The Utilization of Reversible Acetylcholinesterase Inhibitors - Case Study Example

The Utilization of Reversible Acetylcholinesterase Inhibitors in the Management of Alzheimer's Dementia ABSTRACT This review examines some current issues of interest in the literature about the use of reversible acetyl cholinesterase inhibitors in the treatment of Alzheimer’s dementia. The latest theories about the involvement of a putative disease-modifying neuroprotective effect of the reversible acetyl cholinesterase inhibitors are examined and the evidence from both preclinical and clinical trials evaluated. The need for fine tuning protocols clinical testing for long term care settings was discussed, as well the need for specific clinical testing methodologies for evaluating neuroprotective effects as opposed to symptomatic effects. Apparently there is need for more data to confirm current preliminary findings, as well as for more data on head-to-head comparisons of the reversible acetyl cholinesterase inhibitors. INTRODUCTION The purpose of this paper is to review the available literature on the utilization of the reversible acetyl cholinesterase inhibitors in the management of Alzheimer’s dementia. The review will address issues of current interest surrounding the mechanism of action of the reversible acetyl cholinesterase inhibitors, the difficulties associated with designing appropriate clinical trial methodologies, issues concerning the relevance of current trial methodologies to long-term care settings, the current state of knowledge with regard to a putative neuroprotective effect of the reversible acetyl cholinesterase inhibitors, new technological methods for assessing efficacy of reversible acetyl cholinesterase inhibitors, and issues with available information on parallel comparisons between the commonly used reversible acetyl cholinesterase inhibitors. Finally, practical issues surrounding clinical use of the reversible acetyl cholinesterase inhibitors will be reviewed, with a focus on associated adverse drug reactions and optimization of dosage regimens. Alzheimer’s disease is a chronic, progressive, disabling dementia that affects multiple cortical functions including memory, judgment, learning capacity and comprehension. In the United States, there are estimated to be possibly up to 4.8 million cases (Brookmeyer, Gray, & Kawas, 1998). It is predominant among the people over 65 (Hebert et al., 1995) with a prevalence of about 6% to 8%, and more than 50% of people aged 85 years and older experience bouts of dementia (Jay M. Ellis, 2005; Samanta et al., 2006). Given the current population demographic trends in the United States and the prevalence of Alzheimer’s disease, the National Institutes of Health has projected that, by the year 2030, there could be 8.5 million Alzheimer’s patients in America (J. M. Ellis & Ellis, 2005). Alzheimer’s dementia incapacitates the sufferers from performing normal activities of daily living (ADL), and as the disease worsens, they become unable to function without assistance and have to rely on other people for their everyday care, whether family caregivers or nursing home care providers (Bullock & Bullock, 2004; Jay M. Ellis, 2005). This places a considerable burden in social, psychological and economic terms. It has been estimated that Alzheimer’s disease costs the American economy up to $100 billion each year, in both direct costs (hospitalizations, prescriptions, doctor visits or long term care) and indirect costs (productivity losses, stress-induced morbidity in caregivers)(Jay M. Ellis, 2005). Up till the present time, there is no known cure for Alzheimer’s disease. However, there is a number of pharmacological options for treatment, which essentially ameliorate the symptoms of cognitive impairment and slow the progression of the disease. The current mainstays of therapy are reversible acetylcholinesterase inhibitors (donepezil, rivastigmine and galantamine) and the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist memantine (Leonard, 2004; Samanta et al., 2006). This review will focus on the use of the reversible acetylcholinesterase inhibitors. REVIEW OF THE LITERATURE In this review, attention will be given to current theories on the pharmacological mechanism of action of the reversible acetyl cholinesterase inhibitors as well as controversies surrounding the methodology for evaluating treatment outcomes with reversible acetyl cholinesterase inhibitors’ clinical testing. Mechanism of Action The primary pathophysiological event that leads to cognitive deterioration in Alzheimer’s disease sufferers is impaired neurotransmission resulting from a progressive loss of cholinergic neurons which precipitates a decline in the levels of acetylcholine (ACh) in the brain, especially in the temporal and parietal neocortex and hippocampus (Jay M. Ellis, 2005; Leonard, 2004). The amyloid plaques and neurofibrillary tangles that form in the brain of Alzheimer’s disease sufferers are pathologies associated with cholinergic denervation (Francis & Francis, 2006; Whitehouse et al., 1982). Hence, some form of cholinergic replacement will be the logical approach to symptom remission. Of the various possible approaches to cholinergic replacement, the one that has been found most effective is the inhibition of acetylcholinesterase (Samanta et al., 2006). Acetylcholine is hydrolyzed in the brain by two cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Acetylcholinesterase exists in three