• Biomolecules & Therapeutics
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• v.26 no.3
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• pp.274-281
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• 2018

A previous study in humans demonstrated the sustained inhibitory effects of donepezil on acetylcholinesterase (AChE) activity; however, the effective concentration of donepezil in humans and animals is unclear. This study aimed to characterize the effective concentration of donepezil on AChE inhibition and impaired learning and memory in rodents. A pharmacokinetic study of donepezil showed a mean peak plasma concentration of donepezil after oral treatment (3 and 10 mg/kg) of approximately $1.2{\pm}0.4h$ and $1.4{\pm}0.5h$, respectively; absolute bioavailability was calculated as 3.6%. Further, AChE activity was inhibited by increasing plasma concentrations of donepezil, and a maximum inhibition of $31.5{\pm}5.7%$ was observed after donepezil treatment in hairless rats. Plasma AChE activity was negatively correlated with plasma donepezil concentration. The pharmacological effects of donepezil are dependent upon its concentration and AChE activity; therefore, we assessed the effects of donepezil on learning and memory using a Y-maze in mice. Donepezil treatment (3 mg/kg) significantly prevented the progression of scopolamine-induced memory impairment in mice. As the concentration of donepezil in the brain increased, the recovery of spontaneous alternations also improved; maximal improvement was observed at $46.5{\pm}3.5ng/g$ in the brain. In conclusion, our findings suggest that the AChE inhibitory activity and pharmacological effects of donepezil can be predicted by the concentration of donepezil. Further, $46.5{\pm}3.5ng/g$ donepezil is an efficacious target concentration in the brain for treating learning and memory impairment in rodents.

• Journal of Society of Preventive Korean Medicine
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• v.17 no.1
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• pp.77-88
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• 2013

Objectives : This study was aim to evaluate effects of pharmacodynamics and toxicity in combination therapy of donepezil with Gongjindan. Methods : After 10mg/kg of donepezil treatment, Gongjindan 100mg/kg was administered within 5 min. The plasma were collected at 30min before administration, 30min, 1, 2, 3, 4, 6, 8 and 24hrs after end of Gongjindan treatment, and plasma concentrations of donepezil were analyzed using LC-MS/MS methods. PK parameters of donepezil were analysis as compared with donepezil single administered rats. Results : Gongjindan markedly inhibited the absorption of donepezil regardless of sample time, from 30min to 8hrs after end of co-administration comparing with donepezil single treated rats. Especially the absorption of donepezil was significantly decreased at 2hrs after co-administration as compared with donepezil single treated rats, in the present study. Accordingly, the Cmax(-27.76%), $AUC_{0-t}$(-27.22%) and $AUC_{0-inf}$(-26.54%) of donepezil in co-administered rats were significantly decreased as compared with donepezil single treated rats, respectively. Conclusions : Based on the results of the present study, co-administration of Gongjindan decreases the oral bioavailability of donepezil by inhibiting the absorption. It is considered that the more detail pharmacokinetic studies should betested to conclude the effects of Gongjindan on the pharmacokinetics of donepezil, when they were co-administered, like the effects after co-administration with reasonable intervals considering the Tmax of donepezil and after repeated co-administrations.

• Korean Journal of Biological Psychiatry
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• v.18 no.1
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• pp.36-45
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• 2011

Objectives : Though a proportion of Alzheimer's disease(AD) patients treated with donepezil have shown positive response on cognition, but the responders' characteristics are still uncertain. This study attempts to identify whether a single oral dose of donepezil(5mg) can change cognition and the relationship between single dose responder items and long-term responder are examined. Methods : Twenty-three AD patients for single donepezil challenge study group and eleven AD patients for controls were participated in the study. Seven days after baseline study for neuropsychological test and EEG, same studies were rechecked after donepezil medication in study group. In donepezil study groups, 12 weeks after donepezil medication, neuropsychological test and EEG were rechecked. Results : After single donepezil challenge, forward digit span, Rey-Osterrieth Complex Figure Test copy, SVLT delayed recall were significantly improved, and beta spectra power in anterior, theta spectra power in posterior field were significantly decreased. According to linear regression analysis, forward digit span after single donepezil challenge was significantly positive correlated with long-term responders. Conclusions : This study suggests that single donepezil medication can significantly change cognitive functions and EEG in AD patients. Among these responsive items, forward digit span was significantly correlated with long-term responder.

