Cholinesterase Inhibitors

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Cholinesterase Inhibitors

Post by cutthecashflow » Thu Dec 08, 2011 4:01 am

By far not my best work, but still some critique is encouraged


Abstract
This paper explores four published articles that report on the effects of cholinesterase inhibitors (ChEIs) with respect to treatment, efficacy, and caregivers’ experiences in dealing with Alzheimer’s disease (AD). A general background of the topic will be explored, implementing thematic trends that tie the four articles together; as well as, what the student hoped to learn by selecting the respective topic and corresponding journal articles. A brief summary of each journal article will be covered individually along with the methods unique to each publication. Finally, an article synopsis will be provided integrating the common findings, limitations, theory development, and future research directions of ChEIs across a wide spectrum of interrelated topics.
Keywords: cholinesterase inhibitors, Alzheimer’s disease, caregivers

Introduction
Due to continuing advances in medical technology, people throughout the world are living longer; resulting in a higher proportion of individuals reaching the age of increased risk for Alzheimer’s disease (AD). Small and Bullock (2011) report that in 2006, an estimated 26.6 million people suffered from AD and this number is expected to quadruple by 2050, putting the estimated number of people suffering from AD over 100 million. This will undoubtedly place excess strain on geriatricians, psychiatrists, neurologists (Raschetti et al., 2005), families, and caregivers (Small & Bullock, 2011; Smith, Kobayashi, Chappell, & Hoxsey, 2011). Currently there is no cure for Alzheimer’s disease and related dementias (ADRD), but second-generation cholinesterase inhibitors (ChEIs) have been shown to treat the symptoms of mild to moderate AD (Burns, Spiegel, & Quarg, 2004; Raschetti et al., 2005; Small & Bullock, 2011; Smith et al., 2011).


ChEIs include the drugs donezepil (Aricept®), rivastigmine (Exelon®), galantamine (Reminyl®) (Raschetti et al., 2005), and tacrine (Cognex®) (Smith et al., 2011). ChEIs are thought to work by acting as an agonist to acetylcholine (Ach) causing an increase in synaptic Ach levels, which ultimately results in enhanced cholinergic neurotransmission (Burns et al., 2004). These drugs show preferential selectivity for the hippocampus and cerebral cortex, the regions of the brain that show the largest cholinergic deficits in patients with AD (Burns et al., 2004). ChEIs have produced mixed results, with some researchers claiming little efficacy (Smith et al., 2011) and others claiming substantial increases in the quality of life for patients with AD (Small & Bullock, 2011). A common consensus emerges however, in that; ChEIs will not prevent, but only postpone, the inevitable cognitive debilitation of patients with AD (Burns et al., 2004; Raschetti et al., 2005; Small & Bullock, 2011; Smith et al., 2011).


Common debate over the appropriate treatment methodology of ChEIs has focused on the importance of early diagnosis of AD, optimal treatment initiation (later vs. sooner), optimal dosing (high dose ChEIs sooner vs. high dose ChEIs later), and optimal treatment duration (Small & Bullock, 2011). Subsequent sections of this paper will include an analysis of four different peer reviewed publications; touching upon the effectiveness of ChEIs in AD (Raschetti et al., 2005), defining optimal treatment with ChEIs in AD (Small & Bullock, 2011), the efficacy of ChEIs in subjects with moderately severe AD (Burns et al., 2004), and the current controversial promises made to caregivers of the effectiveness of ChEIs for AD and related dementias (Smith et al., 2011).


Raschetti, R., Maggini, M., Sorrentino, G.C., Martini, N., Caffari, B., & Vanacore, N. (2005). A cohort study of effectiveness of acetylcholinesterase inhibitors in Alzheimer’s disease. European Journal of Clinical Pharmacology, 61, 361-368.


The authors wished to investigate the effectiveness of cholinesterase inhibitors (ChEIs) by examining the Cronos study undertaken by the Italian Ministry of Health and the National Institute of Health. More specifically, their goal was to characterize the population of Alzheimer’s disease (AD) patients treated with ChEIs, analyze their effectiveness and drug safety in the clinical practice, identify variables that may predict the response to therapy, and inform physicians and caregivers about the correct use of these drugs. This study was conducted on (N = 5,462) patients treated with ChEIs at (N = 118) Italian AD units.


