Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.8 (cholinesterase)
 12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Therapeutic strategies aimed to treat Alzheimer disease (AD) may either produce an attenuation of symptoms or slow down deterioration by attenuating progression of the disease. Presently, cholinesterase inhibitors (ChEI) have shown the most promising therapeutical effects. The best documented clinical efficacy of ChEI are studies of THA (tacrine, tetrahydroaminoacridine). The results of five recent studies in a total of 1,242 patients are reported here. Based on differences from placebo in scoring, a gain of 2-12 (MMSE) or 5-6 (ADAS) months in deterioration can be seen for a THA treatment of 2-3 months duration. This suggests that if treatment with THA will be extended to a longer period, the drug effect may not be only a symptomatic improvement but a slow-down of disease course. A similarity of THA's effect in AD with L-deprenyl effects in Parkinson is suggested.
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PMID:Therapy of Alzheimer disease: symptomatic or neuroprotective? 788 2

Therapeutic strategies aimed to treat Alzheimer's disease (AD) may either produce an attenuation of symptoms or slowdown deterioration by attenuating progression of the disease. Presently, cholinesterase inhibitors (ChEI) have shown the most promising therapeutic effects. The best documented clinical efficacy of ChEI are studies of THA (tacrine, tetrahydroaminoacridine). The results of five recent studies in a total of 1,242 patients are discussed. Based on differences from placebo in scoring, a gain of 2-12 (MMSE) or 5-6 (ADAS) in deterioration can be seen for a THA treatment of 2-3 mo duration. This suggests that if treatment with THA will be extended to a longer period, the drug effect may not be only a symptomatic improvement but also a slowdown of disease course. A similarity of THA's effect in AD with L-deprenyl effects in Parkinson's is suggested.
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PMID:Therapy for Alzheimer's disease. Symptomatic or neuroprotective? 788 87

The paper reviews the results obtained with velnacrine, a cholinesterase inhibitor and potential Alzheimer's disease agents, in early clinical studies in healthy volunteers and patients with probable Alzheimer's disease (AD). In healthy subjects, the compound was demonstrated to reverse cognitive impairment induced by scopolamine. Single doses of velnacrine improved performance of patients with AD in simple recognition tasks and enhanced regional cerebral blood flow in prefrontal-parietal areas. In a short crossover-study, velnacrine was demonstrated to be significantly (< 0.05) superior to placebo in the cognitive behaviour subscale of the ADAS, a word recognition task and, in trend, also on the Clinical Global Impression of Improvement.
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PMID:Pharmacodynamic and early clinical studies with velnacrine. 812 34

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.
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PMID:The efficacy and safety of donepezil in patients with Alzheimer's disease: results of a US Multicentre, Randomized, Double-Blind, Placebo-Controlled Trial. The Donepezil Study Group. 891 35

Donepezil HCI is a piperidine-based reversible acetylcholinesterase (AChE) inhibitor, chemically distinct from other cholinesterase (ChE) inhibitors and rationally designed to treat the symptoms of Alzheimer's disease (AD). It is highly selective for AChE in the central nervous system (CNS), with little or no affinity for butyrylcholinesterase (BuChE). In preclinical studies in animals, donepezil produced increased CNS acetylcholine. The resultant enhancement of cholinergic activity gave rise to improved performance by rats on tests of learning and memory, with no evidence of hepatic or renal toxicity. In subsequent phase I clinical evaluations in healthy volunteers, donepezil demonstrated favorable pharmacokinetic, pharmacodynamic and safety profiles. Its long terminal disposition half-life supported once-daily administration, with no requirement for dose modification in the elderly or in patients with renal or hepatic impairment. A 14-week, phase II dose-finding study in patients with mild to moderate AD (Clinical Dementia Rating [CDR], 1-2; Mini-Mental State Examination [MMSE], 10-26) showed that donepezil at a dose of 5 mg/day produced highly significant improvements in cognition (as measured by the Alzheimer's Disease Assessment Scale, cognitive subscale [ADAS-cog]). Subsequently, two pivotal parallel-group, placebo-controlled phase III trials (of 15 and 30 weeks' duration) showed highly statistically significant improvements in ADAS-cog, MMSE, Clinician's Interview-Based Impression of Change with caregiver input (CIBIC plus) and CDR-SB (Sum of the Boxes) scores, compared with placebo, in mild to moderate AD patients treated with either 5 or 10 mg/day donepezil. Adverse events in the phase II and III trials were mild and transient and resolved with continued donepezil administration. The donepezil clinical trials program has shown that this drug is a clinically effective and well-tolerated once-daily treatment for the symptoms of mild to moderate AD.
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PMID:Perspectives in the management of Alzheimer's disease: clinical profile of donepezil. 985

