Acetylcholinesterase inhibitors in Alzheimer’s disease (1999)

Alzheimer’s Disease (AD) is the most common single cause of dementia in our ageing society. Traditionally thought of as an untreatable degenerative condition, recent advances in drug therapy have challenged this view. The disease is characterised by an insidious decline in cognitive and non-cognitive function. Classically, short and long-term memory is impaired while language skills, concentration and attention are often affected. This results in impaired ability to learn and retain new skills as well as the loss of existing ones. Non-cognitive function is the global term used to describe problems such as depression, agitation, personality changes, delusions and hallucinations. These factors have a significant impact on patient behaviour and a very real impact on the quality of life for both patients and caregivers. Diagnosis of AD is clinically based, and using the NINCDS-ADRDA criteria (Table 1) [ 1], a diagnosis of probable or possible AD can be made. Definitive diagnosis relies on pathological confirmation, which in the majority of cases is rarely completed. With the development of AD specific treatments, definition of AD from other types of dementia is very important. The pathogenesis of AD has not yet been elucidated. It is widely accepted that a combination of genetic susceptibility factors and environmental triggers are responsible for late onset sporadic AD, the most common form of the disease. An understanding of the disease mechanism remains elusive, and is the key to developing a disease modifying agent. Currently, it is proposed that beta amyloid protein, abnormal tau protein or possibly both play key factors in the development of disease. It has been widely postulated that oxidative damage and a slow inflammatory process are two possible mechanisms involved. As yet, no product with proven disease modifying properties is available, and current treatments offer symptomatic benefit only. The development of acetylcholinesterase (AChe) inhibitor drugs has followed the finding that cholinergic pathways in the cerebral cortex and basal forebrain are compromised in AD [ 2] and the resultant cholinergic deficit contributes to the cognitive impairment of these patients [ 3]. Although many believe this ‘cholinergic hypothesis’ to be important, others feel it represents a less significant component of the disease process [ 4]. Many other neurotransmitters are affected in AD, and the relative importance of each in relation to clinical findings has not been fully elucidated. Initial work focused on the use of acetylcholine precursors, using a similar rationale to dopamine therapy in Parkinson’s disease. A series of small trials using precursors such as choline and phosphatidylcholine showed no reliable improvement in cognitive function, with only 10 out of 43 trials reporting any positive effect [ 5]. There has been renewed interest in muscarinic agonists drugs, which when first introduced, had major problems with adverse cholinergic effects. Better understanding of the molecular pathology of muscarinic receptors and their subtypes has led to the development of more specific agonists. Drugs such as xanomeline, milameline, and civimeline have reached clinical trials, and the improvements seen in cognitive function are reviewed by Avery et al. [ 6]. There are also claims that these drugs have disease modifying properties, with effects on APP processing and tau phosphorylation. Muscarinic agonists remain in trial, but have yet to fulfil their potential in AD treatment. The only group of drugs currently licensed for AD treatment is the AChe inhibitors, which act through inhibition of the enzyme acetylcholinesterase (AChe), responsible for the breakdown of ACh in the neural synapse. A meta-analysis of the early AChe inhibitor treatments was encouraging [ 7] and these proceeded to larger placebo controlled double-blind trials. The advent of treatment for dementia has brought with it a confusing array of ‘dementia’ assessments, many designed specifically for the therapeutic trials. The majority of these are unfamiliar to physicians, as they have limited value in clinical settings. However, a cursory understanding of the many scores and abbreviations is essential for reviewing the published data (Table 2). The primary outcome measures in these trials most commonly include the ADAS Cog (Alzheimer’s Disease Assessment Scale Cognitive Subscale), some form of global assessment such as the CIBIC (Clinicians Interview-Based Impression of Change) scale or the CGIC (Clinical Global Impression of Change) and a staging scale for dementia, the CDR (Clinical Dementia Rating scale). The ADAS Cog has been the mainstay of cognitive testing in recent dementia trials [ 8]. It assesses the major cognitive functions of memory, language, attention, orientation, praxis and reasoning. It is scored from 0 to 70, with a higher score indicating increasing severity. The test is most sensitive in the middle phase of disease, with moderately severe AD patients gaining approximately 7–11 points per year [ 9, 10]. The CIBIC Score, usually performed by a separate rater, is information from patient and carer (CIBIC-Plus) obtained during interview and focuses on general well being, cognition, behaviour and activities of daily living (ADL). It provides a global assessment of deterioration in the absence of any knowledge of the psychometric test performance. It was derived from the CGIC, a similar rating to the CIBIC score employed in earlier donepezil and tacrine trials [ 