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)

SDZ ENA 713 (ENA 713) is an acetylcholinesterase inhibitor being developed as a potential treatment for Alzheimer's disease (AD). A prior Phase II safety and efficacy study used an upper dose limit of 6 mg/day ENA 713. The present study was designed to assess the safety and tolerability of higher doses of ENA 713 in probable AD patients. Fifty AD patients (22M; 28F, mean age 68 yrs, range 45-90) were assigned to a fixed, nine-week dose escalation schedule in which they were randomized to receive up to 12 mg/day of ENA 713 bid (n=20) or tid (n=20), or placebo (n=10) followed by a one-week washout. Mg/day dose escalation for the bid and tid ENA 713 groups was identical, beginning with 2 mg/day on Days 1 to 3 and escalating to 12 mg/day in Weeks 8 and 9. Doses through 12 mg/day were well tolerated. Most adverse events were mild to moderate in severity and of limited duration, most commonly headache, nausea, dizziness, and diarrhea. Three of forty patients on ENA 713 discontinued, all due to adverse events. Two experienced nausea and vomiting; the third experienced an unrelated mild atrial fibrillation.
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PMID:Safety/tolerability trial of SDZ ENA 713 in patients with probable Alzheimer's disease. 861 73

Galanthamine is a selective acetylcholinesterase inhibitor which has shown potential for the treatment of Alzheimer's disease. Galanthamine is selective for acetylcholinesterase versus butyrylcholinesterase; however, the drug produces greater enzyme inhibition in human erythrocytes than in human brain tissue. Galanthamine attenuates drug-and lesion-induced cognitive deficits in animal models of learning and memory. Preliminary results in patients with Alzheimer's disease have reported galanthamine to be associated with a reduction in cognitive deterioration on some neuropsychiatric rating scales. Nausea and vomiting are the most commonly reported adverse effects; liver toxicity has not been reported to date.
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PMID:Galanthamine. 881 86

Reduced cholinergic transmission is a key neurotransmitter dysfunction in Alzheimer's Disease (AD). NXX-066, a physostigmine analog and acetylcholinesterase (AChE) inhibitor, has demonstrated activity in animal models of memory function, and was well tolerated in healthy subjects up to a single dose of 64 mg and multiple doses of 60 mg QD for seven days. Since AChE inhibitors are often tolerated differently in AD patients than in healthy volunteers, a randomized, placebo-controlled, double-blind, single-center, inpatient bridging study was conducted to determine the maximum tolerated dose (MTD) of NXX-066 in the target patient population. Seven consecutive panels of eight AD patients each (6 active, 2 placebo) received fixed oral doses of NXX-066 (20, 30, 40, 50, 60, 70, or 80 mg BID) for seven days. Initiation of each subsequent panel (dose group) was contingent upon the tolerability of lower dose levels. The MTD was determined to be 70 mg BID when four of six patients receiving 80 mg BID were prematurely discontinued from the study due to nausea and/or vomiting, accompanied in some patients by mild to moderate dizziness, headache, asthenia, and gastric symptoms. Wide variability in plasma levels of NXX-066 was observed in all dose panels. AChE inhibition in whole blood correlated with both maximum plasma concentration and dose; however, AChE inhibition was not predictive of adverse events. In this study, AD patients tolerated larger daily doses of NXX-066 on a BID regimen than healthy normal subjects had tolerated with QD dosing. Further studies are warranted to examine whether differing tolerability between patients and healthy subjects or the reduced dosing interval explains these findings.
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PMID:NXX-066 in patients with Alzheimer's disease: a bridging study. 1021 Feb 64

Galanthamine (or galantamine, Reminyl) is a tertiary alkaloid acetylcholinesterase inhibitor (AChEI) which has been approved in several countries for the symptomatic treatment of senile dementia of the Alzheimer's type. Derived from bulbs of the common snowdrop and several Amaryllidaceae plants, (-)-galanthamine (GAL) has long been used in anaesthetics to reverse neuromuscular paralysis induced by turbocurarine-like muscle relaxants and more recently, has been shown to attenuate drug- and lesion-induced cognitive deficits in animal models of learning and memory. GAL directly inhibits acetylcholinesterase activity, while demonstrating much weaker activity on butyrylcholinesterase (BuChE). GAL also stimulates pre- and postsynaptic nicotinic receptors, although the clinical significance of this finding is yet unclear. Numerous variants and analogues of GAL have also been developed, with varying potency in inhibiting AChE activity. GAL is readily absorbed after oral administration, with a t(max) of 52 min and a plasma elimination t(1/2) of 5.7 h. The efficacy of GAL administered to Alzheimer's disease (AD) patients has been well demonstrated by large-scale clinical trials. Typical of AChEIs, the most common adverse events associated with GAL are nausea and vomiting. In conclusion, evidence to date suggests galanthamine to be similar to other AChEIs in improving cognitive function in AD patients.
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PMID:Review of the acetylcholinesterase inhibitor galanthamine. 1106 Aug 14

