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)

Cholinesterase inhibitors (ChEIs) have shown positive symptomatic effects on cognition, activities of daily living, and behavior in patients with Alzheimer's disease (AD). Rivastigmine is a slowly reversible ChEI that inhibits acetylcholinesterase and butyrylcholinesterase. We evaluated the effects of long-term rivastigmine treatment on cognitive function and plasma levels of ChE activity, and the relationship between ChE activity and cognition. Patients with mild AD (n = 11) treated with rivastigmine for 12 months were compared with matched groups of untreated patients with AD (n = 21) or mild cognitive impairment (MCI; n = 22) representing the natural course of the pre-clinical and very early stage of disease. For untreated AD patients, neuropsychological assessment was made at baseline and 12 months. Determination of ChE activity in plasma and assessment of global cognition, episodic memory, visuospatial ability, and attention were performed at 0 (baseline), 3, 6, and 12 months for treated AD patients and untreated MCI patients. At 12 months, cognitive function was slightly improved or maintained in mild AD patients treated with rivastigmine. In contrast, cognition was markedly worsened in untreated AD patients and unchanged or slightly worsened in untreated MCI patients. In the group of treated AD patients, there was a significant correlation between plasma ChE inhibition and cognition, particularly in relation to attention. This effect was most apparent at 3 months of treatment. In conclusion, a clear beneficial effect of rivastigmine was shown on cognitive function for patients with mild AD and plasma values of ChE inhibition were associated with attention.
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PMID:Preserved cognitive function after 12 months of treatment with rivastigmine in mild Alzheimer's disease in comparison with untreated AD and MCI patients. 1506 27

A simple and sensitive reversed-phase liquid chromatography coupled with electrospray-mass spectrometry was developed and validated for the simultaneous determination of rivastigmine, a cholinesterase inhibitor, and its major metabolite NAP 226-90 in rat plasma and brain homogenates. Rivastigmine and NAP 226-90 were extracted from plasma and brain by ethyl acetate and, after drying under nitrogen, re-dissolved in acetonitrile and separated isocratic by HPLC on a C(18) column and quantified by single ion monitoring mass spectrometer. The mean (+/-SD) extraction efficiency for rivastigmine in plasma and brain was 93 +/- 2 and 95 +/- 2% (n = 5) of NAP 226-90 in a drug range of 10-100 pmol/mL or pmol/g. The method proved to be linear within the tested range (regression coefficient, r = 0.9999, n = 5). Intra- and inter-day precision coefficients of variation and accuracy bias were acceptable (within 15%, n = 5) over the entire range for both compounds using plasma or brain samples. The limits of quantification were 0.5 pmol/mL plasma and 2.5 pmol/g brain for rivastigmine and 1 pmol/mL plasma and 5 pmol/g brain for NAP 226-90, respectively. The analytical technique was used to determine the concentrations of rivastigmine and its metabolite NAP 226-90 in rat plasma and brain after oral drug administration. The concentrations of the parent drug and its major metabolite were compared to a pharmacodynamic parameter, the ex vivo inhibition of acetylcholinesterase.
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PMID:A simple, rapid and sensitive method for simultaneous determination of rivastigmine and its major metabolite NAP 226-90 in rat brain and plasma by reversed-phase liquid chromatography coupled to electrospray ionization mass spectrometry. 1510 1