The effectiveness of long-term treatment of Alzheimer's disease with cholinesterase inhibitors is a matter of controversy. We evaluated the effects of prolonged treatment with eptastigmine in 176 patients with mild to moderate Alzheimer's disease participating in the open-label extension phase of a 25-week double-blind, placebo-controlled trial of eptastigmine. The effects of eptastigmine on cognition and daily functioning were evaluated with the cognitive portion of the Alzheimer's Disease Assessment Scale (ADAS-Cog) and the Instrumental Activities of Daily Living (IADL) scale, respectively. Safety was monitored by physical examination, laboratory tests, vital functions and electrocardiogram measurements and by the assessment of adverse events. One hundred and fifty-three patients (87%) completed 1 year of treatment, 77 patients (44%) 18 months and 33 patients (19%) 2 years of treatment. Patients treated for 2 years showed an improvement of mean ADAS-Cog scores compared to baseline for 31 weeks and mean IADL scores remained close to baseline for 25 weeks. Cognitive and functional scores then worsened as expected in this progressive disease. After 2 years, patients deteriorated compared to baseline by 13.4 points on the ADAS-Cog and 6.1 points on IADL. Historical untreated controls with identical disease severity are expected to have an annual worsening of approximately 10.9 points on ADAS-Cog and 4.9 points on IADL. Thus patients treated with eptastigmine for 2 years had a benefit of 8.5 points on ADAS-Cog and 3.8 points on IADL. These benefits translate to about 9 months difference between eptastigmine-treated patients and untreated historical patients. The drug was generally well tolerated with 14 patients (7.9%) withdrawing due to adverse events. Adverse events, not necessarily drug-related, were recorded in 66 patients (37.5%) and were transient and generally mild in severity. This study indicates that prolonged treatment with eptastigmine is safe and produced a clinically long-term benefit in patients with Alzheimer's disease.
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PMID:Two-year treatment of Alzheimer's disease with eptastigmine. The Eptastigmine Study Group. 1002 88

The efficacy of four cholinesterase inhibitors (tacrine, donepezil, rivastigmine, metrifonate) and Ginkgo special extract EGb 761 in Alzheimer's disease were compared. The differences in the effects of the active substance and placebo on cognition were measured on the ADAS-Cog scale, taking into account the different degrees of dementia in the various studies and the dropout rate due to adverse drug reactions. Efficacy, expressed as the delay in symptom progression or the difference in response rate between active substance and placebo, showed no major differences between the four cholinesterase inhibitors and the Ginkgo special extract. Only tacrine exhibited a high dropout rate due to adverse drug reactions. In view of this, the subject of new prescriptions should be critically reviewed. Second-generation cholinesterase inhibitors (donepezil, rivastigmine, metrifonate) and Ginkgo special extract EGb 761 should be considered equally effective in the treatment of mild to moderate Alzheimer's dementia.
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PMID:Cholinesterase inhibitors and Gingko extracts--are they comparable in the treatment of dementia? Comparison of published placebo-controlled efficacy studies of at least six months' duration. 1075 47

