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Broader Considerations of Higher Doses of Donepezil in the Treatment of Mild, Moderate, and Severe Alzheimer's Disease

Broader Considerations of Higher Doses of Donepezil in the Treatment of Mild, Moderate, and... Hindawi Publishing Corporation International Journal of Alzheimer’s Disease Volume 2012, Article ID 707468, 4 pages doi:10.1155/2012/707468 Review Article Broader Considerations of Higher Doses of Donepezil in the Treatment of Mild, Moderate, and Severe Alzheimer’s Disease Camryn Berk and Marwan Sabbagh The Cleo Roberts Center for Clinical Research, Banner Sun Health Research Institute, 10515 W. Santa Fe Dr, Sun City, AZ 85351, USA Correspondence should be addressed to Marwan Sabbagh, marwan.sabbagh@bannerhealth.com Received 24 August 2011; Accepted 29 October 2011 Academic Editor: Anton P. Porsteinsson Copyright © 2012 C. Berk and M. Sabbagh. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Donepezil, a highly selective acetylcholinesterase inhibitor (AChEI), is approved as a symptomatic treatment mild, moderate, and severe Alzheimer’s disease (AD). Donepezil exerts its treatment effect through multiple mechanisms of action including nicotinic receptor stimulation, mitigation of excitotoxicity, and influencing APP processing. The use of donepezil at higher doses is justified given the worsening cholinergic deficit as the disease advances. Donepezil has been investigated in several clinical trials of subjects with moderate-to-severe AD. While the side effects are class specific (cholinergically driven), demonstrable benefit has been shown at the 10 mg dose and the 23 mg doses. Here, we review the clinical justification, efficacy, safety, and tolerability of use of donepezil in the treatment of moderate-to-severe AD. 1. Introduction with modest but debatable impact on disease progression from mild to moderate is concerned, decreasing speed of pro- Alzheimer’s disease is an age-related progressive neurological gression from the earliest signs of cognitive impairment to disorder that ultimately results in cognitive and behavioral severe dementia and finally death [2, 3]. dysfunction and functional loss. These later stages of disease An important component of Alzheimer’s disease man- are impacting an increasingly large number of people each agement is the group of caregivers who support Alzheimer’s year. At present, the treatment of Alzheimer’s disease (AD) is patients. As Alzheimer’s disease progresses, the demands on limited to symptomatic therapy. As symptoms worsen and the caregiver increase; often this takes a toll on the care pro- the effects of late-stage Alzheimer’s disease become more vider in the form of health problems of their own, stress, severe, there is an urgent need for new and novel treatment anxiety, depression, fatigue, and other physical and emotion- options. Of the 5.3 million people estimated to be afflicted al problems [4]. Donepezilisavaluable treatmentoptionnot with AD in the United States, more than half are suspected to just for its capacity as a selective inhibitor of acetylcholin- have moderate-or-severe disease. Because these stages of AD esterase for the patients but also for its capacity to ease the can last for several years, the difficulty presented to both pa- burden of the caregiver by prolonging the AD patient’s ability tients and caregivers increases dramatically in advanced to perform self-care tasks and delaying the progression of stages [1]. symptoms that would impact a caregiver [5]. Donepezil, a highly selective acetylcholinesterase inhibi- tor (AChEI), is one of only two treatments approved in the 2. Overview United States for use beyond the mild-to-moderate stage. While it can slow progression modestly and treat symptoms, Donepezil has a mode of action based on inhibiting acetyl- it cannot halt progression of the actual disease or ultimately cholinesterase selectively. Cholinergic function is improved stop the decline in cognitive and functional abilities. Agents when there are greater concentrations of acetylcholine in the such as donepezil create notable symptomatic improvements brain, and the depletion of acetylcholine that is common 2 International Journal of Alzheimer’s Disease with AD patients is positively affected with a donepezil reg- basocortical degeneration, donepezil induced cortical sprou- imen. Additionally, cholinesterase inhibitors hypothetically ting, mitigating reduction in cholinergic neurotransmission could operate within the scope of the “amyloid hypothesis” [14]. of AD pathogenesis. Donepezil in particular has been shown to attenuate neurotoxicity of amyloid beta peptide Aβ as well 3. Efficacy as influencing APP processing [6]. In accordance with the cascade concept, therapies that directly target the accumu- Donepezil has been found to be one of the most effective lation, aggregation, and deposition of amyloid beta peptide symptomatic treatments for AD available on the market with Aβ and effectively reduce the inciting event may be more additional potential as a disease-modifying therapy. Many effective than distally targeted treatments, such as those that but not all studies have shown that both when compared to target neurotransmitter deficits. a placebo, donepezil has proven to have significant efficacy In addition to attenuating Aβ neurotoxicity, donepezil in reducing the severity of neuropsychiatric symptoms in pa- also has an effect on cholinergic deafferentation. Cell bodies tients with mild-to-moderate AD and patients in more severe in the nucleus basalis in the brain are the origin of cholinergic stages of the disease [15]. Additionally, donepezil has been tracts, the axons of which are prolific in the cerebral cortex found to be effective in symptomatic treatment in a variety of and in the pedunculopontine nucleus with expansion into dosing levels giving it variability as a treatment option. In an the thalamus. Loss of cholinergic neurons in the nucleus bas- open-label, multicenter, Phase 3 extension study of the safety alis are a hallmark of the earliest stages of AD. The functional and efficacy of donepezil in patients with Alzheimer’s disease deafferentation of the cholinergic neurons is thought to in- [15], the primary efficacy measures were the Alzheimer’s Dis- duce Aβ production in the cerebral cortex, which is what be- ease Assessment Scale-cognitive subscale (ADAS-Cog) and gins the cascade to neurodegeneration. Donepezil disrupts the CDR-Sum of the Boxes (CDR-SB). These measures were the mechanism by which Aβ generation occurs following evaluated in a 152-week long extension study on patients cholinergic deafferentation by interfering with the process aged 50 and older that participated in at least one of the pre- that leads to the exposing of the toxic N-terminal region of vious phases of donepezil trials, with a total patient number APP during the preferential processing of the amyloid pre- (n) of 763. Among this population, the most common reason cursor protein. One way donepezil interupts this process is by for study discontinuation (46% of discontinued patients) cholinergic input to cortical neurons [7]. was departure due to the commercialization of donepezil Donepezil also impacts nicotinic receptors in the cortex after the successful completion of nonextension trials, allow- through upregulation. At clinically relevant concentrations, ing for prescriptive use of the drug [15], but of those that donepezil decreases the reduction of nicotinic acetylcholine completed the study declined from baseline significantly less receptor expression in the cerebral cortex of AD patients and than the placebo arm in the same period with regards to prevents some of the reduction in nicotinic binding that cor- ADAS-Cog scores. After a three-week placebo washout, the relates to disease severity. This process reduces glutamate mean change for patients using CDR-SB scores actually im- neurotoxicity and also has been shown to inhibit excitotoxic proved above baseline for the experimental arm and declined injury, which is significant regarding AD pathogenesis and in the placebo arm. progression [8]. In comparison studies with rivastigmine and galanta- Other mechanisms of action indicate donepezil could mine, specifically a 52-week trial [16] and a 12-week trial provide a treatment option for affecting the cellular and mol- [17] showed that regarding cognitive function, there is no ecular processes of neurodegeneration rather than sympto- statistically significant difference between patients treated matic treatment. Donepezil has been found to influence ace- with donepezil versus those treated with galantamine, nor is tylcholinesterase isoform expression by inhibiting the expre- there a difference regarding behavior when comparing ssion of the AChE-S form and causing an increase in the ex- 10 mg/day of donepezil to 24 mg/day of galantamine. Sim- pression of the AChE-R form through reduction of cholin- ilarly, rivastigmine and donepezil have been found to have esterase, generating neuroprotective effects [9]. Donepezil comparable effects on cognition and behavior [18, 19]and has also been shown to upregulate nicotinic receptors in the similar gastrointestinal side effects profiles [20]. cerebral cortex, increasing nicotinic acetylcholine receptor expression and nicotinic binding [10]. Furthermore, under conditions of upregulations donepezil has been proven to 4. Safety and