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:3.1.1.8 (cholinesterase)
12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study sought to examine the feasibility of prolonged assessment of acetylcholinesterase (AChE) activity in the cerebrospinal fluid (CSF) of volunteers and to test the hypothesis that rivastigmine (ENA-713; Exelon, Novartis Pharma AG, Basel, Switzerland) selectively inhibits AChE in CSF in humans at a dose producing minimal inhibition of the peripheral enzyme. Lumbar CSF samples were collected continuously (0.1 mL x min(-1)) for 49 hours from eight healthy volunteers who took either placebo or a single oral dose of rivastigmine (3 mg). CSF specimens and samples of blood cells and blood plasma were analyzed at intervals for rivastigmine and its metabolite NAP 226-90 ([-] [3-([1-dimethylaminolethyl)-phenol]), erythrocyte AChE activity, CSF AChE activity, and plasma and CSF butyrylcholinesterase (BuChE) activity. Safety evaluations were performed 23 hours after drug dosing and at the end of the study. Evaluable data were obtained from six subjects. The mean time to maximal rivastigmine plasma concentration (tmax) was 0.83 +/- 0.26 hours, the mean maximal plasma concentration (Cmax) was 4.88 +/- 3.82 ng x mL(-1), the mean plasma area under the concentration versus time curve (AUC0-infinity) was 7.43 +/- 4.74 ng x hr x mL(-1), and the mean plasma t1/2 was 0.85 +/- 0.115 hours. The concentration of rivastigmine in CSF was lower than the quantification limit for assay (0.65 ng x mL(-1)), but NAP 226-90 reached a mean Cmax of 3.14 +/- 0.57 ng x mL(-1). Only minimal inhibition of erythrocyte AChE activity (approximately 3%) was observed. Inhibition of AChE in the CSF after rivastigmine administration was significantly greater than after placebo for up to 8.4 hours after the dose and was maximal (40%) at 2.4 hours. Plasma BuChE activity was significantly lower after rivastigmine than after placebo, but this was not clinically relevant. BuChE activity in CSF was significantly lower after rivastigmine than after placebo for up to 3.6 hours after dosing, but this difference was not sustained. This study confirms the feasibility of using continuous measurement of AChE activity in CSF over prolonged periods, that rivastigmine markedly inhibits CSF AChE after a single oral dose of 3 mg, and that the inhibition of central AChE is substantially greater than that of peripheral AChE or BuChE.
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PMID:Preferential cerebrospinal fluid acetylcholinesterase inhibition by rivastigmine in humans. 1058 86

Rivastigmine (Exelon-Novartis) is the second cholinesterase inhibitor marketed for symptomatic treatment of mild to moderately severe Alzheimer's dementia, and follows [symbol: see text] donepezil (Aricept-Eisai; Pfizer). Previously, we have been "unconvinced of the value of donepezil in routine clinical practice". Rivastigmine has been promoted with the slogan "Beyond cognition: improving functional ability". Does rivastigmine offer useful benefits in Alzheimer's disease?
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PMID:Rivastigmine for Alzheimer's disease. 1082 50

The efficacy of a centrally active cholinesterase inhibitor, rivastigmine tartrate (ENA 713; Exelon, in patients with mild to moderately severe Alzheimer's disease was evaluated in a 26-week open-label extension of a 26-week, double-blind, placebo-controlled study. By 52 weeks, patients originally treated with 6-12 mg/day rivastigmine had significantly better cognitive function than patients originally treated with placebo.
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PMID:A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer's disease. 1152 67

In-vivo metabolic measures with positron emission tomography using (18)F-fluorodeoxyglucose (FDG-PET) have demonstrated hypometabolism in temporal, frontal, and hippocampal areas during the early stages of Alzheimer's disease (AD). Progression of the dementia in AD involves compromised cholinergic functioning. Cholinesterase inhibitors have demonstrated efficacy in improving cognition and behaviour in AD. In this study, we demonstrate the usefulness of FDG-PET in measuring the progression of untreated AD and its modification by treatment with rivastigmine (Exelon, Novartis Pharmaceuticals, East Hanover, New Jersey, USA), a centrally selective cholinesterase inhibitor of the carbamate type. Patients with mild to moderate probable AD (Mini-Mental Status Exam scores of 10-26, inclusive) were enrolled in a double-blind, placebo controlled comparison of three fixed daily doses of rivastigmine (3, 6, or 9 mg/d) or placebo for 26 wk. FDG-PET scans were obtained on 27 patients at baseline and following 26 wk of treatment using the Snodgrass Picture Naming activation task. A total of 71.4% of the patients treated with placebo deteriorated clinically compared to only 25.0% of the patients treated with rivastigmine (chi2 = 4.8; p & 0.03). Rivastigmine-responders (i.e. those who clinically improved or remained clinically stable as measured by the Clinicianaposs Interview-Based Impression of Change-plus) showed a marked increase in brain metabolism (p <0.01) involving, but not limited to, structures comprising the memory-related cortices and the prefrontal system. These metabolic changes were not observed in the placebo-treated patients or the rivastigmine non-responders. Of note is that responders increased hippocampal metabolism by 32.5% (p < 0.03) compared to a non-significant decrease in the non-responders (6.4%) and placebo-treated patients (4.1%). These results are consistent with the literature suggesting that FDG-PET can sensitively measure the progression of AD and its improvement with cholinesterase inhibitors. Rivastigmine prevented the expected deterioration in clinical status and dramatically increased brain metabolic activity in a majority of patients.
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PMID:Brain metabolic and clinical effects of rivastigmine in Alzheimer's disease. 1160 28

