Intervention Review

Metrifonate for Alzheimer's disease

  1. Jess López-Arrieta1,*,
  2. Lon Schneider2

Editorial Group: Cochrane Dementia and Cognitive Improvement Group

Published Online: 19 APR 2006

Assessed as up-to-date: 28 FEB 2008

DOI: 10.1002/14651858.CD003155.pub3

How to Cite

López-Arrieta J, Schneider L. Metrifonate for Alzheimer's disease. Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.: CD003155. DOI: 10.1002/14651858.CD003155.pub3.

Author Information

  1. 1

    Hospital Universitario La Paz-Cantoblanco, Geriatric Department, Madrid, Spain

  2. 2

    University of Southern California Keck School of Medicine, Los Angeles, CA, USA

*Jess López-Arrieta, Geriatric Department, Hospital Universitario La Paz-Cantoblanco, Ctra de Colmenar km 14,500, Madrid, 28049, Spain. pdarrieta@wanadoo.es. jlopezar.hgugm@salud.madrid.org.

Publication History

  1. Publication Status: Stable (no update expected for reasons given in 'What's new')
  2. Published Online: 19 APR 2006

SEARCH

 

Abstract

  1. Top of page
  2. Abstract
  3. Plain language summary
  4. 摘要

Background

Metrifonate is a long-acting irreversible cholinesterase inhibitor, originally used to treat schistosomiasis. Its potential to enhance central nervous system cholinergic neurotransmission led to clinical trials for the treatment of people with Alzheimer's disease (AD). Although low incidence of serious side effects occurred during short-term use as an antihelmintic, in studies of the treatment of AD extending over six months, 20 patients experienced respiratory paralysis and problems with neuromuscular transmission. These findings have led to a halt to trials of metrifonate for AD and Bayer, the pharmaceutical company, has withdrawn its FDA application.

Objectives

1) To establish the efficacy of metrifonate for patients with Alzheimer's disease, in terms of cognition, global impression, functional activity, non cognitive symptoms, rate of institutionalization and mortality.
2) To assess the safety and tolerability of metrifonate.

Search methods

The Cochrane Dementia and Cognitive Improvement Group's Specialized Register was searched on 29 February 2008 using the term metrifonat*. The CDCIG Specialized Register contains records from all major health care databases (The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS) as well as from many trials databases and grey literature sources. One of the authors (LS), as member of the Metrifonate Study Group, has had the opportunity to contact other metrifonate trialists to obtain data from potentially non published data of metrifonate clinical trials.

Selection criteria

All unconfounded, randomized double-blind clinical controlled trials comparing metrifonate to placebo in people with AD.

Data collection and analysis

Data were extracted by the two reviewers, cross-checked, and pooled when appropriate and possible.

Main results

Most studies assessed changes in cognitive function, global function, activities of daily living, behavioural problems, severity of disease and adverse events. Occasionally the results were not reported in sufficient detail to allow extraction of data for the meta-analyses. The treatment regimens were varied: loading doses were used in some trials. The range of maintenance doses and studies were not pooled unless the treatment regimens were considered comparable. The lengths of treatment varied from 6 to 26 weeks and studies were not pooled unless the treatment duration was similar. The results are derived from the ITT populations.

Metrifonate at various doses, fixed and loading doses, was associated with significant cognitive improvement compared to placebo, except for weekly doses where there was no difference from placebo: MMSE (metrifonate 60-80 mg/day with initial loading at 26 weeks; metrifonate 50 mg/day fixed dose with no initial loading at 26 weeks MD 1.85, 95% CI 1.06 to 2.64, p<0.00001); ADAS-Cog (metrifonate 60-80 mg/day with initial loading at 26 weeks MD -3.24, 95% CI -4.40 to -2.08, p<0.00001)

In most trials, there was improvement in clinical global impression: CIBIC-Plus (metrifonate 30-55 mg/day, approximately 0.65 mg/kg body weight, with initial loading at 26 weeks MD -0.25, 95% CI -0.41 to -0.09 p=0.002; metrifonate 50 mg/day fixed dose with no initial loading at 26 weeks MD -0.20, 95% CI -0.39 to -0.01, p=0.04).

There were generally-significant drug-placebo differences in activities of daily living but this often depended on sample size and the characteristics of the instrument used: DAD (metrifonate 30-55 mg/day, 0.65 mg/kg body weight, with initial loading at 26 weeks MD 2.72, 95% CI 0.66 to 4.77, p=0.01; metrifonate 50 mg/day fixed dose with no initial loading at 26 weeks MD 4.07, 95% CI 0.29 to 7.85, p=0.03)

Also there were differences associated with metrifonate compared with placebo for different doses of metrifonate in scores on a behavioural symptom scale, caregiver burden scale, and severity of disease scale.

Adverse events occurring more often with metrifonate included abdominal pain, bloating, bradycardia, diarrhoea, leg cramps, nausea and rhinitis and were described as mostly mild and transient, but occasionally moderately severe, and infrequently severe and serious. Analysis of the number of patients suffering at least one mild, moderate, severe or serious adverse event before the end of treatment showed that there was usually no difference between placebo and metrifonate.

Authors' conclusions

Metrifonate given once per day appears to be related to clinical response in cognition, global improvement, and activities of daily living in patients with mild to moderate Alzheimer's disease.
Tolerability is good with adverse events as expected from a cholinesterase inhibitor, but with a low incidence of neuromuscular dysfunction and respiratory failure, too low to be detected in this review. It has been withdrawn from further development.

 

Plain language summary

  1. Top of page
  2. Abstract
  3. Plain language summary
  4. 摘要

Metrifonate for Alzheimer's disease

Metrifonate cannot be recommended for the treatment of Alzheimer's disease.