• Korean Journal of Biological Psychiatry
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• v.12 no.2
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• pp.98-106
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• 2005

Objectives:Donepezil is a widely used drug for the treatment of patients with Alzheimer's disease(AD). The aim of the present study was to clarify the efficacy and the characteristics of responders to donepezil. Methods:Patients with probable AD(n=80;75.7 years) and small vessel dementia(SVD)(n=18;77.8 years) who received donepezil were retrospectively analyzed using Alzheimer's registry, and three questions were asked:1) Does donepezil therapy improves cognitive symptoms in patients with dementia? 2) If donepezil improves cognitive symptoms, which items of the K-MMSE are improved? 3) What are the characteristics of responder to donepezil medication? Results:1) After donepezil medication, cognitive function measured by the K-MMSE was significantly improved in both types of dementia(AD and SVD), However, statistical differences were not found between these groups. 2) In a clinical trial of donepezil, the patients performed better than before mediation on K-MMSE items assessing orientation, recall, construction, concentration, calculation. 3) In AD, the K-MMSE score before medication was closely related with response of donepezil. Conclusion:This study suggests that donepezil improves various cognitive functions in both types of dementia, and the responsive group had significantly lower K-MMSE scores than the non-responsive group before medication.

• Journal of Society of Preventive Korean Medicine
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• v.17 no.2
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• pp.139-155
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• 2013

Purpose : This study was aim to evaluate effects of pharmacodynamics and toxicity in combination therapy of donepezil with Gongjindan. The effects of Gongjindan co-administration on the pharmacokinetics (PK) of donepezil were observed after single and 7-day repeated oral co-administration with 1.5hr-intervals, to evaluate synergic pharmacodynamics and reduce toxicity of combination therapy of donepezil with Gongjindan. Materials and Methods : After 10mg/kg of donepezil treatment, Gongjindan100mg/kg was administered with 1.5hr-intervals. The plasma were collected at 30min before administration, 30min, 1, 2, 3, 4, 6, 8 and 24hrs after end of first and last 7th donepezil treatment, and plasma concentrations of donepezil were analyzed using LC-MS/MS methods. Results : Gongjindan markedly inhibited the absorption of donepezilregardless of sample time, from 30min to 8hrs after end of first 1.5hr-interval co-administration as compared with donepezil single treated rats. Especially the absorption of donepezil was significantly decreased at 2, 4, 6 and 8hrs after co-administration as compared with donepezilsingle treated rats. Accordingly, the Cmax (-26.236%), $AUC_{0-t}$(-26.02%) and $AUC_{0-inf}$(-25.90%) of donepezil in 1.5hr-interval co-administered rats were dramatically decreased as compared with donepezilsingle treated rats, respectively. However, no meaningful changes on the plasma donepezil concentrations and pharmacokinetic parameters were detected after end of last 7th 1.5hr-interval co-administration as compared with donerezil single treated rats, except for non-significant slight increases of Tmax(16.67%) detected in co-administered rats as compared with donepezil single treated rats. Conclusion : These findings are considered as direct evidences that Gongjindan also decreased oral bioavailability of donerezil as inhibited the absorptions, when they were co-administered with 1.5hr-intervals, but they may be adapted after 7 days continuous repeated l.5hr-interval co-administration.