A stratified random sample by region of 118 AD units was selected and information was collected from all patients enrolled in these units from September 1, 2000 to December 31, 2001. A total of 7,395 patients were initially selected for data collection. Patients were followed up until the occurrence of the first of the following events: discontinuation of therapy for any reason, a Mini Mental State Examination (MMSE) score less than 10, admission to a hospital or nursing home, death, or December 31, 2002. Every patient in the study was provided one of three ChEIs (donepezil, rivastigmine, galantamine) free of charge under their physician’s discretion for participating in the study. Of the 7,395 patients selected, 1,933 were excluded because of a previous treatment with ChEIs; resulting in a grand total of 5,462 patients in the cohort with a mean age of 76. Of the 5,462 remaining patients, 2,609 patients discontinued treatment for the following reasons: failure to return (N = 1,672), switching study drug (N = 282), adverse events (N = 204), treatment failures (N = 177), MMSE<10 (N = 124), noncompliance (N = 57), death (N = 24), admission to hospital or nursing home (N = 4), and cause not reported (N = 65).


Research findings indicated that patients treated with galantamine were in poorer health than those treated with donepezil or rivastigmine. Overall, the mean change from baseline in MMSE scores showed an improvement of 0.5 points (± 3.0), but scores on activities of daily living (ADL) and instrumental activities of daily living (IADL) were practically unchanged (ADL, -0.1 ± 0.9; IADL, -0.2 ± 1.5). During the 9-month observation period, 783 (14.3%) of patients experienced at least one adverse drug reaction (ADR) and half of the ADRs occurred within the first 3 months of therapy. The most frequent ADRs were gastrointestinal and psychiatric disorder; this was attributed to the mechanism of action of the drugs and to the natural history of the disease. Old age, concomitant diseases, use of other central nervous system drugs, and high dosage of ChEIs were associated with developing ADRs.


In undertaking such a large study the authors were able to identify some rare and clinically relevant events, which were unlikely to be detected by clinical trials (e.g. atrio-ventricular blocks, stroke, epileptic seizure, urinary incontinence, myocardial infarction, and syncope). Likewise, the authors were able to determine that higher incidences of adverse events were found with galantamine and rivastigmine compared to that of donepezil. However, this study did suffer from some limitations. First, these results are not comparable to clinical trials due to the lack of a comparison non-treated cohort. Second, the patients in this study were on average older than those in clinical trials, with mean ages being 76 years and 72-73 years respectively. This age discrepancy could account for some of the ADRs that may not be evident in clinical trials. Finally, the specific reasons for discontinuing the treatment in these patients are unknown, hindering a full description of the safety of the study drugs.


Small, G., & Bullock, R. (2011). Defining optimal treatment with cholinesterase inhibitors in Alzheimer’s disease. Alzheimer’s & Dementia, 7, 177-184.


The goal of the authors in this publication was to provide a review of past treatment with cholinesterase inhibitors (ChEIs) on Alzheimer’s disease (AD) and a look ahead to possible future treatments. More specifically, the authors state that “the objective of this article was to consider what constitutes optimal AD treatment with cholinesterase inhibitors” (p.177). The authors addressed and reviewed four critical dimensions for treatment with ChEIs: early diagnosis, optimal treatment initiation, optimal dosing, and optimal treatment duration. A brief look into each dimension will be explored along with two proposed models for ChEI treatment.


A generally accepted notion amongst clinicians is that the timely detection and diagnosis of dementia is paramount to the treatment process. Usually, early detection is not encountered, as most individuals diagnosed with AD are already in the moderate stages. This has led to two different treatment initiations (i.e., later and sooner) of ChEIs, both of which show therapeutic effects in different ways. Individuals treated at a later time period in the course of AD (moderate) tend to exhibit a greater treatment response to ChEIs than those treated earlier in the progression of AD (mild). However, in a double-blind study on the effectiveness of treatment initiation (i.e., a delayed treatment start), individuals who received a placebo early in the disease, failed to catch up with those who received treatment for the entire time, suggesting potential benefits of starting therapy early.


Another issue encountered with ChEI therapy is administering the correct optimal dose to patients. ChEIs exhibit dose-response relationships, meaning that higher doses tend to be more effective than lower doses. However, many patients are given suboptimal doses as they are unable to reach an optimal dose due to the associated side affects of ChEIs (e.g., gastrointestinal and psychiatric disorders). A promising solution to this problem is to lower the maximal plasma concentrations of the ChEIs so that patients have an increased likelihood of reaching optimal doses. One way that this can be accomplished is through the use of a transdermal patch rather than oral administration, so that ChEIs can be delivered in a continuous fashion instead of large plasma fluctuations that are common to oral administration.


