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

Activity of the enzyme which synthesizes acetylcholine, choline acetyltransferase, was estimated in the neocortex of three series of control and demented cases. Clinically demented cases were divided into those with the classical neuropathological features of Alzheimer's disease (numerous neocortical plaques and tangles) and those with Lewy bodies in the brain stem and cortex (together with plaques and variable neurofibrillary pathology). In the Lewy body cases neocortical choline acetyltransferase was consistently lower than in the classical Alzheimer-type cases. Two of the Lewy body cases with extremely low cholinergic activity were responders in therapeutic trials of the cholinesterase inhibitor, tacrine, and the combined data suggest that cholinergic therapy may be particularly relevant to patients with Lewy body type dementia.
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PMID:Neocortical cholinergic activities differentiate Lewy body dementia from classical Alzheimer's disease. 801 43

This article has discussed various possible pharmacologic approaches to Alzheimer's disease. Despite generally encouraging results, no agent to date has proved to be dramatically effective. At present, treatment options are limited for the clinicians. Tacrine is available on the market. In the doses recommended, efficacy is modest, and side effects require vigilance in monitoring. Other cholinesterase inhibitors may be approved for clinical use in the near future but are likely to have similar modest clinical effects. L-deprenyl is marketed for Parkinson's disease but has not been adequately tested for efficacy in Alzheimer's disease. Newer drugs in earlier stages of development are generally intended to affect cholinergic systems in various other ways. The effects of these drugs on behavioral symptoms, in severe dementia, and in non-Alzheimer's dementia have not been adequately assessed. In the absence of known cause, and in the face of uncertainty regarding pathophysiology, efforts in the near future will focus on encouraging theoretical leads, sensible empiric trials, and symptomatic treatment research. Although public anticipation will be raised over each announced "breakthrough," only results from carefully conducted trials should be accepted.
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PMID:Emerging drugs for Alzheimer's disease. Mechanisms of action and prospects for cognitive enhancing medications. 802 37

Tacrine, a centrally acting cholinesterase inhibitor, may improve cognitive and functional status in patients with mild to moderate Alzheimer's disease. In recent controlled trials, patients have shown improvement in cognitive assessment scores, but the clinical significance of such benefits remains unclear. Appropriate diagnostic evaluation is necessary to prevent inappropriate treatment in patients with non-Alzheimer's dementia. Hepatotoxicity and gastrointestinal symptoms are common adverse effects of tacrine, and frequent monitoring of liver function is required.
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PMID:Tacrine therapy for the dementia of Alzheimer's disease. 807 12

The pharmacokinetic of some centrally acting cholinesterase inhibitors that have been used to improve memory in patients with dementia of Alzheimer's type, was compared. The original compound in this class, physostigmine has an elimination half-life of 20-30 min. Galanthamine, tacrine and the metabolite 1-hydroxytacrine (velnacrine) have longer elimination half-lives of 1.6-6 hours mainly due to a larger volume of distribution. The concentration of tacrine in the cerebrospinal fluid (CSF) was less than the average plasma concentration in the dosing interval; a ratio of 0.74. The concentration of 1-hydroxytacrine and other metabolites of tacrine in the CSF were higher than the average concentrations of the compounds in plasma.
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PMID:Pharmacokinetic studies of cholinesterase inhibitors. 812 33

After reviewing the evidence for cholinergic pathology in Alzheimer's disease and related disorders, this paper reviews strategies for treating dementia using cholinomimetic drugs. Special attention is paid to cholinesterase inhibitors, particularly tacrine, the drug recently approved by the FDA. New studies suggesting that muscarinic and nicotinic cholinergic receptor active drugs may be more effective will be reviewed. Brief mention will be made of strategies to slow the progression of Alzheimer's disease.
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PMID:Cholinergic therapy in dementia. 812 38

Among various attempts to enhance cholinergic neurotransmission in AD clinical trials with cholinesterase inhibitors have been most promising. In this study positron emission tomography (PET) was used to investigate how long-term treatment with cholinesterase inhibitors like tacrine could induce changes in the functional activity of Alzheimer brains. PET investigations measuring cerebral blood flow, glucose metabolism, nicotinic and muscarinic receptors have repeatedly been performed in patients treated with tacrine up to 2.5 years. Changes in nicotinic receptors and blood flow were observed after 3 weeks of treatment while changes in glucose metabolism were measured after 3 months of treatment. Following longer period of treatments and increase in dose of tacrine improvements were measured by PET. The most significant effects were found in patients with early forms of the dementia. The findings suggest that longer treatment may not only be symptomatic but might slow down the disease process.
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PMID:Effect of long-term treatment with tacrine (THA) in Alzheimer's disease as visualized by PET. 812 43