• YAKHAK HOEJI
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• v.46 no.3
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• pp.185-191
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• 2002

Alzheimer's disease (AD) involves neuronal degeneration with impaired cholinergic transmission, particularly in areas of the brain associated with learning and memory. Several cholinesterase inhibitors are widely prescribed to ameliorate the cognitive deficits in AD patients. In an attempt to examine if tacrine and donepezil, two well-known cholinesterase inhibitors, exhibit additional pharmacological actions in primary cultured rat cortical cells, we investigated the effects on neuronal injuries induced by glutamate or N-methyl-D-aspartate (NMDA), $\beta$-amyloid fragment ( $A_{{beta}25-35)}$), and various oxidative insults. Both tacrine and donepezil did not significantly inhibit the excitotoxic neuronal damage induced by glutamate. However, tacrine inhibited the toxicity induced by NMDA in a concentration-dependent fashion. In addition, tacrine significantly inhibited the $A_{{beta}25-35)}$-induced neuronal injury at the concentration of 50 $\mu$M. In contrast, donepezil did not reduce the NMDA- nor $A_{{beta}25-35)}$-induced neuronal injury. Tacrine and donepezil had no effects on oxidative neuronal injuries in cultures nor on lipid peroxidation in vitro. These results suggest that, in addition to its anticholinesterase activity, the neuroprotective effects by tacrine against the NMDA- and $A_{{beta}25-35)$-induced toxicity may be beneficial for the treatment of AD. In contrast, the potent and selective inhibition of central acetylcholinesterase appears to be the major action mechanism of donepezil.

• Journal of Oriental Neuropsychiatry
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• v.30 no.3
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• pp.199-207
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• 2019

Objectives: The purpose of this study was to evaluate the neuroprotective effects of donepezil and 33 kinds of herbal extract combinations in SH-SY5Y cells with $A{\beta}_{25-35}$ treatment. Methods: MTT assay was performed to measure the cell viability of each herbal extract combined with donepezil against $A{\beta}$-induced neurotoxicity. The most active extracts were then subjected to assess the effects on CREB phosphorylation and COX-2 expressions through the western blot analysis. Results: There were eight herbal extracts representing significant increase on the cell viability: 1) Erycibe obtusifolia, 2) Polygonum multiflorum, 3) Polygala tenuifolia, 4) Illicium verum, 5) Santalum album, 6) Loranthus parasticus, 7) Platycladus orientalis, and 8) Zanthoxylum piperitum. Especially, when Santalum album and donepezil were treated together, the phosphorylation of CREB significantly increased and COX-2 protein expression was significantly inhibited. Conclusions: Among the screened herbal extracts, combination treatment of each of the eight herbs and donepezil showed neuroprotective effects in SH-SY5Y cells. Additionally, the combination of Santalum album and donepezil suggested cognitive improvement by up-regulation of p-CREB and down-regulation of COX-2.

• Journal of Yeungnam Medical Science
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• v.38 no.1
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• pp.65-69
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• 2021

Donepezil is a cholinesterase inhibitor used extensively to treat Alzheimer disease. The increased cholinergic activity is associated with adverse effects, therefore gastrointestinal symptoms, including nausea, vomiting, and diarrhea, are common. Hypokalemia is a rare adverse event that occurs in less than 1% of donepezil-treated patients. Although hypokalemia of mild and moderate grade does not present serious signs and symptoms, severe hypokalemia often results in prolonged hospitalization and mortality. Herein, we report a case of hypokalemia developed after the initiation of donepezil therapy for cognitive impairment.

• Bulletin of the Korean Chemical Society
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• v.30 no.9
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• pp.2007-2010
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• 2009

Donepezil hydrochloride is a reversible acetylcholinesterase inhibitor that is used in the treatment of Alzheimer’s disease to improve the cognitive performance. It shows different crystalline forms including hydrates. Therefore, it is very important to confirm the polymorphic forms in the formulations of pharmaceutical materials because polymorphs of the same drug often exhibit significant differences in solubility, bioavailability, processability and physical/chemical stability. In this paper, four different forms of donepezil hydrochloride were prepared and characterized using X-ray powder diffraction, Fourier transform infrared, and solid-state nuclear magnetic resonance (NMR) spectroscopy. This study showed that solid-state NMR spectroscopy is a powerful technique for obtaining structural information and the polymorphology of pharmaceutical solids.

• Bulletin of the Korean Chemical Society
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• v.30 no.4
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• pp.969-971
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• 2009