Huperzine A for Alzheimer's disease
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the efficacy and safety of Huperzine A for the treatment of patients with AD.
Background
Alzheimer's disease (AD) is the most common cause of dementia affecting older people. It is initially characterized by memory loss, followed by a more general cognitive decline, inability to perform activities of daily living (ADL), and behavioral symptoms, such as wandering, agitation, depression and anxiety.
AD has become a major public health problem around the world due to its increasing prevalence, long duration, caregiver burden, and high financial cost of care. A meta‐analysis (Jorm 1987) based on 22 international studies found that the prevalence of AD differed significantly from study to study. However, this meta‐analysis demonstrated that the prevalence increased exponentially with age. In the United States, approximately 1.6 ‐ 2.4 million Americans suffered from Alzheimer's disease and related dementia in 2001(Rice 2001) and the prevalence of AD is projected to quadruple to one in 45 Americans in the next 50 years across all ages (Brookmeyer 1998). In Canada, the prevalence of dementia was about 8% in 1991 among seniors over the age of 65 years and increased to 34% among those aged 85 years or more (CSHA 1994). The age‐standardized incidence of dementia in Canada has been estimated at 21.8 per thousand for females and 19.1 per thousand for males (Baumgarten 1994). The prevalence of AD is expected to increase 3‐ to 4‐fold in Canada during the next 50 years ( Brookmeyer 1998; USGAO 1998) resulting in upwards of 10 million cases by the year 2050 (Brookmeyer 1998; Evans 1990). In China, the prevalence of AD varied considerably from 0.94% to 5.98% among those aged 60 years or older across different regions (Zhang 1998; Lu 1998; Li 1999; Zhou 2001; He 2002). Generally, the life expectancy of a patient with AD after diagnosis is 9 to 10 years (Taylor 2000). It is estimated to cost in excess of $100 billion per year in the United States (NIA 1998) and is considered the third most costly disease to treat (Meek 1998). It has been estimated that a treatment that delays onset of the disease by just 12 months would decrease the number of persons afflicted with AD by 770,000 more than projected 50 years after initiation of the intervention (Brookmeyer 1998). The impact of such a treatment on healthcare costs would be enormous, saving as much as $36 billion per year (Brookmeyer 1998). These factors justify the intensive efforts to treat or delay onset or progression of AD around the world.
Although there is currently no cure for AD, treatment options do exist. Because a hallmark of the disease is the degeneration of acetylcholine‐containing neurons in the basal forebrain (Rosler 1999), treatments have been focused on increasing acetylcholine levels in the brain. Cholinesterase inhibitors accomplish this by blocking the degradation of acetylcholine, thus increasing the efficacy of the remaining cholinergic neurons (Whitehouse 1981). Cholinesterase inhibitors may improve some aspects of cognitive functioning and slow cognitive decline in patients with AD (Rogers 1991). To date, there are five U.S.A. FDA‐approved drugs that can control symptoms and slow the progression of AD, including tacrine (Gracon 1996), donepezil (Birks 2003), rivastigmine (Birks 2000), galantamine (Loy 2004) and memantine (Areosa 2005).
However, these drugs are not always effective and are expensive, especially for developing countries. This reality drives people to search for other modalities of treatment in an attempt to further improve the outcome of AD, including Chinese herbal medicine.
