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)

Rivastigmine (ENA 713, or carbamoylatine) is an acetylcholinesterase (AChE) inhibitor with brain-region selectivity and a long duration of action. Both preclinical studies and studies in human volunteers have shown that rivastigmine induces substantially greater inhibition of AChE in the central nervous system (CNS) compartment than in the periphery (40% inhibition of central AChE compared with 10% inhibition of plasma butylcholinesterase in healthy volunteers). Moreover, rivastigmine preferentially inhibits the G1 enzymatic form of AChE, which predominates in the brains of patients with Alzheimer's disease (AD). Evidence from animal studies also suggests that rivastigmine is a more potent inhibitor of AChE in the cortex and hippocampus, the brain regions most affected by AD. Absorption of rivastigmine is rapid and almost complete (>96% of the administered dose). Extensive, saturable first-pass metabolism, however, leads to bioavailability of approximately 35% of the administered dose and nonlinear pharmacokinetics. The principal metabolite of rivastigmine has at least 10-fold lower activity against AChE compared with the parent drug. Rivastigmine is completely metabolized; the major route of elimination of the metabolites is renal. Although patients with AD demonstrate 30% to 50% higher plasma concentrations of rivastigmine and its principal metabolite than do healthy elderly patients, there is no evidence of drug accumulation, which is consistent with rivastigmine's short pharmacokinetic half-life. Distribution of rivastigmine into the CNS is extensive, and inhibition of AChE in the cerebrospinal fluid is detectable 1.2 hours after oral dosing in both healthy volunteers and patients with AD. Peak activity is reached somewhat more slowly in AD patients than in healthy subjects, and the inhibitory effects have a longer duration (6.0 vs 2.4 hours and 12.0 vs 8.5 hours, respectively). Rivastigmine is inactivated during the process of interacting with and inhibiting AChE, and, in contrast to other AChE inhibitors, the hepatic cytochrome P-450 (CYP-450) system is not involved in the metabolism of rivastigmine. This reduces its propensity to interact with drugs metabolized by specific CYP-450 isoenzymes. Consistent with rivastigmine's pharmacokinetic and pharmacodynamic profiles, Phase II and III trials have demonstrated that the drug is a well-tolerated and effective treatment for AD.
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PMID:Clinical pharmacology of rivastigmine: a new-generation acetylcholinesterase inhibitor for the treatment of Alzheimer's disease. 973 24

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

Rivastigmine is a carbamate acetylcholinesterase (AChE) inhibitor with central selectivity. Early studies showed that daily doses up to 6 mg/day have some efficacy in patients with dementia of the Alzheimer type (DAT). The present study was designed to assess the safety, tolerability and efficacy of rivastigmine at doses up to 12 mg/day. A total of 114 patients with mild-moderate DAT were randomly assigned to either rivastigmine (b.i.d. (twice daily) or t.i.d. (three times daily)) or placebo in a double-blind fashion titrated to their maximum tolerated dose over 10 weeks followed by an eight-week maintenance phase. The mean maximum tolerated dose was approximately 10 mg/day (b.i.d. or t.i.d.). Gastrointestinal complaints, the majority of which were mild to moderate, were the most frequently reported adverse events. No clinically relevant changes in vital signs, haematology or organ function were detected. Significantly more patients taking rivastigmine b.i.d. were considered improved according to the Clinicians' Interview-Based Impression of Change-Plus (CIBIC-Plus) vs. placebo (57% vs. 16%, respectively; P = 0.027). The Nurses' Observation Scale for Geriatric Patients (NOSGER) (memory component) and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) also improved in the rivastigmine b.i.d. group vs. placebo (mean change from baseline on NOSGER = -0.7 vs. +1.3, respectively; P = 0.037: mean change from baseline on ADAS-cog = -2.7 vs. +0.2, respectively; P = 0.054). Despite the relatively small size and limited duration of the study, the finding that rivastigmine induced changes in the same (positive) direction in all three dimensions measured suggests that rivastigmine at doses of up to 12 mg/day has useful efficacy in patients with mild-moderate DAT. Reports from larger phase III studies confirm this finding. The results of this study also suggest that b.i.d. is the more efficacious regimen and has comparable tolerability to the t.i.d. regimen.
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PMID:A phase II study in patients with Alzheimer's disease to assess the preliminary efficacy and maximum tolerated dose of rivastigmine (Exelon). 1036 94

The effect of rivastigmine on memory impairments induced in rats by scopolamine (0.5 mg/kg) was assessed in the Morris water maze and passive avoidance tests and compared with that of tacrine (2.5-17.7 mg/kg). Rivastigmine, (0.5-2.5 mg/kg) inhibited cholinesterase in the cortex and hippocampus by 21-60% and antagonised the deficits in working and reference memory. Tacrine (12.5 and 17.7 mg/kg) produced significantly less inhibition of cholinesterase in the hippocampus but more in the striatum than rivastigmine (0.75 and 1.5 mg/kg) and only antagonised the deficit in reference memory. Rivastigmine (1.5 and 2.5 mg/kg) or tacrine (12.5 mg/kg), injected immediately after completion of the acquisition trial in the passive avoidance test, antagonised the deficit induced by scopolamine (1 mg/kg) in memory retention. The inability of higher doses of the cholinesterase inhibitors to antagonise memory deficits induced by scopolamine may be related to excessive cholinergic stimulation in the central nervous system.
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PMID:Effect of rivastigmine on scopolamine-induced memory impairment in rats. 1059 14

