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Akinori Akaike - One of the best experts on this subject based on the ideXlab platform.

  • Donepezil attenuates excitotoxic damage induced by membrane depolarization of cortical neurons exposed to veratridine
    European Journal of Pharmacology, 2008
    Co-Authors: Shigeru Akasofu, Hiroo Ogura, Kohei Sawada, Takashi Kosasa, Hiroe Hihara, Akinori Akaike
    Abstract:

    Abstract Long-lasting membrane depolarization in cerebral ischemia causes neurotoxicity via increases of intracellular sodium concentration ([Na + ] i ) and calcium concentration ([Ca 2+ ] i ). Donepezil has been shown to exert neuroprotective effects in an oxygen–glucose deprivation model. In the present study, we examined the effect of Donepezil on depolarization-induced neuronal cell injury resulting from prolonged opening of Na + channels with veratridine in rat primary-cultured cortical neurons. Veratridine (10 µM)-induced neuronal cell damage was completely prevented by 0.1 µM tetrodotoxin. Pretreatment with Donepezil (0.1–10 µM) for 1 day significantly decreased cell death in a concentration-dependent manner, and a potent NMDA receptor antagonist, dizocilpine (MK801), showed a neuroprotective effect at the concentration of 10 µM. The neuroprotective effect of Donepezil was not affected by nicotinic or muscarinic acetylcholine receptor antagonists. We further characterized the neuroprotective properties of Donepezil by measuring the effect on [Na + ] i and [Ca 2+ ] i in cells stimulated with veratridine. At 0.1–10 µM, Donepezil significantly and concentration-dependently reduced the veratridine-induced increase of [Ca 2+ ] i , whereas MK801 had no effect. At 10 µM, Donepezil significantly decreased the veratridine-induced increase of [Na + ] i . We also measured the effect on veratridine-induced release of the excitatory amino acids, glutamate and glycine. While Donepezil decreased the release of glutamate and glycine, MK801 did not. In conclusion, our results indicate that Donepezil has neuroprotective activity against depolarization-induced toxicity in rat cortical neurons via inhibition of the rapid influx of sodium and calcium ions, and via decrease of glutamate and glycine release, and also that this depolarization-induced toxicity is mediated by glutamate receptor activation.

  • Mechanisms of alpha7-nicotinic receptor up-regulation and sensitization to Donepezil induced by chronic Donepezil treatment.
    European journal of pharmacology, 2008
    Co-Authors: Yuki Takada-takatori, Hachiro Sugimoto, Toshiaki Kume, Yuta Ohgi, Tetsuhiro Niidome, Takeshi Fujii, Akinori Akaike
    Abstract:

    alpha7-nicotinic acetylcholine receptors are one of the most abundant subtypes of nicotinic receptors in the brain and have been shown to be involved in the neuroprotective effect of Donepezil. Recently, we showed that in primary culture of rat cortical neurons, chronic Donepezil treatment (10 muM, 4 days) (1) induces the up-regulation of alpha7-nicotinic receptors, (2) enhances the nicotine-induced increase in [Ca(2+)](i) and (3) enhances the sensitivity to the neuroprotective effect of Donepezil. Here we demonstrate the involvement of alpha7-nicotinic receptors in these three effects. Concomitant treatment with nicotinic receptor antagonist inhibited the up-regulation of alpha7-nicotinic receptor, enhancement of the increase in [Ca(2+)](i) induced by nicotine, and enhancement of sensitivity to the neuroprotective effect of Donepezil. Next, using inhibitors of phosphatidylinositol 3-kinase and mitogen-activated protein kinase signaling pathways, we demonstrate the involvement of these pathways in the up-regulation of alpha7-nicotinic receptors and in making the neurons more sensitive to the neuroprotective effects of Donepezil. Concomitant chronic Donepezil treatment with inhibitors of phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways inhibited nicotinic receptor up-regulation and enhancement of the response to nicotine, and enhanced the sensitivity to Donepezil. This study increases understanding of the less-studied mechanism of chronic Donepezil treatment-induced nicotinic receptor up-regulation and increased sensitivity to Donepezil.

  • Mechanism of neuroprotection by Donepezil pretreatment in rat cortical neurons chronically treated with Donepezil.
    Journal of neuroscience research, 2008
    Co-Authors: Yuki Takada-takatori, Hachiro Sugimoto, Toshiaki Kume, Yuta Ohgi, Tetsuhiro Niidome, Takeshi Fujii, Yasuhiko Izumi, Akinori Akaike
    Abstract:

    Previously, we showed that in rat cortical neurons, chronic Donepezil treatment (10 μM, 4 days) up-regulates nicotinic receptors (nAChR) and makes neurons more sensitive to the neuroprotective effect of Donepezil. Here we examined the mechanism of Donepezil-induced neuroprotection in neurons chronically treated with Donepezil. The mechanism of neuroprotection was examined under different conditions of exposure to glutamate, acute and moderate, that induce cell death associated with necrotic and apoptotic cell death, respectively. Concomitant treatment with antagonists of nAChRs but not muscarinic receptors inhibited Donepezil pretreatment-induced neuroprotection against acute glutamate treatment-induced death. Donepezil pretreatment prevented acute glutamate- and ionomycin-induced neurotoxicity, but not S-nitrosocysteine-induced neurotoxicity, suggesting that Donepezil protects neurons via nAChR at levels before nitric oxide synthase activation against acute glutamate neurotoxicity. Concomitant treatment with antagonists of nAChR or phosphatidylinositol 3-kinase (PI3K) signaling inhibitors significantly inhibited neuroprotection against moderate glutamate neurotoxicity and decreased the phosphorylation level of Akt. Neuroprotection was also inhibited by treatment with inhibitor of mitogen-activated protein kinase (MAPK) kinase. These results suggest that Donepezil protects neurons against moderate glutamate neurotoxicity via nAChR-PI3K-Akt and MAPK signaling pathways. This study provides novel insight into the mechanism of Donepezil-induced neuroprotection that involves nAChR up-regulation. © 2008 Wiley-Liss, Inc.

