Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.1.7 (acetylcholinesterase)
28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cholinergic hypothesis of Alzheimer's disease (AD) has strongly influenced research on learning and memory over the last decade. However, there has been limited success treating AD dementia with cholinomimetics. Furthermore, there are indications that other neurotransmitter systems affected by this disease may be involved in cognitive processes. Animal studies have suggested that norepinephrine and acetylcholine may interact in learning and memory. The current experiments investigate this interaction in a step-down passive avoidance paradigm after coadministration of acetylcholinesterase inhibitors and alpha 2-adrenoceptor antagonists. Administration of acetylcholinesterase inhibitors heptylphysostigmine (0.625-5.0 mg/kg, IP), tacrine (2.5-10.0 mg/kg, PO), velnacrine (0.312-2.5 mg/kg, SC), and galanthamine (0.312-2.5 mg/kg IP) each enhanced retention of a passive avoidance response at selected moderate doses administered 30-60 min prior to training. The alpha 2-adrenoceptor antagonists idazoxan (0.312-2.5 mg/kg, IP), yohimbine (0.078-0.312 mg/kg, IP) and P86 7480 (0.156-0.625 mg/kg, IP) alone failed to enhance learning in this paradigm. Coadministration of a subthreshold dose of heptylphysostigmine (0.625 mg/kg, IP) with doses of idazoxan, yohimbine or P86 7480 enhanced passive avoidance learning. This synergistic interaction may represent effects of antagonism of presynaptic alpha 2-adrenoceptor since coadministration of heptylphysostigmine and the selective postsynaptic alpha 2-adrenoceptor antagonist SKF 104856 did not result in enhanced learning. Taken together these data suggest noradrenergic activation through pre-synaptic alpha 2-adrenoceptor blockade may potentiate cholinergic activity in the formation of a long-term memory trace. These observations may have implications for the treatment of AD with cholinergic and adrenergic agents.
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PMID:Alpha 2-adrenoceptor antagonists potentiate acetylcholinesterase inhibitor effects on passive avoidance learning in the rat. 873 50

Galanthamine is a selective acetylcholinesterase inhibitor which has shown potential for the treatment of Alzheimer's disease. Galanthamine is selective for acetylcholinesterase versus butyrylcholinesterase; however, the drug produces greater enzyme inhibition in human erythrocytes than in human brain tissue. Galanthamine attenuates drug-and lesion-induced cognitive deficits in animal models of learning and memory. Preliminary results in patients with Alzheimer's disease have reported galanthamine to be associated with a reduction in cognitive deterioration on some neuropsychiatric rating scales. Nausea and vomiting are the most commonly reported adverse effects; liver toxicity has not been reported to date.
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PMID:Galanthamine. 881 86

Alzheimer's disease is a progressive neurodegenerative disorder primarily manifesting as a loss of memory. Senile plaques and neurofibrillary tangles are the major histopathological alteration in the brain of Alzheimer's disease patients. A considerable deficiency of cholinergic neurons is a consistent finding in Alzheimer's disease. Therefore, many therapeutic strategies to augment cerebral concentration of acetylcholine such as cholinergic precursors, cholinergic receptor agonists, cholinesterase inhibitors and acetylcholine release modulators have been evaluated in Alzheimer's disease. Although cholinesterase inhibitors such as tacrine and galanthamine offer modest clinical benefits, other cholinergic agents have proved to be of limited therapeutic value. Efforts to enhance monoaminergic neurotransmission have also been largely disappointing. Therefore, emphasis is not being put on the use of combination of two class of drugs. Moreover, use of therapeutic agents based on the putative pathogenic etiology of the disease such as excitotoxicity, amyloidosis, aluminium accumulation, inflammatory mechanisms and free radical production is being evaluated. Desferrioxamine, non-steroidal anti-inflammatory drugs, prednisone, dapsone, vitamin E and idebenone are some such agents that are currently under investigation for the preventive or palliative effect in Alzheimer's disease. Neurotrophic factors such as nerve growth factor, brain derived neurotrophic factor and epidermal growth factor have shown promising results in animal studies. However, novel methods for delivering these molecules into the brain required to be developed before launching their clinical trials in man.
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PMID:Pharmacological basis of drug therapy of Alzheimer's disease. 956 41

This review starts with an historical background of the pharmacological development of tacrine almost fifty years ago (1949). Tacrine is the first drug to be tested, clinically, on a large scale and to be registered (1993) for treatment of Alzheimer's disease. For the first time, clinical results of four second generation cholinesterase inhibitors (ChEI) (donepezil, ENA 713, eptastigmine and metrifonate) are reviewed and compared with other ChEI such as tacrine, physostigmine and galanthamine. Data based on more than 6000 patients show that second generation drugs are well tolerated and show evidence of clinical efficacy. Differences are mainly due to frequency of side effects, number of drop outs and percentage of improved patients. These results also demonstrate the presence of clinical efficacy for all ChEI tested so far. Clinical mechanism of action, levels of efficacy and differences among various ChEI are discussed. Future potential indications are suggested. The present data indicate that optimization of effects prolongation and maintenance of clinical gains will depend on further knowledge of the compounds pharmacodynamic properties.
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PMID:Invited review: Cholinesterase inhibitors for Alzheimer's disease therapy: from tacrine to future applications. 967 39