Rivastigmine is a cholinesterase inhibitor (ChEI) with a structural formula different from that of currently available ChEIs. Tacrine and donepezil are classified as short-acting or reversible agents since binding to acetylcholinesterase enzyme (AChE) is hydrolyzed within minutes. Rivastigmine is classified as an intermediate-acting or pseudo-irreversible agent due to its long inhibition on AChE of up to 10 hours. Preclinical biochemical studies indicated that rivastigmine has central nervous system selectivity over peripheral inhibition. It ameliorated memory impairment in rats with forebrain lesions. The drug is rapidly absorbed orally, with a bioavailability of 0.355 and low protein binding (40%). Its elimination half-life is less than 2 hours, and it is converted to an inactive metabolite at the site of action, bypassing hepatic metabolic pathways. Its disposition essentially is unaltered in patients with renal or hepatic impairment. It also has dose-dependent effects on AChE inhibition. In the two large multicenter clinical trials (total 1324 patients) that used a forced-dosage titration scheme, rivastigmine 6-12 mg/day was superior to placebo on three cognitive and functioning scales (p<0.001). Gastrointestinal symptoms are the most frequently reported adverse events. They occurred mostly during the dosage titration phase and decreased during the maintenance phase. Rivastigmine offers clinicians another therapeutic agent to treat Alzheimer's disease.
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PMID:Rivastigmine, a new-generation cholinesterase inhibitor for the treatment of Alzheimer's disease. 1064 71

Non-selective acetylcholinesterase (AChE) inhibitors are known hypotensive agents. The purpose of the present investigation was carried out to ascertain whether rivastigmine, a selective carbamate-type inhibitor of AChE, which inhibits selectively an isoform of this enzyme found almost exclusively in the central nervous system, is able to depress the intraocular pressure (IOP) in normotensive rabbits. IOP was monitored with a TonoPen XL in conscious adult rabbits before and hourly up to 8 hr after administration of the drug. Baseline measurements without treatment and after one single topical application of rivastigmine [1% (n=8); 2% (n=4); and 5% (n=6)] to the right eye and of the vehicle alone to the left one were performed. Rivastigmine reduced the IOP of treated eyes significantly (p<0.05) in a dose-independent manner. Maximal effects of 23.2% (5% rivastigmine), 19.6% (2% rivastigmine) and 15.2% (1% rivastigmine) were achieved 1, 3 and 5 hr after application of the drug. A non-significant reduction of IOP in the contralateral eye was also observed. Rabbits evidenced no signs of discomfort after administration of rivastigmine. No conjunctival discharge or other signs of drug related local toxicity were found. Rivastigmine, a selective antagonist of AChE, lowers IOP significantly and may thus be of potential use in glaucoma therapy.
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PMID:Topical rivastigmine, a selective acetylcholinesterase inhibitor, lowers intraocular pressure in rabbits. 1067 28

This study compared the effect of rivastigmine on cholinesterase (ChE) activity in different brain regions, heart, skeletal muscle and plasma and on the cognitive impairment induced by scopolamine (0.5 mg/kg) in male and female rats. Rats were injected s.c. with saline or rivastigmine (0.75-2.5 mg/kg) or physostigmine (0.05 mg/kg) and killed 30-120 min later. Amelioration of scopolamine-induced memory deficits by rivastigmine (0.75 mg/kg) was assessed in the Morris water maze. There were no gender differences in spatial memory or basal ChE activity in the brain or other organs. Rivastigmine (0.75 and 1.5 mg/kg) and physostigmine (0.05 mg/kg) caused significantly greater ChE inhibition in females than in males (P<0.01) in the cerebral cortex, hippocampus and striatum, but not in the periphery 30 and 60 min after injection. Rivastigmine was also more effective in antagonising the scopolamine-induced spatial memory impairment in female than in male rats. Ovariectomy did not affect the degree of enzyme inhibition by rivastigmine in any brain area. Orchidectomy completely abolished the difference in enzyme inhibition. It is concluded that a testicular hormone suppresses the effect of rivastigmine, by reducing the amount of drug reaching the brain or its interaction with ChE.
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PMID:Gender differences in the effect of rivastigmine on brain cholinesterase activity and cognitive function in rats. 1069 15

Alzheimer's disease (AD) is often associated with multiple comorbidities and subsequent polypharmacy. Treatment of AD with acetylcholinesterase (AChE) inhibitors can carry a risk of drug interaction with multiple medications often prescribed for other co-existing illnesses. Rivastigmine is an AChE inhibitor that is enzymatically cleaved by AChE, minimally metabolized by cytochrome P450 enzymes, has low protein binding, has a short plasma half-life, and a relatively short duration of action. Such properties make it ideal for use in this patient population. A pharmacodynamic analysis of rivastigmine administered concomitantly with other medications (22 different therapeutic classes) did not reveal any significant pattern of increase in adverse events that would indicate a drug interaction. In summary, rivastigmine was well tolerated and safely administered to a population receiving multiple medications for 'real-world' comorbidities.
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PMID:Lack of adverse pharmacodynamic drug interactions with rivastigmine and twenty-two classes of medications. 1071 82

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

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


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