Just as higher doses tend to show the greatest potential for therapeutic treatment, so does prolonged administration of ChEIs. The longer individuals stay on ChEIs, the more apt they are to experience less time with the extreme debilitating effects of AD. However, AD patients average only 4 to 5 months of treatment with ChEIs. This is in part due to high medication burden, co-morbidities, forgetfulness, and perceived lack of effectiveness. Considering the effectiveness associated with the importance of compliance to AD therapies over the long term, a clear need exists to improve compliance in this setting.


The authors offer two potential models that can be followed for strategic treatment options. Model A aims to keep high dose-cholinesterase inhibition in reserve for later, and model B aims to target and maintain patients on the highest recommended ChEI dose as quickly as possible. More specifically, in model A the clinician would assign a low dose to the patient immediately, until a meaningful decline in cognitive ability was evident, whereupon an increase in dosage would be administered. This process would be repeated until the maximum dosage is reached and then applied until no longer effective. In model B, the clinician would prescribe treatment immediately, advancing to the maximum dose as soon as possible in order to allow the patient to live the highest quality of life possible with the remaining time that he or she has left.


The importance of a literature review on ChEIs, as conducted in this study, allows clinicians to contemplate and discuss multiple treatment options with caregivers and individuals with AD. Furthermore, a literature review will often spark ideas and generate discourse for new studies and research methodologies to be implemented into the current realm of ChEI theory and practice.


Burns, A., Spiegel, R., & Quarg, P. (2004). Efficacy of rivastigmine in subjects with moderately severe Alzheimer’s disease. International Journal of Geriatric Psychiatry, 19, 243-249.


This article wished to address the effectiveness of rivastigmine, a cholinesterase inhibitor (ChEI), in subjects with severe Alzheimer’s disease (AD). Previous research has shown that patients with moderate AD tend to respond more strongly to ChEI treatment than patients with mild AD. This observation led the authors to question whether patients with more severe cases of AD also respond positively to ChEI treatment. Few studies up to this date (2004) had assessed the effectiveness of ChEI treatment in individuals with severe AD, prompting the authors to carry through with their investigation.


This study was a retrospective statistical analysis of data derived from three 6-month, multicenter, double-blind, placebo controlled, parallel group studies, which investigated the effects of rivastigmine in subjects with probable AD. Individuals who score less than 15 on the Mini Mental State Examination (MMSE) are considered to have moderately severe to severe cognitive impairment and a score of 10 on the MMSE corresponds to the upper limit of the range defining severe cognitive impairment. In light of these facts, the analysis conducted focused on subjects who had the greatest cognitive impairment (i.e., MMSE scores between 10 and 12). In total, 117 subjects were identified, of whom 62 received rivastigmine 6-12 mg/day and 55 received placebo.


Overall, rivastigmine had a positive effect on the rate of cognitive decline in subjects with severe AD. After 26 weeks, there was a small improvement for subjects treated with rivastigmine on the MMSE, with a mean change in baseline of -.08 points on the MMSE compared with -2.5 points in the placebo group (p = 0.02).Similar results were found with respect to activities of daily living (ADL), albeit not statistically significant (p = .061). These results suggested that rivastigmine is clinically effective in subjects with severe AD.


This study is important in that it demonstrates that individuals suffering from severe AD can derive the benefits from treatment with ChEIs, and show a strong response to treatment in a similar fashion to individuals who suffer from mild to moderate AD. Furthermore, this study carries importance, in that, if nursing home residents who are suffering from severe AD can show marked declines in ADL, then fewer resources and time can be spent on these individuals and some independent activities can be preserved for a longer period of time. The main limitation of this study is the relatively small sample size when compared to other studies of ChEIs in clinical populations. The more subjects a study has, the higher the statistical power, and in turn, the authors are able to present their findings with higher confidence. Another limitation is that subjects with severe AD may have trouble interpreting and reporting adverse events; something that should be controlled for in future studies assessing the benefits of ChEIs in patients with severe AD.


Smith, A., Kobayashi, K., Chappell, N., & Hoxsey, D. (2011). The controversial promises of cholinesterase inhibitors for Alzheimer’s disease and related dementias: A qualitative study of caregivers’ experiences. Journal of Aging Studies, 25, 397-406.


