Effect of butyrylcholinesterase genotype on the response to rivastigmine or donepezil in younger patients with Alzheimer's disease
ABSTRACT A randomized double-blind trial evaluated the efficacy and tolerability of rivastigmine, an inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and donepezil, an AChE-selective inhibitor, in patients with Alzheimer's disease over a 2-year period. A retrospective analysis showed differential responses to cholinesterase inhibitors (ChE-Is) in patients younger than 75 years. This analysis investigated the effect of BuChE genotype on response to ChE-I therapy in these patients. In a retrospective analysis, patients younger than 75 who had consented to pharmacogenetic analysis were divided into groups according to BuChE genotype. Efficacy measures were the Severe Impairment Battery (SIB), Neuropsychiatric Inventory (NPI), Global Deterioration Scale (GDS), Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL). Changes on efficacy parameters were calculated for rivastigmine-treated and donepezil-treated patients in both groups. Of 114 (34.1%) patients younger than 75 who were successfully assessed for BuChE genotype, 76 (66.7%) were homozygous for wild-type BuChE, and 38 (33.3%) carried at least one BuChE K-variant allele. Wild-type BuChE carriers showed significantly greater responses to rivastigmine than to donepezil on the SIB, ADCS-ADL, GDS and NPI. No significant between-treatment differences in efficacy were observed in BuChE K-variant carriers, although adverse events were more frequent in rivastigmine-treated patients. In this retrospective analysis, Alzheimer's disease patients younger than 75 with wild-type BuChE exhibited differential efficacy to rivastigmine, while BuChE K-variant carriers experienced similar long-term treatment effects with both agents. These differences may reflect rivastigmine's ability to inhibit BuChE and AChE.
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- "Thus, donepezil is expected to produce a detrimental diseasemodifying effect in individuals with overactive glia and a beneficial disease-modifying effect in those with hypofunctioning glia. Emerging evidence supports these hypotheses     . Among AChE inhibitors, only PAS inhibitors block effects of AChE on A␤ fibril formation . "
ABSTRACT: Cholinesterase enzymes metabolize acetylcholine (ACh). Inhibition of acetylcholinesterase (AChE) in damaged but functional cholinergic synapses in the brains of dementia patients increases intrasynaptic ACh. This enhances cholinergic neurotransmission and improves cognition. There is a window of opportunity for this symptomatic treatment effect that opens and closes during the course of dementia depending on when significant synaptic damage occurs. Cholinesterases also metabolize extrasynaptic ACh with butyrylcholinesterase (BuChE) apparently playing the major dynamic role in extracellular ACh homeostasis. Extracellular ACh plays a key regulatory role in controlling the reactivity and functional states of non-excitable cells, such as neuroglia. Current inhibitors of cholinesterases (ChEIs) have similar effects on intrasynaptic ACh, but differ markedly in abilities to upregulate extracellular AChE, inhibit BuChE, and influence the fibrilization of amyloid-β peptides. Importantly, ChEIs can have detrimental disease modifying effects in particular individuals characterized by age, gender, and genotype. In contrast, preliminary evidence suggests that the right dose of the right ChEI in the right patient might significantly slow the progression of neurodegenerative processes. For a particular patient, understanding the condition of cholinergic synapses and the reactivity and functional status of neuroglia could allow administration of appropriate ChEI therapy for symptomatic and disease modifying benefits.Journal of Alzheimer's disease: JAD 11/2014; 44(4). DOI:10.3233/JAD-142268 · 4.15 Impact Factor
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- "Comparing the pharmacological profiles of donepezil and rivastigmine, it is known that donepezil is a specific acetylcholinesterase inhibitor, while rivastigmine is a dual cholinesterase inhibitor (ChEI) that is capable of inhibiting butyrylcholinesterase, another enzyme involved in acetylcholine degradation.4 The different efficacies of these ChEIs are also reported in clinical settings;5–7 however, it is not evident that these differences are due to the different pharmacological profiles mentioned above. It is also conceivable that the pharmacological differences among the ChEIs result in different profiles of adverse events, including neuropsychiatric symptoms. "
ABSTRACT: Rivastigmine, galantamine, and memantine, in addition to donepezil, which has been on the market over 10 years, have been available for the treatment of Alzheimer's disease (AD) since 2011 in Japan, leading a new stage in the medical treatment of AD. We studied two AD patients showing sudden deterioration of behavioral and psychological symptoms of dementia (BPSD) associated with switching from rivastigmine to donepezil after the clinical trial of rivastigmine. In the patients, rivastigmine seemed to be more beneficial than donepezil for the control of BPSD. Although It was not obvious whether their different responses to the two cholinesterase inhibitors were due to the different pharmacological profiles, ie, the presence of inhibition of butyrylcholinesterase in rivastigmine, a particular cholinesterase inhibitor might be more effective in particular AD cases. Further investigations are needed to confirm the difference, and to identify the measures for selecting the most appropriate medication for each AD patient.Neuropsychiatric Disease and Treatment 01/2013; 9:49-53. DOI:10.2147/NDT.S37688 · 1.74 Impact Factor
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- "The inconsistent pattern of response to cholinergic therapy in adolescents with DS suggests the possibility of genetic or epigenetic factors that could affect response to cholinergic therapy. Additional investigation may identify genetic modifiers that could influence outcome of individuals with DS (Blesa et al. 2006). "
ABSTRACT: Following the completion of a 20-week, open-label study of the safety and efficacy of liquid rivastigmine for adolescents with Down syndrome, 5 of the 10 adolescents in the clinical trial continued long-term rivastigmine therapy and 5 did not. After an average period of 38 months, all 10 subjects returned for a follow-up assessment to determine the safety and efficacy of long-term rivastigmine use. Rivastigmine was well tolerated and overall health appeared to be unaffected by long-term rivastigmine use. Performance change on cognitive and language measures administered at the termination of the open-label clinical trial was compared between the two groups. No between-group difference in median performance change across the long-term period was found, suggesting that the long-term use of rivastigmine does not improve cognitive and language performance. However, two subjects demonstrated remarkable improvement in adaptive function over the long-term period. Both subjects had received long-term rivastigmine therapy. The discussion addresses the challenge of assessing cognitive change in clinical trials using adolescents with Down syndrome as subjects and the use of group versus individual data to evaluate the relevance of medication effects.Journal of child and adolescent psychopharmacology 12/2010; 20(6):517-20. DOI:10.1089/cap.2009.0099 · 2.93 Impact Factor