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Velnacrine for Alzheimer's disease

  • Review
  • Intervention

Authors


Abstract

Background

Alzheimer's disease (AD) is the commonest cause of dementia affecting older people. One of the therapeutic strategies aimed at ameliorating the clinical manifestations of Alzheimer's disease is to enhance cholinergic neurotransmission in relevant parts of the brain by the use of cholinesterase inhibitors to delay the breakdown of acetylcholine released into synaptic clefts. Tacrine, the first of the cholinesterase inhibitors to undergo extensive trials for this purpose, was associated with significant adverse effects including hepatotoxicity. Velnacrine is a derivative of tacrine.

Objectives

To determine the clinical efficacy and safety of velnacrine for patients with dementia of Alzheimer's type.

Search methods

The trials were identified from a last updated search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 8 January 2004 using the terms velnacr* and 'HP 029'. The CDCIG SR is regularly updated and contains records from all major health care databases and a great many ongoing trial databases.

Selection criteria

All unconfounded, double-blind, randomized trials in which treatment with velnacrine was administered for more than two weeks to patients with dementia of the Alzheimer's type and its effects compared with those of placebo in a parallel group of patients.

Data collection and analysis

One reviewer (JSB) applied study selection criteria, assessed the quality of studies and extracted data.

Main results

Four trials, involving 899 participants, were included. Cutler 1990 reported only the adverse events, and omitted the results for the placebo group. Medication was stopped for all in the highest dose group after the fourth day because one member suffered a tonic seizure. It is not possible to report any comparisons with placebo. Antuono 1995 reported benefit for velnacrine at endpoint for the CGI-C, and the Physical Self-maintenance Scale (PGIR), but not for the Carers Assessment of Time Activity (CATS). These results could not be checked because the relevant information was not reported, and we cannot assess the effect on the results of the higher number of non-completers from the velnacrine group. Treatment was discontinued because of safety reasons in 135 patients, mostly due to an abnormal liver function tests. There was a significant difference in favour of placebo compared with the combined treatment group for the number with an abnormal liver function test before the end of treatment at 24 weeks [105/297 vs 4/152, OR =20.23, 95% CI 7.29 to 56.18, p<0.00001]. There was a significant difference in favour of placebo compared with the combined treatment group for the number of withdrawals before the end of treatment at 24 weeks [130/297 vs 39/152, OR =2.26, 95% CI 1.47 to 3.47, p=0.0002].

Results are available for the dose replication phases of Zemlan 1996a and Zemlan 1996b. All the patients had taken velnacrine within two weeks prior to this phase and were identified as responders to velnacrine defined by improvement on the ADAS-Cog. Both studies reported a significant benefit for velnacrine compared with placebo for the ADAS-cog, but the results could not be checked because the relevant information was not reported. Neither study reported any benefit for velnacrine for the other efficacy measures. There was a significant difference in favour of placebo compared with the treatment group for the number with elevated liver transaminases before the end of treatment at 6 weeks [45/153 vs 29/156, OR =1.82, 95% CI 1.07 to 3.11, p=0.03]. There was a significant difference in favour of placebo compared with the treatment group for the number of withdrawals before the end of treatment at 6 weeks [68/211 vs 47/215, OR =1.70, 95% CI 1.10 to 2.62, p=0.02].

Authors' conclusions

There has been no research into the use of velnacrine as a cognitive enhancer in the treatment of Alzheimer's disease since 1994. The FDA peripheral and CNS drug advisory board voted unanimously against recommending approval. This review shows the toxic nature of velnacrine, and provides no evidence of efficacy. There are no grounds for further research into velnacrine.

摘要

背景

Velnacrine用於治療阿茲海默症

阿茲海默症(AD)是老年癡呆症最常見的原因。改善阿茲海默症臨床症狀的方式之一是利用cholinesterase抑制劑,延緩乙醯膽鹼(Acetylcholine)分解釋放到兩神經元之間縫隙,進而提升大腦中膽鹼能藥物神經傳遞。 Tacrine是第一個針對此目的進行大規模試驗的cholinesterase抑制劑,並且具有重大的不良反應,像是肝細胞毒性等有關。Velnacrine是tacrine衍生物。

目標

確認velnacrine用於阿茲海默症失智患者的臨床效果及安全性。

搜尋策略

2004年1月8日使用velnacr* 以及 ‘HP 029’搜尋the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group。 這CDCIG SR資料庫規律地更新,並且包含來自主要健康照護資料庫及許多進行中試驗資料庫更新後的文章。

