Action of cholinesterase inhibitors in patients’ brains
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《神经病学神经外科学杂志》
Correspondence to:
K Herholz
Department of Neurology, University of Cologne, and Max-Planck-Institute for Neurological Research, Gleuler Str. 50, 50931 Cologne, Germany; karl.herholz@pet.mpin-koeln.mpg.de
Cholinesterase inhibitors in patients’ brains
Keywords: Alzheimer’s disease; cholinesterase inhibitor; clinical trials; positron emission tomography
Cholinesterase (ChE) inhibitors are the only class of drug that have consistently shown improvement in cognitive function in patients with mild to moderate Alzheimer’s disease. Unfortunately, improvement is generally rather small.1 Recent clinical trials have caused considerable controversy about their actual benefit and indications. On one hand, some studies suggest more extensive use because improvement of cognitive function has also been observed in vascular dementia, dementia with Lewy bodies, and Parkinson’s disease with dementia. However, on the other hand a recent study in community resident patients with mild to moderate Alzheimer’s disease concluded that benefits were "below minimally relevant thresholds."2
On the background of this confusing situation, studies are particularly welcome that provide clues as to how ChE inhibitors exert their moderate effect in patients and how we could increase their efficacy. In this issue, such information is provided in a study by Bohnen et al,3 (see page 315) which measured the actual inhibition of cortical acetylcholine esterase (AChE) activity by donepezil in vivo and studied the correlation of the degree of inhibition with the cognitive effects. Several observations were made that indicate directions for improving therapy.
The inhibition of cortical AChE activity by donepezil at the recommended dose of 10 mg daily was rather low (on average 16–24% depending on cortical regions) and it varied considerably among patients. Although somewhat higher values had been measured with a slightly different tracer by other authors cited in the paper, inhibition of human cerebral AChE is much less than observed in peripheral blood,4 which is in contrast to findings in rats.5 Thus, dosage, pharmacokinetics, or specific binding of the drug to human cerebral AChE appear to be suboptimal, and this had not become evident during preclinical and clinical phases of drug development and testing.
The study also indicates that the degree of cerebral AChE inhibition makes a clinical difference because it was significantly correlated with measures of executive function and attention. This indicates that it could indeed be worthwhile to increase inhibition in selected patients, e.g. by higher dosage if side effects permit. It is expected that similar positron emission tomography (PET) studies will be performed to measure inhibition of cerebral butyrylcholine esterase (BChE) for selection and development of drugs that achieve higher effective levels of acetylcholine by additional inhibition of this degradation pathway.6
Another interesting aspect is that the relatively small inhibition effects were observed in temporal and parietal association cortex—structures that are thought to be of pivotal importance for episodic and semantic memory—that did not benefit significantly from treatment in this and other studies. One would wish to see similar studies with other ChE inhibitors to determine whether this is a property of the entire class of drugs.
It is gratifying that such direct in vivo assessments of pharmacological action are happening now, which means that we do not depend solely on large trials with clinical outcome measures that are, of course, of utmost clinical importance but often tell very little about the mechanisms that explain interindividual variation. One can hope that this will ultimately provide rational means to improve treatment of individuals, which is in the primary interest of patients and doctors.
REFERENCES
Rockwood K . Size of the treatment effect on cognition of cholinesterase inhibition in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2004;75:677–85.
Courtney C, Farrell D, Gray R, et al. Long-term donepezil treatment in 565 patients with Alzheimer’s disease (AD2000): randomised double-blind trial. Lancet 2004;363:2105–15.
Bohnen NI, Kaufer DI, Hendrickson R, et al. Degree of inhibition of cortical acetylcholinesterase activity and cognitive effects by donepezil treatment in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2005;76:315–9.
Kuhl DE, Minoshima S, Frey KA, et al. Limited donepezil inhibition of acetylcholinesterase measured with positron emission tomography in living Alzheimer cerebral cortex. Ann Neurol 2000;48:391–5.
Kosasa T, Kuriya Y, Matsui K, et al. Inhibitory effects of donepezil hydrochloride (E2020) on cholinesterase activity in brain and peripheral tissues of young and aged rats. Eur J Pharmacol 1999;386:7–13.
