Gene/Protein Disease Symptom Drug Enzyme Compound
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 31,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Donepezil is a specific and potent acetylcholinesterase inhibitor according to in vitro data. It displays primarily noncompetitive inhibitory activity. In vivo, donepezil inhibited acetylcholinesterase activity in human erythrocytes and increased extracellular acetylcholine levels in the cerebral cortex and hippocampus of the rat. Donepezil demonstrated efficacy in tests of reference memory in animals, but had less consistent activity in tests of working memory. Donepezil 5 or 10 mg/day was associated with significant improvements in cognitive function [assessed by the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog)] after 14 and 30 weeks and patient global function (Clinician's Interview-based Impression of Change incorporating caregiver input score) after 30 weeks, compared with placebo, in patients with mild to moderate Alzheimer's disease. After 2 years, donepezil 5 or 10 mg/day was associated with an ADAS-cog score approximately 4 points better than would be expected in untreated patients with mild to moderate Alzheimer's disease. The most common adverse events reported in association with donepezil 5 mg/day were gastrointestinal events (nausea/vomiting, diarrhoea, gastric upset and constipation) and dizziness. No hepatotoxicity was reported after 12 weeks' treatment.
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PMID:Donepezil. 910 96

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, and dosage and administration of donepezil are reviewed. Donepezil is a synthetic noncovalent reversible inhibitor of acetylcholinesterase (AChE) for the treatment of mild to moderate dementia associated with Alzheimer's disease. In contrast to tacrine hydrochloride, the only comparable agent currently approved by FDA, donepezil exhibits a relatively high degree of selectivity for neuronal AChE as opposed to butyrylcholinesterase. It has a half-life of 60 hours in young adults and 104 hours in elderly patients. In clinical trials, donepezil has been associated with significant improvements in Alzheimer's Disease Assessment Scale-cognitive subscale and Clinical Interview-Based Impression of Change scores. The most common adverse effects associated with donepezil are nausea, diarrhea, anorexia, and vomiting, which are most likely to occur during dose initiation or adjustment. Hepatotoxicity, a dose-limiting adverse effect that sometimes requires discontinuation of tacrine, has not been reported with donepezil. Donepezil does not appear to interact with theophylline, cimetidine, warfarin, or digoxin. Ketoconazole and quinidine inhibit the metabolism of donepezil in vitro, but there is a lack of clinical data showing that these drugs decrease the clearance of donepezil. The initial recommended dosage is 5 mg daily before bedtime, with a dosage increase to 10 mg after four to six weeks according to the patient's response and tolerance. Donepezil appears to be preferable to tacrine as the initial agent for patients with mild to moderate dementia associated with Alzheimer's disease.
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PMID:Donepezil: an anticholinesterase inhibitor for Alzheimer's disease. 942 50

Alzheimer's disease is characterized by degeneration of various structures in the brain, with development of amyloid plaques and neurofibrillary tangles. Deficiencies of acetylcholine and other neurotransmitters also occur. Pharmacologic treatment of the disease generally seeks to correct the histopathology, the biochemical derangements or their effects. The only drugs labeled to date for the treatment of cognitive symptoms in patients with Alzheimer's disease are two cholinesterase inhibitors that prevent the breakdown of acetylcholine in the synapse. Both medications are associated with modest improvements in cognitive function. However, all benefit is lost when these drugs are discontinued; the disease then progresses to the level seen in placebo-treated patients. Tacrine, the first cholinesterase inhibitor to be so labeled, must be taken four times daily and is associated with hepatic toxicity. Donepezil is taken once daily. Side effects of the cholinesterase inhibitors include nausea, vomiting and diarrhea, which tend to subside after the titration period. Other drugs that have shown some promise in the treatment of Alzheimer's disease are vitamin E, estrogen, selegiline and a mixture of ergoloid mesylates. Anti-inflammatory drugs and nicotine are also being studied for their effects as neuroprotectors or neurotransmitter enhancers. The caregivers of patients with Alzheimer's disease may see little effect from these or other investigational agents, but nursing home placement may be delayed.
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PMID:New drugs for Alzheimer's disease. 978 82