11]. The CDR [ 12] is a consensual report from all assessors, on six main functional domains; memory, orientation, judgement, community affairs, home and hobbies and personal care. The scale defines mild, moderate and severe dementia. Secondary outcome measures used in trials are more variable, and attempt to assess areas such as daily function and quality of life. Mini-mental state examination (MMSE) [ 13] and Activities of Daily Living (ADL) [ 14] are cited along with less well known assessments such as the Geriatric Evaluation by Relatives Rating Instrument (GERRI) [ 15], the Progressive Deterioration Scale (PDS) [ 16] and the Global Deterioration Scale (GDS) [ 17] which is used as a measure of severity rather than deterioration. Non cognitive function is more difficult to quantify, and assessments usually encompass some form of behavioural rating scale such as the ADAS noncognitive Score, neuropsychiatric inventory (NPI) [ 18] or the Behavioural Pathology in Alzheimer’s Disease (BEHAVE-AD) [ 19]. A lack of consensus regarding appropriate non-cognitive and functional assessments is reflected in the variety of scales used. An obvious need for standardisation became apparent, and in 1989, the American Food and Drug Administration (FDA) published guidelines outlining what they felt constituted a clinical response in dementia treatment [ 20]. This has since been employed by the European Medicine Evaluation Agency (EMEA) [ 21]. They designated a change of 4 points or more on an ADAS Cog score within a clinical trial setting to represent a significant clinical effect. This was based on the calculation that the ‘average’ AD patient will show a decline in their ADAS Cog score of 7 to 11 points per year in the middle stages of disease [ 9, 10]. Thus, an improvement of 4 points in the ADAS Cog is felt to represent a gain of 6 months in terms of delaying decline. Due to the heterogenous nature of AD, a 6 month delay can represent a huge variation in clinical terms. In practice this can mean improved insight, better memory with less repeated questioning, improved fluency in language, improved recognition of people, and revived interest in hobbies or everyday events. A problem with using the ADAS Cog as a gold standard is that factors such as mood, behaviour and functional ability are not considered. Certain AChe inhibitor trials have highlighted positive effects (in addition to the 4-point ADAS Cog improvement) on neuropsychiatric symptoms, in particular hallucination [ 22], and ADLs [ 23]. In reference to this problem, the FDA and EMEA have highlighted the importance of global assessments in conjunction with cognitive scores, and these are included as measures of primary efficacy in clinical trials. As a group, these drugs show a dose-dependent improvement in symptoms of AD, with varying amounts of systemic cholinergic effects. The early research into AChe inhibitors included tetrahydroaminoacridine (tacrine), physostigmine and velnacrine. Of these, only tacrine proceeded to large-scale clinical trials and commercial launch in the USA and parts of Europe. This has been followed by the more recent products, donepezil, rivastigmine and metrifonate (Table 3). Tacrine, an aminoacridine, has several actions such as monoamine oxidase inhibition, potassium channel blockade and interaction with subtypes of muscarinic and nicotinic receptors. However the most prominent action is as a centrally active reversible cholinesterase inhibitor. Tacrine is rapidly absorbed and cleared by the liver during a first pass metabolism [ 24, 25]. Due to hepatic hydroxylation, tacrine itself has a very low bioavailability when taken orally, at 2% to 3% that of an intravenous dose. The short, markedly variable elimination half-life of tacrine increases from 1.4 to 3.6 h with higher doses and multiple dosing. The relationship between dosage and bioavailability is not proportional e.g. doubling the dose may triple or quadruple bioavailability. Tacrine is rapidly taken up into the brain where its concentration is tenfold that in plasma [ 25, 26]. In summary the characteristics of tacrine’s pharmacokinetics are dose nonlinearity, extensive distribution, and rapid elimination through hepatic transformation, mainly into the hydroxy metabolite velnacrine. Donepezil is a specifically designed piperidine derivative with reversible acetylcholinesterase inhibitor activity. It has a much higher specificity for acetylcholinesterase inhibition compared with tacrine [ 27] and its CNS selectivity is highlighted by the lack of activity in peripheral tissue such as cardiac tissue or gut smooth muscle [ 28]. The pharmacokinetics are linear and dose proportional, with peak plasma levels after approximately 4 h. Plasma steady state appears to be reached between 14 and 21 days with a long half-life of over 70 h [ 29]. Excretion is slow and occurs via renal and the cytochrome P450 system although it is not impaired in patients with hepatic or renal impairment [ 30]. Rivastigmine is a brain selective carbamate AChe inhibitor. It is known as a ‘pseudo-irreversible’ inhibitor because it mimics ACh by binding with the enzyme AChe forming a carbamylated This of ACh for several after the drug has been from the Thus, a half-life of only rivastigmine has a of action of 10 h [ donepezil, rivastigmine has CNS selectivity [ with specific effect in the cortex and [ Rivastigmine not to plasma and is by during the enzyme This hepatic and the drug is rapidly through the has a as a treatment for in the late was it as a potential treatment for AD on the of its It has a