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Results of this small open study suggest that donepezil augmentation of stimulants is not well tolerated and does not appear useful for the treatment of residual ADHD and/or EF deficits.
Although several case reports suggested that donepezil hydrochloride can induce bradycardia or atrioventricular block, the details remain unclear. We implemented a study of the impact of donepezil hydrochloride administration on PR, RR, and QT intervals.
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Acute gastrointestinal events (mostly manifested by nausea, vomiting, or loss of appetite) are class effects of all cholinesterase inhibitors, which are prescribed for the treatment of Alzheimer's disease. The underlying mechanism, however, has been unclear. Because corticotropin-releasing hormone is related to appetite control, we focused on the activation of the hypothalamo-pituitary-adrenal system and food intake following the administration of the cholinesterase inhibitor, donepezil, in rats. We monitored the plasma concentrations of adrenocorticotropic hormone, c-Fos, in the paraventricular nucleus, and intakes of rat chow for 3 h after the first administration of donepezil, and 2 weeks later, after daily administration of donepezil. The intragastric administration of 3 mg/kg of donepezil significantly increased the plasma adrenocorticotropic hormone levels and c-Fos expression in the paraventricular nucleus, and decreased the food intake on the first day. The increase in adrenocorticotropic hormone and loss of appetite after oral administration of the drug were attenuated after daily administration for 2 weeks.
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Previous publications have shown beneficial effects of cholinergic medication on obstructive sleep apnea (OSA) in Alzheimer's disease (AD) patients. We hypothesized that cholinergic medication could also improve OSA in non-AD patients. The present study evaluated the effects of donepezil on OSA in non-AD patients.
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Acetylcholinesterase inhibitor drugs. The approach to the treatment of Alzheimer's dementia has been greatly modified by the acetylcholinesterase inhibitor drugs, first donepezil (Aricept) and then rivastigmine (Exelon) and galantamine (Reminyl), and the ever-increasing number of demented people forces us to be familiar with their use. All three drugs practically share the same contraindications. Their side effects are directly related to the increased amount of acetylcholine in the synaptic cleft, they are mainly gastrointestinal in nature, and tend to decrease over time with continued use of the drug. All three medications slightly enhance cognitive performance in most patients, but it is mainly their effect on improving the patients' ability to perform activities of daily living that is remarkable. They are proven to help to delay placement in nursing home, and improve the quality of life for patients and their families. Those drugs nevertheless remain a purely symptomatic treatment, and do not seem to modify the course of the disease.
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All patients were examined annually with standard neuropsychologic tests and received the cholinesterase inhibitor donepezil hydrochloride at a dose of 10 mg/day. The study population (N=69) was divided into two groups: those receiving one or more concomitant medications with significant anticholinergic properties (N=16) and those receiving no concomitant medications with anticholinergic properties (N=53).
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Cholinesterase inhibitors have beneficial effects on the cognitive, functional, and behavioural symptoms of Alzheimers disease (AD). Up to date, they represent almost the only drugs approved by the U.S. Food and Drug Administration agency for AD treatment. The group involves donepezil, rivastigmine and galantamine. Apart from the above mentioned cholinesterase inhibitors, memantine is used for AD treatment as well acting as Nmethyl-D-aspartate (NMDA) non-competitive antagonist. Tacrine (9-amino-1,2,3,4-tetrahydroacridine) was the first cholinesterase inhibitor approved for symptomatic AD treatment. However, its several side effects (hepatotoxicity and gastrointestinal discomfort) limited tacrine further use. Recently, novel tacrine analogues are extensively investigated in endeavour to find less toxic compounds with the "multi-target directed ligand" profile affecting more AD pathological mechanisms. The following study summarizes the knowledge of up to date published tacrine analogues, their structural aspects and biological properties. According to structural aspects, tacrine derivatives are divided into three groups, where they are discussed.
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To evaluate the cost-effectiveness of functional neuroimaging in the work-up of patients at specialized Alzheimer disease clinics.
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The authors tested the hypothesis that behavioral disturbances are reported at significantly lower rates by caregivers of Alzheimer's disease (AD) patients receiving the antidementia drug donepezil, compared with a group of patients receiving no antidementia drug treatment. Patients administered donepezilfor 6 months (n=84) were compared with patients not on donepezil (n=248). Patients taking donepezil had significantly lower levels of behavioral disturbances than patients not receiving this agent (P< or =0.011). Specifically, donepezil patients were described as significantly (P< or =0.05) less likely to be threatening, destroy property, and talk loudly. Also, significantly fewer patients receiving donepezil were treated with sedatives (P< or =0.005). These findings support the growing body of evidence that cholinesterase inhibitors have psychotropic properties and reduce behavioral disturbances in patients with AD.
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Prevalence of treatment by ChIs among subjects with dementia remains weak and varies greatly across Europe. Differences in reimbursement rates and health policies could partly explain these variations, as ChIs could have failed to convince health authorities because the outcomes considered for trials are not used by clinicians in their everyday practice. If donepezil was highly predominant across countries, variations in rivastigmine and galantamine importance could reflect local market specificities.
The study supports the possibility that ST101, in patients receiving a stable dose of donepezil, may provide additional symptomatic benefit in moderate AD.