New galanthamine derivatives, especially bis-interacting ligands 3-5 and 7-9 were prepared in order to interact with the catalytic and the peripheral sites of acetylcholinesterase (AChE). The synthesis, the anticholinesterase activities, and the structure-activity relationships of bis-interacting ligands are reported. Compounds 4d-e were found to be more potent than galanthamine and tacrine in inhibiting AChE.
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PMID:Potent acetylcholinesterase inhibitors: design, synthesis, and structure-activity relationships of bis-interacting ligands in the galanthamine series. 983 13

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

Alzheimer's disease (AD) is characterized in the brain by the deposition of amyloid protein outside the neuron, resulting in the formation of plaques, and inside the neuron with neurofibrillary tangles. It is not yet known what causes these pathologic changes, although age and genetics are major risk factors. The cholinesterase inhibitors tacrine and donepezil block acetylcholinesterase and therefore preserve the neurotransmitter acetylcholine. Three other investigational cholinesterase inhibitors are rivastigmine, metrifonate, and galanthamine. Existing therapies being studied for use in AD include vitamin E, estrogen preparations, and anti-inflammatory agents. The physician's role is to care for both the AD patient and the family, which are profoundly affected by this disease.
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PMID:Alzheimer's disease: seeking new ways to preserve brain function. Interview by Alice V. Luddington. 1002 72

Different cholinomimetics are used in conditions of CNS acetylcholine (ACh) deficit. In this study, we examined the effect of the acetylcholinesterase inhibitor galanthamine in a prolonged alcohol intake model of ACh deficit in male Wistar rats. After 16 weeks of alcohol intake and a 2-week pause, rats administered galanthamine (2.5 mg/kg/day i.p.) showed an improved speed of learning and short-term memory in the shuttle box test as compared to the saline-injected alcoholic group (p < 0.05). Four weeks later, significant improvement in the passive avoidance memory of alcoholic galanthamine-treated rats was noted in the eight-arm radial maze (14 day test duration) as compared to the saline-injected alcoholic group (p < 0.05). During the first week in the shuttle box test, the nonalcoholic galanthamine-treated animals exhibited significantly impaired performance as compared to the untreated nonalcoholic control, while four weeks later, in the eight-arm radial maze, both groups did not differ. Our results show that galanthamine improves the speed of learning, short-term memory and spatial orientation of rats in conditions of prolonged alcohol intake.
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PMID:Effect of the acetylcholinesterase inhibitor galanthamine on learning and memory in prolonged alcohol intake rat model of acetylcholine deficit. 1039 39

Galanthamine is a third-generation cholinesterase inhibitor used against Alzheimer's disease. New analytical methods for the determination of galanthamine in pharmaceutical preparatives and biological fluids, such as urine and serum, were developed. An experimental design and artificial neural network approach were used for method optimization. Thirty-five ppb of galanthamine were determined in serum samples (with addition of 10 mM magnesium chloride and using solid-phase preconcentration).
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PMID:Capillary zone electrophoresis determination of galanthamine in biological fluids and pharmaceutical preparatives: experimental design and artificial neural network optimization. 1045 Nov 7

Huperzine A, a selective inhibitor of acetylcholinesterase, was recently demonstrated to exert an antagonist effect on N-methyl-D-aspartate (NMDA) receptor in rat cerebral cortex. In the present study, the effects of six cholinesterase inhibitors, e.g. huperzine A, huperzine B, tacrine, donepezil (E2020), physostigmine and galanthamine on [3H]dizocilpine (MK-801) binding to synaptic membrane of rat cerebral cortex were compared. Their IC50 values (mean +/- SD) were 36.9 +/- 12.1, 316.8 +/- 93.2, 33.2 +/- 3.7, 135.0 +/- 15.1, 50.4 +/- 7.4, and 3344 +/- 295 microM, respectively. The rank order of potency is tacrine approximately huperzine A > physostigmine > donepezil > huperzine B >> galanthamine. There is no correlation between their activities to inhibit [3H]MK-801 binding and to inhibit acetylcholinesterase (r = +0.563, P = 0.245). The results suggest that most cholinesterase inhibitors available exhibit an antagonist effect on NMDA receptor in rat cerebral cortex in addition to their inhibitory effect on acetylcholinesterase.
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PMID:Comparison of the effects of cholinesterase inhibitors on [3H]MK-801 binding in rat cerebral cortex. 1050 33


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