Rivastigmine, a carbamate inhibitor of acetylcholinesterase, is already in use for treatment of Alzheimer's disease under the trade name of Exelon. Rivastigmine carbamylates Torpedo californica acetylcholinesterase very slowly (k(i) = 2.0 M(-1) min(-1)), whereas the bimolecular rate constant for inhibition of human acetylcholinesterase is >1600-fold higher (k(i) = 3300 M(-1) min(-1)). For human butyrylcholinesterase and for Drosophila melanogaster acetylcholinesterase, carbamylation is even more rapid (k(i) = 9 x 10(4) and 5 x 10(5) M(-1) min(-1), respectively). Spontaneous reactivation of all four conjugates is very slow, with <10% reactivation being observed for the Torpedo enzyme after 48 h. The crystal structure of the conjugate of rivastigmine with Torpedo acetylcholinesterase was determined to 2.2 A resolution. It revealed that the carbamyl moiety is covalently linked to the active-site serine, with the leaving group, (-)-S-3-[1-(dimethylamino)ethyl]phenol, being retained in the "anionic" site. A significant movement of the active-site histidine (H440) away from its normal hydrogen-bonded partner, E327, was observed, resulting in disruption of the catalytic triad. This movement may provide an explanation for the unusually slow kinetics of reactivation.
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PMID:Kinetic and structural studies on the interaction of cholinesterases with the anti-Alzheimer drug rivastigmine. 1188 71

Cholinesterase (ChE) inhibition represents the most efficacious treatment approach for Alzheimer's disease (AD) to date. This multiple-dose study has examined the relationship between inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities in the cerebrospinal fluid (CSF) and cognitive change (measured by the Computerised Neuropsychological Test Battery [CNTB]) following administration of the ChE inhibitor, rivastigmine (Exelon). In 18 patients with mild to moderate AD, CNTB scores, activities of AChE and BuChE in the CSF, and plasma BuChE activity were determined prior to treatment with rivastigmine. Doses of rivastigmine were then titrated (1 mg b.i.d./week) to final doses of 1, 2, 3, 4, 5 or 6 mg b.i.d. (n = 3 per dose). Following treatment with the target dose of rivastigmine for at least 3 days, CNTB scores were re-determined. CSF samples were continuously collected together with plasma samples prior to and for 12 hours after the final dose of rivastigmine, and AChE and BuChE activities determined.AChE in CSF and BuChE in plasma were dose-dependently inhibited by rivastigmine treatment. The inhibition of BuChE in CSF was not clearly dose-dependent. A statistically significant correlation was observed between the change in CNTB summary score and inhibition of AChE activity (r = -0.56, p < 0.05) and BuChE activity (r = -0.65, p < 0.01) in CSF. Improvement in speed-, attention- and memory-related subtests of the CNTB correlated significantly with inhibition of BuChE but not AChE activity in CSF. Weak or absent correlation with change in cognitive performance was noted for inhibition of plasma BuChE. These results indicate that cognitive improvement with rivastigmine in AD is associated with central inhibition of ChEs and support a role for central BuChE in addition to AChE inhibition in modulating cholinergic function in AD.
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PMID:Inhibition of acetyl- and butyryl-cholinesterase in the cerebrospinal fluid of patients with Alzheimer's disease by rivastigmine: correlation with cognitive benefit. 1211 43