Huperzine A, derived from the Chinese club moss Huperzia serrata, has been used for centuries in China as a traditional medicine to treat various disorders of health, including dementia, fever and inflammation. It has now been isolated as a monomeric substance, an alkaloid (Hup, [(5R, 9R, 11E)‐5‐amino‐11‐ethylidene‐5, 6, 9, 10‐tetrahydro‐7‐methyl‐5, 9‐methano‐cycloocteno[b] pyridine‐2(1H)‐one]). Huperzine A is a linearly competitive, reversible inhibitor of acetyl cholinesterase that has both central and peripheral activity with the ability to protect cells against hydrogen peroxide, beta‐amyloid protein (or peptide), glutamate, ischemia and staurosporine‐induced cytotoxicity and apoptosis. These protective effects are related to its ability to attenuate oxidative stress, regulate the expression of apoptotic proteins Bcl‐2, Bax, P53 and caspase‐3, protect mitochondria, and interfere with APP metabolism (Wang 2005). Animal and human studies have shown Huperzine A to be a promising agent for treating acetylcholine‐deficit dementia (including AD) (Liang 2004; Wang 2000; Xu 1995 ). Several clinical trials (Chen 2000; Wang 1999; Xu 1999; Zhang 2002) have been done over the past few years with Huperzine A for AD, showing that Huperzine A appears to offer benefits for some patients with AD without severe adverse effects. But these trials are small in sample size. Recently a report about pharmacological treatment of dementia has been published by McMaster University Evidence‐based Practice Center (Santaguida 2004), in which 186 randomized controlled trials (RCTs) evaluating 97 drugs were summarised. This report stated that there was inconclusive evidence showing Huperzine A to be beneficial for AD. However, this evidence report only included English‐language randomized controlled trials and did not include a lot of trials published in China. Therefore, it still remains uncertain whether the existing evidence is scientifically rigorous enough to support Huperzine A to be recommended for routine use in the treatment of AD. We thus propose to perform a systematic review of trials of Huperzine A, including suitable non‐English trials, to provide the best available evidence for clinical practice and further research.
Objectives
To assess the efficacy and safety of Huperzine A for the treatment of patients with AD.
Methods
Criteria for considering studies for this review
Types of studies
All relevant RCTs looking at the efficacy and safety of Huperzine A for AD will be included, regardless of blinding. In addition we will note the existence of quasi‐RCTs but will not include them in our formal meta‐analyses. If the trial is cross‐over in nature, only data from the first period will be included. There will no limitations to the language and publication type of trials. Individual patient data will not be sought.
Types of participants
Inclusion criteria:
Trials of patients of either sex and 18 years or older with AD of any severity will be included regardless of the disease course and severity. AD must be diagnosed according to any one of the following criteria: (1) the International Classification of Diseases (ICD) version 9 or 10 (ICD 1989; WHO 1992); (2) the Diagnostic and Statistical Manual of Mental Disorders (DSM) III, III‐R, and IV (APA 1980; APA 1987; APA 1994); and (3) the National Institute of Neurological and Communicative Disorders and Stroke ‐ Alzheimer's Disease and Related Disorders Association (NINCDS/ADRDA) (McKhann 1984). The severity of AD will be accepted in whichever classification system the trials specified, such as the MMSE.
Exclusion criteria:
(1) Trials evaluating dementia caused by other diseases except AD.
(2) Trials involving AD patients who are under 18 years in age.
Types of interventions
Trials evaluating huperzine A for patients with AD will be included in the review regardless of doses and dosing schedules and mode of administration. The period of treatment must equal or exceed 1 day. Any duration of follow‐up will be eligible.
We intend to display trials as comparisons as follows in this review:
1.Huperzine A versus placebo only
2.Huperzine A + routine treatment versus placebo + routine treatment
3.Huperzine A + routine treatment versus routine treatment only
4.Huperzine A + routine treatment versus other drugs + routine treatment
The routine treatment includes nursing care, functional exercise and rehabilitation.
Types of outcome measures
Trials will be included that used at least one of the following outcome measures:
Primary outcome measures:
1.The change of cognitive function: global and specific
2.The change of global assessment
3. All cause mortality
Secondary outcome measures :
1. The change of behaviour disturbance
2. The change of functional performance (ADL)
3. Quality of life (QOL)
4. Caregiver burden
5. Adverse events of Huperzine A
Search methods for identification of studies
The Cochrane Dementia and Cognitive Improvement Group's Specialized Register will be searched using the term huperzin*. This Register contains up‐to‐date records of major health care databases like MEDLINE, EMBASE, PsycINFO, CENTRAL AND CINAHL and many ongoing trial databases.
In addition the following sources will be searched for trial reports:
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The China Biological Medicine Database (CBM‐disc 1979 to 2005) which is a database of Chinese biomedical research literature.
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AMED (the Allied and Complementary Medicine Database, 1985 to 2005)
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Ageline (1978 to 2005)
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Reference lists of Alzheimer's disease textbooks, review articles and relevant trials.
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Letters seeking information about unpublished or incomplete trials to investigators known to be involved in previous trials.
