Rapid attainment of steady-state acetylcholinesterase inhibition by administration of metrifonate loading and maintenance doses once-daily in elderly volunteers

Heinig, Roland; Versavel, Mark; Breuel, H.-P.; Kuhlmann, J.

doi:10.1016/s0006-3223(97)87257-5

Cited by 9 publications

(13 citation statements)

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“…Following single-dose oral administration of metrifonate in humans, two phases of red blood cell AChE inhibition are observed (22). First, there is a relatively rapid phase of inhibition which is followed by a second, slower recovery phase of enzyme activity, which L. S. SCHNEIDER AND E. GIACOBINI occurs approximately 8 h after peak inhibition.…”

Section: Human Pharmacodynamics Studiesmentioning

confidence: 99%

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Metrifonate: A Cholinesterase Inhibitor for Alzheimer's Disease Therapy

Schneider

Giacobini

1999

CNS Drug Reviews

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Section: Human Pharmacodynamics Studiesmentioning

confidence: 99%

“…Reversal of cholinesterase inhibition is slow and correlates with enzyme resynthesis (31). Despite a high level of AChE and BuChE inhibition (80 to 90%), cholinergic side effects are mild (complaints of slight dizziness or nausea, usually without vomiting) (22,35).…”

Section: Human Pharmacodynamics Studiesmentioning

confidence: 99%

Metrifonate: A Cholinesterase Inhibitor for Alzheimer's Disease Therapy

Schneider

Giacobini

1999

CNS Drug Reviews

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“…The rate of reactivation of acetylcholinesterase is slow and follows a biphasic pattern [8,17]. After a single acute administration of metrifonate to young or elderly volunteers, approximately 50% of the achieved peak inhibition recovers spontaneously with an estimated half-life of 57 min [17].…”

Section: Long Duration Of Action Of Ddvpmentioning

confidence: 99%

“…Although these effects are always dose-related and transient, their occurrence cannot be attributed simply to a certain threshold level of central or peripheral cholinesterase inhibition [7,8]. Other drug-related features must, therefore, be responsible for the relative tolerability of the individual cholinesterase inhibitors.…”

Section: Introductionmentioning

confidence: 99%

The Pharmacological Basis for Metrifonate’s Favourable Tolerability in the Treatment of Alzheimer’s Disease

Schmidt

Heinig²

1998

Dement Geriatr Cogn Disord

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Metrifonate, through its pharmacologically active metabolite 2,2-dichlorovinyl dimethylphosphate (DDVP), is a long-acting cholinesterase inhibitor for the symptomatic treatment of mild-to-moderate Alzheimer’s disease. Clinical studies with Alzheimer patients have demonstrated the favourable safety and tolerability profile of this drug. Metrifonate, at therapeutic doses for Alzheimer’s disease, achieves high levels of cholinesterase inhibition, i.e. ≧70%, without the need for dose escalation. This is a consequence of the low rate of fluctuation of enzyme activity during therapy with metrifonate. This, in turn, is due to the protracted hydrolytic transformation of metrifonate into DDVP, the resulting smooth onset of cholinesterase inhibition, and the subsequent long duration of action which far outlasts the presence of the active drug in the body. Both metrifonate and DDVP are rapidly metabolized and eliminated from the body. Further, their metabolism does not involve the cytochrome P450 system and both compounds show low plasma protein binding. These pharmacokinetic features account, at least in part, for the favourable safety and tolerability profile of metrifonate as they suggest a minimal risk of drug-drug interactions with other likely co-medications in the long-term therapy of Alzheimer patients.

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“…Initially, inhibition of AChE by DDVP is competitive [7,8] and cholinesterase is preferentially inhibited in those areas of the brain deficient in cholinergic function. Inhibition later becomes irreversible and, thus, repeated dosing results in a gradual increase in AChE inhibition towards target levels [9], an effect achieved with reversible inhibitors only by progressive dose titration. This, together with the fact that metrifonate metabolism is independent of the cytochrome P450 system and that metrifonate has low protein binding (!20%), supports the good tolerability profile of the drug and allows attainment of high levels of AChE inhibition [data on file, Bayer AG].…”

Section: Introductionmentioning

confidence: 99%

The Clinical Trial Protocol of the Metrifonate in ALzheimer’s Trial (MALT)

McKeith

1998

Dement Geriatr Cogn Disord

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The promising results of early trials in Alzheimer’s disease with the acetylcholinesterase inhibitor metrifonate prompted initiation of the Metrifonate in ALzheimer’s Trial (MALT). MALT is an international, randomized, double-blind, placebo-controlled, parallel-group study which was designed to determine, over a 26-week period, the efficacy, tolerability and safety of two doses of metrifonate in patients with probable Alzheimer’s disease. A total of 605 patients were randomized to receive either a daily dose of oral metrifonate 40/50 mg (n = 200, by body weight <65 kg/≧65 kg) or metrifonate 60/80 mg (n = 197, by body weight <65 kg/≧65 kg). Patients were assessed in the key symptom domains of Alzheimer’s disease, i.e. cognition, behavioural and psychiatric disturbances, activities of daily living and global function. In summary, administration of metrifonate for 26 weeks to the intent-to-treat population significantly benefited cognitive performance, global function and certain aspects of behaviour and functional ability compared with placebo. These efficacy results were associated with high levels of acetylcholinesterase inhibition and a good safety and tolerability profile. The protocol of MALT is discussed here. Full results of the study will be available in a separate publication.

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Rapid attainment of steady-state acetylcholinesterase inhibition by administration of metrifonate loading and maintenance doses once-daily in elderly volunteers

Cited by 9 publications

References 0 publications

Metrifonate: A Cholinesterase Inhibitor for Alzheimer's Disease Therapy

Metrifonate: A Cholinesterase Inhibitor for Alzheimer's Disease Therapy

The Pharmacological Basis for Metrifonate’s Favourable Tolerability in the Treatment of Alzheimer’s Disease

The Clinical Trial Protocol of the Metrifonate in ALzheimer’s Trial (MALT)

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