There is evidence that GH secretion is reduced in normal elderly subjects as well as in patients with Alzheimer's disease (AD). To clarify the mechanisms underlying this GH hyposecretory state in 14 elderly subjects (age 65-75 years) and 15 AD patients (age 61-78 years), we studied the effects of both pyridostigmine (PD, 120 mg orally), a cholinesterase inhibitor, and arginine (ARG, 0.5 g/kg i.v.), two substances likely acting via inhibition of hypothalamic somatostatin, on GH response to GHRH (1 microgram/kg i.v.). The GH response to PD alone was also studied. Twenty-two young healthy volunteers were studied as control group. Basal GH levels were similar in young, elderly and AD subjects (0.7 +/- 0.2, 0.8 +/- 0.2 and 0.9 +/- 0.2 microgram/l). IGF-I levels were lower (p < 0.005) in elderly (73.9 +/- 8.2 microgram/l) and in AD subjects (108.0 +/- 5.9 micrograms/l) than in young subjects (288.7 +/- 22.1 micrograms/l); however, they were higher (p < 0.01) in AD patients than in the elderly subjects. The PD-induced GH release did not significantly differ in young, elderly and AD subjects while the GH responses to GHRH in the elderly (AUC: 297.9 +/- 49.2 micrograms/l) and in AD subjects (437.6 +/- 93.5 micrograms/l/h) were lower (p < 0.01) than in young subjects (658.6 +/- 100.1 micrograms/l/h). PD potentiated the GH response to GHRH both in elderly and in AD subjects (901.7 +/- 222.4 and 1,070.3 +/- 207.2 micrograms/l/h, p < 0.005) but these responses were lower (p < 0.0001) than those recorded in young subjects (2,041.1 +/- 245.6 micrograms/l/h).(ABSTRACT TRUNCATED AT 250 WORDS)
Dementia
PMID:Growth hormone secretion in Alzheimer's disease: studies with growth hormone-releasing hormone alone and combined with pyridostigmine or arginine. 813 94

The effects of pre-treatment with ENA-713, an acetylcholinesterase (AChE) inhibitor, on changes in pre- and postsynaptic cholinergic indices in gerbil brain following transient ischemia were studied at 4 and 14 days after recirculation. In the ischemic group, hippocampal acetylcholine (ACh) level was significantly reduced (to 23% of sham-operated controls) at 4 days post-ischemia, but this reduction was completely prevented by ENA-713 treatment. Choline acetyltransferase (ChAT) and cholinesterase (ChE) activities were not significantly changed at 4 and 14 days post-ischemia. Although the maximum number (Bmax) of muscarinic ACh receptor (mACh-R) binding in the hippocampus was decreased (to 44%) without any change in affinity at 14 days post-ischemia, this decrease was also inhibited by ENA-713 treatment. In addition, histological experiment indicated that ENA-713 inhibited ischemia-induced pyramidal cell loss in the hippocampal CA1 regions. Thus, these findings suggest that ENA-713 has protective, neurotrophic and therapeutic effects on cerebrovascular type dementia due to cerebral ischemia.
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PMID:Acetylcholinesterase inhibitor ENA-713 protects against ischemia-induced decrease in pre- and postsynaptic cholinergic indices in the gerbil brain following transient ischemia. 818 20

Transdermal delivery of cholinesterase inhibitors (ChEI) for treatment of dementia would have advantages associated with continuous dosing and enhanced compliance, but feasibility depends on achieving desired levels of central nervous system enzyme inhibition. We developed a patch technique for assessing delivery of ChEI in rats and examined two organophosphate compounds, metrifonate and DDVP, and a carbamate, heptylphysostigmine, for production of peripheral and central nervous system ChE inhibition at target levels. With DDVP, a log-dose/percent brain AChE inhibition was obtained over a range of 10-65% inhibition within a 10-fold concentration of inhibitor in the patch. Brain cholinesterase was inhibited up to seven days after a 24-h patch application. Long-term inhibition was greater than that attained after intramuscular injection, but without the rapid initial inhibition peak seen with the latter route. In contrast to DDVP, sustained high levels of brain enzyme inhibition could not be produced by transdermal delivery of metrifonate or heptylphysostigmine. Apparently DDVP has features, i.e., liquid state in pure form and high inhibitor potency, which make it particularly suitable for patch administration.
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PMID:Transdermal patch delivery of acetylcholinesterase inhibitors. 823 60

Neurochemical evidence indicates that cognitive impairment in dementia of Alzheimer type (DAT) is related to degeneration of cholinergic neurons in the brain. A pharmacological approach is treatment with a cholinesterase inhibitor such as tetrahydroaminoacridine (THA). THA treatment of 17 patients with DAT was studied with a double-blind crossover design with three types of treatment, THA + lecithin, THA + placebo and placebo + placebo. Each treatment period was 6 weeks with wash out periods of 2 weeks. The treatment was evaluated with clinical ratings, psychometric testing, EEG and regional cerebral blood flow (rCBF) measurements. No significant clinical differences between treatment periods were found in the total sample, but marked individual differences were observed. The patients were subdivided into three outcome groups based on four clinical measures: 6 patients improved (responders), 5 patients were mainly unchanged, and 6 patients showed further deterioration during the trial period of 26 weeks. Pretreatment rCBF in responders differed significantly from that of the deteriorated patients. EEG showed more high frequency activity among responders. Hepatotoxic side effects were observed in several cases. Three subjects showed marked increases of liver enzymes, with normalization following dose reduction. The majority of patients who improved or remained unchanged during the study chose to continue THA treatment in an open trial.
Dementia
PMID:Oral tetrahydroaminoacridine treatment of Alzheimer's disease evaluated clinically and by regional cerebral blood flow and EEG. 835 4


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