Tolerability maintain neuroprotective actions are lower drug concentra- tions and reduce glutamate toxicity [8]. Donepezil has been In patients with moderate-to-severe Alzheimer’s disease, shown to mitigate the effects of oxidative stress in a strepto- donepezil has been found to be safe and well tolerated at dos- zotocin-induced model of dementia in mice, indicating use es up to 23 mg, with an increase in adverse events over lower against free radicals that may be implicated in AD [11]. dosages, most of which dissipate after the first month of Donepezil treatment has also resulted in improved cerebral treatment [1, 21]. In a randomized, double-blind study, 1371 blood flow in patients with mild cognitive impairment, with patients (mean age: 73.8 years, 62.8% female, 73.5% white) no reduction after six months compared to statistically signi- from 219 different sites in Asia, Europe, Australia, North ficant reduction in the placebo cohort [12, 13]. Potential America, South America, and South Africa were analyzed for mechanisms of action also include enhancing neuroplastic comparative effects of 10 mg/day donepezil and 23 mg/day activity through cholinergic modulation. In rodent models of donepezil. All patients had an MMSE of less than 20 and International Journal of Alzheimer’s Disease 3 assessed for changes in cognition and global functioning as the placebo group reported significant increases in stress over assessed using least square regressions as well as deviation the same period. Treatment of moderate-to-severe AD with from baseline between the two cohorts. At the highest doses, donepezil has also been associated with a much more gradual the most significant adverse events reported in safety trials increase in time a caregiver spends caring for a patient with were nausea, vomiting, and diarrhea; in the event that these progressing disease compared to patients who received a symptoms did not dissipate, dosages were reduced to im- placebo [24]. prove tolerability. Nevertheless, a certain percent of partic- As indicated in the aforementioned Doody study, the ipants did not tolerate donepezil even after the dose was adverse events experienced when treated with donepezil are reduced. Donepezil has proven to be safe and well tolerated transient and mild, often resolving themselves without the as well as effective in the treatment of moderate-to-severe AD need for dose modification but in the rare cases resolution is [21]. elusive, lowering the dosage is an effective way to decrease Donepezil has been found to be an effective option for adverse events. 92% of patients in the study experienced maintaining a desirable quality of life and prolonging patient at least one treatment-related adverse event, with only 28% performance of activities of daily living (ADL); under study (214) of patients experiencing a serious (grade 3 or 4) AE; in of 290 (mean age: 73.6 years, range 48–92) patients random- the case of 27% (203), the serious nonfatal AEs experienced ized into a 24-week, double-blind, placebo-controlled study, was determined to be not related to donepezil treatment. donepezil demonstrated a vastly slower decline trajectory Treatment with donepezil also indicated no clinically signif- than placebo in ADLS in patients with moderate-to-severe icant results or changes in clinical laboratory tests, physical AD [22]. Using the Disability Assessment for Dementia examinations, or electrocardiograms. The results of this (DAD), the Instrumental Acitvities of Daily living (IADL) study indicated that donepezil is a safe and effective agent for scale, and the Physical Self-Maintenance Scale (PSMS), re- long-term treatment of moderate-to-severe disease [15]. searchers have determined that moderate-to-severe AD pa- tients taking donepezil were improved in tasks such as the use 5. Conclusions of household appliances, managing personal mail, moving around in and outside of homes, understanding explanations It is broadly recognized that potent disease modifying agents or new situations, and maintaining leisure activities as com- are needed to prevent the progression of Alzheimer’s disease. pared to moderate-to-severe AD patients who took a placebo While the “amyloid hypothesis” of AD pathogenesis is still [22, 23]. In a six-month study, assessing responder rates of unproven, there is substantial evidence that suggests that moderate-to-severe AD patients taking donepezil in a long- inhibiting Aβ plaque formation will be a valuable approach term care facility, greater proportions of patients defined as for achieving this goal. But the foundation of AD manage- responders to donepezil showed significant stabilization or ment will continue to include a cholinesterase inhibitor