This article attempts to explore caregivers’ views, experiences, and perceptions of family members being treated with cholinesterase inhibitors (ChEIs). For a long time, clinicians have debated the effectiveness of ChEIs with mixed results. Those in favor of ChEIs hold that these drugs significantly improve cognitive function over relatively short periods of time when compared to a placebo. Opponents of ChEIs take note of studies that lack convincing evidence for benefits regarding functional and behavioral outcomes, as well as quality of life measures. However, research is lacking in the area of caregivers’ perception of the effects of ChEIs on their treated family members or on the caregiver’s own quality of life. This study attempted to answer the following three issues: (1) how caregivers create meaning about ChEIs; (2) how caregivers appraise the drug’s effects on their treated relatives; and (3) how ChEIs impact the relationship and interactions between caregivers and treated relatives.


The authors recruited 25 caregivers with a relative taking ChEIs from the Caregiver Appraisal Study (CAS), a study which is a part of the Alzheimer Drug Therapy Initiative (ADTI), a program of several studies created by the province of British Columbia to study ChEIs over a 5 year period. The relatives being cared for ranged in their diagnoses: 17 had AD; three had vascular dementia; one had Lewy body dementia; and four were described as having “dementia.” Relatives had been prescribed ChEIs for periods of 1 to 7 years, with an average of 3.2 years. Data were collected via narrative methodology, an approach that combines ethnomethodology and Foucauldian discourcse analysis to interpret the activities of individuals, as well as, how social structures gave meaning to their experience. During the course of the interview, subjects were encouraged to talk openly about their expectations of ChEIs, their experiences with the drug’s effects on relatives, and the impact of treatment on the care giving relationship.


Caregivers described their expectations of ChEIs in terms of two benefits: slowing the decline of dementia and improving memory. Caregivers generally described having modest expectations of the drugs; however, three mentioned that their expectations were “unrealistic.” Pharmaceutical manufacturers of ChEIs claim that cognitive symptoms are improved through the use of these drugs. However, only two caregivers reported seeing noticeable improvements in cognitive performance. The remaining caregivers remarked that there were no substantive changes in cognitive performance. By contrast, 17 of the caregivers noticed some level of psychological improvement, which they attributed to the effects of ChEIs. More specifically, they felt that the ChEIs made their relatives more amenable and agreeable. When asked if ChEIs had met their expectations, only five reported that the drugs had effectively improved their relatives’ condition. The overall dominant tone throughout the interview about the benefits of ChEIs was one of ambivalence and uncertainty.


This study was important because the caregivers offered rich narratives that allowed the authors to explore ChEI treatment as lived experiences in the context of the care giving relationship. Likewise, this study explored an area of research that has little empirical work behind it, paving the way for related research and revised methodology in the future. The major limitation of this study is that the narratives do no permit objective determination of the effectiveness of ChEIs, or lack thereof. Without quantitative data, it becomes increasingly difficult to accurately assess the findings of a study, especially one that is based solely on qualitative data. Furthermore, the subjects interviewed in this study had no reference point with which to compare their relative with, or they had an unwillingness to take their relative off of the medication to compare the effects of ChEIs during and after pharmacological adherence. This lack of control further exacerbates the call for future research on the topic with enhanced methodology.


Article Synopsis


The common findings from these studies include: cholinesterase inhibitors (ChEIs) are most effective for mild to moderate severity Alzheimer’s disease (AD), psychological functioning tends to improve with treatment, gastrointestinal disorders are a common side effect, and activities of daily living either show marked improvements or a significant slowing in decline. Some of the more interesting findings included the discrepancy between caregivers and clinicians in the perception of overall effectiveness of the drugs; with caregivers reporting fewer efficacies than clinicians. This is interesting because even though caregivers are less convinced that the drugs are working, they are still reluctant to remove the AD patient from the medication due to fear of a rapid increase in cognitive decline.

However, caregivers perceptions may be due to the fact that ChEIs are maximally effective at higher doses and many patients are unable to reach an optimal dose because of their inability to deal with aversive effects of the drugs. Perhaps most interesting were some of the associated side effects that were noticed in the Italian Ministry of Health and the National Institute of Health study. These side effects (e.g., atrio-ventricular blocks, stroke, epileptic seizure, etc.) were not reported in any other peer reviewed journal read by the student. This goes to show that the larger the sample size, the more information that can potentially be discovered.


