ArticleJournal of Alzheimer's disease : JAD2017
Cholinesterase Inhibitor Therapy in Alzheimer's Disease: The Limits and Tolerability of Irreversible CNS-Selective Acetylcholinesterase Inhibition in Primates.
Article in Journal of Alzheimer's disease : JAD, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
26 citing papers in PubMed, 1 synthesis or guideline pooled it, 50 citations in OpenAlex.
- Alzheimer's Disease: Efficacy of Mono- and Combination Therapy. A Systematic Review.Journal of geriatric psychiatry and neurology · 2022Pooled it
- Phytochemical based on nanoparticles for neurodegenerative alzheimer disease management: Update review.Discover nano · 2025Review
- Article
- Deciphering the Role of Peroxisome Proliferator-activated Receptor α and Phosphodiesterase Type 5 Targets in Alzheimer's Disease.CNS & neurological disorders drug targets · 2024Review
- Advancements in the Application of Nanomedicine in Alzheimer's Disease: A Therapeutic Perspective.International journal of molecular sciences · 2023Review
- Emerging Alzheimer's disease therapeutics: promising insights from lipid metabolism and microglia-focused interventions.Frontiers in aging neuroscience · 2023Review
- Recent Progress in Research on Mechanisms of Action of Natural Products against Alzheimer's Disease: Dietary Plant Polyphenols.International journal of molecular sciences · 2022Review
- A regio- and stereoselective Heck-Matsuda process for construction of γ-aryl allylsulfonyl fluorides.RSC advances · 2022Article
- New benzamide derivatives and their nicotinamide/cinnamamide analogs as cholinesterase inhibitors.Molecular diversity · 2022Article
- Novel insights on acetylcholinesterase inhibition by Convolvulus pluricaulis, scopolamine and their combination in zebrafish.Natural products and bioprospecting · 2022Article
- Dietary Plant Polyphenols as the Potential Drugs in Neurodegenerative Diseases: Current Evidence, Advances, and Opportunities.Oxidative medicine and cellular longevity · 2022Review
- Pharmacological implications of ipriflavone against environmental metal-induced neurodegeneration and dementia in rats.Environmental science and pollution research international · 2021Article
- Synthesis and Hybrid SAR Property Modeling of Novel Cholinesterase Inhibitors.International journal of molecular sciences · 2021Article
- Anti-Neurodegenerative Benefits of Acetylcholinesterase Inhibitors in Alzheimer's Disease: Nexus of Cholinergic and Nerve Growth Factor Dysfunction.Current Alzheimer research · 2021Review
- The botanical origin and antioxidant, anti-BACE1 and antiproliferative properties of bee pollen from different regions of South Korea.BMC complementary medicine and therapies · 2020Article
- Mitochondrial Dysfunctions: A Red Thread across Neurodegenerative Diseases.International journal of molecular sciences · 2020Review
- Improving Anti-Neurodegenerative Benefits of Acetylcholinesterase Inhibitors in Alzheimer's Disease: Are Irreversible Inhibitors the Future?International journal of molecular sciences · 2020Review
- Article
- SAR-mediated Similarity Assessment of the Property Profile for New, Silicon-Based AChE/BChE Inhibitors.International journal of molecular sciences · 2019Article
- Recent Developments in Metal-Based Drugs and Chelating Agents for Neurodegenerative Diseases Treatments.International journal of molecular sciences · 2019Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
3 authors at 3 institutions in 2 countries.
Funding
Abstract
Irreversible acetylcholinesterase (AChE) inhibition accumulates to high levels in the central nervous system (CNS) because AChE turnover in the brain is much slower than in peripheral tissues. As expected from this CNS selectivity, the irreversible AChE inhibitor methanesulfonyl fluoride (MSF) produces significant cognitive improvement in Alzheimer's disease patients without the gastrointestinal toxicity that plagues other AChE inhibitors. However, without dose-limiting gastrointestinal toxicity, one shortcoming of the prior human studies of MSF is that the upper limits of CNS AChE inhibition that might be tolerated could not be tested. Therefore, in this study, monkeys were treated with escalating intramuscular (IM) doses of MSF that culminated with several weeks of 1.5 mg/kg dosing, more than eight times the prior human clinical dose, still without signs of toxicity. Brain biopsies showed that ∼80% AChE inhibition had been produced and that the new synthesis of cortical AChE had a half-time (t1/2) of ∼12 days. A single IM dose of 1.5 mg/kg MSF produced ∼59% inhibition in cerebrospinal fluid (CSF) AChE as measured one day later. This corresponds to a peak of ∼80% inhibition in CSF AChE at the time of the injection, recovering with a t1/2 of 2.4 days. Computational analyses suggest that MSF at clinically relevant doses could theoretically produce a steady-state AChE inhibition between 65% and 85% in the CNS. These data suggest that the full therapeutic advantage of AChE inhibition therapy can be realized without interference from dose-limiting gastrointestinal toxicity if an irreversible inhibitor is employed.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.