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Intracerebroventricular (ICV) injection of streptozotocin (STZ) causes cognitive impairment in rats. ICV STZ is known to impair cholinergic neurotransmission by decreasing choline acetyltransferase (ChAT) levels, glucose and energy metabolism in brain and synthesis of acetyl CoA. However, no reports are available regarding the cholinesterase inhibitors in this model. In aging brain, reduced energy metabolism increases glutamate release, which is blocked by L-type calcium channel blockers. These calcium channel blockers have shown beneficial effects on learning and memory in various models of cognitive impairment. The present study was designed to investigate the influence of chronic administration of donepezil (cholinesterase inhibitor, 1 and 3 mg/kg) and lercanidipine (L-type calcium channel blocker, 0.3 and 1 mg/kg) on cognitive impairment in male Sprague-Dawley rats injected twice with ICV STZ (3 mg/kg) bilaterally on days 1 and 3. ICV STZ injected rats developed a severe deficit in learning and memory indicated by deficits in passive avoidance paradigm and elevated plus maze as compared to control rats. Cholinesterase activity in brain was significantly increased in ICV STZ injected rats. Donepezil dose-dependently inhibited cholinesterase activity and improved performance in memory tests at both the doses. Lercanidipine (0.3 mg/kg) showed significant improvement in memory. When administered together, the effect of combination of these two drugs on memory and cholinesterase activity was higher than that obtained with either of the drugs when used alone.
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We studied 12 patients with mild AD (mean [SEM] Mini-Mental State Examination score, 24.0 [0.7]; mean Clinical Dementia Rating score, 1.0) who had been taking donepezil hydrochloride for more than 6 months from the placebo arm of a larger 24-week study (n = 24, 4 scans on weeks 0, 6, 12, and 24, respectively).
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Twenty-five participants with mild to moderate AD, planned for donepezil treatment, were recruited from mental health services for older adults in this open-labeled study. Assessments before commencing donepezil included Mini-Mental State Examination, Neuropsychiatric Inventory, Bristol Activities of Daily Living, and the University of Pennsylvania Smell Identification Test. After 3 months of treatment, the primary outcome measure, the Clinician Interview Based Impression of Change plus caregiver input (CIBIC-plus), was completed, and the baseline assessments were repeated.
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Eleven women and 11 men (mean +/- SD age = 45.4+/-8.5 years) completed donepezil trials. Nineteen patients with memory loss rated improvement while taking 5 mg/day of donepezil (p<.001); subsequently, 6 rated further improvement with 10 mg/day (p = .057). Donepezil, 5 mg/day, also reduced ratings of dry mouth (N = 16; p<.001) and constipation (N = 11; p<.05). Side effects included insomnia, nausea, vomiting, and diarrhea; surprisingly, 2 bipolar patients became manic within hours of starting donepezil. Sixteen patients (72%) continued donepezil for an average of 7 months. Consideration of family histories suggested that donepezil response in affective illness may be an early indicator of vulnerability to dementia of the Alzheimer's type.
These preliminary results suggest that donepezil may have a potentially protective effect in Alzheimer's disease. Larger, longer-term confirmatory studies of the medication's effects are warranted.
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Anticholinesterases (antiChEs) are used to treat Alzheimer's disease. The comparative effects of two antiChEs, methanesulfonyl fluoride (MSF) and donepezil, on the extracellular levels of ACh in the hippocampus were investigated by in vivo microdialysis in freely moving rats. MSF at 1 and 2 mg/kg produced a dose-dependent increase in ACh efflux from 10 min to at least 3 hrs after injection. At 2 mg/kg, the increase was still present at 24 hr. Donepezil at 1 mg/kg showed a similar but smaller effect, and, paradoxically, 2 mg/kg showed no consistent effect. MSF at 1 and 2 mg/kg decreased acetylcholinesterase activity in the hippocampus to 54.8 and 20.1% of control, respectively. These results suggest that MSF is a suitable candidate for the treatment of Alzheimer's disease.
In an effort to limit the cost of medications being used for Alzheimer's disease, the Bedford VA Hospital began an initiative to transition patients to the generic sustained-release galantamine SA. A chart review was performed using the VA computerized patient record for all patients transitioned from either donepezil or rivastigmine to galantamine. Progress notes were reviewed for the first three months following initial medication exchange to determine galantamine tolerability and reasons for discontinuation.
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2012 brought additional evidence regarding the benefits of exercise in older persons in showing morbidity compression in those most active. Several studies invite to revise therapeutic targets in older diabetics, especially those with cognitive impairment or dementia where a value of 8 to 9% for HbAlc might be a good compromise. On the dementia side, a study suggests that biological and structural abnormalities associated with Alzheimer's disease might occur as early as 25 years before its first clinical manifestations. On the therapeutic side, ginkgo and the double therapy with memantine and donepezil did not make it in RCTs, and two studies about treatments for behavioral symptoms of dementia showed that interruption could be deleterious.
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14.5% of the patients showed intolerance to the treatment with ChEIs during the first 15 days. Of those patients who initially tolerated the treatment, 18.5% gave it up after a mean duration of 13.36 months and a mean dose of 7.5 mg/day of donepezil or 14.3 mg/day of galantamine. The mean duration of the treatment in patients who did not abandon the treatment was 25.4 months and the mean dose was 8.1 mg/day of donepezil or 20.0 mg/day of galantamine. There were no differences in the mortality rate between patients treated with donepezil or galantamine (13.7 versus 12.2; P = 0.75). The multivariate analysis through binary logistic regression showed that the variables associated with mortality were male gender, older age, heart failure, treatment with antipsychotic drugs and a high score on the Global Deterioration Scale.