title: Preclinical pharmacology of metrifonate.
abstract: Alzheimer's disease is a chronic neurodegenerative disorder that is characterized by memory impairment, cognitive dysfunction, behavioral disturbances, and deficits in activities of daily living. A consistent observation in these patients is that cholinergic neurons are affected and deteriorate over time, leading to decreased levels of acetylcholine (ACh). Acetylcholinesterase (AChE) inhibitors, which attempt to prevent the breakdown of ACh, may be classified as short acting, intermediate acting, and long acting based on AChE regeneration time. Metrifonate is converted by a nonenzymatic process to the long-acting cholinesterase inhibitor 2,2-dichlorovinyl dimethyl phosphate (DDVP). Acetylcholinesterase inhibition produced by metrifonate occurs rapidly, is dose dependent, can be detected by inhibition measured in red blood cells, and can be reversed by oxime administration. Metrifonate and DDVP improved performance in young rats; cognitive improvement in aged rats also was observed. Both agents were well tolerated and did not have significant effects on various preclinical pharmacologic safety tests.
authors.affiliation: Department of Pharmacy Practice and Pharmaceutical Sciences, Mercer University, Atlanta, Georgia 30341, USA.
authors.forename: M W
authors.initials: MW
authors.lastname: Jann
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000110:Acetylcholinesterase / Q000097:blood / Q000378:metabolism; D000375:Aging / Q000502:physiology; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007473:Ion Channels / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014236:Trichlorfon / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D002800:Cholinesterase Inhibitors; D007473:Ion Channels; D014236:Trichlorfon; D000110:Acetylcholinesterase; D005947:Glucose; D000109:Acetylcholine