The deficiency in cholinergic neurotransmission in Alzheimer's disease has led to the development of cholinesterase inhibitors as the first-line treatment for symptoms of this disease. The clinical benefits of these agents include improvements, stabilisation or less than expected decline in cognition, function and behaviour. The common mechanism of action underlying this class of agents is an increase in available acetylcholine through inhibition of the catabolic enzyme, acetylcholinesterase. There is substantial evidence that the cholinesterase inhibitors, including donepezil, galantamine and rivastigmine, decrease acetylcholinesterase activity in a number of brain regions in patients with Alzheimer's disease. There is also a significant correlation between acetylcholinesterase inhibition and observed cognitive improvement. However, the cholinesterase inhibitors are reported to have additional pharmacological actions. Rivastigmine inhibits butyrylcholinesterase with a similar affinity to acetylcholinesterase, although it is not clear whether the inhibition of butyrylcholinesterase contributes to the therapeutic effect of rivastigmine. Based on data from preclinical studies, it has been proposed that galantamine also potentiates the action of acetylcholine on nicotinic receptors via allosteric modulation; however, the effects appear to be highly dependent on the concentrations of agonist and galantamine. It is not yet clear whether these concentrations are related to those achieved in the brain of patients with Alzheimer's disease within therapeutic dose ranges. Preclinical studies have shown that donepezil and galantamine also significantly increase nicotinic receptor density, and increased receptor density may be associated with enhanced synaptic strengthening through long-term potentiation, which is related to cognitive function. Despite these differences in pharmacology, a review of clinical data, including head-to-head studies, has not demonstrated differences in efficacy, although they may have an impact on tolerability. It seems clear that whatever the subsidiary modes of action, clinical evidence supporting acetylcholinesterase inhibition as the mechanism by which cholinesterase inhibitors treat the symptoms of Alzheimer's disease is accumulating. Certainly, as a class, the currently approved cholinesterase inhibitors (donepezil, galantamine, rivastigmine and tacrine) provide important benefits in patients with Alzheimer's disease and these drugs offer a significant advance in the management of dementia.
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PMID:Cholinesterase inhibitors used in the treatment of Alzheimer's disease: the relationship between pharmacological effects and clinical efficacy. 1513 13

Cholinesterase inhibitors used to treat the symptoms of Alzheimer's disease (AD) inhibit both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), albeit to different degrees. Because central and peripheral neurons, including intrinsic cardiac neurons located on the surface of the mammalian heart, express both BuChE and AChE, we studied spontaneously active intrinsic cardiac neurons in the pig as a model to assess the effects of inhibition of AChE compared to BuChE. Neuroanatomical experiments showed that some porcine intrinsic cardiac neurons expressed AChE and/or BuChE. Enzyme kinetic experiments with cholinesterase inhibitors, namely, donepezil, galantamine, (+/-) huperzine A, metrifonate, rivastigmine, and tetrahydroaminoacridine, demonstrated that these compounds differentially inhibited porcine AChE and BuChE. Donepezil and (+/-) huperzine A were better reversible inhibitors of AChE, and galantamine equally inhibited both the enzymes. Tetrahydroaminoacridine was a better reversible inhibitor of BuChE. Rivastigmine caused more rapid inactivation of BuChE as compared to AChE. Neurophysiological studies showed that acetylcholine and butyrylcholine increase or decrease the spontaneous activity of the intrinsic cardiac neurons. Donepezil, galantamine, (+/-) huperzine A, and tetrahydroaminoacridine changed spontaneous neuronal activity by about 30-35 impulses per minute, while rivastigmine changed it by approximately 100 impulses per minute. It is concluded that (i) inhibition of AChE and BuChE directly affects the porcine intrinsic cardiac nervous system, (ii) the intrinsic cardiac nervous system represents a suitable model for examining the effects of cholinesterase inhibitors on mammalian neurons in vivo, and (iii) the activity of intrinsic cardiac neurons may be affected by pharmacological agents that inhibit cholinesterases.
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PMID:Cholinesterase inhibitors modify the activity of intrinsic cardiac neurons. 1524 45