isoforms: G1, G4 and G2. The brain contains the G1 and G4 types, while the G2 type is found in skeletal muscle and blood-forming cells (Jay M. Ellis, 2005). Galantamine and donepezil are specific acetyl cholinesterase inhibitors; whereas tacrine and rivastigmine inhibit both acetyl cholinesterase and BuChE (tacrine is more specific for BuChE than Acetyl cholinesterase ). Galantamine and donepezil are rapidly reversible, but rivastigmine is a slowy reversible inhibitor. Rivastigmine shows specificity for the acetyl cholinesterase isoforms G1 and G4, raising the theoretical possibility of causing less peripheral side effects. Galantamine is proposed to act via a dual mechanism. Not only does it inhibit acetyl cholinesterase , it also activates nicotinic acetyl choline receptors as an allosterically potentiating ligand (Jay M. Ellis, 2005). Several suggestions have been made as to the possible implications of these differences in the pharmacological profiles of the reversible acetyl cholinesterase inhibitors in terms of clinical differences and comparative advantages, but the studies done have not been extensive enough to definitively confirm the tentative conclusions(Machado & Caramelli, 2006). However, a growing body of evidence is pointing toward the direction of a possible additional mechanism of action for the reversible acetyl cholinesterase inhibitors, one which is not due to cholinesterase inhibition. This is the neuroprotective mechanism, which has become the new focus of preclinical testing and clinical trials (Jay M. Ellis, 2005; Machado & Caramelli, 2006; Nordberg & Nordberg, 2006; Samanta et al., 2006). Using an oxygen-glucose deprivation (OGD) model of ischemia in rat pheochromocytoma (PC12) cells, Zhou et al (Zhou, Fu, & Tang, 2001)found that donepezil had a protective effect against ischemia. In a later study, a similar effect was observed by Akasofu et al in rat neuronal cultures with donepezil but not with tacrine, rivastigmine or galantamine (Akasofu, Kosasa, Kimura, & Kubota, 2003). These in vitro results were correlated by in vivo experiments using a rat hypoperfusion model of ischemia in which cognitive impairment was measured by escape latency and hippocampal cell loss (A. Akaike & Akaike, 2006). An important limitation of these studies is that the approach used does not allow for the elucidation of the mechanism involved, whether it is due to cholinesterase inhibition or not. A new approach to in vitro testing employed a glutamate-induced neurotoxicity model. (glutamate neurotoxicity has been shown (Akinori Akaike, Tamura, Yokota, Shimohama, & Kimura, 1994)to be implicated in the cell death that accompanies Alzheimer’s disease and other dementias). It was found that donepezil, galantamine, and tacrine were potent inhibitors of glutamate toxicity (Takada et al., 2003). The distinct advantage of this study was that it provided evidence for the hypothesis that a mechanism other than cholinesterase inhibition is involved in the neuroprotective effect. First, physostigmine, a highly potent anticholinesterase was found to have no neuroprotective effect. Also, neostigmine and pyridostigmine which are only peripheral acetyl cholinesterase inhibitors actually showed some neuroprotective activities. A final clue was provided by dose-response relationships in the study: the concentration at which donepezil showed neuroprotection was more than ten times its IC50 value for acetyl cholinesterase inhibition (A. Akaike & Akaike, 2006). This lends credence to the suggestion that two different mechanisms may be at work, but it does not tell us how the alternative mechanism works. A current explanation is that this neuroprotective effect may be working via a nicotinic receptor mechanism. It has been shown in previous studies that nicotine is a potent inhibitor of glutamate-induced neurotoxicity. Current evidence indicates that donepezil regulates nicotinic receptor function. This may be either by increasing nicotinic ACh receptor expression, or by allosteric modulation. To confirm the possible involvement of a nicotinic mechanism, the classical pharmacological approach of testing in the presence of antagonists was employed. The neuroprotective effect of donepezil against glutamate-induced toxicity was tested in the presence of both nicotinic and muscarinic receptor antagonists (Takada et al., 2003). Interestingly, the results were similar to what is seen with nicotine. The nicotinic receptor antagonist mecylamine inhibited the neuroprotective effect of donepezil, while the muscarinic receptor antagonist scopolamine had no effect on donepezil neuroprotection. Selective inhibitors of neuronal nicotinic receptors inhibited the neuroprotective effect of donepezil and galantamine, but not tacrine. The summary of the preclinical evidence points to the fact that the degenerative effects of Alzheimer’s disease may be occurring through different pathways, and the reversible acetyl cholinesterase inhibitors may actually be working through more than one mechanism to modify the progression of Alzheimer’s dementia. Clinical Evaluation of Treatment Outcomes: Concerns and Controversies One of the thorny issues with defining the benefits of reversible acetyl cholinesterase inhibitors use in treatment is that objective clinical evaluation is not readily attainable. This puts into question the value of inferences drawn from clinical studies, and we face the dilemma of potentially false positives or false negatives in research