such improvement compared with placebo on individual efficacy as donepezil. A multitude of well-controlled clinical studies measures including the severe impairment battery (SIB) (≥0, have demonstrated the cognitive benefit of this agent. In ≥4or ≥7 points) and Mini-Mental State Examination (≥0 addition, by interfering with the process that leads to the or ≥3 points), and positive trends on the ADCS-ADL-severe exposing of the toxic N-terminal region of APP during the (≥3 points) and the neuropsychiatric inventory (NPI) cluster preferential processing of the amyloid precursor, donepezil based on mood items. All 3 composite measures of efficacy disrupts the mechanism by which Aβ generation occurs fol- showed a significantly higher proportion of responders in the lowing cholinergic deafferentation. As new therapeutics donepezil group. The responders had a similar distribution come on line, the next advance in AD patient management between the 2 subgroups of cognitive and functional disease will come from understanding how they synergize with severity at baseline. The donepezil-treated patients taking donepezil or other cholinesterase inhibitors. psychotropic drugs showed significantly greater improve- Going forward, the role donepezil plays in disease man- ment on the SIB, less deterioration on the ADCS-ADL, and agement should not be limited solely to cholinestrase inhi- had higher Clinical Global Impression of Improvement bition at the level of neurotransmitter. Rather, as preclinical scores and a trend toward lower NPI scores [23]. evidence amply demonstrates, the drug affects on cellular In addition to assessing patient conditions, caregivers and molecular processes should be exploited for their depth were assessed using the Caregiver Stress Scale (CSS) for the and breadth of influence at every stage of disease. first time in a clinical trial to measure a caregiver’s status re- garding cognitive status, overload, relational deprivation, Acknowledgment job-caregiving conflict, economic strains, role captivity, loss of self, care-giving competence, personal gain, management The paper is supported by NIA P30 AG019610 and Banner of distress, and expressive support. Statistical analysis of effi- Sun Health Research Institute. cacy was based on change from baseline of MMSE scores. Ac- cording to the caregiver journal assessments, patients treated References with donepezil were more likely to be capable of interacting with caregivers and others, engaging and being interested in [1] M. Sabbagh and J. Cummings, “Progressive cholinergic de- conversations with others, and enjoying leisurely activities. cline in Alzheimer’s disease: consideration for treatment with Caregivers of donepezil-treated patients remained close to donepezil 23 mg in patients with moderate to severe symp- their baseline assessments of stress levels while caregivers for tomatology,” BMC Neurology, vol. 11, p. 21, 2011. 4 International Journal of Alzheimer’s Disease [2] M. N. Sabbagh, S. Richardson, and N. Relkin, “Disease-modi- [17] R. W. Jones, H. Soininen, K. Hager et al., “A multinational, fying approaches to Alzheimer’s disease: challenges and op- randomised, 12-week study comparing the effects of donepe- portunities-lessons from donepezil therapy,” Alzheimer’s and zil and galantamine in patients with mild to moderate Alzhei- Dementia, vol. 4, no. 1, supplement 1, pp. S109–S118, 2008. mer’s disease,” International Journal of Geriatric Psychiatry, vol. 19, no. 1, pp. 58–67, 2004. [3] M.N.Sabbagh,M.R.Farlow, N. Relkin, andT.G.Beach,“Do cholinergic therapies have disease-modifying effects in Alzhei- [18] R. Bullock, J. Touchon, H. Bergman et al., “Rivastigmine and mer’s disease?” Alzheimer’s and Dementia,vol. 2, no.2,pp. donepezil treatment in moderate to moderately-severe Alzh- 118–125, 2006. eimer’s disease over a 2-year period,” Current Medical Research and Opinion, vol. 21, no. 8, article 3079, pp. 1317–1327, 2005. [4] H. Feldman, S. Gauthier, J. Hecker et al., “Efficacy of donepezil on maintenance of activities of daily living in patients with [19] D. G. Wilkinson, A. P. Passmore, R. Bullock et al., “A multi- moderate to severe Alzheimer’s disease and the effect on national, randomised, 12-week, comparative study of donep- caregiver burden,” Journal of the American Geriatrics Society, ezil and rivastigmine in patients with mild to moderate Alzhe- vol. 51, no. 6, pp. 737–744, 2003. imer’s disease,” International Journal of Clinical Practice, vol. 56, no. 6, pp. 441–446, 2002. [5] R. C. Mohs, R. S. Doody, J. C. Morris et al., “A 1-year, placebo- controlled preservation of function survival study of donepezil [20] R. A. Hansen, G. Gartlehner, A. P. Webb, L. C. Morgan, C. G. in AD