Cholinesterase inhibitors are currently the most established treatment strategy in Alzheimer's disease. The treatment effect appears mainly to be symptomatic. Effects on progression of the disease following long term treatment, and possible neuroprotective effects, have been investigated. Delay until nursing home placement has been reported. Three cholinesterase inhibitors, tacrine, donepezil and rivastigmine, are in clinical use. Other cholinesterase inhibitors, such as galantamine (galanthamine), metrifonate, physostigmine, eptastigmine, are currently under clinical evaluation. So far the efficacy appears to be comparable between the various cholinesterase inhibitors; treatment for up to 6 months has produced an improvement in Alzheimer's Disease Assessment Scale -- Cognitive Subscale score (ADAS-cog) of between 1.8 and 4.9 in patients with Alzheimer's disease. Tacrine, donepezil, galantamine and physostigmine are reversible inhibitors of acetylcholinesterase and butyrylcholinesterase, while metrifonate is considered to be an irreversible inhibitor and rivastigmine a pseudoirreversible inhibitor. Tacrine and physostigmine have lower bioavailability, 17 to 37% and 3 to 8%, respectively, than the other cholinesterase inhibitors such as rivastigmine, galantamine and donepezil (40 to 100%). The elimination half-life is considerably longer for donepezil (70 to 80h) in comparison to most of the other cholinesterase inhibitors (0.3 to 12h). Donepezil is therefore administered once daily in comparison to rivastigmine which is administered twice daily and tacrine which is administered 4 times daily. Simultaneous food intake lowers the plasma concentration of tacrine and reduces the adverse effects of rivastigmine. Drugs like theophylline and cimetidine have been reported to change the pharmacokinetics of tacrine and donepezil. In contrast, concomitant medication with various drugs with rivastigmine does not seem to cause any drug interactions in patients with Alzheimer's disease. Tacrine, donepezil and galantamine are metabolised via the cytochrome P450 (CYP) liver enzymes. Active metabolites are known for tacrine and galantamine. Rivastigmine is not metabolised via CYP enzymes, but via esterases and is excreted in the urine. Tacrine is associated with hepatotoxicity while other cholinesterase inhibitors seem devoid this adverse effect. Increased liver enzyme values have been observed in 49% of patients with Alzheimer's disease treated with tacrine. Rechallenge with tacrine reduces the incidence of elevated liver enzyme levels. Peripheral cholinergic adverse effects are common for the cholinesterase inhibitors, with an incidence ranging between 7 to 30%. For some cholinesterase inhibitors, such as rivastigmine, the cholinergic adverse effects such as nausea, vomiting, dizziness, diarrhoea and abdominal pain can be reduced by slowing the rate of dose titration.
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PMID:Cholinesterase inhibitors in the treatment of Alzheimer's disease: a comparison of tolerability and pharmacology. 988 90

Donepezil (donepezil hydrochloride, E-2020, Aricept, Eisai), launched in March 1997, was the first drug to be marketed for the symptomatic treatment of Alzheimer's disease (AD) in the UK. It had been launched a year earlier in the US where clinicians had already had experience of tacrine (THA). Donepezil is a piperidine based, potent, specific, non-competitive and reversible inhibitor of acetylcholinesterase (AChE). It is structurally dissimilar from other established cholinesterase inhibitors, namely THA (an acridine compound) and the carbamates, physostigmine and rivastigmine and has a pharmacokinetic and tolerability profile distinct from these agents. Experimentally, donepezil inhibits AChE activity in human erythrocytes and increases extracellular acetylcholine levels in the cerebral cortex and the hippocampus of the rat. Pharmacologically, donepezil has a half-life of approximately 70 h lending itself to once daily administration. The most common adverse events reported in clinical trials have been gastrointestinal, typically nausea, vomiting, diarrhoea and constipation. Headache, dizziness and sleep disturbance have also been reported; there has been no evidence of hepatotoxicity. Clinically a number of placebo-controlled trials have shown that donepezil 5 or 10 mg daily was associated with significant improvements in cognitive function, as assessed by the Alzheimer's disease Assessment Scale-cognitive subscale (ADAS cog) after 12 or 24 weeks treatment. Significant improvements in global function and activities of daily living have also been demonstrated after 24 weeks treatment compared with placebo in patients with mild to moderate AD. Donepezil was the first rational treatment available in the UK for this disabling condition and as such received considerable attention. Much of the original attention was negative, ostensibly based on the scientific view that there was not enough published evidence to justify widespread use, but this was driven by concerns about the potentially high drug costs if all patients with AD were eligible to receive it. Considerable data have now been produced from Phase II, III and post-marketing surveillance. This drug evaluation will review the basic pharmacology of donepezil and place it in context with the trial data and the author's clinical experience with the drug.
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PMID:The pharmacology of donepezil: a new treatment of Alzheimer's disease. 1124 55

