Results suggests that donepezil may be effective in improving memory in adolescents with severe TBI and warrant further examination.
Production of new neurons in the subventricular zone (SVZ) continues into adulthood. Neuroblasts generated in the SVZ migrate in chains rostrally toward the olfactory bulb (OB), where they are differentiated into olfactory interneurons. In this paper, we will review our recent studies on production, migration and survival of newly-generated neurons in the adult mouse brain. Although the precise mechanisms controlling the migration of neuroblasts remain unclear, some molecules related to cell adhesion, cytoskeletal regulation or attractive/repulsive cues have been shown to be involved in this process. We have recently demonstrated that neuroblast migration parallels cerebrospinal fluid flow caused by integrated beating of ependymal cilia. While SVZ neuroblasts migrate only toward the OB under physiological conditions, we found that they could reach striatum in a mouse model of focal ischemia using blood vessels as their scaffold. The majority of the newly-generated neurons are known to die before they are integrated into neuronal circuits. However, we found that their survival could be promoted by the long-term administration of donepezil, an acetylcholinesterase inhibitor that is widely used for the treatment of Alzheimer's disease. Understanding more precise and comprehensive mechanisms of adult neurogenesis should lead to future development of regenerative therapies for neuropsychiatric diseases.
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Data were obtained from a total of 1022 patients and their caregivers, and showed a mean age of 78.4 ± 6.62 years, 62.61% being women, and mostly having a family caregiver. The switch to rivastigmine patches was mainly instigated on the initiative of the physician (82.39%) or on request of the caregiver (21.23%) or patient (10.37%). Reasons for the switch included improving ease of administration (56.65%), tolerability (36.79%), efficacy (31.60%), and adherence (18.59%). Prior treatment with oral rivastigmine versus donepezil or galantamine increased the probability of switching in order to improve ease of administration (odds ratio, oral rivastigmine versus donepezil 4.20, P < 0.0001; odds ratio, oral rivastigmine versus galantamine 3.55, P < 0.0001). Conversely, previous treatment with donepezil or galantamine produced an approximate four-fold increase in the odds of switching due to lack of efficacy. A higher level of education as well as more concomitant diseases increased the probability of switching because of intolerance.
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Compared with the model group, the 3rd - 5th day escape latency were all shortened in each medication group. The expressions of Bax, Abeta, and betaAPP decreased in the cortex and hippocampus. The numbers of platform crossing increased. The expression of Bcl-2 in the cortex increased. The expression of Bcl-2 in the hippocampus increased in the donepezil hydrochloride group and the QLR group with statistical difference (P<0.01, P<0.05). Compared with the donepezil hydrochloride group, the expression of betaAPP increased in the cortex and hippocampus of the saponin group. The expression of Abeta in the cortex and hippocampus decreased, the expression of Bax in the hippocampus decreased, and the expression of Bcl-2 in the cortex increased in the QLR group. The escape latency was obviously postponed at day 3 -5, the platform crossing times decreased, the expression of Bcl-2 in the cortex and hippocampus decreased in the saponin group, showing statistical difference (P<0.05, P<0.01).
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To evaluate the efficacy and safety of donepezil in patients with Alzheimer's disease (AD) who discontinue memantine due to a lack of efficacy or not being well tolerated.
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The aim of this article was to provide an overview of the ChE inhibitors widely used in AD, focusing on key pharmacologic differences among agents and how these may translate into important differences in safety, tolerability, and efficacy in clinical practice.
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Cistanche tubulosa (Schenk) R. Wight (CT) is commonly used to treat forgetfulness by traditional Chinese physicians. This study presents the ameliorating effects of CT extract which was quantified with three phenylpropanoid glycosides in Alzheimer's disease (AD)-like rat model.