patients,” Neurology, vol. 57, no. 3, pp. 481–488, 2001. Moore, and D. E. Jonas, “Efficacy and safety of donepezil, gala- ntamine, and rivastigmine for the treatment of Alzheimer’s [6] S. A. Jacobson and M. N. Sabbagh, “Donepezil: potential neu- roprotective and disease-modifying effects,” Expert Opinion on disease: a systematic review and meta-analysis,” Clinical Inter- ventions in Aging, vol. 3, no. 2, pp. 211–225, 2008. Drug Metabolism and Toxicology, vol. 4, no. 10, pp. 1363–1369, 2008. [21] M. R. Farlow, S. Salloway, P. N. Tariot et al., “Effectiveness and [7] T. G. Beach, P. E. Potter, Y. M. Kuo et al., “Cholinergic deaf- tolerability of high-dose (23 mg/d) versus standard-dose (10 mg/d) donepezil in moderate to severe Alzheimer’s dis- ferentation of the rabbit cortex: a new animal model of Aβ de- position,” Neuroscience Letters, vol. 283, no. 1, pp. 9–12, 2000. ease: a 24-week, randomized, double-blind study,” Clinical Therapeutics, vol. 32, no. 7, pp. 1234–1251, 2010. [8] Y. Takada-Takatori, T. Kume, M. Sugimoto, H. Katsuki, H. [22] H. Feldman, S. Gauthier, J. Hecker, B. Vellas, P. Subbiah, Sugimoto, and A. Akaike, “Acetylcholinesterase inhibitors used in treatment of Alzheimer’s disease prevent glutamate and E. Whalen, “A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer’s disease,” neurotoxicity via nicotinic acetylcholine receptors and phos- phatidylinositol 3-kinase cascade,” Neuropharmacology, vol. Neurology, vol. 57, no. 4, pp. 613–620, 2001. 51, no. 3, pp. 474–486, 2006. [23] V. Jelic, A. Haglund, J. Kowalski, S. Langworth, and B. Win- blad, “Donepezil treatment of severe Alzheimer’s disease in [9] A. Nordberg, “Mechanisms behind the neuroprotective nursing home settings. A responder analysis,” Dementia and actions of cholinesterase inhibitors in Alzheimer disease,” Geriatric Cognitive Disorders, vol. 26, no. 5, pp. 458–466, 2008. Alzheimer Disease and Associated Disorders,vol. 20, no.1,pp. S12–S18, 2006. [24] A. Wimo, B. Winblad, S. N. Shah, W. Chin, R. Zhang, and T. McRae, “Impact of donepezil treatment for Alzheimer’s dis- [10] T. Kume, M. 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Broader Considerations of Higher Doses of Donepezil in the Treatment of Mild, Moderate, and Severe Alzheimer's Disease

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Hindawi Publishing Corporation
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Copyright © 2012 Camryn Berk and Marwan Sabbagh. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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10.1155/2012/707468
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Abstract

Hindawi Publishing Corporation International Journal of Alzheimer’s Disease Volume 2012, Article ID 707468, 4 pages doi:10.1155/2012/707468 Review Article Broader Considerations of Higher Doses of Donepezil in the Treatment of Mild, Moderate, and Severe Alzheimer’s Disease Camryn Berk and Marwan Sabbagh The Cleo Roberts Center for Clinical Research, Banner Sun Health Research Institute, 10515 W. Santa Fe Dr, Sun City, AZ 85351, USA Correspondence should be addressed to Marwan Sabbagh, marwan.sabbagh@bannerhealth.com Received 24 August 2011; Accepted 29 October 2011 Academic Editor: Anton P. Porsteinsson Copyright © 2012 C. Berk and M. Sabbagh. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Donepezil, a highly selective acetylcholinesterase inhibitor (AChEI), is approved as a symptomatic treatment mild, moderate, and severe Alzheimer’s disease (AD). Donepezil exerts its treatment effect through multiple mechanisms of action including nicotinic receptor stimulation, mitigation of excitotoxicity, and influencing APP processing. The use of donepezil at higher doses is justified given the worsening cholinergic deficit as the disease advances. Donepezil has been investigated in several clinical trials of subjects with moderate-to-severe AD. While the side effects are class specific (cholinergically driven), demonstrable benefit has been shown at the 10 mg dose and the 23 mg doses. Here, we review the clinical justification, efficacy, safety, and tolerability of use of donepezil in the treatment of moderate-to-severe AD. 1. Introduction with modest but debatable impact on disease progression from mild to moderate is concerned, decreasing speed of pro- Alzheimer’s disease is an age-related progressive neurological gression from the earliest signs of cognitive impairment to disorder that ultimately results in cognitive and behavioral severe dementia and finally death [2, 3]. dysfunction and functional loss. These later stages of disease An important component of Alzheimer’s disease man- are impacting an increasingly large number of people each agement is the group of