Data collection and analysis
Selection of Studies
Two reviewers [Jun Li and Li Cao] will independently check the titles and abstracts of trials for inclusion based on selection criteria outlined previously. The full text of the article will be retrieved if there is any doubt whether the article should be excluded or not. Disagreement will be resolved by discussion with a third member [Hongmei Wu] of the AD research group if necessary.
Quality Assessment
No specific scoring system or checklists will be used to assess the methodological quality of the included studies. Rather, the methodological quality of studies will be documented using the following internal validity criteria in this review:
(1) Method of randomization: a method to generate the sequence of randomization will be regarded as appropriate if it allowed each study participant to have the same chance of receiving each intervention and the investigators could not predict which treatment was next. Methods of allocation using date of birth, date of admission, hospital numbers, or alternation should not be regarded as appropriate.
(2) Concealment of allocation: It will be scored A (adequate), B (unclear), or C (inadequate), following criteria adopted from the Cochrane Reviewers Handbook and Schulz et al (Schulz 1995).
A ‐ Adequate measures to conceal allocations such as central randomisation; serially numbered, opaque, sealed envelopes; or other description that contained convincing elements of concealment.
B ‐ Unclearly concealed trials, in which the authors either did not report an allocation concealment approach at all, or reported an approach that did not fall into one of the categories in (A).
C ‐ Inadequately concealed trials, in which the method of allocation was not concealed, such as alteration methods or use of case record numbers.
(3) Blinding (both of participants and outcome assessors): A study must be regarded as double blind if the word "double blind" is used. The method will be regarded as appropriate if it is stated that neither the person doing the assessments nor the study participant could identify the intervention being assessed, or if in the absence of such a statement the use of active placebos, identical placebos, or dummies is mentioned.
(4) Intention‐to‐treat analysis: Whether an intention‐to‐treat analysis is possible on all patients from the published data (i.e. whether there were any exclusions from the trial after randomization), and the number of patients who were lost to follow‐up. If there were no withdrawals, it should be stated in the article.
Quality assessment will be performed by two independent reviewers [Jun Li and Li Cao] and disagreement reported and resolved by a third member [Hongmei Wu]. These criteria will not form exclusion criteria, however will be described in the Table of Included Studies.
Data Extraction
Information on patients, methods, interventions, outcomes, and results will be extracted independently by two reviewers [Jun Li and Li Cao] using a self‐developed data extraction form. Disagreements will be resolved by a third member [Hongmei Wu] or through discussion. For dichotomous outcomes (such as all cause mortality, numbers experiencing adverse effects and so on), the number of participants experiencing the event and the total number of participants in each arm of the trial will be extracted. For continuous outcomes (such as the change of cognitive function and behaviour disturbance and QOL), the mean value and standard deviation for the changes in each arm of the trial will be extracted along with the total number in each group.
Data on the number of patients with each outcome event and by allocated treatment group, irrespective of compliance or follow‐up, will be sought to allow an intention‐to‐treat analysis. If the above data will not be available in the trials reports, additional information will be sought by correspondence with the principal authors.
Data Analysis
For dichotomous outcomes (such as mortality) results will be expressed as relative risk (RR) with 95% confidence intervals (CI). Data will be pooled using the fixed effects model unless there is evidence of heterogeneity. Where continuous scales of measurement are used to assess the effects of treatment (such as the change of cognitive function and behavior disturbance, QOL, ADL), the weighted mean difference (WMD) will be used, or the standardised mean difference (SMD) if different scales have been used or there are major differences between the trials as evidenced by heterogeneity. Heterogeneity will be analysed using a chi squared test on N‐1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I2 test (Higgins 2003).
Subgroup analysis will be used to explore possible sources of heterogeneity (e.g. participants, treatments). Heterogeneity among participants could be related to age, sex, educational level, comorbidity and the severity of AD. Heterogeneity in treatments could be related to the dose and duration of therapy.
Sensitivity analysis will be performed to assess the effects of including
‐ only those trials with adequate concealment of randomisation
‐ only those trials which were double blind
Adverse effects will be tabulated and assessed with descriptive techniques. Where possible, the risk difference with 95% CI will be calculated for each adverse effect, either compared to no treatment or to another agent.
If sufficient RCTs are identified, an attempt will be made to examine for publication bias using a funnel plot (Egger 1997).
