Treatment and Management of Dementia Due to Alzheimer’s Disease

Molano, Jennifer Rose V.; Bratt, Robin; Shatz, Rhonna

doi:10.1007/s11940-015-0363-4

Cited by 4 publications

(4 citation statements)

References 80 publications

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“…When we tested the hybrids against Ef BChE, we observed a similar trend to that seen against EeAChE. In general, 1,4-chalcone-donepezil hybrids (16) were better than 1,3-chalcone-donepezil hybrids (15) at inhibiting Ef BChE, with the exception of compounds with 2 carbon (15a, 0.020 ± 0.002 µM) and 4 carbon linkers (15b, 0.03 ± 0.01 µM). In the case of 1,3-chalcone-donepezil hybrids, the compounds with 2 and 4 carbon linkers (15a and 15b) were much better than donepezil (2.0 ± 0.10 µM) at inhibiting Ef BChE.…”

Section: Bche Inhibitionsupporting

confidence: 62%

“…In general, most of these compounds were able to inhibit the actions of EeAChE and Ef BChE with low to sub-micromolar IC 50 values. In general, 1,4-chalcone-donepezil hybrids (16) were better at inhibiting EeAChE and Ef BChE than 1,3-chalcone-donepezil hybrids (15), with the exception of 15f against EeAChE and 15a and 15b against Ef BChE. The presence of shorter linkers between chalcones and donepezil seemed to have a positive impact on EeAChE and Ef BChE inhibition.…”

Section: Discussionmentioning

confidence: 88%

“…Since increasing age is the most common risk factor for the development of AD, barring the implementation of an effective treatment or prevention of AD, the number of people with AD will increase significantly if the current population lifespan trends continue. The few medications that are approved for AD (donepezil, tacrine, rivastigmine, galantamine (acetylcholinesterase inhibitors (AChEIs)) and memantine (N-methyl-d-aspartate (NMDA) receptor antagonist) provide only limited symptomatic relief rather than affecting disease progression or providing a cure [14][15][16][17]. Since the number of AD-related drugs used in AD patients is limited, there is an urgent need for novel therapeutic candidates to treat this brain disorder.…”

Section: Introductionmentioning

confidence: 99%

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Combining Chalcones with Donepezil to Inhibit Both Cholinesterases and Aβ Fibril Assembly

et al. 2019

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The fact that the number of people with Alzheimer's disease is increasing, combined with the limited availability of drugs for its treatment, emphasize the need for the development of novel effective therapeutics for treating this brain disorder. Herein, we focus on generating 12 chalcone-donepezil hybrids, with the goal of simultaneously targeting amyloid-β (Aβ) peptides as well as cholinesterases (i.e., acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)). We present the design, synthesis, and biochemical evaluation of these two series of novel 1,3-chalcone-donepezil (15a-15f) or 1,4-chalcone-donepezil (16a-16f) hybrids. We evaluate the relationship between their structures and their ability to inhibit AChE/BChE activity as well as their ability to bind Aβ peptides. We show that several of these novel chalcone-donepezil hybrids can successfully inhibit AChE/BChE as well as the assembly of N-biotinylated Aβ oligomers. We also demonstrate that the Aβ binding site of these hybrids differs from that of Pittsburgh Compound B (PIB).Molecules 2020, 25, 77 2 of 32 Despite extensive research efforts, the causative factors of AD remain unclear [18]. However, various characteristics, such as low levels of acetylcholine (ACh), accumulation of amyloid-β (Aβ) deposits, tau (τ) protein aggregation, oxidative stress, inflammation, metal ion imbalance, and breakdown of homeostatic systems, play crucial roles in AD progression [19][20][21][22][23][24][25]. Currently, most of the primary therapeutic options for treating AD are based on AChEIs [26][27][28][29][30][31]. Low levels of acetylcholine (ACh) can lead to cognitive and memory deficits. The two types of cholinesterases present in the central nervous system, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), are capable of hydrolyzing ACh [32][33][34][35]. In healthy brains, BChE plays a secondary role to AChE, but as AD progresses the activity and expression of BChE in the brain increases [36]. Although developing inhibitors against these enzymes alone will not lead to a cure, combining their effect with another hallmark of AD progression, such as Aβ peptide accumulation, could potentially be beneficial. The accumulation of Aβ peptides in the cerebral cortex of the brain has been suggested as a part of AD pathogenesis [37,38]. Thus, additionally preventing the aggregation of Aβ and/or disrupting the existing Aβ plaques are potential therapeutic approaches for treating AD [22,[39][40][41].There are currently reports in the literature investigating new scaffolds with two or more pharmacophores connected to each other through a linker aimed at interacting with more than one biological target [42][43][44][45][46][47][48][49][50][51]. Previously, our group as well as others studied donepezil, the current drug of choice for treating AD with its AChE and BChE inhibiting capacity [52][53][54][55][56][57]. In addition, we explored the use of chalcone derivatives as AChE inhibitors as well as Aβ peptide and metal-Aβ complex-targeting compounds [58,59]. Here, we ...