選擇標準

選擇標準如下: 1.所有未受干擾、雙盲、隨機分配試驗。 2.使用velnacrine於阿茲海默症失智患者超過2周,並且與平行的安慰劑組患者比較。

資料收集與分析

一位回顧者(JSB)應用了研究篩選標準,評估研究品質並且摘取資料。

主要結論

四項臨床試驗,涉及899位參加者,被納入。 Cutler 1990年的研究僅報告不良事件,且省去了安慰劑組,而在第4天時,由於1位成員強直發作(tonic seizure),因此所有最高劑量群在第四天後都停止藥物治療,因此無法報導與安慰劑的比較。 Antuono 1995年的研究報告velnacrine對於臨床整體印象(CGIC)以及身體自我照顧 量表(Physical Selfmaintenance Scale (PGIR))具有效益,但是沒有報告到照護者時間活動模式評量(the Carers Assessment of Time Activity (CATS))。 不過由於並沒有報導相關資訊,因此無法檢查這些結果;而且我們無法評估velnacrine組中,為數眾多的未完成試驗者的療效。 有135人因為安全的因素中止治療,多數退出的原因是因為肝功能檢測不正常。 將24周治療結束時將安慰劑組與綜合治療組的肝功能不正常檢驗結果的數目做比較,顯著較偏好使用安慰劑[105/297 vs 4/152, OR = 20.23, 95% CI 7.29 to 56.18, p<0.00001]。 與綜合治療組比較,在24周治療結束前撤回治療的數目,顯著偏好採用安慰劑組[130/297 vs 39/152, OR = 2.26, 95% CI 1.47 to 3.47, p = 0.0002]。 可利用Zemlan 1996a及Zemlan 1996b的劑量重複階段得到結果。所有的病患在該階段前的兩周內已服用velnacrine,若能夠改善ADASCog,則定義為對velnacrine有反應者,並予以鑑別出來。 兩研究的報告都指出,以ADASCog進行鑑識,velnacrine的療效顯著,但是這些結果不能被加以檢驗,因為沒有報告相關資訊。 沒有一個研究都指出採用其他測量方式,可以顯現velnacrine具有療效。 第六周治療結束前,在肝臟血清轉胺基酵素上升數量方面,較偏好使用安慰劑[45/153 vs 29/156,OR = 1.82, 95% CI 1.073.11,p = 0.03]。 第六周治療結束前,在退出治療方面,明顯偏向使用安慰劑[68/211 vs 47/215, OR = 1.70, 95% CI 1.10 – 2.62, p = 0.02]。

作者結論

自1994年之後已沒有velnacrine作為認知增強記來治療阿茲海默症的研究。FDA周邊及中樞神經藥物諮詢委員會(The FDA peripheral and CNS drug advisory board)一致投票不許批准。本回顧顯示velnacrine有毒的特性,且提出該藥功效無佐證。沒有立場對於velnacrine做進一步的研究。

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

Velnacrine對於阿茲海默症病人無效益。 改善阿茲海默症臨床症狀的方式之一是利用cholinesterase抑制劑,延緩乙醯膽鹼(Acetylcholine)分解釋放到兩神經元之間縫隙,進而提升大腦中膽鹼能藥物神經傳遞。 Tacrine是第一個針對此目的進行大規模試驗的cholinesterase抑制劑,並且具有重大的不良反應,像是肝細胞毒性等有關。Velnacrine是一種tacrine的衍生物。1994年有證據顯示該藥物有毒性且與tacrine有一相似的方式,並且停止所有研究。 FDA周邊及中樞神經藥物諮詢委員會(The FDA peripheral and CNS drug advisory board)一致投票同意反對批准。

Plain language summary

Velnacrine is not beneficial for people with Alzheimer's disease

Alzheimer's disease (AD) is the commonest cause of dementia affecting older people. One of the therapeutic strategies aimed at ameliorating the clinical manifestations of Alzheimer's disease is to enhance cholinergic neurotransmission in relevant parts of the brain by the use of cholinesterase inhibitors to delay the breakdown of acetylcholine released into synaptic clefts. Tacrine, the first of the cholinesterase inhibitors to undergo extensive trials for this purpose, was associated with significant adverse effects including hepatotoxicity. Velnacrine is a derivative of tacrine. There is evidence that it is toxic in a similar way to tacrine and all research stopped in 1994. The FDA peripheral and CNS drug advisory board voted unanimously against recommending approval.

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