/day).(a) Extensive Metabolizers (EM); (b) Intermediate Metabolizers (IM); Poor Metabolizers (PM); (d) Ultra-rapid Metabolizers (UM).
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f3-ndt-3-303: CYP2D6-related therapeutic response in Alzheimer’s disease. Influence of CYP2D6 genotypes on cognitive performance during treatment with a multifactorial therapy (CDP-choline, 500 mg/day; piracetam, 1600 mg/day; nicergoline, 5 mg/day; donepezil, 5 mg/day).(a) Extensive Metabolizers (EM); (b) Intermediate Metabolizers (IM); Poor Metabolizers (PM); (d) Ultra-rapid Metabolizers (UM).

Mentions: In the first CYP2D6-related pharmacogenetic study with a combination therapy (donepezil + CDP-choline + piracetam + nicergoline) in AD, EMs improved their cognitive function (MMSE score) from 21.58 ± 9.02 at baseline to 23.78 ± 5.81 after 1-year treatment (r = +0.82; a Coef. = +20.68; b Coef.: +0.4). IMs also improved from 21.40 ± 6.28 to 22.50 ± 5.07 (r = +0.96; a Coef. = +21.2; b Coef. = +0.25), whereas PMs and UMs deteriorate from 20.74 ± 6.72 to 18.07 ± 5.52 (r = −0.97; a Coef. = +21.63; b Coef. = −0.59), and from 22.65 ± 6.76 to 21.28 ± 7.75 (r = −0.92; a Coef. = +23.35; b Coef. = −0.36), respectively. According to these results, PMs and UMs were the worst responders, showing a progressive cognitive decline with no therapeutic effect, and EMs and IMs were the best responders, with a clear improvement in cognition after 1 year of treatment (Figures 1, 2). Among EMs, AD patients harbouring the *1/*10 genotype (r = +0.97; a Coef. = +19.27; b Coef. = +0.55) responded better than patients with the *1/*1 genotype (r = +0.44; a Coef.= +22.10; b Coef. = +0.25). The best responders among IMs were the *1/*3 (r = +0.98; a Coef. = +20.65; b Coef. = 1.18), *1/*6 (r = 0.93; a Coef. = +22.17; b Coef. = +0.44) and *1/*5 genotypes (r = +0.70; a Coef. = +19.96; b Coef. = +0.25), whereas the *1/*4, *10/*10, and *4/*10 genotypes were poor responders. Among PMs and UMs, the poorest responders were carriers of the *4/*4 (r = −0.98; a Coef. = +19.72; b Coef. = −0.91) and *1xN/*1 genotypes (r = −0.97; a Coef. = +24.55; b Coef. = −0.98), respectively (Figure 3). The CYP2D6-related therapeutic responses can be modified by the presence of the APOE-4/4 genotype which converts EMs and IMs in poor responders (Cacabelos 2007).


Donepezil in Alzheimer's disease: From conventional trials to pharmacogenetics.

Cacabelos R - Neuropsychiatr Dis Treat (2007)

CYP2D6-related therapeutic response in Alzheimer’s disease. Influence of CYP2D6 genotypes on cognitive performance during treatment with a multifactorial therapy (CDP-choline, 500 mg/day; piracetam, 1600 mg/day; nicergoline, 5 mg/day; donepezil, 5 mg/day).(a) Extensive Metabolizers (EM); (b) Intermediate Metabolizers (IM); Poor Metabolizers (PM); (d) Ultra-rapid Metabolizers (UM).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2654795&req=5