  • Neuroprotective action of Donepezil mediated by neuronal nicotinic receptors
    Psychogeriatrics, 2006
    Co-Authors: Akinori Akaike, Hiroshi Katsuki, Toshiaki Kume, Yuki Takada-takatori
    Abstract:

    AChE inhibitors used in the treatment in Alzheimer’s disease such as Donepezil are effective in preventing glutamate neurotoxicity. In primary cultures of the cortical neurons, Donepezil prevents glutamate neurotoxicity when the drug is applied 8–24 hr prior to glutamate exposure. Neuroprotective effect of Donepezil is antagonized by mecamylamine, dihydro-β-erythoridine and metyllcaconitine. Prolonged (more than 4 days) exposure of the cultures to Donepezil induces an increase in the nicotine-induced Ca2+ influx and number of neurons expressing α4 and α7 subunits of nicotinic receptors. Donepezil also prevents apoptotic neuronal death induced by glutamate. Inhibitors for non-receptor type tyrosine kinase, Fyn and janus-activated kinase 2, suppress the neuroprotective effect of Donepezil. Neuroprotective effect of Donepezil is also suppressed by a phosphatidylinositol 3-kinase (PI3K) inhibitor. Phosphorylation level of Akt, an effector of PI3K, and the expression level of Bcl-2 increase with Donepezil. These results suggest that Donepezil prevents glutamate neurotoxicity through α4- and α7-nicotinic acetylcholine receptors (nAChRs), followed by activation of PI3-Akt pathway but independent from activation of ion channels associated with nAChRs. α4- and α7-nAChRs may play an important role in promoting survival of cortical neurons under oxidative stress caused by excitotoxicity.

  • Up-regulation of nicotinic acetylcholine receptors by central-type acetylcholinesterase inhibitors in rat cortical neurons.
    European journal of pharmacology, 2005
    Co-Authors: Toshiaki Kume, Hiroshi Katsuki, Yuki Takada, Atsushi Yonezawa, Hachiro Sugimoto, Mitsuhiro Sugimoto, Toshiaki Yamaguchi, Akinori Akaike
    Abstract:

    We previously reported that Donepezil, a central-type acetylcholinesterase inhibitor, showed neuroprotective action via alpha4-and alpha7-nicotinic acetylcholine receptors against glutamate neurotoxicity in rat cortical culture. The present study was performed to investigate whether the neuroprotective action of acetylcholinesterase inhibitors is accompanied by the alteration of expression and function of nicotinic receptors. Four days treatment with acetylcholinesterase inhibitors (10 microM) enhanced the nicotine-induced increase of the intracellular calcium concentration. Immunoblot analysis revealed that Donepezil increased both alpha4 and alpha7 subunit proteins. Donepezil and galanthamine increased the number of cells expressing alpha4- and alpha7-nicotinic receptors in immunocytochemical analysis. We examined whether up-regulation of nicotinic receptors affected the neuroprotective action of acetylcholinesterase inhibitors. Under up-regulating conditions, Donepezil and galanthamine exerted neuroprotective action at lower concentrations. These results suggest that Donepezil and galanthamine up-regulate nicotinic receptors in cortical neurons, and that the up-regulation of nicotinic receptors may make cortical neurons more sensitive to the neuroprotective action of Donepezil and galanthamine.

Toshiaki Kume - One of the best experts on this subject based on the ideXlab platform.

  • Mechanisms of alpha7-nicotinic receptor up-regulation and sensitization to Donepezil induced by chronic Donepezil treatment.
    European journal of pharmacology, 2008
    Co-Authors: Yuki Takada-takatori, Hachiro Sugimoto, Toshiaki Kume, Yuta Ohgi, Tetsuhiro Niidome, Takeshi Fujii, Akinori Akaike
    Abstract:

    alpha7-nicotinic acetylcholine receptors are one of the most abundant subtypes of nicotinic receptors in the brain and have been shown to be involved in the neuroprotective effect of Donepezil. Recently, we showed that in primary culture of rat cortical neurons, chronic Donepezil treatment (10 muM, 4 days) (1) induces the up-regulation of alpha7-nicotinic receptors, (2) enhances the nicotine-induced increase in [Ca(2+)](i) and (3) enhances the sensitivity to the neuroprotective effect of Donepezil. Here we demonstrate the involvement of alpha7-nicotinic receptors in these three effects. Concomitant treatment with nicotinic receptor antagonist inhibited the up-regulation of alpha7-nicotinic receptor, enhancement of the increase in [Ca(2+)](i) induced by nicotine, and enhancement of sensitivity to the neuroprotective effect of Donepezil. Next, using inhibitors of phosphatidylinositol 3-kinase and mitogen-activated protein kinase signaling pathways, we demonstrate the involvement of these pathways in the up-regulation of alpha7-nicotinic receptors and in making the neurons more sensitive to the neuroprotective effects of Donepezil. Concomitant chronic Donepezil treatment with inhibitors of phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways inhibited nicotinic receptor up-regulation and enhancement of the response to nicotine, and enhanced the sensitivity to Donepezil. This study increases understanding of the less-studied mechanism of chronic Donepezil treatment-induced nicotinic receptor up-regulation and increased sensitivity to Donepezil.