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This study was designed to determine 1) whether repeated exposures to the acetylcholinesterase inhibitors (AChEIs) galantamine (GAL) or donepezil (DON) resulted in positive effects on nerve growth factor (NGF) and its receptors, cholinergic proteins, and cognitive function in the aged rat, and 2) whether GAL had any advantages over DON given its allosteric potentiating ligand (APL) activity at nicotinic acetylcholine receptors. Behavioral tests (i.e., water maze and light/dark box) were conducted in aged Fisher 344 rats during 15 days of repeated (subcutaneous) exposure to either GAL (3.0 or 6.0 mg/kg/day) or DON (0.375 or 0.75 mg/kg/day). Forty-eight hours after the last drug injection, cholinergic receptors were measured by [(125)I]-(+/-)-exo-2-(2-iodo-5-pyridyl)-7-azabicyclo[2.2.1]heptane ([(125)I]IPH; epibatidine analog), (125)I-alpha-bungarotoxin ((125)I-BTX), [(3)H]pirenzepine ([(3)H]PRZ), and [(3)H]-5,11-dihydro-11-[((2-(2-((dipropylamino)methyl)-1-piperidinyl)ethyl)amino)carbonyl]-6H-pyrido(2,3-b)(1,4)-benzodiazepin-6-one methanesulfonate ([(3)H]AFDX-384, or [(3)H]AFX) autoradiography. Immunochemical methods were used to measure NGF, high (TrkA and phospho-TrkA)- and low (p75 neurotrophin receptor)-affinity NGF receptors, choline acetyltransferase (ChAT), and the vesicular acetylcholine transporter (VAChT) in memory-related brain regions. Depending on dose, both GAL and DON enhanced spatial learning (without affecting anxiety levels) and increased [(125)I]IPH, [(3)H]PRZ, and [(3)H]AFX (but decreased (125)I-BTX) binding in some cortical and hippocampal brain regions. Neither AChEI was associated with marked changes in NGF, NGF receptors, or VAChT, although DON did moderately increase ChAT in the basal forebrain and hippocampus. The results suggest that repeated exposures to either GAL or DON results in positive (and sustained) behavioral and cholinergic effects in the aged mammalian brain but that the APL activity of GAL may not afford any advantage over acetylcholinesterase inhibition alone.
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64.7% remained on treatment beyond 6 months, 57.9% beyond 1 year and 12.5% beyond 4 years. 56% remained alive at 4 years - almost twice the number predicted. Mean MMSE score amongst patients in treatment did not deteriorate over 4 years. Survival, retention in treatment, maintenance/improvement of cognition was greater with high baseline MMSE. Non-cognitive symptoms, carer stress and weight change remained low throughout.
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We wanted to analyse the rapid neurobehavioural effects based on acetylcholinesterase inhibitors from Tephrosia purpurea in zebrafish.
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At 2 years, MMSE scores were significantly worse for patients receiving anticholinergic medications than for those not on anticholinergics.
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Centrally acting cholinesterase inhibitors (ChEIs) improve cognitive functions in Alzheimer's disease (AD) and other forms of dementia. Evaluation of treatment efficacy is based mainly on subjective assessment methods such as standardized neuropsychological tests. Therefore, an additional objective tool for the evaluation of drug response would be most helpful.Thirty-two patients suffering from dementia of several etiologies were treated with ChEIs (tacrine 19, donepezil 5, rivastigmine 8). Cognitive response was assessed pre ChEIs initiation (baseline) and after 26 weeks, as optimal tolerated doses were achieved and maintained (endpoint). Evaluation included repeated measurements of Mini Mental State Examination (MMSE), Alzheimer's disease assessment scale cognitive part (ADAS-cog) and P300. For statistical analysis we used ANOVA with repeated measures and Pearson correlation coefficient. Results demonstrated improvement of mean ADAS-cog by 2.0 points (from 29.4, n = 31 to 27.4, n = 29; p = 0.08) while MMSE remained almost unchanged (20.1, n = 29 to 19.8, n = 28). Mean P300 latency reduced significantly by 24 ms (from 383 +/- 7.9 msec, n = 32 to 359 +/- 7 msec, n = 32; p = 0.0001). However mean amplitudes did not change significantly from baseline to endpoint (13.5 +/- 6.2, n = 31 to 12.8 +/- 6.1, n = 31). Significant correlations were found between mean ADAS-cog and mean P300 latency at baseline and end-point (R = 0.485 p = 0.019, R = 0.626 p = 0.001 respectively, n = 23) and between mean MMSE and P300 latency at baseline and endpoint (R = -0.420 p = 0.046, R = -0.703 p < 0.001 respectively, n = 23). Our data suggests that P300 is a reliable instrument for assessment of cognitive response to ChEIs in demented patients.
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Alzheimer disease (AD) is a chronic neurodegenerative disease that is characterized by its gradual progression. At present, the cause and mechanism of AD are yet unclear, and there is no effective therapy for treating it. With development of global aging, the prevalence rate of AD is increasing. The life quality of elderly people is affected severely by AD that is ultimately life-threatening. Recently, study on treating AD with traditional Chinese medicine (TCM) has deepened.
A total of 101 individuals with MS who were enrolled in a clinical trial on cognition underwent a brief neuropsychological battery and completed questionnaires related to vocation, mood, fatigue, and personality. Neurological impairment was measured with the Expanded Disability Status Scale (EDSS).