Rivastigmine, a cholinesterase inhibitor, is successfully used for the symptomatic therapy of Alzheimer's disease (AD) in the clinic. The drug has a very low potential for drug-drug interactions, as has been demonstrated within large clinical trials. Memantine, recently approved by the FDA for the treatment of moderate to severe AD, acts as a low affinity, non-competitive NMDA-antagonist, on a completely different neurotransmitter system, the glutamatergic system. Given the different sites of action, the possibility to combine a cholinergic with a glutamatergic intervention as potentially superior AD therapy has recently been proposed. In vitro studies have demonstrated that memantine, when added to reversible AChE inhibitors, such as tacrine, donepezil or galantamine, did not interfere with the inhibitory action of any of these drugs. The results from the present study provide evidence that rivastigmine as a pseudo-irreversible (or slow-reversible) AChE inhibitor shares this property described for reversible inhibitors, since memantine (1-100 microM), irrespective of whether given prior to or after rivastigmine did not influence rivastigmine's AChE inhibition in vitro. A similar observation was also made under in vivo conditions (ex vivo measurements): following a 21 day chronic, oral administration of 6 micromol/kg rivastigmine alone or of a combination of rivastigmine plus memantine (6 micromol/kg p.o. of either of the two compounds), an identical degree of AChE inhibition was observed. The concentrations of rivastigmine, its metabolite NAP 226-90 and memantine were measured in the brain of the same animals. Following an equimolar oral dose (6 micromol/kg) of both compounds, the brain level of memantine exceeded that of rivastigmine + metabolite, by a factor of around 30, when measured 2 h after the final dosing, irrespective of the duration of treatment (acute, for 3 or 21 days). This indicates that neither of the two drugs showed accumulation but also, and more importantly, that memantine does not modulate the prime therapeutic action of rivastigmine (AChE inhibition) in vitro or in vivo. Clinical trials using a combination of both drugs will provide a final proof of whether a combination therapy would lead to an increased efficacy in AD patients.
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PMID:Co-administration of memantine has no effect on the in vitro or ex vivo determined acetylcholinesterase inhibition of rivastigmine in the rat brain. 1527 30

The efficacy and tolerability of the cholinesterase inhibitor rivastigmine in the treatment of Alzheimer disease (AD) have been demonstrated in several clinical trials, which included patients with a wide range of dementia severities. To investigate the association between severity of disease and treatment response, the combined data from three large randomized, placebo-controlled trials were analyzed. The pooled patient population was stratified into three cohorts showing moderately severe (Mini-Mental State Examination score [MMSE] < or = 15), moderate (MMSE 16-22), and mild (MMSE > or = 22) dementia. In each cohort, the effects of rivastigmine 6 to 12 mg/day versus placebo were evaluated using the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-cog) and the Progressive Deterioration Scale. Rivastigmine 6 to 12 mg/day maintained ADAS-cog scores at or above placebo levels in all cohorts, while cognitive deterioration with placebo was progressive and severity dependent. Activities of daily living showed statistically significant benefits with rivastigmine across all severity cohorts.
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PMID:Disease stage in Alzheimer disease and treatment effects of rivastigmine. 1549 17

Rivastigmine (1), an acetylcholinesterase (AChE) inhibitor approved in 2000 for the treatment of Alzheimer disease, bears a carbamate moiety in its structure, which is able to react covalently with the active site of the enzyme. Kinetic and structural studies on the interaction of 1 with different cholinesterases have been published, giving deeper, but not definitive, insights on the catalysis mechanism. On the basis of these findings and in connection with our previous studies on a series of benzopyrano[4,3-b]pyrrole carbamates as AChE inhibitors, we designed a series of conformationally restricted analogues of 1 by including the dimethylamino-alpha-methylbenzyl moiety in different tricyclic systems. A superimposition between the conformation of 1 and the carbon derivative 4, as obtained from Monte Carlo simulations, supported the idea that the tricyclic derivatives might act as rigid analogues of 1. The biological profile of 4-9, assessed in vitro against human AChE and BChE, validated our rational design. Compound 5, bearing a sulfur-containing system, showed the highest inhibitory activity, being 192-fold more potent than 1. In the present study, the most potent inhibitors were always methyl derivatives 3-5, endowed with a nanomolar range potency, whereas the ethyl ones were 40 times less potent. A reasonable explanation for this finding might be a steric hindrance effect between the ethyl group of 1 and His440 in the active site, as already suggested by the crystal structure of the complex AChE/1. The unfavorable influence of the carbamic N-alkyl chain on AChE inhibition is less striking when considering BChE inhibition, since BChE is characterized by a bigger acyl binding pocket than AChE. In fact, methyl carbamates 3-5 did not show AChE/BChE selectivity, whereas compounds 6-9 were significantly more potent in inhibiting BChE than AChE activity. At 100 microM, 5 was found to inhibit the AChE-induced aggregation only by 19% likely because it is not able to strongly interact with the peripheral anionic site of AChE, which plays an essential role in the Abeta aggregation mediated by the enzyme but is lacking in BChE structure.
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PMID:Design, synthesis, and biological evaluation of conformationally restricted rivastigmine analogues. 1553 49