  • Mechanism of neuroprotection by Donepezil pretreatment in rat cortical neurons chronically treated with Donepezil.
    Journal of neuroscience research, 2008
    Co-Authors: Yuki Takada-takatori, Hachiro Sugimoto, Toshiaki Kume, Yuta Ohgi, Tetsuhiro Niidome, Takeshi Fujii, Yasuhiko Izumi, Akinori Akaike
    Abstract:

    Previously, we showed that in rat cortical neurons, chronic Donepezil treatment (10 μM, 4 days) up-regulates nicotinic receptors (nAChR) and makes neurons more sensitive to the neuroprotective effect of Donepezil. Here we examined the mechanism of Donepezil-induced neuroprotection in neurons chronically treated with Donepezil. The mechanism of neuroprotection was examined under different conditions of exposure to glutamate, acute and moderate, that induce cell death associated with necrotic and apoptotic cell death, respectively. Concomitant treatment with antagonists of nAChRs but not muscarinic receptors inhibited Donepezil pretreatment-induced neuroprotection against acute glutamate treatment-induced death. Donepezil pretreatment prevented acute glutamate- and ionomycin-induced neurotoxicity, but not S-nitrosocysteine-induced neurotoxicity, suggesting that Donepezil protects neurons via nAChR at levels before nitric oxide synthase activation against acute glutamate neurotoxicity. Concomitant treatment with antagonists of nAChR or phosphatidylinositol 3-kinase (PI3K) signaling inhibitors significantly inhibited neuroprotection against moderate glutamate neurotoxicity and decreased the phosphorylation level of Akt. Neuroprotection was also inhibited by treatment with inhibitor of mitogen-activated protein kinase (MAPK) kinase. These results suggest that Donepezil protects neurons against moderate glutamate neurotoxicity via nAChR-PI3K-Akt and MAPK signaling pathways. This study provides novel insight into the mechanism of Donepezil-induced neuroprotection that involves nAChR up-regulation. © 2008 Wiley-Liss, Inc.

  • Neuroprotective action of Donepezil mediated by neuronal nicotinic receptors
    Psychogeriatrics, 2006
    Co-Authors: Akinori Akaike, Hiroshi Katsuki, Toshiaki Kume, Yuki Takada-takatori
    Abstract:

    AChE inhibitors used in the treatment in Alzheimer’s disease such as Donepezil are effective in preventing glutamate neurotoxicity. In primary cultures of the cortical neurons, Donepezil prevents glutamate neurotoxicity when the drug is applied 8–24 hr prior to glutamate exposure. Neuroprotective effect of Donepezil is antagonized by mecamylamine, dihydro-β-erythoridine and metyllcaconitine. Prolonged (more than 4 days) exposure of the cultures to Donepezil induces an increase in the nicotine-induced Ca2+ influx and number of neurons expressing α4 and α7 subunits of nicotinic receptors. Donepezil also prevents apoptotic neuronal death induced by glutamate. Inhibitors for non-receptor type tyrosine kinase, Fyn and janus-activated kinase 2, suppress the neuroprotective effect of Donepezil. Neuroprotective effect of Donepezil is also suppressed by a phosphatidylinositol 3-kinase (PI3K) inhibitor. Phosphorylation level of Akt, an effector of PI3K, and the expression level of Bcl-2 increase with Donepezil. These results suggest that Donepezil prevents glutamate neurotoxicity through α4- and α7-nicotinic acetylcholine receptors (nAChRs), followed by activation of PI3-Akt pathway but independent from activation of ion channels associated with nAChRs. α4- and α7-nAChRs may play an important role in promoting survival of cortical neurons under oxidative stress caused by excitotoxicity.

  • Up-regulation of nicotinic acetylcholine receptors by central-type acetylcholinesterase inhibitors in rat cortical neurons.
    European journal of pharmacology, 2005
    Co-Authors: Toshiaki Kume, Hiroshi Katsuki, Yuki Takada, Atsushi Yonezawa, Hachiro Sugimoto, Mitsuhiro Sugimoto, Toshiaki Yamaguchi, Akinori Akaike
    Abstract:

    We previously reported that Donepezil, a central-type acetylcholinesterase inhibitor, showed neuroprotective action via alpha4-and alpha7-nicotinic acetylcholine receptors against glutamate neurotoxicity in rat cortical culture. The present study was performed to investigate whether the neuroprotective action of acetylcholinesterase inhibitors is accompanied by the alteration of expression and function of nicotinic receptors. Four days treatment with acetylcholinesterase inhibitors (10 microM) enhanced the nicotine-induced increase of the intracellular calcium concentration. Immunoblot analysis revealed that Donepezil increased both alpha4 and alpha7 subunit proteins. Donepezil and galanthamine increased the number of cells expressing alpha4- and alpha7-nicotinic receptors in immunocytochemical analysis. We examined whether up-regulation of nicotinic receptors affected the neuroprotective action of acetylcholinesterase inhibitors. Under up-regulating conditions, Donepezil and galanthamine exerted neuroprotective action at lower concentrations. These results suggest that Donepezil and galanthamine up-regulate nicotinic receptors in cortical neurons, and that the up-regulation of nicotinic receptors may make cortical neurons more sensitive to the neuroprotective action of Donepezil and galanthamine.

  • nicotinic acetylcholine receptor mediated neuroprotection by Donepezil against glutamate neurotoxicity in rat cortical neurons
    Journal of Pharmacology and Experimental Therapeutics, 2003
    Co-Authors: Yuki Takada, Hiroshi Katsuki, Atsushi Yonezawa, Shuji Kaneko, Hachiro Sugimoto, Toshiaki Kume, Akinori Akaike
    Abstract:

    Donepezil is a potent and selective acetylcholinesterase (AChE) inhibitor developed for the treatment of Alzheimer9s disease. To elucidate whether Donepezil shows neuroprotective action in addition to amelioration of cognitive deficits, we examined the effects of Donepezil on glutamate-induced neurotoxicity using primary cultures of rat cortical neurons. A 10-min exposure of cultures to glutamate followed by a 1-h incubation with glutamate-free medium caused a marked loss of viability, as determined by Trypan blue exclusion. Glutamate neurotoxicity was prevented by 24-h pretreatment of Donepezil in a concentration-dependent manner. Among AChE inhibitors examined, Donepezil and certain AChE inhibitors such as tacrine and galanthamine showed potent neuroprotective action, although physostigmine did not affect glutamate neurotoxicity. Neuroprotective action of Donepezil was antagonized by mecamylamine, a nicotinic acetylcholine receptor (nAChR) antagonist, but not by scopolamine, a muscarinic acetylcholine receptor antagonist. Furthermore, both dihydro-β-erythroidine, an α4β2-neuronal nAChR antagonist, and methyllycaconitine, an α7-nAChR antagonist, each also significantly antagonized the effect of Donepezil. Next, we examined the effects of Donepezil on glutamate-induced apoptosis. Exposure of 100 μM glutamate to cortical neurons for 24 h induced apoptotic neuronal death and nuclear fragmentation. Donepezil for 24 h before and 24 h during glutamate exposure prevented nuclear fragmentation and glutamate-induced apoptosis. These results suggest that Donepezil not only protects cortical neurons against glutamate neurotoxicity via α4β2- and α7-nAChRs but also prevents apoptotic neuronal death.

