Metrifonate: A Cholinesterase Inhibitor for Alzheimer's Disease Therapy

Schneider, Lon S.; Giacobini, Ezio

doi:10.1111/j.1527-3458.1999.tb00083.x

Cited by 5 publications

(3 citation statements)

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“…In the past years, it was investigated for the treatment of Alzheimer’s disease. Metrifonate, at various fixed and loading doses, was associated with significant cognitive improvement compared to placebo, where the slow-release break-down byproduct, 2,2-dichlorovinyl dimethyl phosphate (DDVP), is supposed to be the active component [ 21 , 22 ]. The broad activity of metrifonate is perhaps not surprising considering its mechanism of action; metrifonate is a cholinergic drug, acting as an irreversible non-selective acetylcholinesterase and butyrylcholinesterase inhibitor [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

“…Metrifonate, at various fixed and loading doses, was associated with significant cognitive improvement compared to placebo, where the slow-release break-down byproduct, 2,2-dichlorovinyl dimethyl phosphate (DDVP), is supposed to be the active component [ 21 , 22 ]. The broad activity of metrifonate is perhaps not surprising considering its mechanism of action; metrifonate is a cholinergic drug, acting as an irreversible non-selective acetylcholinesterase and butyrylcholinesterase inhibitor [ 21 ]. There is a history of active cholinergic anthelmintics including pyrantel and levamisole, which are both selective nAChR agonists, and ivermectin and moxidectin, which are modulators of glutamate-gated ion channels and nAChRs [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

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Evaluation of an FDA approved library against laboratory models of human intestinal nematode infections

et al. 2016

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BackgroundTreatment options for infections with soil-transmitted helminths (STH) - Ascaris lumbricoides, Trichuris trichiura and the two hookworm species, Ancylostoma duodenale and Necator americanus - are limited despite their considerable global health burden. The aim of the present study was to test the activity of an openly available FDA library against laboratory models of human intestinal nematode infections.MethodsAll 1,600 drugs were first screened against Ancylostoma ceylanicum third-stage larvae (L3). Active compounds were scrutinized and toxic compounds, drugs indicated solely for topical use, and already well-studied anthelmintics were excluded. The remaining hit compounds were tested in parallel against Trichuris muris first-stage larvae (L1), Heligmosomoides polygyrus third-stage larvae (L3), and adult stages of the three species in vitro. In vivo studies were performed in the H. polygyrus and T. muris mice models.ResultsFifty-four of the 1,600 compounds tested revealed an activity of > 60 % against A. ceylanicum L3 (hit rate of 3.4 %), following incubation at 200 μM for 72 h. Twelve compounds progressed into further screens. Adult A. ceylanicum were the least affected (1/12 compounds active at 50 μM), while eight of the 12 test compounds revealed activity against T. muris L1 (100 μM) and adults (50 μM), and H. polygyrus L3 (200 μM). Trichlorfon was the only compound active against all stages of A. ceylanicum, H. polygyrus and T. muris. In addition, trichlorfon achieved high worm burden reductions of 80.1 and 98.9 %, following a single oral dose of 200 mg/kg in the T. muris and H. polygyrus mouse model, respectively.ConclusionDrug screening on the larval stages of intestinal parasitic nematodes is feasible using small libraries and important given the empty drug discovery and development pipeline for STH infections. Differences and commonalities in drug activities across the different STH species and stages were confirmed. Hits identified might serve as a starting point for drug discovery for STH.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-016-1616-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Evaluation of an FDA approved library against laboratory models of human intestinal nematode infections

et al. 2016

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“…The main way for galantamine metabolism occurs through CYP isoenzymes 2D6 and 3A4. Metrifonate [19,56,57] Metrifonate a long-acting irreversible inhibitor of ChEI is not an approved AD drug because of risk of neuromuscular transmission dysfunction and respiratory paralysis. Even if metrifonate has proven a strong and important clinical effect it was abandoned after Phase III.…”

Section: Traditional Cheismentioning

confidence: 99%

Alzheimer’s Disease Pharmacotherapy in Relation to Cholinergic System Involvement

et al. 2019

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Alzheimer’s disease, a major and increasing global health challenge, is an irreversible, progressive form of dementia, associated with an ongoing decline of brain functioning. The etiology of this disease is not completely understood, and no safe and effective anti-Alzheimer’s disease drug to prevent, stop, or reverse its evolution is currently available. Current pharmacotherapy concentrated on drugs that aimed to improve the cerebral acetylcholine levels by facilitating cholinergic neurotransmission through inhibiting cholinesterase. These compounds, recognized as cholinesterase inhibitors, offer a viable target across key sign domains of Alzheimer’s disease, but have a modest influence on improving the progression of this condition. In this paper, we sought to highlight the current understanding of the cholinergic system involvement in Alzheimer’s disease progression in relation to the recent status of the available cholinesterase inhibitors as effective therapeutics.

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Metrifonate

Montgomery¹

2009

xPharm: The Comprehensive Pharmacology Reference

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Metrifonate: A Cholinesterase Inhibitor for Alzheimer's Disease Therapy

Cited by 5 publications

References 50 publications

Evaluation of an FDA approved library against laboratory models of human intestinal nematode infections

Evaluation of an FDA approved library against laboratory models of human intestinal nematode infections

Alzheimer’s Disease Pharmacotherapy in Relation to Cholinergic System Involvement

Metrifonate

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