caregivers who support Alzheimer’s year. At present, the treatment of Alzheimer’s disease (AD) is patients. As Alzheimer’s disease progresses, the demands on limited to symptomatic therapy. As symptoms worsen and the caregiver increase; often this takes a toll on the care pro- the effects of late-stage Alzheimer’s disease become more vider in the form of health problems of their own, stress, severe, there is an urgent need for new and novel treatment anxiety, depression, fatigue, and other physical and emotion- options. Of the 5.3 million people estimated to be afflicted al problems [4]. Donepezilisavaluable treatmentoptionnot with AD in the United States, more than half are suspected to just for its capacity as a selective inhibitor of acetylcholin- have moderate-or-severe disease. Because these stages of AD esterase for the patients but also for its capacity to ease the can last for several years, the difficulty presented to both pa- burden of the caregiver by prolonging the AD patient’s ability tients and caregivers increases dramatically in advanced to perform self-care tasks and delaying the progression of stages [1]. symptoms that would impact a caregiver [5]. Donepezil, a highly selective acetylcholinesterase inhibi- tor (AChEI), is one of only two treatments approved in the 2. Overview United States for use beyond the mild-to-moderate stage. While it can slow progression modestly and treat symptoms, Donepezil has a mode of action based on inhibiting acetyl- it cannot halt progression of the actual disease or ultimately cholinesterase selectively. Cholinergic function is improved stop the decline in cognitive and functional abilities. Agents when there are greater concentrations of acetylcholine in the such as donepezil create notable symptomatic improvements brain, and the depletion of acetylcholine that is common 2 International Journal of Alzheimer’s Disease with AD patients is positively affected with a donepezil reg- basocortical degeneration, donepezil induced cortical sprou- imen. Additionally, cholinesterase inhibitors hypothetically ting, mitigating reduction in cholinergic neurotransmission could operate within the scope of the “amyloid hypothesis” [14]. of AD pathogenesis. Donepezil in particular has been shown to attenuate neurotoxicity of amyloid beta peptide Aβ as well 3. Efficacy as influencing APP processing [6]. In accordance with the cascade concept, therapies that directly target the accumu- Donepezil has been found to be one of the most effective lation, aggregation, and deposition of amyloid beta peptide symptomatic treatments for AD available on the market with Aβ and effectively reduce the inciting event may be more additional potential as a disease-modifying therapy. Many effective than distally targeted treatments, such as those that but not all studies have shown that both when compared to target neurotransmitter deficits. a placebo, donepezil has proven to have significant efficacy In addition to attenuating Aβ neurotoxicity, donepezil in reducing the severity of neuropsychiatric symptoms in pa- also has an effect on cholinergic deafferentation. Cell bodies tients with mild-to-moderate AD and patients in more severe in the nucleus basalis in the brain are the origin of cholinergic stages of the disease [15]. Additionally, donepezil has been tracts, the axons of which are prolific in the cerebral cortex found to be effective in symptomatic treatment in a variety of and in the pedunculopontine nucleus with expansion into dosing levels giving it variability as a treatment option. In an the thalamus. Loss of cholinergic neurons in the nucleus bas- open-label, multicenter, Phase 3 extension study of the safety alis are a hallmark of the earliest stages of AD. The functional and efficacy of donepezil in patients with Alzheimer’s disease deafferentation of the cholinergic neurons is thought to in- [15], the primary efficacy measures were the Alzheimer’s Dis- duce Aβ production in the cerebral cortex, which is what be- ease Assessment Scale-cognitive subscale (ADAS-Cog) and gins the cascade to neurodegeneration. Donepezil disrupts the CDR-Sum of the Boxes (CDR-SB). These measures were the mechanism by which Aβ generation occurs following evaluated in a 152-week long extension study on patients cholinergic deafferentation by interfering with the process aged 50 and older that participated in at least one of the pre- that leads to the exposing of the toxic N-terminal region of vious phases of donepezil trials, with a total patient number APP during the preferential processing of the amyloid pre- (n) of 763. Among this population, the most common reason cursor protein. One way donepezil interupts this process is by for study discontinuation (46% of discontinued patients) cholinergic input to cortical neurons [7]. was departure due to the commercialization of donepezil Donepezil also impacts nicotinic receptors in the cortex after the successful completion of nonextension trials, allow- through upregulation. At clinically relevant concentrations, ing for prescriptive use of the drug [15], but of those that donepezil decreases the reduction of nicotinic acetylcholine completed the study declined from baseline significantly less receptor expression in the cerebral cortex of AD patients and than the placebo arm in the same period with regards to prevents some of the reduction in nicotinic binding that cor- ADAS-Cog scores. After a three-week placebo washout, the relates to disease severity. This process reduces glutamate mean change for patients using CDR-SB scores actually im- neurotoxicity and also has been shown to inhibit excitotoxic proved above baseline for the experimental arm and declined injury, which is significant regarding AD pathogenesis and in the placebo arm. progression [8]. In comparison studies with rivastigmine and galanta- Other mechanisms of action indicate donepezil could mine, specifically a 52-week trial [16] and a 12-week trial provide a treatment option for affecting the cellular and mol- [17] showed that regarding cognitive function, there is no ecular processes of neurodegeneration rather than sympto- statistically significant difference between patients treated matic treatment. Donepezil has been found to influence ace- with donepezil versus those treated with galantamine, nor is tylcholinesterase isoform expression by inhibiting the expre- there a difference regarding behavior when comparing ssion of the AChE-S form and causing an increase in the ex- 10 mg/day of donepezil to 24 mg/day of galantamine. Sim- pression of the AChE-R form through reduction of cholin- ilarly, rivastigmine and donepezil have been found to have esterase, generating neuroprotective effects [9]. Donepezil comparable effects on cognition and behavior [18, 19]and has also been shown to upregulate nicotinic receptors in the similar gastrointestinal side effects profiles [20]. cerebral cortex, increasing nicotinic acetylcholine receptor expression and nicotinic binding [10]. Furthermore, under conditions of upregulations donepezil has been proven to 4. Safety and Tolerability maintain neuroprotective actions are lower drug concentra- tions and reduce glutamate toxicity [8]. Donepezil has been In patients with moderate-to-severe Alzheimer’s disease, shown to mitigate the effects of oxidative stress in a strepto- donepezil has been found to be safe and well tolerated at dos- zotocin-induced model of dementia in mice, indicating use es up to 23 mg, with an increase in adverse events over lower against free radicals that may be implicated in AD [11]. dosages, most of which dissipate after the first month of Donepezil treatment has also resulted in improved cerebral treatment [1, 21]. In a randomized, double-blind study, 1371 blood flow in patients with mild cognitive impairment, with patients (mean age: 73.8 years, 62.8% female, 73.5% white) no reduction after six months compared to statistically signi- from 219 different sites in Asia, Europe, Australia, North ficant reduction in the placebo cohort [12, 13]. Potential America, South America, and South Africa were analyzed for mechanisms of action also include enhancing neuroplastic comparative effects of 10 mg/day donepezil and 23 mg/day activity through cholinergic modulation. In rodent models of donepezil. All patients had an MMSE of less than 20 and International Journal of Alzheimer’s Disease 3 assessed for changes in cognition and global functioning as the placebo group reported significant increases in stress over assessed using least square regressions as well as deviation the same period. Treatment of moderate-to-severe AD with from baseline between the two cohorts. At the highest doses, donepezil has also been associated with a much more gradual the most significant adverse events reported in safety trials increase in time a caregiver spends caring for a patient with were nausea, vomiting, and diarrhea; in the event that these progressing disease compared to patients who received a symptoms did not dissipate, dosages were reduced to im- placebo [24]. prove tolerability. Nevertheless, a certain percent of partic- As indicated in the aforementioned Doody study, the ipants did not tolerate donepezil even after the dose was adverse events experienced when treated with donepezil are reduced. Donepezil has proven to be safe and well tolerated transient and mild, often resolving themselves without the as well as effective in the treatment of moderate-to-severe AD need for dose modification but in the rare cases resolution is [21]. elusive, lowering the dosage is an effective way to decrease Donepezil has been found to be an effective option for adverse events. 