Harriet M. Lamb - One of the best experts on this subject based on the ideXlab platform.

  • Donepezil
    Drugs & Aging, 2000
    Co-Authors: Mukta Dooley, Harriet M. Lamb
    Abstract:

    Donepezil (E-2020) is a reversible, noncompetitive, piperidine-type cholinesterase inhibitor. It is selective for acetylcholinesterase rather than butyrylcholinesterase. Donepezil 5 and 10 mg/day significantly improved cognition and global clinical function compared with placebo in well designed short term trials (14 to 30 weeks) in 161 to 818 patients with mild to moderate Alzheimer’s disease. Beneficial effects on cognition were observed from week 3 of treatment. Donepezil 10 mg/day significantly delayed the deterioration in activities of daily living (ADL) [by 55 weeks] compared with placebo in a retrospective analysis of 1 trial, and in the largest trial significantly improved patients’ abilities to perform complex tasks. However, no significant improvement in function was observed with Donepezil 5 mg/day in another trial. In the 2 trials of longest duration Donepezil (5 and 10mg) significantly delayed symptomatic progression of the disease. While there was no evidence for a positive effect of Donepezil on patients’ quality of life, there are no validated measures of this parameter specific to patients with Alzheimer’s disease. Donepezil (5 and 10mg) significantly reduced caregiver burden. Long term efficacy data suggest that improvements in cognition, global function or ADL are maintained for about 21 to 81 weeks with Donepezil (10 mg/day in most patients). Donepezil is generally well tolerated with the majority of adverse events being mild and transient. Predictably, most events were cholinergic in nature and generally related to the gastrointestinal and nervous systems. The incidence of these events was significantly higher with Donepezil 10mg than with placebo in short term clinical trials; however, this may have been due to the 7-day dose increase schedule used in these studies and can be minimised by increasing the dose after a longer (6-week) period. The incidence of serious adverse events was generally similar between Donepezil 5 and 10mg (4 to 10%) and placebo (5 to 9%) in short term trials. 26% of patients receiving Donepezil (5 and 10mg) reported serious events over a 98-week period in a long term trial. Importantly, there was no evidence of hepatotoxicity with this drug. Conclusions. Donepezil (5 and 10mg) is an agent with a simple once-daily dosage schedule which improves cognition and global clinical function in the short (up to 24 weeks) and long term (up to about 1 year) in patients with mild to moderate Alzheimer’s disease. Improvements in ADL were also observed with Donepezil 10 mg/day. Adverse events associated with Donepezil are mainly cho- linergic. Donepezil has been extensively studied and should be considered as a first-line treatment in patients with mild to moderate Alzheimer’s disease. Pharmacodynamic Properties Donepezil is defined as a mixed inhibitor of acetylcholinesterase exhibiting primarily noncompetitive, but also some competitive, inhibition of this enzyme. Donepezil inhibited acetylcholinesterase (from the electric eel and human erythrocyte) more potently than tacrine in in vitro studies. As with other cholinesterase inhibitors, Donepezil less potently inhibited acetylcholinesterase from senile plaques in the cortex of patients with moderate to severe Alzheimer’s disease than that from other fractions of diseased brain or from the cortex of individuals with no neurological disease in an in vitro study. Donepezil selectively inhibits acetylcholinesterase rather than butyrylcholin-esterase and was more selective for this enzyme than tacrine and physostigmine in in vitro and ex vivo (rat) studies. The ratio of the concentrations of Donepezil needed to produce a 50% inhibition (IC50) of human butyrylcholinesterase to the IC50 of acetylcholinesterase was 405: 1. Acetylcholinesterase in skeletal muscle (rodent) was inhibited to a greater extent by Donepezil than that from the brain (rodent) or erythrocytes (human). A similar effect was observed with tacrine, rivastigmine and physostigmine, although Donepezil inhibited all 3 isoenzymes more potently than these agents. However, in another study Donepezil more potently inhibited cholinesterase from rodent brain than that from the plasma, heart or pectoral muscle. In contrast, tacrine less potently inhibited brain cholinesterase than that in other tissues. The inhibitory effects of Donepezil on erythrocyte acetylcholinesterase appears to correspond closely to that in the rodent cortex. Donepezil dose-relatedly inhibits erythrocyte acetylcholinesterase, as shown in studies in patients with Alzheimer’s disease receiving dosages of 1 to 10 mg/day for 12 to 98 weeks. Mean percentage inhibition was 64% with Donepezil 5mg and 75 to 77% with Donepezil 10mg at 6 or 12 weeks. Donepezil significantly increased extracellular acetylcholine levels in rat hippocampus and cortex and was more potent than tacrine in producing this effect. Extracellular noradrenaline (norepinephrine) and dopamine, but not serotonin (5-hydroxytryptamine; 5-HT), levels in the cortex were increased by Donepezil in rats. Donepezil produced centrally-mediated cholinergic effects in rodent models. No peripherally-mediated effects were observed in 1 study but were apparent in another study. However, some peripheral effects were more prominent, and both types of effects persisted for longer, with tacrine. Induced deficits in working and reference memory and attention are significantly reversed by Donepezil, as shown in various animal models of cognitive impairment. Similarly, Donepezil attenuated naturally occurring memory deficits in young rats. In general, Donepezil is more potent than tacrine at enhancing cognition and attention according to animal studies. Pharmacokinetic Properties The maximum plasma concentration (C_max), area under the plasma concentration-time curve (AUC) and the mean Donepezil concentration at steady state are linearly proportional to dosage but clearance is independent of dose, as seen in single or multiple dose studies in volunteers. After single dose oral Donepezil (5 to 10mg) the C_max (7.2 to 25.6 μg/L) is achieved in 2.4 to 4.4 hours [time to C_max (t_max)], as seen in volunteers. The AUC ranges from about 500 to 1000 μg/L and the volume of distribution (Vd) from about 755 to 837L (or 14 L/kg with Donepezil 5mg). The absorption of Donepezil is not affected by the presence of food. Donepezil is highly protein bound (about 93 to 96%). After repeated administration (5 or 10 mg/day for 21 or 28 days), steady state is achieved within 14 to 22 days. Generally, t_max and Vd values are similar to those observed with single dose Donepezil, but C_max appears to be higher. Donepezil is largely metabolised by the cytochrome P450 isoenzymes 3A4 and 2D6, and undergoes extensive first-pass metabolism. The main metabolites are a hydrolysis product, 2 glucuronide conjugates and an oxidation product. Only 1 of these metabolites is active and has similar activity to that of the parent drug. Elimination of Donepezil and its metabolites is primarily via the renal route. After single doses of Donepezil 5 to 10mg, the elimination half-life (t½), renal clearance (CL_r) and total body clearance (CL) were independent of dose, as seen in volunteers. CL at steady state appears to be similar to values achieved after single doses but t½ appears to be longer than that observed with the corresponding single dose. In elderly patients receiving single doses of Donepezil 2mg, t_max, mean residence time and t½ were significantly longer and Vd was significantly greater than values in young volunteers. In general, impaired renal or hepatic function do not affect the pharmacokinetic parameters of Donepezil, as observed in single dose studies. C_max was significantly higher (37.5%) in patients with impaired hepatic function compared with healthy volunteers, although this was not considered to be clinically significant. Donepezil does not have clinically significant effects on the pharmacokinetic parameters of digoxin, theophylline, warfarin, ketoconazole or cimetidine. Further, neither ketoconazole nor cimetidine have clinically significant effects on Donepezil pharmacokinetics. Therapeutic Efficacy Donepezil 