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We searched the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 28th September, 2005. As the searches in MEDLINE, EMBASE, CINAHL and PsycINFO for the Specialized Register would not necessarily have picked up all delirium prevention trials, these databases were searched again on 28th October, 2005. We also examined reference lists of retrieved articles, reviews and books. Experts in this field were contacted and the Internet searched for further references and to locate unpublished trials.
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A randomized crossover design was performed in 20 healthy volunteers. In the two study periods, a single 5 mg dose of either capsule or tablet was administered to each volunteer. After spiked with the internal standard (phenoprolamine) and treated with saturated sodium bicarbonate, plasma was extracted with ethyl acetate and separated with a C18 reversed phase column. LC-ESIMS was used in the selected ion monitoring (SIM) mode with target ions at m/z 380 for donepezil and m/z 344 for phenoprolamine. The fragmentor voltage was 120 V. The main pharmacokinetic parameters of donepezil and the bioequivalence of its two preparations were calculated.
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Twenty-four patients were recruited. After a mean duration of 129 ± 37 days, 14 patients returned taking 5 mg (n=4) or 10 mg (n=10) donepezil per day. Twelve patients experienced decreases in their insulin-like growth factor-1 levels, one had no change, and one experienced an increase. Their mean insulin-like growth factor-1 level dropped by 13%, from 113 ± 31 ng/ml to 98 ± 28 ng/ml (p<0.001).
To compare directly, in the same patient cohort, the ease of use and tolerability of donepezil and galantamine in the treatment of Alzheimer's disease (AD), and investigate the effects of both treatments on cognition and activities of daily living (ADL).
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BPSD were measured at baseline and after 24 months in 113 mild/moderate AD patients, included in the double-blind randomized trial ASCOMALVA, by the Neuropsychiatric Inventory (NPI). Two matched groups were compared: group A treated with donepezil (10 mg/day) plus choline alphoscerate (1200 mg/day), and group B treated with donepezil (10 mg/day) plus placebo.
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Tolerance to the analgesic effect of opioids is a pharmacological phenomenon that occurs after their prolonged administration. It has been shown that morphine-induced tolerance is associated with apoptosis in the central nervous system and neuroprotective agents which prevented apoptosis signaling could attenuate tolerance to the analgesic effects. On the other hand donepezil, an acetylcholinesterase inhibitor, has been reported to have neuroprotective effects. Therefore in this study, the effect of systemic administration of donepezil on morphine-induced tolerance and apoptosis in the rat cerebral cortex and lumbar spinal cord was evaluated. Various groups of rats received morphine (ip) and different doses of donepezil (0, 0.5, 1, 1.5 mg/kg/day). Nociception was assessed using tail flick apparatus. Tail flick latency was recorded when the rat shook its tail. For apoptosis assay other groups of rats received the above treatment and apoptosis was evaluated by in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method.
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A new series of phthalimide derivatives (compounds 4a-4j) were synthesized via Gabriel protocol and subsequently amidation reaction was performed using various benzoic acid derivatives. Then, the corresponding anti-acetylcholinesterase activity of the prepared derivatives (4a-4j) was assessed by utilization of the Ellman's test and obtained results were compared to donepezil. Besides, docking study was also carried out to explore the likely in silico binding interactions.
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One-hundred forty patients with DLB, recruited from 48 specialty centers in Japan, were randomly assigned to receive placebo or 3, 5, or 10 mg of donepezil hydrochloride daily for 12 weeks (n = 35, 35, 33, and 37, respectively). Effects on cognitive function were assessed using the Mini-Mental State Examination (MMSE) and several domain-specific neuropsychological tests. Changes in behavior were evaluated using the Neuropsychiatric Inventory, caregiver burden using the Zarit Caregiver Burden Interview, and global function using the Clinician's Interview-Based Impression of Change-plus Caregiver Input (CIBIC-plus). Safety measures included the Unified Parkinson's Disease Rating Scale part III.
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The measured pharmacokinetic and pharmacodynamic parameters for both 5 and 10 mg day(-1) donepezil administered in the evening are in good agreement with previous results obtained with morning administration, indicating no time of dosing effect.
Our experimental structure of the E2020-TcAChE complex pinpoints specific interactions responsible for the high affinity and selectivity demonstrated previously. It shows that E2020 has a unique orientation along the active-site gorge, extending from the anionic subsite of the active site, at the bottom, to the peripheral anionic site, at the top, via aromatic stacking interactions with conserved aromatic acid residues. E2020 does not, however, interact directly with either the catalytic triad or the 'oxyanion hole', but only indirectly via solvent molecules.