We evaluated the efficacy and safety of the centrally acting cholinesterase inhibitor, rivastigmine tartrate, for patients with mild to moderately severe Alzheimer's disease (AD) with or without concurrent vascular risk factors (VRF). Patients (45-90 years of age) were randomized to placebo (n = 235), low-dose rivastigmine (1-4 mg/day, n = 233), or high-dose rivastigmine (6-12 mg/day, n = 231) for 26 weeks. Efficacy measures included the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), the Clinician's Interview Based Impression of Change (CIBIC-Plus), the Progressive Deterioration Scale (PDS), the Global Deterioration Scale (GDS), and the Mini-Mental State Examination (MMSE). For efficacy and safety analysis, patients were categorized by baseline Modified Hachinski Ischemic Score (MHIS) for the determination of VRF (MHIS > 0: presence of VRF; MHIS = 0: absence of VRF). As early as 12 weeks, the mean change from the baseline ADAS-Cog score was significantly different for those patients treated with high-dose rivastigmine compared with placebo controls in both MHIS categories. However, the treatment difference between high-dose rivastigmine and placebo at each time-point was larger for patients with MHIS > 0. The proportion of responders was significantly greater in the high-dose rivastigmine group for each level of improvement. No differences were noted between treatment groups regarding safety evaluations. Rivastigmine is effective in both categories of patients, and those with VRF experience greater clinical benefit (cognition, activities of daily living, and disease severity).
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PMID:An efficacy and safety analysis of Exelon in Alzheimer's disease patients with concurrent vascular risk factors. 1080 36

This retrospective analysis assessed the efficacy of metrifonate in the treatment of mild to moderate Alzheimer's disease (AD). Those four studies meeting Food and Drug Administration guidelines for establishing the efficacy of an AD therapeutic agent were pooled for further analysis. Data were included from all patients valid for the intent-to-treat analyses (last observation carried forward). Patients received once daily placebo (n = 550), metrifonate 30-60 mg (by weight, n = 769) or 60/80 mg (by weight, n = 197). Metrifonate 60/80 mg significantly improved the cognitive abilities [AD Assessment Scale - Cognitive Subscale (ADAS-Cog), p = 0.0001; Mini Mental State Examination (MMSE), p = 0.0001], psychiatric and behavioral disturbances (Neuropsychiatric Inventory, p = 0.039; ADAS - Noncognitive Subscale, p = 0.0001), performance of instrumental and basic activities of daily living (Disability Assessment for Dementia, p = 0.0002) and global status (Clinician's Interview-Based Impression of Change with Caregiver Input, p = 0.0001) of AD patients when compared with placebo. Metrifonate effects across these domains were dose related. Metrifonate 60/80 mg significantly improved the cognitive performance relative to both placebo and to baseline as evaluated by both the ADAS-Cog and the MMSE. Metrifonate is the first cholinesterase inhibitor consistently shown under prospective, placebo-controlled conditions to improve significantly behavior in addition to cognition, function in activities of daily living and global functional status of patients with mild to moderate AD.
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PMID:Metrifonate therapy in Alzheimer's disease: a pooled analysis of four randomized, double-blind, placebo-controlled trials. 1086 46

Memory assessment in pharmaceutical trials has to date been mainly performed in Alzheimer's disease. North American and European Medical Evaluating Agencies recommend guidelines. Tests need to be simple and short, and sensitive enough to assess changes over a wide range of severity to avoid floor or ceiling effect. They require inter-rater reliability and face validity. They should be at least appropriate for different languages and culture, correlate well with universally accepted estimates of a function and have several parallel forms available to avoid a training effect. Memory is assessed with sub-tests of composite scales assessing a number of cognitive functions including episodic memory. The ADAS-Cog has become the standard instrument since it was used for the approval of tacrine and other cholinesterase inhibitors. Some studies have assessed more specifically different sub-systems of memory. However, autobiographical, remote or prospective memory, as well as metamemory, has not been explored in pharmaceutical trials.
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PMID:[Memory: therapeutic approach. Clinical evaluation]. 1109 29


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