Physostigmine for dementia due to Alzheimer's disease
Editorial Group: Cochrane Dementia and Cognitive Improvement Group
Published Online: 23 APR 2001
Assessed as up-to-date: 1 JUN 2008
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
How to Cite
Coelho Filho JMJMC, Birks J. Physostigmine for dementia due to Alzheimer's disease. Cochrane Database of Systematic Reviews 2001, Issue 2. Art. No.: CD001499. DOI: 10.1002/14651858.CD001499.
- Publication Status: New search for studies and content updated (no change to conclusions)
- Published Online: 23 APR 2001
The main pharmacological approach for the treatment of Alzheimer's disease (AD) has been based on the use of agents potentiating cholinergic transmission, particularly by inhibiting acetylcholinesterase (AChE), the enzyme that destroys acetylcholine after it has been secreted into the synaptic clefts. Physostigmine is an AChE inhibitor originally extracted from calabar beans. It is licensed in many countries as an agent for reversing the effect of drugs and poisons causing the anticholinergic syndrome. Studies conducted more than 20 years ago suggested that physostigmine could improve memory in people with or without dementia. Investigation of this property has been limited by the very short half-life of physostigmine. Various forms of administering the drug have been tried to overcome this problem, most recently a controlled-release (CR) oral formulation, and a skin patch.
To determine the clinical efficacy and safety of physostigmine in Alzheimer's disease.
The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (CDCIG), The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL and LILACS were searched on 10 January 2008 using the terms: physostigmine OR syrapton OR antilirium. The CDCIG Specialized Register contains records from all major health care databases (CENTRAL, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS) as well as from many trials databases and grey literature sources.
We asked Forest Laboratories and Pharmax, owners of the rights to market physostigmine for Alzheimer's disease, for additional data and reports of clinical trials but we did not receive any information.
All relevant unconfounded, double-blind, randomized, placebo-controlled trials in which physostigmine was administered for more than one day to patients with dementia of Alzheimer type.
Data collection and analysis
Data were extracted independently by two reviewers (JMC and JB), pooled where appropriate and possible, and the weighted or standardized mean differences or Peto odds ratios (95% CI) were estimated. Where possible, intention-to-treat analysis was used.
Fifteen studies were included using four different methods of administration of physostigmine. Four studies, 29 people, used intravenous infusion; seven, 131 people, used a conventional oral form; four, 1456 people, used a controlled-release oral form, and one study of 181 people used a verum skin patch.
There are no usable results from the intravenous infusion trials,
The few results from the trials of the conventional oral form showed no benefit of physostigmine compared with placebo.
The results from two of the four studies of the controlled-release physostigmine apply only to a group of patients identified as responders in a pre-randomization titration period. The best dose physostigmine was associated with improvement on the ADAS-Cog score compared with placebo at 6, 12 weeks. There were statistically significantly higher numbers of patients from the physostigmine group withdrawing from the trial (22/183 vs 2/183)(OR 5.92, 95% confidence limits 2.59 to 13.54, p<0.0001) and suffering at least one event of nausea, vomiting, diarrhoea, anorexia, dizziness, stomach pain, flatulence or sweating compared with placebo at 6 weeks. There were statistically significantly higher numbers of patients from the physostigmine group withdrawing from the trial due to adverse events (13/83 vs 5/93)(OR 3.05, 95% CI 1.15 to 8.07, p=0.02) and suffering at least one event of nausea, vomiting, diarrhoea, anorexia, dizziness, stomach pain, tremor, asthenia or sweating compared with placebo at 12 weeks. When no attempt was made to identify responders and all relevant patients with Alzheimer's disease were randomized, fixed dose physostigmine (mean 33 mg/day) was associated with a statistically significantly higher number withdrawing (234/358 vs 31/117)(OR 4.82, 95% CI 3.17 to 7.33, p<0.00001), withdrawing due to adverse events (196/358 vs 10/117) (OR 6.54, 95%CI 4.29 to 9.95, p<0.00001) and suffering at least one event of nausea, vomiting, diarrhoea, anorexia, dizziness, stomach pain, dyspepsia, sweating, asthenia, dyspnoea or abnormal dreaming, but with no benefit on cognition compared with placebo at 24 weeks.