5 and 10 mg/day significantly improved cognition and global clinical function in trials of 14 to 30 weeks duration (including 2- to 6-week placebo-washout periods). In these trials in 161 to 818 patients with mild to moderate Alzheimer’s disease, the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog), Mini-Mental Status Examination (MMSE) and Clinician’s Interview-Based Impression of Change (CIBIC plus) scores significantly improved compared with placebo, and significantly fewer Donepezil recipients had treatment failure according to Clinical Global Impression of Change scores. Furthermore, clinically meaningful improvements were observed in more patients receiving Donepezil 5 and 10mg than placebo according to various parameters; a change of ≥4 points from baseline in ADAS-cog (about 38% with Donepezil 5mg and 54 or 60% with Donepezil 10mg vs 27 or 30% with placebo), no decline in ADAS-cog scores (about 80% with Donepezil 5 and 10mg vs 58% with placebo) and a score of ≤3 in CIBIC plus (21 to 32% with Donepezil 5mg and 25 to 38% with Donepezil 10mg vs 11 to 18% with placebo). Significant changes in cognition were observed from 3 weeks of the start of treatment. Donepezil 10 mg/day significantly improved patients’ abilities to perform complex tasks compared with placebo in the largest trial, and in a retrospective Kaplan-Meier analysis of another trial, Donepezil 10 mg/day delayed the loss of ADL by 55 weeks compared with placebo. Donepezil 5 mg/day did not significantly improve function according to the activities of daily living (ADL) scale in 1 trial. In the 2 trials of longest duration Clinical Dementia Rating Scale-Sums of Boxes (CDR-SB) scores significantly improved with Donepezil (5 and 10 mg/day) compared with placebo, thus suggesting that Donepezil slows symptomatic progression of the disease. Although, Donepezil 5 and 10 mg/day generally does not appear to improve patients’ quality of life, no quality-of-life assessment has been validated in this group of patients. Donepezil 5 and 10mg significantly reduced caregiver burden according to 2 preliminary study reports. When Donepezil treatment was stopped during a 2- to 6-week placebo-washout period, all efficacy parameters tended towards or were worse than (generally not statistically significant vs placebo) baseline values, thus indicating a deterioration in symptoms on drug withdrawal. However, a rebound effect on treatment withdrawal is not expected according to the manufacturers’ prescribing information. There was a significant correlation between plasma Donepezil concentrations, the level of erythrocyte acetylcholinesterase inhibition and changes in cognition or global function. In 2 nonblind, noncomparative long term extensions of short term trials in patients with mild to moderate Alzheimer’s disease, improvements in cognition and global clinical function were maintained until weeks 38 to 51 and 26 to 39, respectively, with Donepezil (generally 10 mg/day). After this time, ADAS-cog and CDR-SB scores deteriorated, representing disease progression, but Donepezil delayed the deterioration compared with that expected in untreated patients. In a preliminary report of another trial, cognition (assessed by ADAS-cog) was maintained for up to about 81 weeks with Donepezil 10 mg/day in patients showing a response to treatment. Similarly, compared with placebo, global clinical function and cognition significantly improved from weeks 24 to 52 and ADL improved at week 52 with Donepezil 10 mg/day in a preliminary report of the first long term double-blind, randomised long term (52 weeks) trial. In another 1-year double-blind, randomised trial Donepezil 10 mg/day significantly delayed the median time to clinically significant loss of function by about 21 weeks (5 months). Donepezil doses recommended in Japan are lower than those employed elsewhere. Two short term trials (8 or 12 weeks) and 1 long term study (24 to 48 weeks) conducted in Japan in 39 to 187 patients with mild to moderate Alzheimer’s disease receiving these lower doses (2 to 5 mg/day) generally did not support the findings of these previously mentioned studies. However, Donepezil 5 mg/day significantly improved ADAS-Jcog (Japanese version of ADAS-cog) and final global improvement rating (FGIR) scores in a short term trial when only patients with mild to moderate Alzheimer’s disease whose baseline ADAS-Jcog scores were ≥15 were assessed. Tolerability Donepezil is generally well tolerated. Most adverse events are mild, transient and cholinergic in nature. In short term trials (12 to 24 weeks’ treatment) in patients with mild to moderate Alzheimer’s disease, the overall incidence of adverse events appeared to be similar between Donepezil 5 mg/day (67 or 79%) and placebo (65 to 76%) but higher with Donepezil 10 mg/day (78 or 86%). Compared with withdrawal rates observed with placebo (1 to 10%), the incidence of treatment discontinuation appeared to be similar with Donepezil 5mg (4 to 9%) but higher with the 10mg dosage (9 to 18%). Individual adverse events occurring more frequently with Donepezil (5 and 10mg) than with placebo were generally related to the gastrointestinal system, but also included insomnia, fatigue and muscle cramps. In the largest trial gastrointestinal and nervous system adverse events were significantly more common with Donepezil (5 and 10mg) than with placebo. The high incidence of these events with Donepezil 10mg was probably due to the rapid increase (after 1 week) to this dose level, and can be reduced by increasing the dose over a 6-week period. After long term treatment (98 weeks) the overall cumulative incidence of adverse events with Donepezil (10 mg/day in most patients) was 83% and adverse events resulted in treatment discontinuation in 4% of patients in a sole trial. The most common events in this trial were agitation, dizziness, pain, urinary tract infection, diarrhoea, common cold, upper respiratory tract infection, headache, nausea, confusion, insomnia and accidents (incidence >5%). The incidence of serious adverse events was greater with Donepezil 10mg (10%) than with the 5mg dosage (5%) or placebo (6%) in 1 short term trial, but a similar incidence was observed between Donepezil (5 and 10mg) and placebo in other trials (4 vs 5% and 9 vs 9%). After long term use serious adverse events occurred in 26% of Donepezil recipients over a 98-week period, but most were considered not to be related to treatment. Serious events led to treatment discontinuation by 7% of patients in the long term trial. Heart rate decreased with Donepezil (5 and 10mg) but this was not considered clinically significant and the incidence of bradycardia with Donepezil did not differ significantly from that observed with placebo. No clinically significant changes to vital signs or haematological or biochemical parameters are observed with Donepezil and, importantly, hepatotoxicity has not occurred. Dosage and Administration Donepezil is indicated in patients with mild to moderate Alzheimer’s disease. In countries other than Japan it is recommended that treatment should be initiated with a 5mg dose administered orally at night, and should be given for 4 to 6 weeks before increasing the daily dose to 10mg. In Japan, treatment is initiated with a 3mg daily dosage which is increased to 5 mg/day after 1 to 2 weeks. Donepezil does not interfere with the metabolism of theophylline, warfarin, cimetidine or digoxin, and neither cimetidine nor digoxin affect the metabolism of Donepezil. Donepezil does not appear to interact with selective serotonin reuptake inhibitors, antipsychotics or anti-Parkinsonian treatment, as seen in long term studies. No significant interaction is observed between Donepezil and ketoconazole according to a short term trial in healthy volunteers. However, there is potential for pharmacodynamic interaction with anticholinergic drugs, succinylcholine and other neuromuscular blocking agents, and cholinergic agonists. Cholinesterase inhibitors may augment the actions of succinylcholine and other muscle relaxants, have vagotonic effects on heart rate and may have the potential to cause generalised seizures. Patients with a history of asthma or obstructive pulmonary disease should be prescribed these drugs with care, and those at risk of developing ulcers should be monitored while receiving these agents.