results. The literature is replete with submissions concerning this subject, and the following issues will be highlighted in this section: Validity of guidelines in view of possibly flawed trials Relevance of community-based trials to long-term care settings Development of reliable protocols for clinical testing of neuroprotective effects. Based on evaluation of the available evidence from randomized clinical trials, the National Institute for Health and Clinical Excellence and the American Academy of Neurology both recommend the use of the reversible acetyl cholinesterase inhibitors rivastigmine, donepezil, and galantamine for the management of mild to moderate Alzheimer’s disease (Doody et al., 2001; Jay M. Ellis, 2005; Samanta et al., 2006). However, a 2005 systematic review of 22 clinical trials which form the majority of the evidence upon which these recommendations were based featured a sweeping criticism of the methodologies employed in the studies (Kaduszkiewicz et al., 2005). In addition, this review flawed the adoption of results from those trials because the clinical benefits obtained were small. These studies used a number of assessment criteria including ADAS-cog (Alzheimer’s disease assessment scale – cognitive subscale); CIBIC-plus (clinician’s interview-based impression of change with caregiver input); primary end point determination using time in days to reach clinically evident decline, neuropsychiatric inventory the Gottfries-Brane-Steen scale; CGIC (clinical global impression of change) scale, and the PDS (progressive deterioration scale). In the review, several methodological flaws were pointed out by the authors. The first was the use of several primary end points without correction for multiple comparisons which would have modified the significance of the purported benefits. Many of the trials missed intention to treat analysis, in spite of the fact that some patients had been excluded from analysis after randomization. Also, the handling of incomplete data (dropouts) using the last observation carried forward (LOCF) method was criticized, because in a progressive disease like Alzheimer’s, such a treatment could misinterpret discontinuation of treatment (due to side effects) as reduced progression of disease. Also, none of the trial reported exact dropout times. These flaws, combined with the minimal benefits on rating scales recorded from the studies, and the considerable occurrence of side effects, led to the authors’ conclusion that the guidelines recommending Reversible acetyl cholinesterase inhibitors treatment are not justified based on the evidence, and do not account for the methodological flaws in the original studies. While this review is a highly valuable one, it has been pointed out by Machado et al (Machado & Caramelli, 2006)that the body of available evidence cannot be entirely discarded on the strength of these objections. While it is true that the heterogeneity of clinical response to treatment with reversible acetyl cholinesterase inhibitors can easily confound clinical evaluation, other objective evidence has come to light which further argues strongly for the benefits of reversible acetyl cholinesterase inhibitors in Alzheimer’s disease management. A study has shown improvement of attention in trials with galantamine, using computerized neuropsychological tests, and a positron emission tomography study revealed that patients who responded to galantamine showed improvement in metabolic patterns in parts of the brain responsible for attention control (Mega et al., 2005). Khang et al (Khang et al., 2004) did an analysis on the applicability of available data on the use, benefits and costs of cholinesterase inhibitors to long-term care settings. Most studies evaluating reversible acetyl cholinesterase inhibitors have been community-based, and this introduces some issues with inferences to a long-term care setting, where issues are different in certain respects (Blesa & Blesa, 2004). For example, they noted that only one randomized, controlled trial has been done in a nursing home setting with moderate to severe dementia, and the nursing home study lasted 24 weeks, hence was unable to provide confirmation of benefit in long-term use. Although the results from the nursing home trial appeared to contraindicate their stand in that they showed that the benefits of therapy are not limited by setting, it was noteworthy that the study showed that benefits of therapy were not limited by age or disease severity. Another problem with the study was that the outcome evaluation utilized scores of the mean Mini-Mental Status Exam (MMSE). It is doubtful as to whether the MMSE is highly applicable in advanced dementia, as compared to other scales which can detect functional and behavioral improvement. On the overall, the data for nursing homes is inadequate and equivocal. It is also suggested that future clinical trials in nursing homes should include outcome measures that are not emphasized in community settings for obvious reasons. Such measures will include falls, weight loss, use of physical and chemical restraints, decubitus ulcers, and the use of psychotropics. Another problem highlighted was that cost-effectiveness studies in the community setting do not automatically apply to the long-term setting. This is because patients on the margins of institutionalization in a community setting will be rated as demanding the highest level of support, whereas this class of patients in the nursing home