short half-life in plasma but has long activity in the CNS to its activity. It is to the active metabolite It is this that to the for the and provides AChe inhibition in the CNS [ It is rapidly absorbed and to the although in specificity for In it remains to and the cytochrome P450 clinical of the drug only cholinergic effects with levels of AChe inhibition and short treatment [ The of metrifonate in long-term treatment is currently with recent trials a possible with muscle The early trials of tacrine interest by reporting improvements in cognitive function but the small of patients limited their In the of tacrine by et only patients the treatment [ However, most of the findings in the larger trials that In clinical trials patients in the and tacrine showed a clinically response in of In of the larger trials clinically significant improvements seen in the ADAS Cog score CIBIC and at a dose of [ These not significant for the doses of tacrine in this although they seen to a in [ of patients the higher dose of tacrine at showed the significant 4 points or more improvement in ADAS However this to in the to to the huge at this dosage [ patients because of in The results of a up of AD patients in the phase of the trial [ showed that patients tacrine at had of home than the drug or on doses [ patients less to be than patients but these results need to be with to of the The major are that the treatment was not was it after a relationship between higher dose tacrine treatment and more be published data on the long term effects of tacrine in the group of patients only scores on the Scale a measure of in patients on dose tacrine indicating less decline. There no significant group on the the or the Activities of Daily Living The that was that tacrine had no at after therapy [ A meta-analysis of trials of tacrine patients with AD was published [ This which only focused on the first of that tacrine has an but effect on cognitive function and the They also that effects on measures of behavioural of clinical and functional was not affected. The that that their was not to and which have to the other cholinesterase the relationship between treatment effect and dose was difficult to assess because in most the dose for each patient was to the dose. is lack of controlled data on clinically points such as and the lack of long-term also it is not possible to assess the effects of therapy a long these or when it is to treatment. they out that of the cholinesterase inhibitors has reliable controlled data on such as and or other of long-term efficacy and that such trials It is from this meta-analysis and the long-term [ that of well designed long term trials major because of to placebo and donepezil was the first AChe inhibitor for in the It was with with of rather than In a 14 double-blind trial patients testing doses of and There was a significant in the ADAS Cog score with the and dose when compared with and for an dose response This for improvement was also seen in the global with treatment in the group compared with in the placebo group [ As a of this higher doses in trials. The most published donepezil trials have compared and 10 with placebo a dose improvement in cognitive and global function [ of the trial, ADAS Cog scores showed an from placebo of and for and 10 [ This trial also published data using the 4-point ADAS Cog with of the cases on 10 compared with of on the are of this dose group the 4-point The CIBIC score was significant at and more improved at 10 when compared to of life scores not show but the CDR score showed a significant mean drug placebo of for both and 10 at for the trial with and of the and 10 the an improved effect There is term data with results of an using up to of donepezil [ The improvements in ADAS Cog and seen at and The lack of a placebo group the clinical decline of in the ADAS in the group is to be less than that seen in a group of when the ADAS scores are taken into This deterioration is also seen in the which showed an decline of points per year compared with a decline of points per year in patients [ The at is similar to that seen in the placebo controlled trials, with no adverse or clinically significant in Rivastigmine a carbamate is the in this group of drugs to be in the The is the to the Rivastigmine phase clinical trials. It is to be the global to of a new treatment for In the that it with to moderately severe AD have been The [ patients with to moderately severe AD to treatment with low dose rivastigmine or higher doses Of the patients into the trial treatment although in the dose rivastigmine group to adverse events. The that a significant of the in the no with a of to the of AD trials. the dose rivastigmine their of on the in to the placebo group with a treatment of points In the of the patients on the dose rivastigmine showed the 4 in the by the FDA to be clinically The not what of on the low dose rivastigmine or placebo this it state what of the dose group this in the deterioration was seen in the CIBIC rating in both and low dose and These and of more rapid onset in the dose A of the dose group showed a clinically improvement in the of activities of daily living with a improvement in the score This benefit was not seen in the low dose A of out in has been published [ 23]. A of patients and to low dose rivastigmine or higher dose rivastigmine the of the the mean dose of rivastigmine was in the higher dose group and in the dose these higher than the doses in the earlier of and The results similar to of the The 4 points or improvement in the was seen in of the higher