Serum Concentrations of Cholinesterase Inhibitors in Patients With Alzheimer’s Dementia Are Frequently Below the Recommended Levels

Abstract

Background: Acetylcholinesterase inhibitors (AChE-I) are recommended for the treatment of cognitive symptoms but also of behavioral and psychological symptoms in dementia. They are widely used not only in Alzheimer's disease, but also in other forms of dementia. Efficacy of treatment might depend on serum concentration of the respective AChE-I. Objective: In patients with mild to moderate Alzheimer's dementia, we measured serum concentrations of hepatically metabolized donepezil and renally excreted rivastigmine and investigated possible modifiers. Additionally, we looked at correlations between serum concentrations and efficacy for both drugs. Methods: Serum concentrations of donepezil and rivastigmine were measured by liquid chromatographytandem mass spectrometry (LC-MS/MS). Real-time quantitative polymerase chain reaction (PCR). Allele specific PCR were performed to determine CYP2D6 genotype and gene dose. Clinical efficacy was assessed by changes of the subtest wordlist delayed recall of the Consortium to Establish a Registry for Alzheimer's Disease-Neuropsychological Assessment Battery (CERAD-NAB). Results: Sixty-seven patients treated with a stable dosage of donepezil 10 mg (n=41) or rivastigmine 9.5 mg (n=26) were included. Mean serum concentration of donepezil and rivastigmine were 41.2 and 6.5 ng/ml, respectively. Serum concentrations were below the recommended range in 73% of the subjects in the donepezil group and in 65% of the participants in the rivastigmine group. When applying a dose-related reference, ranges 63% of patients in the donepezil group and 32% in the rivastigmine group had concentrations below the expected range. Gene dose, sex, and duration of treatment significantly predicted donepezil serum concentration (p=0.046, p=0.001, p=0.030 respectively). Only for rivastigmine did the serum concentration significantly contribute

Phytochemical Analysis, In Vitro Anticholinesterase, Antioxidant Activity and In Vivo Nootropic Effect of Ferula ammoniacum (Dorema ammoniacum) D. Don. in Scopolamine-Induced Memory Impairment in Mice

“…Cholinesterase inhibitors are employed to reduce ACh hydrolysis, thereby increasing the concentration of ACh at the synapses and presynaptic receptors that prevents the death of cholinergic neurons [ 50 ]. Hence, treatment with plant extract (Fa.EtAc) might prevent the breakdown of ACh and increases cholinergic transmission, leading to the amelioration of symptoms [ 3 ] like that of donepezil which is a standard inhibitor of AChE and BChE [ 5 ]. AChE and BChE appear to be simultaneously active in the synaptic hydrolysis of ACh, terminating its neurotransmitter action, and co-regulating levels of ACh which is considered to be the most essential neurotransmitter that controls the regulation of cognitive functions.…”

“…Thus, the inhibition of cholinesterases is considered to be the base while treating AD and this promising strategy is clinically applied everywhere for treating neurodegenerative diseases and is a rational approach. Inhibition of brain cholinesterases (AChE and BChE) by potential inhibitors reinstates the level of ACh and, thus, plays an important role in the treatment of AD, Dementia, and Parkinson’s disease [ 3 ] and the consequences of cholinesterases inhibition are assessed by observing cholinergically mediated processes such as cognition [ 4 ]. Acetylcholine is a key neurotransmitter in the nervous system that interacts with receptors associated with processes of learning and memory.…”

Dose-Related Reference Range as a Tool in Therapeutic Drug Monitoring

“…• The original publication that suggested and defined DRRs in 2008. 7 • The article by Ortner et al 14 in which DRRs ranges were used to identify the cause of low acetylcholine esterase inhibitor concentrations in the pharmacotherapy of dementia. • The article by Fekete et al, 15 in which DRRs were calculated for neuropsychopharmaca in childhood and adolescence.…”

“…The 4 original articles that addressed the scope of this review are as follows:The original publication that suggested and defined DRRs in 2008. 7 The article by Ortner et al 14 in which DRRs ranges were used to identify the cause of low acetylcholine esterase inhibitor concentrations in the pharmacotherapy of dementia.The article by Fekete et al, 15 in which DRRs were calculated for neuropsychopharmaca in childhood and adolescence.The article by Ritscher et al, 16 in which dose-related references were recognized to be superior in evaluating adherence.…”

Editorial: Cognitive Impairment: Therapy Momentum in the Continuum of Life

“…Cholinesterase inhibitors do not perform well in clinical practice and a high number of patients seem not to respond to the approved therapeutic doses. Polymorphisms, such as that of CYP2D6, may mediate drug metabolism and lead to low drug circulating levels in about two thirds of the cases (Ortner et al, 2020). In this issue, Lu et al discuss a large array of genetic polymorphisms, such as CYPs and ATP-binding cassette transporters, as well as those involved in acetyl-or butyrylcholinesterase constitutive signaling and inhibition that influence donepezil PK/PD.…”