The goal of this study was to determine whether rivastigmine, a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), has any effect on delirium in vascular dementia (VaD). The results from this follow-up study suggest that although delirium is frequent in elderly, cognitively impaired patients, it might not be a simple consequence of acute disease and hospitalization. Rather, delirium can be secondary to brain damage and to metabolic disturbances. According to the Lewy body dementia model, delirium could be induced by a lack of acetylcholine in the brain. Rivastigmine may help reduce the frequency of delirium episodes and help shorten their duration. Additional studies are required to better define the causes of delirium, which currently has no definitive treatment.
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PMID:Cholinesterase inhibition as a possible therapy for delirium in vascular dementia: a controlled, open 24-month study of 246 patients. 1563 41

An isocratic, reversed-phase liquid chromatographic (RPLC) method was developed for the quantitative determination of Rivastigmine hydrogen tartrate, a cholinesterase inhibitor in bulk drugs and in pharmaceutical dosage forms. The developed method is also applicable for the related substance determination of Rivastigmine hydrogen tartrate in bulk drugs. The chromatographic separation was achieved on a Waters X Terra RP18 (250 mm x 4.6 mm, 5 microm) column using aqueous 0.01 M sodium-1-heptane sulphonate (pH: 3.0 with dilute phosphoric acid)-acetonitrile (72:28, v/v) as a mobile phase. The chromatographic resolution between Rivastigmine and its potential impurity, namely (S)-3-(1-dimethylaminoethyl) phenol (Imp 1) was found to be greater than four. Forced degradation studies were performed for Rivastigmine hydrogen tartrate bulk drug using acid (0.5 N hydrochloric acid), base (0.5 N sodium hydroxide), oxidation (3% hydrogen peroxide), heat (60 degrees C) and UV light (254 nm). No degradation was observed for Rivastigmine hydrogen tartrate except in base hydrolysis and the formed degradation product was found to be Imp 1. The mass balance of Rivastigmine hydrogen tartrate was close to 100 in all the stress conditions. The limit of detection (LOD) and limit of quantification (LOQ) of Imp 1 were found to be 100 and 300 ng/ml, respectively, for 10 microl injection volume. The percentage recovery of Imp 1 in bulk drug sample was ranged from 95.2 to 104.3. The active pharmaceutical ingredient was extracted from its finished dosage form (capsule) using water. The percentage recovery of Rivastigmine hydrogen tartrate was ranged from 99.2 to 101.3 and 98.6 to 101.5 in bulk and pharmaceutical formulation samples, respectively. Rivastigmine hydrogen tartrate sample solution and mobile phase were found to be stable for at least 48 h. The developed method was validated with respect to linearity, accuracy, precision, robustness and forced degradation studies prove the stability indicating power of the method.
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PMID:A stability indicating LC method for rivastigmine hydrogen tartrate. 1566 43

This analysis aimed to assess mini-mental state examination (MMSE) scores in patients with Alzheimer's disease who received rivastigmine, an inhibitor of acetylcholinesterase and butyrylcholinesterase, for up to 5 years. Rivastigmine data came from two pooled open-label extensions of four 6-month, randomised, placebo-controlled trials. Projections of decline, had the same patients not been treated, were made using a baseline-dependent mathematical model. MMSE data were available for 1998 rivastigmine-treated patients and 657, 298 and 83 were still on treatment at 3, 4 and 5 years, respectively. The mean (+/-SD) baseline MMSE score was 19.3 (+/-4.9). Projected mean scores in model-based untreated patients declined below 10 points on the MMSE at about 3 years, while the mean MMSE score of patients who remained on rivastigmine stayed above 10 points for 5 years.
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PMID:Cognitive performance in Alzheimer's disease patients receiving rivastigmine for up to 5 years. 1585 67


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