  • Donepezil: a review of its use in Alzheimer's disease.
    Drugs & aging, 2000
    Co-Authors: Mukta Dooley, Harriet M. Lamb
    Abstract:

    Donepezil (E-2020) is a reversible, noncompetitive, piperidine-type cholinesterase inhibitor. It is selective for acetylcholinesterase rather than butyrylcholinesterase. Donepezil 5 and 10 mg/day significantly improved cognition and global clinical function compared with placebo in well designed short term trials (14 to 30 weeks) in 161 to 818 patients with mild to moderate Alzheimer's disease. Beneficial effects on cognition were observed from week 3 of treatment. Donepezil 10 mg/day significantly delayed the deterioration in activities of daily living (ADL) [by 55 weeks] compared with placebo in a retrospective analysis of 1 trial, and in the largest trial significantly improved patients' abilities to perform complex tasks. However, no significant improvement in function was observed with Donepezil 5 mg/day in another trial. In the 2 trials of longest duration Donepezil (5 and 10 mg) significantly delayed symptomatic progression of the disease. While there was no evidence for a positive effect of Donepezil on patients' quality of life, there are no validated measures of this parameter specific to patients with Alzheimer's disease. Donepezil (5 and 10 mg) significantly reduced caregiver burden. Long term efficacy data suggest that improvements in cognition, global function or ADL are maintained for about 21 to 81 weeks with Donepezil (10 mg/day in most patients). Donepezil is generally well tolerated with the majority of adverse events being mild and transient. Predictably, most events were cholinergic in nature and generally related to the gastrointestinal and nervous systems. The incidence of these events was significantly higher with Donepezil 10 mg than with placebo in short term clinical trials; however, this may have been due to the 7-day dose increase schedule used in these studies and can be minimised by increasing the dose after a longer (6-week) period. The incidence of serious adverse events was generally similar between Donepezil 5 and 10 mg (4 to 10%) and placebo (5 to 9%) in short term trials. 26% of patients receiving Donepezil (5 and 10 mg) reported serious events over a 98-week period in a long term trial. Importantly, there was no evidence of hepatotoxicity with this drug. Conclusions. Donepezil (5 and 10 mg) is an agent with a simple once-daily dosage schedule which improves cognition and global clinical function in the short (up to 24 weeks) and long term (up to about 1 year) in patients with mild to moderate Alzheimer's disease. Improvements in ADL were also observed with Donepezil 10 mg/day. Adverse events associated with Donepezil are mainly cholinergic. Donepezil has been extensively studied and should be considered as a first-line treatment in patients with mild to moderate Alzheimer's disease.