Rivastigmine tartrate is a dual-action cholinesterase inhibitor shown to improve language, cognition, and global functioning in patients with Alzheimer's disease, likely via increased availability of cerebral acetylcholine. Because cholinergic receptor abnormalities can contribute to the neuropathology of autistic spectrum disorders, rivastigmine tartrate could prove to be an effective therapy for affected children. Observations of improved behavior and language output from prior open-label and double-blind treatment of autistic children with donepezil, another cholinesterase inhibitor, prompted this 12-week open-label study with rivastigmine tartrate of 32 autistic patients. Therapeutic indices were the Childhood Autistic Rating Scale, Gardner's Expressive and Receptive One-Word Picture Vocabulary tests, and the Conners' Parent Rating Scale. Testing administered at baseline, 6 weeks, and 12 weeks showed gains in both expressive speech and overall autistic behavior over baseline. These improvements were statistically significant and supported the hypothesis that treatment with cholinergic enhancing drugs in autistic spectrum disorders yields positive therapeutic effects.
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PMID:Treating autistic spectrum disorders in children: utility of the cholinesterase inhibitor rivastigmine tartrate. 1776 62

Kinetics of hydrolysis of acetylcholine and acetylthiocholine by two types of acetylcholinesterase and butyrylcholinesterase inhibited by 13 new inhibitors (5 carbamates and 8 carbazates--hydrazinium derivatives) was measured in vitro in a batch reactor at 25 degrees C, pH 8, ionic strength 0.11 M and enzyme activity 3.5 U by four nondependent analytical methods. Sevin, rivastigmin (Exelon) and galantamin (Reminyl) served as comparative inhibiting standards. Kinetics of hydrolyses inhibited by all studied carbamates, sevin, carbazates (with exceptions) and rivastigmin (with exceptions) can be simulated by the competitive inhibition model with irreversible reaction between enzyme and inhibitor. Galantamin does not fulfil this model. In positive simulations, the value of inhibition (carbamoylation) rate constant k3 was calculated, describing the reaction velocity between the given enzyme and inhibitor. Physiologically important hydrolyses of acetylcholine catalyzed by acetylcholinesterase from electric eel or bovine erythrocytes and butyrylcholinesterase from horse plasma can be most quickly inhibited by carbamoylation of the mentioned enzymes by the 3-N,N-diethylaminophenyl-N'-(1-alkyl) carbamates 4 and 5. Probably this is due to a long enough hydrocarbon aliphatic substituent (hexyl and octyl) on the amidic nitrogen atom. The tested carbazates failed as inhibitors of cholinesterases. The regeneration ability of the inhibited enzymes was not measured.
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PMID:Kinetics of 13 new cholinesterase inhibitors. 1698 25

Alzheimer's disease is the most common form of dementia in industrialized countries. In the European Union, about 54% of dementia cases are believed to be due to Alzheimer's disease. The condition is an age-related neurodegenerative disorder characterized by multiple cognitive deficiencies, including loss of memory, judgment, and comprehension. These manifestations are accompanied by behavioral and mood disturbances. Although no cure has yet been discovered for Alzheimer's disease, symptomatic therapies are now widely available and offer significant relief to patients and benefits to caregivers in terms of reduced care burden. At the start of the 21st century, health technology assessments recommended three agents for the symptomatic treatment of mild to moderate Alzheimer disease: rivastigmine, donepezil, and galantamine. Rivastigmine (Exelon, Novartis Basel-Switzerland) is a slowly reversible inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), while donepezil (Aricept, Pfizer, New York, USA) and galantamine (Reminyl, Janssen, New Jersey, USA) show no functional inhibition of BuChE, and are considered AChE-selective, rapidly-reversible inhibitors. The efficacy of all three agents has been evaluated in large, double-blind, placebo-controlled clinical trials of up to 6 months' duration. Rivastigmine treatment in mild to moderate Alzheimer's disease improves cognition, activities of daily living, and global function.
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PMID:Rivastigmine in the treatment of Alzheimer's disease: an update. 1804 73

Neuron and synapse loss together with neurotransmitter dysfunction have, along with Abeta deposition and neurofibrillary tangles, been recognized as hallmarks of Alzheimer's disease (AD). Furthermore, clinical and preclinical studies point to neuronal loss and associated neurochemical alterations of several transmitter systems as a main factor underlying both cognitive and neuropsychiatric symptoms. Treatment for the cognitive decline in AD, based on early findings of a cholinergic deficit, has been in the clinic for more than a decade but provides only modest benefit in most patients. Therefore there is still considerable scope for new treatments that demonstrate greater efficacy against cognitive dysfunction in spite of the fact that the mainstays of current treatments, the cholinesterase inhibitors Aricept, Exelon and Reminyl (Razadyne) will become generic over the next few years. However, the most important area for drug development is for the treatment of behavioural disturbance in AD since many existing treatments have limited efficacy and have potentially life-threatening side effects. This review examines the neurochemical underpinning of both cognitive and neuropsychiatric symptoms in dementia and provides some basis for rational drug development.
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PMID:Neurochemical basis for symptomatic treatment of Alzheimer's disease. 2015 62


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