Ideally, treatment for Alzheimer's disease (AD) should prevent or cure the disease. Unfortunately, these goals appear unobtainable in the foreseeable future. Nevertheless, symptomatic relief is a feasible treatment option for AD patients and is available currently in the form of cholinesterase inhibitors such as tacrine, donepezil, metrifonate and rivastigmine. Donepezil is a second-generation, piperidine-class, selective and reversible acetylcholinesterase inhibitor. Four double-blind, placebo-controlled clinical trials of donepezil, involving over 1900 individuals with mild to moderate AD, have been published recently. In all trials, significant improvements in cognition were observed consistently for both therapeutic doses of donepezil (5 and 10 mg/d), relative to placebo. Similar donepezil-associated benefits were reported for global functioning. In addition, in one 24-wk, multinational clinical trial, patients receiving donepezil (10 mg/d) performed better than placebo-treated patients in their ability to perform complex daily functioning tasks. Donepezil was well tolerated in all trials, with approx. 79% of all donepezil-treated patients completing the studies compared with approx. 84% of placebo-treated patients. The most common adverse events associated with donepezil were generally cholinergic-induced and gastrointestinal in nature (e.g. nausea, diarrhoea, and vomiting) which were generally mild, transient and tended to occur after the dose was increased to 10 mg/d from 5 mg/d after 1 wk only. Sleep disturbances also occurred as the clinical trials utilized a bedtime dosing regimen. There was no evidence of organ toxicity or clinically significant treatment-emergent laboratory test abnormalities. Thus, donepezil appears to be a beneficial symptomatic treatment for patients with mild to moderate AD.
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PMID:Management of cognition and function: new results from the clinical trials programme of Aricept(R) (donepezil HCl). 1134 20

The management of dementia patients encompasses pharmacologic, behavioral, and psychosocial intervention strategies. Before pharmacologic intervention is instituted, it is important that sources of excess disability and comorbidity be eliminated or reduced. Identification of comorbid medical and psychiatric conditions, such as depression and delirium, should be identified and appropriately treated. Providing caregivers with education, support, and practical advice is a critical component of the management of the demented patient. The current standard of care for pharmacologic management of the cognitive and functional disabilities of AD consists of the combination of a cholinesterase inhibitor and high-dose vitamin E. This standard is based on the results of large-scale, double-blind, placebo-controlled trials. Cholinesterase inhibitors are the only FDA-approved pharmacologic treatments for AD. Cholinesterase inhibitors have been shown to be effective in the treatment of the cognitive, behavioral, and functional deficits of AD. Large-scale placebo-controlled trials of tacrine, donepezil, rivastigmine, and galantamine have demonstrated moderate benefits in patients with mild to moderate AD. Donepezil, rivastigmine, and galantamine are the first-line choices in the treatment of AD because of their lack of hepatotoxicity, ease of administration, few significant drug-drug interactions, and mild to moderate side effects. There are few contraindications to the use of cholinesterase inhibitors. Known hypersensitivity to a specific drug or its derivatives is the only true contraindication. Cautious administration of cholinesterase inhibitors is advised in patients who have a previous history of allergy or adverse reactions to prior cholinesterase inhibitors, severe liver disease, preexisting bradycardia, peptic ulcer disease, current alcoholism, asthma, or chronic obstructive pulmonary disease. Nausea, vomiting, diarrhea, and anorexia are the most common side effects of cholinesterase inhibitors. These gastrointestinal side effects can be minimized by gradual dose increases, administration with food, adequate hydration, and judicious use of an antiemetic. Vitamin E has been demonstrated to slow the progression of AD in several small and one large placebo-controlled trials. Because of its low cost and safety, it is recommended in addition to a cholinesterase inhibitor for the treatment of AD. There are no FDA-approved treatments for DLB and VaD. One small placebo-controlled trial demonstrated that rivastigmine may be effective in the treatment of DLB. More large-scale placebo-controlled trials are needed to confirm the results of this study. Treatment of VaD focuses on the control, identification, and management of cerebrovascular disease and vascular risk factors. Although there are no peer-reviewed reports on the efficacy of cholinesterase inhibitors for VaD or mixed AD/VaD, early reports suggest that these agents may also be effective for mixed AD/VaD. The indications for the use of cholinesterase inhibitor drugs are eventually likely to broaden to include DLB, mixed AD/VaD, and AD in its more advanced stages.
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PMID:Pharmacologic treatments of dementia. 1217 Oct 61