Hachiro Sugimoto - One of the best experts on this subject based on the ideXlab platform.

  • Mechanisms of alpha7-nicotinic receptor up-regulation and sensitization to Donepezil induced by chronic Donepezil treatment.
    European journal of pharmacology, 2008
    Co-Authors: Yuki Takada-takatori, Hachiro Sugimoto, Toshiaki Kume, Yuta Ohgi, Tetsuhiro Niidome, Takeshi Fujii, Akinori Akaike
    Abstract:

    alpha7-nicotinic acetylcholine receptors are one of the most abundant subtypes of nicotinic receptors in the brain and have been shown to be involved in the neuroprotective effect of Donepezil. Recently, we showed that in primary culture of rat cortical neurons, chronic Donepezil treatment (10 muM, 4 days) (1) induces the up-regulation of alpha7-nicotinic receptors, (2) enhances the nicotine-induced increase in [Ca(2+)](i) and (3) enhances the sensitivity to the neuroprotective effect of Donepezil. Here we demonstrate the involvement of alpha7-nicotinic receptors in these three effects. Concomitant treatment with nicotinic receptor antagonist inhibited the up-regulation of alpha7-nicotinic receptor, enhancement of the increase in [Ca(2+)](i) induced by nicotine, and enhancement of sensitivity to the neuroprotective effect of Donepezil. Next, using inhibitors of phosphatidylinositol 3-kinase and mitogen-activated protein kinase signaling pathways, we demonstrate the involvement of these pathways in the up-regulation of alpha7-nicotinic receptors and in making the neurons more sensitive to the neuroprotective effects of Donepezil. Concomitant chronic Donepezil treatment with inhibitors of phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways inhibited nicotinic receptor up-regulation and enhancement of the response to nicotine, and enhanced the sensitivity to Donepezil. This study increases understanding of the less-studied mechanism of chronic Donepezil treatment-induced nicotinic receptor up-regulation and increased sensitivity to Donepezil.

  • Mechanism of neuroprotection by Donepezil pretreatment in rat cortical neurons chronically treated with Donepezil.
    Journal of neuroscience research, 2008
    Co-Authors: Yuki Takada-takatori, Hachiro Sugimoto, Toshiaki Kume, Yuta Ohgi, Tetsuhiro Niidome, Takeshi Fujii, Yasuhiko Izumi, Akinori Akaike
    Abstract:

    Previously, we showed that in rat cortical neurons, chronic Donepezil treatment (10 μM, 4 days) up-regulates nicotinic receptors (nAChR) and makes neurons more sensitive to the neuroprotective effect of Donepezil. Here we examined the mechanism of Donepezil-induced neuroprotection in neurons chronically treated with Donepezil. The mechanism of neuroprotection was examined under different conditions of exposure to glutamate, acute and moderate, that induce cell death associated with necrotic and apoptotic cell death, respectively. Concomitant treatment with antagonists of nAChRs but not muscarinic receptors inhibited Donepezil pretreatment-induced neuroprotection against acute glutamate treatment-induced death. Donepezil pretreatment prevented acute glutamate- and ionomycin-induced neurotoxicity, but not S-nitrosocysteine-induced neurotoxicity, suggesting that Donepezil protects neurons via nAChR at levels before nitric oxide synthase activation against acute glutamate neurotoxicity. Concomitant treatment with antagonists of nAChR or phosphatidylinositol 3-kinase (PI3K) signaling inhibitors significantly inhibited neuroprotection against moderate glutamate neurotoxicity and decreased the phosphorylation level of Akt. Neuroprotection was also inhibited by treatment with inhibitor of mitogen-activated protein kinase (MAPK) kinase. These results suggest that Donepezil protects neurons against moderate glutamate neurotoxicity via nAChR-PI3K-Akt and MAPK signaling pathways. This study provides novel insight into the mechanism of Donepezil-induced neuroprotection that involves nAChR up-regulation. © 2008 Wiley-Liss, Inc.

  • Up-regulation of nicotinic acetylcholine receptors by central-type acetylcholinesterase inhibitors in rat cortical neurons.
    European journal of pharmacology, 2005
    Co-Authors: Toshiaki Kume, Hiroshi Katsuki, Yuki Takada, Atsushi Yonezawa, Hachiro Sugimoto, Mitsuhiro Sugimoto, Toshiaki Yamaguchi, Akinori Akaike
    Abstract:

    We previously reported that Donepezil, a central-type acetylcholinesterase inhibitor, showed neuroprotective action via alpha4-and alpha7-nicotinic acetylcholine receptors against glutamate neurotoxicity in rat cortical culture. The present study was performed to investigate whether the neuroprotective action of acetylcholinesterase inhibitors is accompanied by the alteration of expression and function of nicotinic receptors. Four days treatment with acetylcholinesterase inhibitors (10 microM) enhanced the nicotine-induced increase of the intracellular calcium concentration. Immunoblot analysis revealed that Donepezil increased both alpha4 and alpha7 subunit proteins. Donepezil and galanthamine increased the number of cells expressing alpha4- and alpha7-nicotinic receptors in immunocytochemical analysis. We examined whether up-regulation of nicotinic receptors affected the neuroprotective action of acetylcholinesterase inhibitors. Under up-regulating conditions, Donepezil and galanthamine exerted neuroprotective action at lower concentrations. These results suggest that Donepezil and galanthamine up-regulate nicotinic receptors in cortical neurons, and that the up-regulation of nicotinic receptors may make cortical neurons more sensitive to the neuroprotective action of Donepezil and galanthamine.