Metrifonate is a long-acting irreversible cholinesterase inhibitor. We reviewed the evidence for its efficacy in Alzheimer's disease and assessed adverse events and tolerability. At various doses it was associated with significant cognitive improvement compared to placebo, improvement in clinical global impression, and activities of daily living.

Neuromuscular dysfunction with life-threatening respiratory failure and death was reported by the pharmaceutical company and FDA, and the drug will not be further developed.

 

摘要

  1. Top of page
  2. Abstract
  3. Plain language summary
  4. 摘要

背景

Metrifonate用於阿茲海默症

Metrifonate是一種長效不可逆之cholinesterase抑制劑,它原本用來治療血吸蟲病。由於該藥物可能增強中樞神經系統cholinergic神經傳導物質,因此被應用於處理阿茲海默症病患的臨床試驗中。 Metrifonate當作驅蟲藥時,雖然短期使用發生嚴重副作用的機率很低,但在超過6個月的阿茲海默症病患治療研究中,20位受試者感受到呼吸上的麻痺以及神經肌肉傳導上的問題。這些發現使metrifonate用於阿茲海默症的試驗暫停,且Bayer製藥公司已經將其對FDA遞出的申請撤回。

目標

1) 藉由認知、整體診斷印象、具機能的活動、非認知性的症狀、機構化比率及死亡率,確認metrifonate對於阿茲海默症患者的療效。 2)評估metrifonate的安全性及耐受性。

搜尋策略

於2005年12月5日以metrifonat*搜尋The Cochrane Dementia and Cognitive Improvement Group's Specialized Register。 該登錄中心(Register)定期更新來自重要的健康照護資料庫(MEDLINE、EMBASE、CINAHL、PsycINFO)與許多試驗資料庫的記錄。 由於回顧的作者之一是Metrifonate Study Group成員,因此有機會可以連絡其他metrifonate 試驗者以取得metrifonate尚未發表的臨床試驗數據。

選擇標準

所有未受干擾(unconfounded)、隨機雙盲的臨床對照試驗,進行metrifonate及安慰劑運用在AD病患之比較。

資料收集與分析

資料由兩位評論家篩檢、再次覆核、並在適當及可能時進行合併(pooled)。

主要結論

大多數研究評估認知功能、整體功能、日常生活活動、行為問題、疾病的嚴重度以及不良的事件的改變。 由於偶發的實驗結果未清楚交代結果。因此無法進行統合分析(metaanalyses)。 治療藥劑有很多種:某些試驗使用速效劑量(loading doses)。只有在治療藥劑可以比較的情況下才會合併維持治療的範圍及研究。 治療的時間長度由6周到26周,除非治療期間相似,否則不會合併各研究。實驗結果來自於治療意向實驗族群。 除了每周的劑量與安慰劑無差異以外,不同Metrifonate劑量、固定及速效的劑量與安慰劑相比較,可以顯著改善認知:MMSE(metrifonate 6080mg/天,並且在26週時給予初劑量(initial loading);metrifonate 50mg/天,在26週時給予固定劑量而不採用初劑量 MD 1.85, 95% CI 1.062.64, p<0.00001); ADASCog (metrifonate 60−80天,並且在26週時給予初劑量 MD −3.24, 95% CI −4.40 – −2.08, p<0.00001)。 多數的試驗當中,臨床整體印象具有改善: CIBICPlus (metrifonate 30 – 55 mg/天,約每公斤體重服用0.65 mg, 並於26週時採用初始劑量 MD −0.25, 95% CI −0.41 to −0.09 p = 0.002;metrifonate 50 mg/天,26週時採用固定劑量而不採用初始劑量 MD −0.20, 95% CI −0.39 to 0.01, p = 0.04). 針對日常活動,藥物安慰劑有著一般顯著的差異,但這常與樣本多少及所使用的評估工具特性有關:失智症的失能評估(DAD) (metrifonate 30 – 55 mg/day, 0.65 mg/體重kg,於26週使用初始劑量MD 2.72, 95% CI 0.66 到 4.77, p = 0.01; metrifonate 50 mg/天,26周時採用固定劑量而不採用初始劑量 MD 4.07, 95% CI 0.29 到 7.85, p = 0.03)。此外,不同劑量的metrifonate與安慰劑相比,在行為症狀尺度、 照顧者負荷尺度及疾病嚴重度尺度等分數上亦有所差異。 使用metrifonate造成的不良事件包括腹疼、鼓脹、心搏過緩、腹瀉、腿痙攣、嘔吐及鼻炎,情況大多溫和且短暫,程度偶爾較大,但並不常出現嚴重及危急的狀況。 分析治療結束前至少感受到一次輕度、中度、重度或嚴重不良事件的病患數量,顯示安慰劑與metrifonate間通常並無差異。

作者結論

對於輕度到中度阿茲海默症的病患,每日給予一次Metrifonate與臨床上認知、整體改善以及日常生活的活動之表現有關。該藥物作為cholinesterase抑制劑時,一如預期病患對於不良事件(如副作用等)的耐受度良好,不過由於神經肌肉失能與呼吸衰竭的發生率過低,因此無法在本回顧當中偵測出來。目前已經暫停開發該藥物。

翻譯人

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

不建議以Metrifonate治療阿茲海默症。Metrifonate是一種長效不可逆的cholinesterase抑制劑。 我們回顧它對阿茲海默症的療效,並且評估不良事件及耐受度。 不同劑量Metrifonate與安慰劑相比,顯著改善了認知能力、臨床的整體印象及日常生活的活動。 不過藥廠及FDA報告顯示會造成神經 −肌肉喪失功能,以及呼吸衰竭及死亡,因此將不會再進一步開發此藥物。