will require the least intensive care. Thus prospective specific studies to evaluate cost-effectiveness should be done for nursing home setting, rather than applying data from the community setting. Clinical testing for neuroprotective effects Another current challenge with clinical testing for reversible acetyl cholinesterase inhibitors is developing appropriate methodologies for evaluating the veracity of recent claims of neuroprotective effects that have been strongly suggested from preclinical tests and trials of long-term utilization. This problem, and suggested solutions were extensively discussed by Mori et al (Mori et al., 2006). The central problem is that, because the reversible acetyl cholinesterase inhibitors can provide symptomatic relief via their primary mode of action, this can mask any long-term neuroprotective effects which it could have, and thus it is difficult to define benefits as being evidence of neuroprotection using standard evaluation protocols. The following approaches to solving this problem have been proposed: clinical trials with a delaying end point design, clinical trials with a withdrawal design, clinical trials with a randomized start design, functional brain imaging studies, surrogate measuring of disease modification using imaging technologies. Clinical trials with a delaying end point design: The time to reach a disease milestone (usually nursing home placement) has been used as a strategy in trials, based on the assumption that if intervention is neuroprotective, it should delay nursing home placement in a post-treatment period of substantial duration. Some studies have demonstrated these effects, but there are still concerns that it is not certain if the delay in institutionalization with reversible acetyl cholinesterase inhibitors treatment is due to a neuroprotective effect on surviving neurons, or a masking of neurodegeneration by symptomatic effects. Clinical trials with a withdrawal design: The withdrawal design is based on detecting the persistence of benefit after withdrawal between treated and control groups. The problem here is that the design assumes a perfect relationship between underlying pathology and cognitive performance. Some studies have shown promise but the inconsistencies observed and the inadequacy of data still advise caution on adoption of current results. Clinical trials with randomized start design The randomized start approach is based on a placebo control phase and an extension phase, where patients taking placebo will then start on the reversible acetyl cholinesterase inhibitors. The latency in improvement of these patients will indicate that the benefit from the reversible acetyl cholinesterase inhibitors is not just symptomatic but disease-modifying. However, ethical issues may arise with the last two methods since the drugs are known or expected to modify the course of the disease. In addition to the above, some innovative technology based approaches are currently under consideration, which are functional brain imaging and the use of surrogate markers of neuronal function. Functional brain imaging It has been suggested that brain imaging of regional cerebral perfusion and glucose metabolism can be used to test the progression of pathology and dysfunction in Alzheimer’s disease, in place of cognitive testing. While a few trials have provided promising results, it is still an issue of concern that the conservation in brain perfusion and glucose metabolism may be equally facilitated by cholinesterase inhibition as well as neuroprotective effects. Hence, there is still a potential for confounding effects. Surrogate measurements of disease progression using imaging technologies The evaluation of surrogate markers has been suggested as a way to obtain evidence of neuroprotective effects that is not confounded by symptomatic effects. Hippocampal atrophy associated with neurofibrillary tangles, plaque and neuronal cell loss, is a marker of Alzheimer’s disease, and magnetic resonance imaging techniques have been developed to quantify it. At present, this volumetric technique provides the most objective marker of disease modification, with a consistency that allows for lowering the estimated sample sizes for clinical trials. Other methods of computerized atrophy evaluation are in the testing phase. Other markers under investigation are N-acetylaspartate (NAA), which is localized in neurons, tau protein and beta amyloid in cerebrospinal fluid. Initial results have using these techniques have demonstrated benefit with reversible acetyl cholinesterase inhibitors, but more randomized controlled trials will be required to validate them (Mori et al., 2006). Head-To-Head Comparisons of Reversible Acetyl Cholinesterase Inhibitors One area of interest is in head-to-head comparisons of the widely used reversible acetyl cholinesterase inhibitors, donepezil, galantamine and rivastigmine. Although some studies have been done to compare these based on clinical effect, such studies are few and the data is insufficient to draw firm conclusions from, until more data is available. This is nonetheless an important area to delve into, because some initial information has suggested that patients could be switched between the drugs in event of intolerance to adverse effect profiles of one or due to lack of efficacy of one. The only way to develop a scientific protocol for therapeutic switching is to have evidenced-based data for guideline development. DISCUSSION The introduction