dose group compared to in the placebo group in the CIBIC rating also seen in both treatment at with placebo group, dose group and higher dose group or improvement in the The assessment of activities of daily living using the showed less deterioration between the higher dose group and placebo in the of the but this finding was not significant in the more patients in the higher dose group improved by at than in the placebo group effects on the in the dose is AChe inhibitor which has reached phase clinical trials. In a small highlighted the potential benefit of metrifonate in AD [ This has been followed by two larger trials, dosage and efficacy in over patients [ have been with the major donepezil with a dose and dose of metrifonate showed an and in the ADAS Cog score compared with score also reached a significant change from placebo in the and dose with an of and [ in a trial of dose was a significant change in the with a between the and placebo group In the of was less in the group [ The is a non-cognitive assessment and an where AChe inhibitors have The clinical trial with metrifonate has been a of adverse in the clinical Many of the effects of the AChe inhibitors are to peripheral cholinergic effects. and the most Of the patients tacrine in clinical trials, had levels than the of on at and had levels than the Although in all cases tacrine the the data that of levels was for all patients on tacrine [ and in of patients placebo and of on The majority of adverse to moderate in as by the [ significant drug effects on or or such as the seen in all trials of donepezil and as to moderate and using low doses of donepezil, and and placebo for a of showed an of of and [ In trials using higher the of and muscle more common in patients on 10 compared with both placebo and of donepezil during a trial [ This higher of at 10 was to rapid dose since in phase the 10 dose was more and no The of was and of patients to and 10 of donepezil In this trial, of the adverse felt to be treatment [ The only was a low in patients 10 donepezil two of which to disease. An report of donepezil showed the of after to be similar to the and also to be in nature [ Of the patients to be to and 14 of which to treatment. other seen in the of both the trials and the trial with rivastigmine was not with any for significant effects on and or in the during the trial but it was not to drug treatment. to dose and of limited In the dose group the of and was and compared with and 3% in the placebo The and most commonly in the dose phase and treatment. The other the cholinergic and finding was that the mean in the group while the placebo group by There no in levels between the rivastigmine group and the placebo group [ In metrifonate and constituted of all and and and the only symptoms seen with higher dose metrifonate compared with placebo with a than [ adverse in but a dose in was seen on with patients to during the phase [ significant in or in With the development of new AChe inhibitors, characteristics have been improved to clinical rivastigmine and metrifonate have from the earlier drug selectivity for ACh enzyme inhibition is an in the better effect of donepezil and A lack of CNS specificity in metrifonate treatment may play a in the problems of peripheral cholinesterase inhibition is reflected in a higher of adverse [ rivastigmine and metrifonate with a of Tacrine has the dosage 4 Donepezil has the half-life 70 and both donepezil and metrifonate can be as a daily Rivastigmine daily although this has been as in dose it is accepted that less patients and It is also postulated that better of the drugs is in to the AChe inhibition with of This the in enzyme inhibition, and cholinergic effects. The in clinical trials with tacrine [ has not been seen with the which are through the A of the of these drugs is the of this is a for treatment in not In the of AD and AChe inhibitors, have been much more extensive than for other disease The has been not and as a has been on patients may benefit from these is much to where are such as in cardiac or rather than in areas of such as or the of AD in the USA at of which is and the value of to and [ for a of of which will to with the by the or of [ AD cognition, and treatment with AChe inhibitors not only has for the but can and delay In the earlier data that tacrine of approximately per [ In a small of a decline in in moderate to living at home was seen to each year [ It has been that donepezil patients have a delay in deterioration in for year compared with placebo [ at have taken into of at each of disease and the of disease in and all these factors are donepezil at and 10 has been to be [ This is by patients less in the state of severe dementia, with the higher of this data is since it is based on a of clinical and also long term data led the to no in for the donepezil and placebo with of in the the is a key in of and more data on the of A recent also that of symptomatic drug therapy be only a months of be [ These also be on with AChe inhibitors is of the of for AD have a where treatments are with assessments of and of community where assessment and diagnosis of AD, of an AChe inhibitor is as early as since not all patients to treatment It is that and fully the of treatment. The guidelines of the drug in the absence of any clinical response [ a patient is seen to the to treatment remains that of the and is at with the when treatment is can to any The effect of treatment the and for both patient and the of and in the absence of any other it is that AChe inhibitor therapy is for patients with to moderate