The double dose (delivering mean dose 12 mg/day) was associated with statistically significantly higher numbers suffering at least one adverse event of vomiting, nausea, or abdominal cramps, and the lower dose (delivering mean dose 5.7mg/day) was associated with statistically significantly higher numbers suffering gastrointestinal complaints compared with placebo at 24 weeks. There was no difference between physostigmine (higher and lower dose) and placebo for numbers improved (CGIC) at 24 weeks.
The evidence of effectiveness of physostigmine for the symptomatic treatment of Alzheimer's disease is limited. Even in a controlled release formulation designed to overcome the short half-life, physostigmine showed no convincing benefit and adverse effects remained common leading to a high rate of withdrawal.
Plain language summary
Limited evidence of effectiveness of physostigmine for the symptomatic treatment of Alzheimer's disease
Physostigmine is an acetylcholinesterase inhibitor; it works by obstructing the enzyme responsible for ACh destruction in the synaptic cleft. Studies conducted more than 20 years ago suggested that physostigmine could improve memory in people with or without dementia. Investigation of this property has been limited by the very short half-life of physostigmine. Various forms of administering the drug have been tried to overcome this problem, most recently a controlled-release (CR) oral formulation, and a skin patch. An additional limiting factor has been a high incidence of adverse effects, including nausea, vomiting and diarrhoea. Physostigmine appears to have no advantage over some newer anticholinesterase drugs. The short half-life remains a serious disadvantage and requires complex forms of administration. There is no reason to recommend further research into this drug.
在使用最新的研究登錄，該登錄系統包括MEDLINE, EMBASE, PsycINFO, CINAHL及許多這期更新之試驗資料庫。 在2005年8月5號，根據以下關鍵字搜尋：physostigmine, “physostigmine salcicylate”, synapton, antilirium。我們詢問Forest Laboratories and Pharmax公司針對阿茲海默氏症在使用physostigmine的市場調查，但是並沒有得到新增的資訊
資料經適當合併後由兩個審查者(JMC & JB)分別分析，統計指標包含加權或標準平均差，或危險係數。在可能情況下盡量使用意圖治療分析法(intentiontotreat analysis)
以四種不同的physostigmine投予方法搜尋到十五個相關研究。有四個研究，共收入二十九個病人，使用靜脈針劑；有七個研究，一百三十一個人，使用傳統口服劑型；四個研究，1456個人，使用口服緩釋劑型，另外有一個研究總共181人，使用經皮貼劑。 在靜脈針劑部分沒有可用結果。傳統口服劑型僅有的結論顯示physostigmine並沒有明顯的助益，如果跟對照組相比的話。針對緩釋劑型有兩個研究顯示有一群失智症病人在隨機分配之前對藥物有反應。藥效反應最好的時間，如果根據ADAScog的分數而言是在投藥6與12周後。另外統計顯示有意義的差別在於physostigmine使用的族群較容易因為副作用在第六個星期退出試驗(22/183 vs 2/183)(OR 5.92, 95% confidence limits 2.59 to 13.54, p<0.0001)。副作用包括噁心，嘔吐，下痢，食慾不振，頭暈，胃痛，冒冷汗，或腸胃氣漲。另外也有較高比例的病人因為副作用在第十二的星期退出試驗(13/83 vs 5/93)(OR 3.05, 95% CI 1.15 to 8.07, p = 0.02)，症狀包含至少一次的噁心，嘔吐，下痢，食慾不振，頭暈，肚痛，顫抖，無力，冒冷汗。physostigmine平均每日劑量為33毫克有統計顯著上的較高比例退出實驗(234/358 vs 31/117)(OR 4.82, 95% CI 3.17 to 7.33, p<0.00001),退出是因為副作用(196/358 vs 10/117) (OR 6.54, 95%CI 4.29 to 9.95, p<0.00001)，包含至少一次噁心，嘔吐，下痢，食慾不振，頭暈，胃痛，消化不良，冒冷汗，無力，喘不不過氣或者做噩夢，但是與對照組相比，在24周的智能評估上並沒有顯著幫助。有關經皮貼劑方面，使用雙倍的劑型(一日平均12毫克)，有較高比率有顯著的副作用，包括嘔吐，噁心，或肚子痛。低劑量劑型(一日平均5.7毫克)在二十四周與對照組相比，有顯著較高的比例有腸胃道的不適。在二十四周高劑量與低劑量貼片跟對照組相比，在症狀改善上，並沒有差異
此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