f3-ndt-3-303: CYP2D6-related therapeutic response in Alzheimer’s disease. Influence of CYP2D6 genotypes on cognitive performance during treatment with a multifactorial therapy (CDP-choline, 500 mg/day; piracetam, 1600 mg/day; nicergoline, 5 mg/day; donepezil, 5 mg/day).(a) Extensive Metabolizers (EM); (b) Intermediate Metabolizers (IM); Poor Metabolizers (PM); (d) Ultra-rapid Metabolizers (UM).
Mentions: In the first CYP2D6-related pharmacogenetic study with a combination therapy (donepezil + CDP-choline + piracetam + nicergoline) in AD, EMs improved their cognitive function (MMSE score) from 21.58 ± 9.02 at baseline to 23.78 ± 5.81 after 1-year treatment (r = +0.82; a Coef. = +20.68; b Coef.: +0.4). IMs also improved from 21.40 ± 6.28 to 22.50 ± 5.07 (r = +0.96; a Coef. = +21.2; b Coef. = +0.25), whereas PMs and UMs deteriorate from 20.74 ± 6.72 to 18.07 ± 5.52 (r = −0.97; a Coef. = +21.63; b Coef. = −0.59), and from 22.65 ± 6.76 to 21.28 ± 7.75 (r = −0.92; a Coef. = +23.35; b Coef. = −0.36), respectively. According to these results, PMs and UMs were the worst responders, showing a progressive cognitive decline with no therapeutic effect, and EMs and IMs were the best responders, with a clear improvement in cognition after 1 year of treatment (Figures 1, 2). Among EMs, AD patients harbouring the *1/*10 genotype (r = +0.97; a Coef. = +19.27; b Coef. = +0.55) responded better than patients with the *1/*1 genotype (r = +0.44; a Coef.= +22.10; b Coef. = +0.25). The best responders among IMs were the *1/*3 (r = +0.98; a Coef. = +20.65; b Coef. = 1.18), *1/*6 (r = 0.93; a Coef. = +22.17; b Coef. = +0.44) and *1/*5 genotypes (r = +0.70; a Coef. = +19.96; b Coef. = +0.25), whereas the *1/*4, *10/*10, and *4/*10 genotypes were poor responders. Among PMs and UMs, the poorest responders were carriers of the *4/*4 (r = −0.98; a Coef. = +19.72; b Coef. = −0.91) and *1xN/*1 genotypes (r = −0.97; a Coef. = +24.55; b Coef. = −0.98), respectively (Figure 3). The CYP2D6-related therapeutic responses can be modified by the presence of the APOE-4/4 genotype which converts EMs and IMs in poor responders (Cacabelos 2007).

Bottom Line: Although donepezil represents a non cost-effective treatment, most studies convey that this drug can provide a modest benefit on cognition, behavior, and activities of the daily living in both moderate and severe AD, contributing to slow down disease progression and, to a lesser exetnt, to delay institutionalization.Patients with vascular dementia might also benefit from donepezil in a similar fashion to AD patients.Some potential effects of donepezil on the AD brain, leading to reduced cortico-hippocampal atrophy, include the following: AChE inhibition, enhancement of cholinergic neurotransmission and putative modulation of other neurotransmitter systems, protection against glutamate-induced excitotoxicity, activation of neurotrophic mechanisms, promotion of non-amyloidodgenic pathways for APP processing, and indirect effects on cerebrovascular function improving brain perfusion.

View Article: PubMed Central - PubMed

Affiliation: EuroEspes Biomedical Research Center, Institute for CNS Disorders, Coruña, Spain; EuroEspes Chair of Biotechnology and Genomics, Camilo José Cela University, Madrid, Spain. rcacabelos@euroespes.com

ABSTRACT
Donepezil is the leading compound for the treatment of Alzheimer's disease (AD) in more than 50 countries. As compared with other conventional acetylcholinesterase inhibitors (AChEIs), donepezil is a highly selective and reversible piperidine derivative with AChEI activity that exhibits the best pharmacological profile in terms of cognitive improvement, responders rate (40%-58%), dropout cases (5%-13%), and side-effects (6%-13%) in AD. Although donepezil represents a non cost-effective treatment, most studies convey that this drug can provide a modest benefit on cognition, behavior, and activities of the daily living in both moderate and severe AD, contributing to slow down disease progression and, to a lesser exetnt, to delay institutionalization. Patients with vascular dementia might also benefit from donepezil in a similar fashion to AD patients. Some potential effects of donepezil on the AD brain, leading to reduced cortico-hippocampal atrophy, include the following: AChE inhibition, enhancement of cholinergic neurotransmission and putative modulation of other neurotransmitter systems, protection against glutamate-induced excitotoxicity, activation of neurotrophic mechanisms, promotion of non-amyloidodgenic pathways for APP processing, and indirect effects on cerebrovascular function improving brain perfusion. Recent studies demonstrate that the therapeutic response in AD is genotype-specific. Donepezil is metabolized via CYP-related enzymes, especially CYP2D6, CYP3A4, and CYP1A2. Approximately, 15%-20% of the AD population may exhibit an abnormal metabolism of AChEIs; about 50% of this population cluster would show an ultrarapid metabolism, requiring higher doses of AChEIs to reach a therapeutic threshold, whereas the other 50% of the cluster would exhibit a poor metabolism, displaying potential adverse events at low doses. In AD patients treated with a multifactorial therapy, including donepezil, the best responders are the CYP2D6-related extensive (EM)(*1/*1, *1/*10) (57.47%) and intermediate metabolizers (IM)(*1/*3, *1/*5, *1/*6, *7/*10) (25.29%), and the worst responders are the poor (PM) (*4/*4)(9.20%) and ultra-rapid metabolizers (UM) (*1xN/*1) (8.04%). Pharmacogenetic and pharmacogenomic factors may account for 75%-85% of the therapeutic response in AD patients treated with donepezil and other AChEIs metabolized via enzymes of the CYP family. The implementation of pharmacogenetic protocols can optimize AD therapeutics.

No MeSH data available.


Related in: MedlinePlus