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Metrifonate benefits cognitive, behavioral, and global function in patients with Alzheimer's disease.

Abstract

OBJECTIVE

To evaluate the efficacy and safety of metrifonate, an acetylcholinesterase inhibitor, in patients clinically diagnosed with probable Alzheimer's disease (AD) of mild to moderate severity.

METHODS

A prospective, 36-week, multicenter, double-blind, randomized, parallel group study of metrifonate in probable AD patients, including a 2-week screening period, a 26-week double-blind treatment period, and a follow-up visit at 8 weeks post-treatment. A total of 24 ambulatory clinics in the United States in a variety of settings, including contract research organizations, public health facilities, and universities. Patients met diagnostic criteria for probable AD as defined by the work group of the National Institute for Neurological and Communicative Diseases and Stroke and the Alzheimer's Disease and Related Disorders Association. Patients had Mini-Mental State Examination (MMSE) scores of 10 to 26 and Ischemic Scores (Rosen Modification) of <4. A total of 408 patients were enrolled. Percentages of patients completing double-blind treatment were 88% and 79% in the placebo and metrifonate groups, respectively. Rates of discontinuation due to adverse events were 4% in the placebo group and 12% in the metrifonate group. Placebo or metrifonate was administered once daily. Metrifonate-treated patients received a loading dose of 100 to 180 mg based on weight (2.0 mg/kg) for 2 weeks, followed by a maintenance dose of 30 to 60 mg based on weight (0.65 mg/kg) for 24 weeks. Primary efficacy variables were the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the Clinician's Interview-Based Impression of Change with Caregiver Input (CIBIC-plus). Secondary efficacy variables included the Neuropsychiatric Inventory (NPI), the Disability Assessment in Dementia, the Global Deterioration Scale (GDS), the ADAS-Noncognitive subscale (ADAS-Noncog), the MMSE, and the Clinician's Interview-Based Impression of Severity with Caregiver Input (CIBIS-plus). Outcome measures reflected changes from baseline at week 26 for all variables. Safety was assessed with incidences of premature termination, treatment-emergent events and mortality, and routine safety evaluations.

RESULTS

After 26 weeks of metrifonate therapy, a 2.86-point treatment difference (p = 0.0001) was observed in the ADAS-Cog scores of the intent-to-treat AD patients. The treatment difference in the mean CIBIC-plus score at this time was 0.28 points (p = 0.0071). At week 26, treatment differences also were observed in the mean NPI total score (p = 0.0161). Analysis of the remaining secondary efficacy variables showed treatment differences that favored metrifonate but did not reach statistical significance. Metrifonate adverse events were predominantly mild in intensity. No hepatotoxicity was observed.

CONCLUSIONS

Metrifonate was safe and well-tolerated. It enhanced not only the cognitive and global function, but also the behavioral function of patients diagnosed with mild to moderate AD. Therefore, metrifonate appears to be useful in the symptomatic treatment of AD.

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  • Authors+Show Affiliations

    ,

    Washington University in St. Louis, School of Medicine, MO 63110-1093, USA.

    , , , , ,

    Source

    Neurology 50:5 1998 May pg 1222-30

    MeSH

    Aged
    Aged, 80 and over
    Alzheimer Disease
    Behavior
    Cholinesterase Inhibitors
    Cognition Disorders
    Double-Blind Method
    Female
    Humans
    Least-Squares Analysis
    Male
    Prospective Studies
    Treatment Outcome
    Trichlorfon

    Pub Type(s)

    Clinical Trial
    Journal Article
    Multicenter Study
    Randomized Controlled Trial
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    9595967

