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)

Parkinson's disease patients may suffer from cognitive impairment and behavioural problems such as apathy, personality changes, speech disturbances and visual hallucinations (Parkinson's disease dementia). However, there is currently no recommended treatment for Parkinson's disease dementia and antipsychotic agents can worsen extrapyramidal symptoms, making them unsuitable for patients with this condition. The observation that patients with Parkinson's disease dementia have extensive cholinergic deficits led to the hypothesis that cholinesterase inhibitors may provide benefits for patients with this condition. Here, we present a case series of patients with Parkinson's disease and dementia who we treated with rivastigmine, a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) that shows brain region-selectivity. The introduction of rivastigmine led to improvements in cognitive and functional abilities, as well as the resolution of behavioural problems and visual hallucinations. Rivastigmine was well tolerated by our patients when the dose was escalated slowly, including one patient who had previously experienced severe side-effects with the AChE-selective inhibitor donepezil. Despite the large number and range of concomitant medications being received by the patients, no side-effects thought to be related to drug-drug interactions were reported. A large, placebo-controlled study is warranted to ascertain the full clinical profile of rivastigmine in Parkinson's disease dementia.
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PMID:Rivastigmine for the treatment of dementia and visual hallucinations associated with Parkinson's disease: a case series. 1224 Jul 87

Alzheimer's disease (AD) is characterized by deterioration in the ability to perform activities of daily living (ADL) in addition to loss of cognitive function and behavioral changes. This decline in day-to-day functioning is increasingly recognized as a source of considerable social, health, and economic costs. Inability to perform ADL results in growing caregiver burden and may lead to the eventual need for alternative care or nursing home placement. The measurement of ADL, which enables monitoring of the effectiveness of therapeutic interventions, can be performed using a number of inventories including the Progressive Deterioration Scale (PDS), the Disability Assessment for Dementia (DAD), and the Alzheimer Disease Cooperative Study ADL (ADCS/ADL) assessment scale. Clinical studies using these and other scales have indicated that cholinesterase (ChE) inhibitors offer an effective approach to treating the functional decline of AD. Donepezil, rivastigmine, and galantamine have been shown in some studies to prevent or slow decline in ADL over treatment periods of one to two years. For instance, in a 24-week study in subjects with moderate to severe AD, donepezil-treated patients remained stable compared with the placebo-treated patients. Rivastigmine has shown improvement or stabilization of PDS scores in patients with mild to moderate disease following 26 weeks of treatment and slowed deterioration in patients with more severe disease. Evidence to date suggests that these agents may not be equally effective at slowing or stabilizing loss in ADL over time and that these differences may reflect differences in pharmacology. In addition to inhibition of acetylcholinesterase (AChE), these compounds have other putative differences in mechanisms of action. Galantamine allosterically modulates the nicotinic receptor and may prevent the loss of ADL. Rivastigmine robustly inhibits butyrylcholinesterase in addition to AChE and therefore acts as a dual ChE inhibitor. Comparative studies evaluating the differential effects of these ChE inhibitors on ADL are awaited.
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PMID:The ABC of Alzheimer's disease: ADL and improving day-to-day functioning of patients. 1263 78

The cholinergic hypothesis suggests that Alzheimer's disease (AD) results from a selective loss in cholinergic neurons with decreased acetylcholine levels. Treatments that increase the level of acetylcholine would be expected to provide clinical benefit. Clinical trials of dietary precursors of acetylcholine and muscarinic receptor agonists have been unsuccessful. Further research is needed to confirm whether nicotine or nicotinic agonists are of value. The most successful approach has been to increase acetylcholine levels by inhibiting cholinesterase function. A number of cholinesterase inhibitors (ChEI) show clinical efficacy including phyostigmine but it is poorly tolerated. Tacrine, the first ChEI to be licensed for AD, needs frequent administration and causes a specific reversible hepatotoxicity. Three ChEI, donepezil, rivastigmine and galantamine are widely available. They are effective in mild to moderate (and possibly severe) AD. Tolerability is improved by slow dose titration and there are a significant number of non-responders. Donepezil appears to be effective, the simplest to use and the best tolerated. Rivastigmine is effective but less well tolerated: galantamine is also very effective with intermediate tolerability. Although there are pharmacological differences between the three compounds, it remains uncertain whether these are clinically relevant. There are still unanswered questions. It is difficult to predict who will respond to the drugs and it is unclear how long treatment benefits last. At present there are little data to support the suggestion of activity beyond symptomatic benefit. Trials are also being conducted in Mild Cognitive Impairment, other dementias and other conditions where cognitive impairment is a problem.
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PMID:Have cholinergic therapies reached their clinical boundary in Alzheimer's disease? 1297 45

We aimed to determine whether the cholinesterase inhibitor rivastigmine, an inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), would improve quality of life and cognitive function in 16 clinically stable subjects affected by schizophrenia in the residual phase. Study subjects began rivastigmine treatment at a dose of 1.5 mg bid. This dose was escalated at monthly intervals in increments of 1.5 mg bid to a maximum of 6 mg bid. All subjects were followed for 12 months. Quality of life was assessed using the Satisfaction with Life Domains Scale (SLDS, a self-report scale containing 10 "satisfaction" items); cognitive function, attentional function, and aspects of learning and memory were evaluated using common neuropsychological tests. Psychopathology was evaluated by means of the Brief Psychiatric Rating Scale (BPRS). Rivastigmine treatment resulted in significant improvements in quality of life, which were paralleled by significant improvements in cognitive function, learning and memory, and trends for improvement in attention. The BPRS factor "anergia" showed significant improvement, while low baseline scores in other psychotic factors did not permit further improvements. There were no reports of nausea or vomiting. In conclusion, rivastigmine significantly improved quality of life in subjects with schizophrenia. These benefits may relate to the drug's effects on cognitive deficits and negative symptoms associated with the condition.
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PMID:Effects of rivastigmine on cognitive function and quality of life in patients with schizophrenia. 1464 12

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


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