92% of patients in the study experienced maintaining a desirable quality of life and prolonging patient at least one treatment-related adverse event, with only 28% performance of activities of daily living (ADL); under study (214) of patients experiencing a serious (grade 3 or 4) AE; in of 290 (mean age: 73.6 years, range 48–92) patients random- the case of 27% (203), the serious nonfatal AEs experienced ized into a 24-week, double-blind, placebo-controlled study, was determined to be not related to donepezil treatment. donepezil demonstrated a vastly slower decline trajectory Treatment with donepezil also indicated no clinically signif- than placebo in ADLS in patients with moderate-to-severe icant results or changes in clinical laboratory tests, physical AD [22]. Using the Disability Assessment for Dementia examinations, or electrocardiograms. The results of this (DAD), the Instrumental Acitvities of Daily living (IADL) study indicated that donepezil is a safe and effective agent for scale, and the Physical Self-Maintenance Scale (PSMS), re- long-term treatment of moderate-to-severe disease [15]. searchers have determined that moderate-to-severe AD pa- tients taking donepezil were improved in tasks such as the use 5. Conclusions of household appliances, managing personal mail, moving around in and outside of homes, understanding explanations It is broadly recognized that potent disease modifying agents or new situations, and maintaining leisure activities as com- are needed to prevent the progression of Alzheimer’s disease. pared to moderate-to-severe AD patients who took a placebo While the “amyloid hypothesis” of AD pathogenesis is still [22, 23]. In a six-month study, assessing responder rates of unproven, there is substantial evidence that suggests that moderate-to-severe AD patients taking donepezil in a long- inhibiting Aβ plaque formation will be a valuable approach term care facility, greater proportions of patients defined as for achieving this goal. But the foundation of AD manage- responders to donepezil showed significant stabilization or ment will continue to include a cholinesterase inhibitor such improvement compared with placebo on individual efficacy as donepezil. A multitude of well-controlled clinical studies measures including the severe impairment battery (SIB) (≥0, have demonstrated the cognitive benefit of this agent. In ≥4or ≥7 points) and Mini-Mental State Examination (≥0 addition, by interfering with the process that leads to the or ≥3 points), and positive trends on the ADCS-ADL-severe exposing of the toxic N-terminal region of APP during the (≥3 points) and the neuropsychiatric inventory (NPI) cluster preferential processing of the amyloid precursor, donepezil based on mood items. All 3 composite measures of efficacy disrupts the mechanism by which Aβ generation occurs fol- showed a significantly higher proportion of responders in the lowing cholinergic deafferentation. As new therapeutics donepezil group. The responders had a similar distribution come on line, the next advance in AD patient management between the 2 subgroups of cognitive and functional disease will come from understanding how they synergize with severity at baseline. The donepezil-treated patients taking donepezil or other cholinesterase inhibitors. psychotropic drugs showed significantly greater improve- Going forward, the role donepezil plays in disease man- ment on the SIB, less deterioration on the ADCS-ADL, and agement should not be limited solely to cholinestrase inhi- had higher Clinical Global Impression of Improvement bition at the level of neurotransmitter. Rather, as preclinical scores and a trend toward lower NPI scores [23]. evidence amply demonstrates, the drug affects on cellular In addition to assessing patient conditions, caregivers and molecular processes should be exploited for their depth were assessed using the Caregiver Stress Scale (CSS) for the and breadth of influence at every stage of disease. first time in a clinical trial to measure a caregiver’s status re- garding cognitive status, overload, relational deprivation, Acknowledgment job-caregiving conflict, economic strains, role captivity, loss of self, care-giving competence, personal gain, management The paper is supported by NIA P30 AG019610 and Banner of distress, and expressive support. Statistical analysis of effi- Sun Health Research Institute. cacy was based on change from baseline of MMSE scores. 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