  • nicotinic acetylcholine receptor mediated neuroprotection by Donepezil against glutamate neurotoxicity in rat cortical neurons
    Journal of Pharmacology and Experimental Therapeutics, 2003
    Co-Authors: Yuki Takada, Hiroshi Katsuki, Atsushi Yonezawa, Shuji Kaneko, Hachiro Sugimoto, Toshiaki Kume, Akinori Akaike
    Abstract:

    Donepezil is a potent and selective acetylcholinesterase (AChE) inhibitor developed for the treatment of Alzheimer9s disease. To elucidate whether Donepezil shows neuroprotective action in addition to amelioration of cognitive deficits, we examined the effects of Donepezil on glutamate-induced neurotoxicity using primary cultures of rat cortical neurons. A 10-min exposure of cultures to glutamate followed by a 1-h incubation with glutamate-free medium caused a marked loss of viability, as determined by Trypan blue exclusion. Glutamate neurotoxicity was prevented by 24-h pretreatment of Donepezil in a concentration-dependent manner. Among AChE inhibitors examined, Donepezil and certain AChE inhibitors such as tacrine and galanthamine showed potent neuroprotective action, although physostigmine did not affect glutamate neurotoxicity. Neuroprotective action of Donepezil was antagonized by mecamylamine, a nicotinic acetylcholine receptor (nAChR) antagonist, but not by scopolamine, a muscarinic acetylcholine receptor antagonist. Furthermore, both dihydro-β-erythroidine, an α4β2-neuronal nAChR antagonist, and methyllycaconitine, an α7-nAChR antagonist, each also significantly antagonized the effect of Donepezil. Next, we examined the effects of Donepezil on glutamate-induced apoptosis. Exposure of 100 μM glutamate to cortical neurons for 24 h induced apoptotic neuronal death and nuclear fragmentation. Donepezil for 24 h before and 24 h during glutamate exposure prevented nuclear fragmentation and glutamate-induced apoptosis. These results suggest that Donepezil not only protects cortical neurons against glutamate neurotoxicity via α4β2- and α7-nAChRs but also prevents apoptotic neuronal death.

  • Discovery and development of Donepezil hydrochloride for the treatment of Alzheimer's disease
    Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan, 1999
    Co-Authors: Hachiro Sugimoto, Yoshiharu Yamanishi, Hiroo Ogura, Youichi Iimura, Kiyomi Yamatsu
    Abstract:

    The most consistent change of neurotransmitter in the brain of Alzheimer's patients is the dramatic decrease of cholinergic innervation due to the loss of neurons in the basal forebrain. The most widely studied acetylcholinesterase inhibitors (AChEIs) have been physostigmine and tacrine. Physostigmine has very short duration, and tacrine has liability to hepatotoxicity. These are the defects of the inhibitors. Our objective was to find a new type of AChEIs that would overcome the disadvantages of physostigmine and tacrine. Through a random screening, we incidentally found an N-benzylpiperazine derivative which showed positive cholinergic behavior in rats. We replaced the N-benzylpiperazine moiety with N-benzylpiperidine moiety and found a dramatic increase in anti-AChE activity. Even after the replacement of an amide group with a ketone group the activity was held. Furthermore, the cyclic-amide derivative showed enhanced inhibitory activity. On the basis of these results, an indanone derivative was designed. Among these indanone derivatives, donepazil hydrochloride (E2020), brand name ARICEPT was found to be the most balanced compound. The clinical studies of Donepezil hydrochloride demonstrated statistically significant effects on ADAS-cog (Alzheimer's Disease Assessment Scale cognitive sub.) and CIBIC Plus (Clinician's Interview-Based Impression of Change plus).

Lawrence Tim Friedhoff - One of the best experts on this subject based on the ideXlab platform.

  • the efficacy and safety of Donepezil in patients with alzheimer s disease results of a us multicentre randomized double blind placebo controlled trial
    Dementia, 1996
    Co-Authors: Sharon L Rogers, Lawrence Tim Friedhoff
    Abstract:

    This study evaluated the efficacy and safety of Donepezil in patients with mild to moderately severe Alzheimer's disease, and examined the relationships between plasma Donepezil concentration, red blood cell acetylcholinesterase (AChE) activity and clinical response. The trial was of a multicenter, double-blind, parallel-group design and patients were randomised to once-daily treatment with either Donepezil (1, 3 or 5 mg) or placebo. The 12-week double-blind phase was followed by a 2-week single-blind placebo washout. 161 patients (55-85 years of age) entered the study and 141 completed treatment. Patients treated with Donepezil showed dose-related improvements in the Alzheimer's Disease Assessment Scale-cognitive subscale score (ADAS-cog) and in MMSF scores. The improvements in ADAS-cog were statistically significantly greater with Donepezil 5 mg/day than with placebo. There was a 50% reduction in the percentage of patients showing clinical decline with Donepezil at 5 mg/day (11%) relative to placebo (20%). In addition, a statistically significant correlation between plasma concentrations of Donepezil and AChE inhibition was demonstrated. A plateau of inhibition (76-84%) was reached at plasma Donepezil concentrations > 50 ng/ml. The correlation between plasma drug concentrations and ADAS-cog (p = 0.014), MMSE (p = 0.023) and patient quality of life scores, assessed by the patient (p = 0.037) were also statistically significant, as was the correlation between AChE inhibition and change in ADAS-cog (p = 0.008). The incidence of treatment-emergent adverse events with all three dosages of Donepezil (64-68%) was comparable to that observed with placebo (65%). Donepezil had no clinically significant effect on vital signs, haematology or clinical biochemistry tests. Importantly, Donepezil was not associated with any hepatotoxicity, as observed with acridine-based cholinesterase inhibitors.