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)

Three new cholinesterase inhibitors, donepezil, rivastigmine, and galantamine, all inhibit the enzyme AChE. Rivastigmine also inhibits BuChE, which could lead to additional benefits in late-stage Alzheimer's disease, but also cause more GI side effects at initiation of therapy. Galantamine is also an allosteric modulator of nicotinic receptors, which could lead to additional efficacy for attention and for behaviors mediated by neurotransmitters other than ACh. We are now entering an exciting era where the options for treating the devastating illness Alzheimer's disease are multiplying and creating a foundation upon which new therapies with new mechanisms of action can be built.
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PMID:The new cholinesterase inhibitors for Alzheimer's disease, Part 1: their similarities are different. 1107 30

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

Rivastigmine (Exelontrade mark, Novartis) is a novel intermediate-acting reversible and non-competitive carbamate acetylcholinesterase (AChE) that was recently introduced for the treatment of Alzheimer's disease (AD). Preclinical studies have shown that rivastigmine has many similarities to other currently available cholinesterase inhibitors (ChEIs) and some important differences. The drug has been evaluated for this use in two well designed, published, adequately powered, Phase III, 26 week clinical trials that included a total of more than 1500 rivastigmine and 700 placebo recipients. Most of these patients had concomitant disorders that were being treated with numerous other drugs. These studies indicate that rivastigmine (6 - 12 mg/day) usually produces cognitive, global and functional changes that indicate significantly less deterioration than was observed with placebo in patients with mild-to-moderate AD, with higher doses producing more benefits. Rivastigmine is beneficial in all three domains (namely cognition, daily activities and behaviour) of AD. Data on long-term efficacy support continued benefits of rivastigmine beyond 6 months. Rivastigmine is generally well-tolerated with no requirement for routine electrocardiogram (ECG) or blood monitoring. Rivastigmine causes adverse events that are generally those expected from a ChEI and mainly involve gastrointestinal system. They are usually mild-to-moderate, of short duration and responsive to dosage reduction. They occur mostly during the dosage titration phase and decrease during the maintenance phase. Clinically significant drug-drug interactions are unlikely. The consistent efficacy in treating all three domains (cognition, daily functioning and behaviour) and good tolerability, particularly with slow titration, makes rivastigmine a good first-line ChEI therapy for the treatment of AD. Therapeutic dose range is 6 - 12 mg/day. Rivastigmine should be started at 1.5 mg b.i.d. with meals and increased at 2 - 4 week intervals to achieve the highest tolerated dose.
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PMID:Review of rivastigmine and its clinical applications in Alzheimer's disease and related disorders. 1133 14

Acetylcholinesterase inhibitors (AChEIs) are the most frequently prescribed drugs for the treatment of Alzheimer's disease (AD). To date, donepezil is prescribed most often, but newer AChEIs have become available. Rivastigmine entered the pharmaceutics market for AD in 2000, and galantamine was approved for use in the United States in February 2001. Some patients with AD may already be taking a cholinesterase inhibitor, but they or their caregivers may want to change therapies for various reasons, such as lack of efficacy or poor tolerability. Therefore, defined protocols for discontinuing one therapy and initiating another therapy (ie, "switching") while maintaining efficacy and minimizing cholinergic toxicity will be essential. A post-hoc analysis of a clinical trial that enrolled patients with and without previous exposure to AChEIs indicated that the efficacy and tolerability of a second and different cholinesterase treatment were similar in both subpopulations of patients. These findings suggest that discontinuation of prior AChEI treatment is not predictive of future poor response to an effective treatment.
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PMID:Switching previous therapies for Alzheimer's disease to galantamine. 1139 69

