Gene/Protein Disease Symptom Drug Enzyme Compound
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 23,468 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Metrifonate is a cholinesterase inhibitor with a long-lasting inhibition that raises brain acetylcholine levels. It is well-absorbed and has limited binding to serum proteins. In preliminary studies of its utility in the treatment of Alzheimer disease's (AD), it led to improvements of cognition or reduced the rate of decline of cognition compared with placebo. It also benefited the global function of these patients. Side effects include nausea, cramping, and diarrhea. Metrifonate has promise as a well-tolerated treatment of the symptoms of AD.
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PMID:Metrifonate: overview of safety and efficacy. 954 64

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

This paper investigates the acute effects of carbofuran in workers of two pesticide-formulating plants. Mean airborne carbofuran concentrations ranged from 0.025 to 1.115 mg/m3 in plant A and from 0.018 to 0.067 mg/m3 in plant B, respectively. In workers of plant A the post-shift blood cholinesterase activity was significantly reduced, compared to pre-shift values. No difference in blood cholinesterase activity was found between pre- and post-shift values in workers of plant B. During the investigation, 25 cases of acute carbofuran poisoning were diagnosed by their clinical picture and depressed cholinesterase activity in blood. Usual symptoms included dizziness, weakness, blurred vision, nausea and sweating. Pallor, epigastric pain, vomiting and chest tightness occurred only in a few cases. Myosis was recorded in 24 cases. Fasciculation of muscle gastrocnemius induced by percussion was found in 6 cases, and four of them had also fasciculation of muscle orbicularis oculi. Inhibition of cholinesterase activity in the blood was related with the clinical features; however, the inhibition was rapidly reversible. In most cases, recovery was complete within 2-3 hours, with or without atropine treatment, after the subjects were removed from exposure. Rapid onset, mild illness and quick recovery are typical characteristics of occupational acute carbofuran poisoning.
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PMID:Acute effects of carbofuran in workers of two pesticide plants. 1021 31

Alzheimer's disease is, in part, characterised by the loss of neurones in the basal forebrain cholinergic cells that project to the cerebral cortex and hippocampus. These impairments have correlated with the memory loss noted in dementia of the Alzheimer's type. This 'cholinergic hypothesis' has led to the rational design of drugs to enhance or stimulate acetylcholine-mediated neurotransmission. Early acetylcholinesterase inhibitors, such as tacrine and physostigmine, are poorly tolerated and have a short duration of action. Rivastigmine is a centrally-selective acetylcholinesterase inhibitor with a relatively long duration of action and is a 'pseudo-irreversible' cholinesterase inhibitor due to slow dissociation of a carbamoyl derivative from the esteratic site of acetylcholinesterase. Preclinical studies confirmed the central selectivity of the drug and its distribution into the cerebrospinal fluid (CSF). Early studies demonstrated that rivastigmine improved cognition and was relatively well-tolerated at moderate doses. Clinical investigations of rivastigmine administered at doses of 6 - 12 mg/day significantly improved cognition, as measured by the ADAS-Cog score, and activities of daily living, as measured by the Progressive Deterioration Scale. Significant global improvements were also noted as measured by the Clinician's Interview Based Impression of Change that required the use of caregiver information. The most frequent adverse effects noted in clinical trials were consistent with peripheral cholinergic stimulation and included nausea, vomiting, abdominal pain, dizziness and diarrhoea. These effects were dose-related and minimised by slow dose-escalation upon initiation of therapy. Rivastigmine undergoes minimal metabolism by the cytochrome P450 system. As a result, it has few drug interactions. The drug is currently marketed widely in over 60 countries worldwide. In the United States, the drug received 'approvable' status subsequent to the NDA filing, and should be available later this year.
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PMID:Rivastigmine, a brain-region selective acetylcholinesterase inhibitor for treating Alzheimer's disease: review and current status. 1113 19

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

According to the cholinergic hypothesis, the impairment of cognitive function and the behavioural disturbances that affect patients with Alzheimer's disease are mainly due to cortical deficiencies in cholinergic transmission. Numerous cholinesterase inhibitors have been investigated for treatment of this disease, the rationale being to support the cholinergic system by blocking the degradation of acetylcholine released from presynaptic neurons. These drugs can be classified as reversible (tacrine, donepezil and galantamine), pseudo-reversible (physostigmine, eptastigmine and rivastigmine) or irreversible (metrifonate) enzyme inhibitors. This article reviews efficacy and tolerability results from 6-month placebo-controlled studies of 7 cholinesterase inhibitors: tacrine (80 to 160 mg/day), donepezil (5 to 10 mg/day), rivastigmine (1 to 12 mg/day), metrifonate (30 to 80 mg/day), eptastigmine (30 to 60 mg/day), physostigmine (30 to 36 mg/day) and galantamine (8 to 32 mg/day). All these agents have demonstrated a statistically significant, although modest, effect versus placebo on the cognitive and global performance of patients with Alzheimer's disease. Dramatic clinical response has been seen in only 3 to 5% of patients. There are no major differences in terms of efficacy between the different drugs. The mean difference between drug and placebo effects on standardised psychometric scales is about 2 to 4 points on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog; a 70-point cognitive scale) and 0.2 to 0.5 points on the Clinician's Interview-Based Impression of Change with Caregiver Input (CIBIC-Plus; a 7-point global scale), or 5 to 14% of the average value of the scales. The most common adverse effects observed after administration of cholinesterase inhibitors are nausea, vomiting, diarrhoea, dizziness, asthenia and anorexia, all symptoms linked to cholinergic overstimulation. These effects are dose related and largely depend on the degree of cholinesterase inhibition. Also important is the rate of onset of cholinesterase inhibition, which depends on the kinetics of enzyme inhibition, the presence and rate of titration, and the pharmacodynamic peak-to-trough fluctuations. A model predicting the incidence of nausea based on acetylcholinesterase inhibition and the half-life of acetylcholinesterase recovery is proposed. In conclusion, cholinesterase inhibitors are the only pharmacological agents proved to be effective for the treatment of Alzheimer's disease in large, long term, double-blind, placebo-controlled trials. While the efficacy of different cholinesterase inhibitors is similar, their tolerability profiles differ. For example, the incidence of nausea (in excess of that seen with placebo) at cognitively effective dosages ranges from 1% with eptastigmine 60 mg/day to 53% with physostigmine 30 mg/day. Differences in tolerability profile may be due to the extent of peripheral acetylcholinesterase inhibition needed to reach clinical efficacy. Other contributing pharmacodynamic factors are the rate of onset of and fluctuations in acetylcholinesterase inhibition at steady state.
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PMID:Pharmacodynamic-tolerability relationships of cholinesterase inhibitors for Alzheimer's disease. 1147 43

(1) The reference symptomatic treatment for mild to moderate Alzheimer's disease is a cholinesterase inhibitor such as donepezil, but efficacy is only moderate and only about 10% of those patients treated actually benefit. (2) Galantamine is the fourth cholinesterase inhibitor to be marketed in France for Alzheimer's disease. The clinical file contains data from five double-blind placebo-controlled trials lasting 3-6 months, but no data comparing galantamine with other drugs. (3) These trials show that about 5-13% of patients treated with galantamine may be improved. (4) Adverse effects are very frequent, and are similar to those of other cholinesterase inhibitors, i.e. nausea, vomiting, diarrhoea, abdominal pain, dyspepsia, etc. (5) For patients who are eligible for drug therapy, the reference treatment is still donepezil, for want of anything better.
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PMID:Galantamine: new preparation. The fourth cholinesterase inhibitor for Alzheimer's disease. 1182 42


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