    Citation

    Morris, J C., et al. "Metrifonate Benefits Cognitive, Behavioral, and Global Function in Patients With Alzheimer's Disease." Neurology, vol. 50, no. 5, 1998, pp. 1222-30.
    Morris JC, Cyrus PA, Orazem J, et al. Metrifonate benefits cognitive, behavioral, and global function in patients with Alzheimer's disease. Neurology. 1998;50(5):1222-30.
    Morris, J. C., Cyrus, P. A., Orazem, J., Mas, J., Bieber, F., Ruzicka, B. B., & Gulanski, B. (1998). Metrifonate benefits cognitive, behavioral, and global function in patients with Alzheimer's disease. Neurology, 50(5), pp. 1222-30.
    Morris JC, et al. Metrifonate Benefits Cognitive, Behavioral, and Global Function in Patients With Alzheimer's Disease. Neurology. 1998;50(5):1222-30. PubMed PMID: 9595967.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Metrifonate benefits cognitive, behavioral, and global function in patients with Alzheimer's disease. AU - Morris,J C, AU - Cyrus,P A, AU - Orazem,J, AU - Mas,J, AU - Bieber,F, AU - Ruzicka,B B, AU - Gulanski,B, PY - 1998/5/22/pubmed PY - 1998/5/22/medline PY - 1998/5/22/entrez SP - 1222 EP - 30 JF - Neurology JO - Neurology VL - 50 IS - 5 N2 - OBJECTIVE: To evaluate the efficacy and safety of metrifonate, an acetylcholinesterase inhibitor, in patients clinically diagnosed with probable Alzheimer's disease (AD) of mild to moderate severity. METHODS: A prospective, 36-week, multicenter, double-blind, randomized, parallel group study of metrifonate in probable AD patients, including a 2-week screening period, a 26-week double-blind treatment period, and a follow-up visit at 8 weeks post-treatment. A total of 24 ambulatory clinics in the United States in a variety of settings, including contract research organizations, public health facilities, and universities. Patients met diagnostic criteria for probable AD as defined by the work group of the National Institute for Neurological and Communicative Diseases and Stroke and the Alzheimer's Disease and Related Disorders Association. Patients had Mini-Mental State Examination (MMSE) scores of 10 to 26 and Ischemic Scores (Rosen Modification) of <4. A total of 408 patients were enrolled. Percentages of patients completing double-blind treatment were 88% and 79% in the placebo and metrifonate groups, respectively. Rates of discontinuation due to adverse events were 4% in the placebo group and 12% in the metrifonate group. Placebo or metrifonate was administered once daily. Metrifonate-treated patients received a loading dose of 100 to 180 mg based on weight (2.0 mg/kg) for 2 weeks, followed by a maintenance dose of 30 to 60 mg based on weight (0.65 mg/kg) for 24 weeks. Primary efficacy variables were the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the Clinician's Interview-Based Impression of Change with Caregiver Input (CIBIC-plus). Secondary efficacy variables included the Neuropsychiatric Inventory (NPI), the Disability Assessment in Dementia, the Global Deterioration Scale (GDS), the ADAS-Noncognitive subscale (ADAS-Noncog), the MMSE, and the Clinician's Interview-Based Impression of Severity with Caregiver Input (CIBIS-plus). Outcome measures reflected changes from baseline at week 26 for all variables. Safety was assessed with incidences of premature termination, treatment-emergent events and mortality, and routine safety evaluations. RESULTS: After 26 weeks of metrifonate therapy, a 2.86-point treatment difference (p = 0.0001) was observed in the ADAS-Cog scores of the intent-to-treat AD patients. The treatment difference in the mean CIBIC-plus score at this time was 0.28 points (p = 0.0071). At week 26, treatment differences also were observed in the mean NPI total score (p = 0.0161). Analysis of the remaining secondary efficacy variables showed treatment differences that favored metrifonate but did not reach statistical significance. Metrifonate adverse events were predominantly mild in intensity. No hepatotoxicity was observed. CONCLUSIONS: Metrifonate was safe and well-tolerated. It enhanced not only the cognitive and global function, but also the behavioral function of patients diagnosed with mild to moderate AD. Therefore, metrifonate appears to be useful in the symptomatic treatment of AD. SN - 0028-3878 UR - https://www.unboundmedicine.com/medline/citation/9595967/Metrifonate_benefits_cognitive_behavioral_and_global_function_in_patients_with_Alzheimer's_disease_ L2 - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&amp;PAGE=linkout&amp;SEARCH=9595967.ui DB - PRIME DP - Unbound Medicine ER -