If this field wishes to advance theory development and contribute to the field’s current state of knowledge it is necessary to collaborate across disciplines and be open to discourse from all directions. From the various readings, it appears that there are two competing ideas with respect to ChEIs: (1) ChEIs significantly enhance the quality of life of individuals suffering from AD and (2) ChEIs are a tool used by pharmaceutical companies and physicians in the pursuit of financial gain, while at the same time, providing a false sense of hope to the caregivers of relatives suffering from AD. If these two schools of thought can put their differences aside and collaborate together, the potential to develop new pharmaceutical drugs and provide innovative psychological care to patients and caregivers could reach unprecedented levels.


The three most common limitations across studies were small sample sizes, lack of controls, and studies of ChEI effectiveness seldom collecting data beyond 6- to 12- months. As was evident in the Cronos study (Raschetti, 2005), large sample sizes provide researchers a means to discover new variables that can contribute to advanced AD theories and enhance the development of ChEIs. Likewise, without a control sample there is no means to compare the results from the study with a similar group who did or did not receive the treatment; as was evident in the care giving study put forth by Smith et al. (2011). Similarly, if studies are only conducted for a short period of time (6 to 12 months), than it becomes increasingly difficult to assess the positive and negative long term effects of ChEIs. Likewise, this theory has not yet come to a consensus on how to best proceed with various pharmokinetic and pharmodynamic issues. For example, most AD patients are not able to take the recommended maximum dose of ChEIs due to the high plasma concentrations that are encountered when a dose is administered orally. Recently, transdermal patches have started to take the place of oral administrations, but future research is needed on the potential aversive effects of providing ChEIs to patients in this fashion.


In undertaking this project I have learned a wealth of information about the pharmacology of treating AD. This has included various principles across multiple disciplines, including: biology, psychology, pharmacology, and sociology. I had always had an idea of how the cholinergic neurons worked in the brain, but had less of an understanding of how these worked in AD. Specifically, I was impressed with the various schematics displayed in the articles showing the projections of cholinergic neurons in the hippocampus and cerebral cortex. I learned the most information about the psychosocial influences of ChEIs on both individuals with AD and the people who care for them. It was interesting to note the various emotions that caregivers and patients were feeling through the progression of AD and how ChEIs could provide a false sense of hope to the people who cared for relatives with AD.

Furthermore, I learned how the pharmaceutical companies push to have these drugs covered under public drug plans through the implications that drugs such as Aricept reduce behavioral problems, but this effect only becomes evident when the drug is no longer prescribed. In other words, the care giver is advised to keep the treated relative on ChEIs in order to avoid having to deal with such problems. In turn, it appears that financial gain appears to play the largest role in the development and distribution of these drugs and it would be beneficial for all people affected by this disease to be better educated on the subject of ChEIs.


References
Burns, A., Spiegel, R., & Quarg, P. (2004). Efficacy of rivastigmine in subjects with moderately severe Alzheimer’s disease. International Journal of Geriatric Psychiatry, 19, 243-249.
Raschetti, R., Maggini, M., Sorrentino, G.C., Martini, N., Caffari, B., & Vanacore, N. (2005). A cohort study of effectiveness of acetylcholinesterase inhibitors in Alzheimer’s disease. European Journal of Clinical Pharmacology, 61, 361-368.
Small, G., & Bullock, R. (2011). Defining optimal treatment with cholinesterase inhibitors in Alzheimer’s disease. Alzheimer’s & Dementia, 7, 177-184.
Smith, A., Kobayashi, K., Chappell, N., & Hoxsey, D. (2011). The controversial promises of cholinesterase inhibitors for Alzheimer’s disease and related dementias: A qualitative study of caregivers’ experiences. Journal of Aging Studies, 25, 397-406.
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Re: Cholinesterase Inhibitors

Post by weedguru_animal » Thu Jan 05, 2012 9:38 am

My friend, that is far too technical and academic, for me to be able to maintain my intrigue after the first few lines. Please, if you will, add some of your own thoughts and feelings, regardless of SCIENCE...and I will happily, thereafter, comment verbosely.
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cutthecashflow
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Re: Cholinesterase Inhibitors

Post by cutthecashflow » Mon Jan 09, 2012 10:57 am

Well once the alcohol wears off for a while, as I'm sure it will in the next few days (classes start again) I will return to the subject at hand. Sometimes having a month off slows my cognitive pace.
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