of the reversible acetyl cholinesterase inhibitors donepezil, galantamine and rivastigmine has provided significant advances in the management of Alzheimer’s dementia, despite the fact that no cure is known at the present. The most important development at the present time is the emergence of the hypothesis that the mechanism of action of the reversible acetyl cholinesterase inhibitors goes beyond the traditionally recognized one of symptomatic improvement resulting from anticholinesterase inhibition. A growing body of evidence, from preclinical experiments utilizing various models of neuronal impairment, to clinical trials involving outcomes evaluation, is strongly suggesting the existence of neuroprotective effects, via some alternative mechanism that may not be unrelated to a nicotinic-agonist pathway. There are minor issues about the direct applicability of preclinical testing to clinical scenarios, given the complexity of assessing outcome in Alzheimer dementia treatment, but the preponderance of evidence argues in favor of the validity of a putative disease-modifying mechanism. In a similar vein, there has been considerable endeavor in the direction of designing appropriate methodology for clinical trials to validate the putative neuroprotective mechanism in clinical settings. This is important given the fact that the classical outcomes research methodologies used in Alzheimer’s disease trials do not adequately provide for distinct identification of disease-modifying effects as opposed to symptomatic effects. The most promising results that have been seen thus far are from MRI volumetric techniques that measure hippocampal atrophy as a surrogate marker of neuronal degeneration. However, more evidence is needed to validate the tentative conclusions from these trials. There are other issues of debate surrounding the design of clinical trials. Some authors have argued that the methodological flaws associated with many randomized controlled trials do not justify the guidelines recommending the use of the reversible acetyl cholinesterase inhibitors in Alzheimer’s disease. Such flaws are to be found in trial design as well as in analysis of results. Given that the reviews of these trials did not address these issues, it is argued that the guidelines may not be strictly justifiable as being rigorously evidence-based. However, their assertions may not be definitively acceptable, given the concordance between positive results from various forms of testing, and the subsequent evidence that has emerged after the publication of their critiques. The applicability of classical outcomes testing carried out in community settings to long-term care settings has also been debated. Apparently, there is need to take extra caution in applying results obtained from community testing to long-term care issues because of important differences. Also, it would be useful to design more tests specifically in nursing home settings, in spite of the logistic problems that could be encountered in doing such studies. Evidence of head-to-head comparisons between the three major reversible acetyl cholinesterase inhibitors in use is scanty and more trials are needed to provide information in this regard, as it could lead to optimization of patient therapy by forming a scientific basis for switching between alternatives as indicated by individual patient responses and peculiarities. In summary, reversible acetyl cholinesterase inhibitors provide the mainstay of therapy for mild to moderate Alzheimer’s dementia, not only by inhibition of acetyl cholinesterase, but also by neuroprotective mechanisms that are presently being elucidated. Designing clinical trials for evaluation of outcomes in Alzheimer’s disease treatment with reversible acetyl cholinesterase inhibitors is fraught with problems because of the subjective nature of the outcomes being measured. However, this is being improved upon by the use of technologies that provide more objective measures of response. Clinical trials need to be designed, and the results evaluated with great care, because of the possibility of drawing erroneous conclusions. More research is needed in the area of making head-to-head comparisons between the different reversible acetyl cholinesterase inhibitors among relevant patient populations. CONCLUSION This review has examined issues related to the use of the reversible acetyl cholinesterase inhibitors donepezil, galantamine and rivastigmine in the treatment of Alzheimer’s dementia. The reversible acetyl cholinesterase inhibitors are promising agents for treatment because of their cholinergic improvement activity, but also because of neuroprotective mechanisms that are just coming to light. Testing for this new mechanism in clinical trials requires the development of new protocols, of which magnetic resonance imaging volumetry has been the most promising to date. Clinical trials need to be specifically designed for long-term care settings, and there is need for further research on head-to-head comparisons of the reversible acetyl cholinesterase inhibitors. With these issues being properly addressed, there seems to be a great future for optimizing the use of the reversible acetyl cholinesterase inhibitors in Alzheimer’s disease, until the day the Holy Grail of a cure for Alzheimer’s is finally found. REFERENCES Akaike, A., & Akaike, A. (2006). Preclinical evidence of neuroprotection by cholinesterase inhibitors. 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