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Section: Bche Inhibitionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

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Combining Chalcones with Donepezil to Inhibit Both Cholinesterases and Aβ Fibril Assembly

et al. 2019

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“…New prescription of this medication requires careful consideration given the potential adverse effects [38], decrease in quality of life [39], and primary treatment indication for mild to moderate dementia [32]. For residents with moderate to severe dementia, memantine is an approved option that can be combined with acetylcholinesterase inhibitors [40]. However, the clinical benefits of memantine in advanced dementia are limited, and its side-effect profile needs to be carefully considered in endof-life care [41][42][43].…”

Section: Comparison With Other Studiesmentioning

confidence: 99%

Prescribing medications of questionable benefit prior to death: a retrospective study on older nursing home residents with and without dementia in Germany

Rausch

Hoffmann

2020

Eur J Clin Pharmacol

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Purpose We studied the prevalence of medications of questionable benefit in the last 6 months of life among older nursing home residents with and without dementia in Germany. Methods A retrospective cohort study was conducted on claims data from 67,328 deceased nursing home residents aged 65+ years who were admitted between 2010 and 2014. We analyzed prescription regimens of medications of questionable benefit in the 180-91-day period and the 90-day period prior to death for residents with dementia (n = 29,052) and without dementia (n = 38,276). Factors associated with new prescriptions of medications of questionable benefit prior to death were analyzed using logistic regression models among all nursing home residents and stratified by dementia. Results A higher proportion of nursing home residents with dementia were prescribed at least one medication of questionable benefit in the 180-91-day (29.6%) and 90-day (26.8%) periods prior to death, compared with residents without dementia (180-91 days, 22.8%; 90 days, 20.1%). Lipid-lowering agents were the most commonly prescribed medications. New prescriptions of medications of questionable benefit were more common among residents with dementia (9.8% vs. 8.7%). When excluding antidementia medication, new prescriptions of these medications were more common among residents without dementia (6.4% vs. 8.0%). The presence of dementia (odds ratio [OR] 1.40, 95% confidence interval [95%CI] 1.32-1.48) and excessive polypharmacy were associated with new prescriptions of medications of questionable benefit prior to death (OR 4.74, 95%CI 4.15-5.42). Conclusion Even when accounting for anti-dementia prescriptions, the prevalence of nursing home residents with dementia receiving medications of questionable benefit is considerable and may require further attention.

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Design, synthesis and biological evaluation of novel donepezil–coumarin hybrids as multi-target agents for the treatment of Alzheimer’s disease

Xie

Lan

Wang

et al. 2016

Bioorganic & Medicinal Chemistry

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Treatment and Management of Dementia Due to Alzheimer’s Disease

Cited by 4 publications

References 80 publications

Combining Chalcones with Donepezil to Inhibit Both Cholinesterases and Aβ Fibril Assembly

Combining Chalcones with Donepezil to Inhibit Both Cholinesterases and Aβ Fibril Assembly

Prescribing medications of questionable benefit prior to death: a retrospective study on older nursing home residents with and without dementia in Germany

Design, synthesis and biological evaluation of novel donepezil–coumarin hybrids as multi-target agents for the treatment of Alzheimer’s disease

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