Darvesh S, Walsh R, Kumar R, et al. Inhibition of Human Cholinesterases by Drugs Used to Treat Alzheimer Disease. Alzheimer Dis Assoc Disord 2003;17:117–26.(K Herholz)
K Herholz
Department of Neurology, University of Cologne, and Max-Planck-Institute for Neurological Research, Gleuler Str. 50, 50931 Cologne, Germany; karl.herholz@pet.mpin-koeln.mpg.de
Cholinesterase inhibitors in patients’ brains
Keywords: Alzheimer’s disease; cholinesterase inhibitor; clinical trials; positron emission tomography
Cholinesterase (ChE) inhibitors are the only class of drug that have consistently shown improvement in cognitive function in patients with mild to moderate Alzheimer’s disease. Unfortunately, improvement is generally rather small.1 Recent clinical trials have caused considerable controversy about their actual benefit and indications. On one hand, some studies suggest more extensive use because improvement of cognitive function has also been observed in vascular dementia, dementia with Lewy bodies, and Parkinson’s disease with dementia. However, on the other hand a recent study in community resident patients with mild to moderate Alzheimer’s disease concluded that benefits were "below minimally relevant thresholds."2
On the background of this confusing situation, studies are particularly welcome that provide clues as to how ChE inhibitors exert their moderate effect in patients and how we could increase their efficacy. In this issue, such information is provided in a study by Bohnen et al,3 (see page 315) which measured the actual inhibition of cortical acetylcholine esterase (AChE) activity by donepezil in vivo and studied the correlation of the degree of inhibition with the cognitive effects. Several observations were made that indicate directions for improving therapy.
The inhibition of cortical AChE activity by donepezil at the recommended dose of 10 mg daily was rather low (on average 16–24% depending on cortical regions) and it varied considerably among patients. Although somewhat higher values had been measured with a slightly different tracer by other authors cited in the paper, inhibition of human cerebral AChE is much less than observed in peripheral blood,4 which is in contrast to findings in rats.5 Thus, dosage, pharmacokinetics, or specific binding of the drug to human cerebral AChE appear to be suboptimal, and this had not become evident during preclinical and clinical phases of drug development and testing.
The study also indicates that the degree of cerebral AChE inhibition makes a clinical difference because it was significantly correlated with measures of executive function and attention. This indicates that it could indeed be worthwhile to increase inhibition in selected patients, e.g. by higher dosage if side effects permit. It is expected that similar positron emission tomography (PET) studies will be performed to measure inhibition of cerebral butyrylcholine esterase (BChE) for selection and development of drugs that achieve higher effective levels of acetylcholine by additional inhibition of this degradation pathway.6
Another interesting aspect is that the relatively small inhibition effects were observed in temporal and parietal association cortex—structures that are thought to be of pivotal importance for episodic and semantic memory—that did not benefit significantly from treatment in this and other studies. One would wish to see similar studies with other ChE inhibitors to determine whether this is a property of the entire class of drugs.
It is gratifying that such direct in vivo assessments of pharmacological action are happening now, which means that we do not depend solely on large trials with clinical outcome measures that are, of course, of utmost clinical importance but often tell very little about the mechanisms that explain interindividual variation. One can hope that this will ultimately provide rational means to improve treatment of individuals, which is in the primary interest of patients and doctors.
REFERENCES
Rockwood K . Size of the treatment effect on cognition of cholinesterase inhibition in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2004;75:677–85.
Courtney C, Farrell D, Gray R, et al. Long-term donepezil treatment in 565 patients with Alzheimer’s disease (AD2000): randomised double-blind trial. Lancet 2004;363:2105–15.
Bohnen NI, Kaufer DI, Hendrickson R, et al. Degree of inhibition of cortical acetylcholinesterase activity and cognitive effects by donepezil treatment in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2005;76:315–9.
Kuhl DE, Minoshima S, Frey KA, et al. Limited donepezil inhibition of acetylcholinesterase measured with positron emission tomography in living Alzheimer cerebral cortex. Ann Neurol 2000;48:391–5.
Kosasa T, Kuriya Y, Matsui K, et al. Inhibitory effects of donepezil hydrochloride (E2020) on cholinesterase activity in brain and peripheral tissues of young and aged rats. Eur J Pharmacol 1999;386:7–13.
Darvesh S, Walsh R, Kumar R, et al. Inhibition of Human Cholinesterases by Drugs Used to Treat Alzheimer Disease. Alzheimer Dis Assoc Disord 2003;17:117–26.(K Herholz)