Diffuse Lewy body disease (DLB) is a neurodegenerative disorder characterized by dementia, fluctuations in mental status, hallucinations, and parkinsonism. Diffuse Lewy body disease is the second most common cause of dementia, following Alzheimer's disease. The treatment of DLB includes cholinergic therapy for cognitive impairment, atypical neuroleptics to alleviate hallucinations, and levodopa/carbidopa to improve parkinsonism. The recognition and diagnosis of DLB has critical treatment implications. Centrally acting cholinesterase inhibitors, such as rivastigmine, donepezil, and galantamine partially reverse decreased cortical cholinergic activity and may improve cognition and neuropsychiatric symptoms in DLB. Rivastigmine has been demonstrated to improve cognition and neuropsychiatric symptoms in patients with DLB without worsening parkinsonian features. Due to the potential adverse events associated with neuroleptics in this population, treatment with cholinesterase inhibitors is currently considered first-line therapy in the treatment of hallucinations and mental status fluctuations in DLB. Exquisite sensitivity to neuroleptic medications is a hallmark of DLB and life-threatening complications have been reported. Caution should be exercised when implementing antipsychotic therapy for the treatment of behavioral disturbances of DLB. When required, atypical neuroleptics with the least extrapyramdial side effects, such as quetiapine, should be used. The parkinsonian features of DLB may respond to dopaminergic therapy with levodopa. If parkinsonian symptoms result in clinical disability, a trial of levodopa is warranted. Unfortunately, dopaminergic medications may worsen hallucinations. Because dopamine agonists have a greater tendency to induce hallucinations and somnolence, levodopa is the treatment of choice for parkinsonism in DLB. Rapid eye movement (REM) sleep behavior disorder (RBD) is now recognized as a feature of DLB. Awareness of the presence of this symptom in patients with DLB is important and treatment with low dose clonazepam may help. Cholinergic aumentation may also improve these symptoms in patients with DLB.
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PMID:Diffuse Lewy Body Disease. 1158 27

Rivastigmine is a cholinersterase inhibitor approved recently for the treatment of Alzheimer's disease (AD). The objective of this study is to characterize the pharmacokinetics-pharmacodynamics of rivastigmine in patients with AD. Eighteen AD patients received doses ranging from 1 to 6 mg bid for about 11 weeks. Rivastigmine and its active (major) metabolite (ZNS 114-666, also called NAP 226-90), plasma, and cerebrospinal fluid (CSF) concentrations were determined together with the AChE activity and computerized neuropsychological test battery (CNTB) scores. Nonlinear mixed-effects modeling of pharmacokinetic and pharmacodynamic data was conducted using NONMEM. Rivastigmine and its metabolite exhibited dose-disproportional pharmacokinetics. The apparent clearance and volume of distribution (plasma) of rivastigmine were estimated to be 120 L/h and 236 L, respectively. The relative bioavailability at the 6 mg dose was about 140%. The metabolite had a clearance of about 100 L/h and a volume of distribution of 256 L. The kinetics of the parent and metabolite in CSF showed an equilibration half-life of about 0.2 and 0.5 hours, respectively. The metabolite levels in CSF correlated very well with the acetylcholinesterase inhibition, with a ZNS 114-666 concentration of about 5.4 microg/L required for half-maximal inhibition of acetylcholinesterase activity. No statistically significant correlation of the CNTB scores with enzyme inhibition, parent or metabolite concentration (plasma/CSF), or rivastigmine dose could be established. The PK-PD model presented in this study can provide valuable information to optimize the drug development of rivastigmine and other related compounds and also in rationalizing dosing recommendations.
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PMID:Pharmacokinetic-pharmacodynamic modeling of rivastigmine, a cholinesterase inhibitor, in patients with Alzheimer's disease. 1158 76

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

Cholinesterase inhibitors have produced the best evidence of clinical efficacy for treating patients with Alzheimer's disease (AD). Many of these drugs selectively inhibit acetylcholinesterase (AChE), but agents that also target butyrylcholinesterase (BuChE) may provide added benefits. As AD progresses, ACh regulation may become increasingly dependent on BuChE and dual inhibitors may provide more sustained efficacy than AChE-selective agents. Dual inhibition may also help to slow the formation of amyloidogenic compounds, providing an important disease-modifying mechanism. Rivastigmine is a dual inhibitor that has demonstrated benefits across the spectrum of AD severity and across the cognitive, functional and behavioural domains of AD. It is a priority for future clinical trials to determine whether agents with dual inhibition properties have greater clinical efficacy.
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PMID:Advances in the treatment of Alzheimer's disease: benefits of dual cholinesterase inhibition. 1180 98

In order to develop new cholinesterase agents effective against Alzheimer's disease (AD) we synthesized some phenylcarbamates structurally related to Rivastigmine and evaluated their in vitro and in vivo biological activity. Among the compounds which displayed the most significant in vitro activity, 1-[1-(3-dimethylcarbamoyloxyphenyl)ethyl]piperidine (31b), in addition to a simple and cheaper synthesis, showed lower toxicity and very similar therapeutic index in comparison with Rivastigmine.
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PMID:Synthesis and cholinesterase activity of phenylcarbamates related to Rivastigmine, a therapeutic agent for Alzheimer's disease. 1185 43

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


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