The tolerability and safety of donepezil HCI in patients with mild to moderate Alzheimer's disease (AD) were examined in an integrated analysis of phase II/III placebo-controlled trials. Patients with mild to moderately severe AD (n=1,920) were randomised to receive donepezil (n=1,291) or placebo (n=629). Adverse events, physical examinations and clinical laboratory tests were assessed. A high completion rate (79%) was achieved in these trials. Of the 1,291 patients receiving donepezil only, 142 (11%) withdrew because of an adverse event compared with 43 of the 629 (7%) placebo patients. The most common adverse events included nausea, diarrhoea, headache, insomnia, dizziness, rhinitis, vomiting, asthenia/fatigue and anorexia. Donepezil had no clinically significant effect on any laboratory evaluations and was not associated with hepatotoxicity. These results demonstrate that donepezil is well tolerated and has a favourable safety profile at clinically effective, once-daily doses of 5 mg and 10 mg.
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PMID:Donepezil: tolerability and safety in Alzheimer's disease. 1246 88

Alzheimer's disease is characterized by the development of senile plaques and neurofibrillary tangles, which are associated with neuronal destruction, particularly in cholinergic neurons. Drugs that inhibit the degradation of acetylcholine within synapses are the mainstay of therapy. Donepezil, rivastigmine, and galantamine are safe but have potentially troublesome cholinergic side effects, including nausea, anorexia, diarrhea, vomiting, and weight loss. These adverse reactions are often self-limited and can be minimized by slow drug titration. Acetylcholinesterase inhibitors appear to be effective, but the magnitude of benefit may be greater in clinical trials than in practice. The drugs clearly improve cognition, but evidence is less robust for benefits in delaying nursing home placement and improving functional ability and behaviors. Benefit for vitamin E or selegiline has been suggested, but supporting evidence is not strong. Most guidelines for monitoring drug therapy in patients with Alzheimer's disease recommend periodic measurements of cognition and functional ability. The guidelines generally advise discontinuing therapy with acetylcholinesterase inhibitors when dementia becomes severe.
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PMID:Pharmacologic treatment of Alzheimer's disease: an update. 1456 91

Opioid-induced sedation is a major complication in patients with cancer pain. This study assessed the effectiveness of donepezil in opioid-induced sedation and related symptoms in patients with cancer pain. Twenty-seven patients who were receiving strong opioids for pain and reported sedation were enrolled. Donepezil 5 mg was given every morning for 7 days. Changes between baseline and Day 7 in sedation, pain, fatigue and other symptoms were evaluated using the Edmonton Symptom Assessment Scale. Fatigue was also measured using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue). Overall usefulness of donepezil was measured by the patient at the end of the study. In 20 evaluable patients, sedation, fatigue, anxiety, well-being, depression, anorexia and problems with sleep were significantly improved. Side effects included nausea, vomiting, diarrhea, muscle and abdominal cramps, and anorexia. Overall, however, the treatment was well tolerated. Donepezil appears to improve sedation and fatigue in patients receiving opioids for cancer pain. Randomized controlled trials of this agent are justified.
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PMID:The effect of donepezil on sedation and other symptoms in patients receiving opioids for cancer pain: a pilot study. 1458 55


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