In functional pharmacological assays, talsaclidine has been described as a functionally preferential M1 agonist with full intrinsic activity, and less pronounced effects at M2- and M3 receptors. In accordance with this, cholinomimetic central activation measured in rabbits by EEG recordings occurred at a 10 fold lower dose than that inducing predominantly M3-mediated side effects. This pharmacological profile is also reflected in the clinical situation: Both in healthy volunteers and in Alzheimer patients--unlike after unspecific receptor stimulation through cholinesterase inhibitors--the mainly M3-mediated gastrointestinal effects (like nausea and vomiting) were not dose-limiting. Rather, sweating and hypersalivation, mediated through muscarinic receptors, occurred dose-dependently and were finally dose-limiting. In contrast to talsaclidine, sabcomeline had a less pronounced functional M1 selectivity in pharmacological assays. This was also shown in anaesthetized guinea pigs where sabcomeline alone induced bronchoconstriction, and in the rabbit EEG where central activation and cholinergic side effects occurred in the same dose range. Neither drug, however, showed convincing improvement of cognitive functions in patients with mild-to-moderate Alzheimer's disease. This asks for a reassessment of the muscarinic hypothesis for the treatment of this disease.
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PMID:Pharmacodynamic profile of the M1 agonist talsaclidine in animals and man. 1139 31

Cholinesterase inhibitors (ChEIs) are dosed in two phases for the treatment of dementia, an initial dose-escalation phase to achieve a therapeutic dose and a maintenance phase where the therapeutic dose is given for long-term therapy. ChEIs are associated with a range of side effects as a result of cholinergic stimulation in different areas of the brain and the periphery Acute, centrally-mediated gastrointestinal events (mostly nausea and vomiting) are class effects of all ChEIs, and are reported mostly during the dose-escalation phase of therapy. These events have been associated more with the dual acetylcholinesterase/butyrylcholinesterase (AChE/BuChE) inhibitor rivastigmine than with the AChE-selective inhibitors donepezil and galantamine, probably due to rivastigmine's higher potency. However, these events can be minimised using slow dose escalation with small dose graduations and administration with food. Other side effects associated with ChEIs include central nervous system events, extrapyramidal symptoms, sleep disturbances and cardiorespiratory events, associated with cholinergic activity in the cortex, caudate nucleus, brainstem and medulla, respectively, and muscle cramps and weakness, cardiorespiratory events and urinary incontinence, associated with peripheral cholinergic activity. These symptoms are mostly reported during the maintenance phase of therapy. They are more frequently reported with donepezil, but are rarely reported with rivastigmine, and galantamine may not have been marketed long enough to make an adequate assessment. These differences are due to the drugs' respective pharmacology. For example, donepezil and rivastigmine are active centrally, in contrast to galantamine, which is more active peripherally. Furthermore, rivastigmine preferentially inhibits the G1 isoform of cholinesterase, predominantly located in the cortex, hippocampus and in neuritic plaques, while donepezil and galantamine are not selective for any cholinesterase isoforms and have wide cholinergic activity both centrally and peripherally The cholinergic activity of rivastigmine, in contrast to donepezil and galantamine, is apparently more targeted at clinically relevant brain sites. The pharmacological profile of rivastigmine results in it having a low potential to interact with other drugs and it may be used with a high margin of safety in patients having a wide variety of concomitant diseases. Donepezil and galantamine may have significant interactions with other drugs that are metabolised by the hepatic cytochrome system and therefore need to be used with caution in patients with many concomitant illnesses. When dosed with care, ChEIs are well tolerated and patient compliance and patient and caregiver acceptability are good. The favourable tolerability and safety profiles of these agents make them suitable first-line therapy for dementia. In addition, patients who have tolerability and/or safety problems in maintenance treatment that limit the use of donepezil or galantamine may benefit from switching to rivastigmine.
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PMID:The tolerability and safety of cholinesterase inhibitors in the treatment of dementia. 1213 67

Since degenerative alterations associated with cholinergic changes in the brains of demented patients occur in specific regions, optimal efficacy may be achieved by targeting the actions of potent cholinesterase inhibitors in relevant regions. When evaluating the activities of these agents, only cerebrospinal fluid (CSF)-based studies in demented patients provide reliable data. Preclinical or healthy volunteer studies of cholinesterase inhibitory activity using plasma or erythrocytes as an enzyme source are inconclusive due to differences between enzymes, their relative activities, and the profiles of their isoforms from different sources, with additional changes during disease progression. Tacrine and rivastigmine inhibit both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the CSF of Alzheimer's disease patients. Both enzymes are involved in the breakdown of acetylcholine (ACh) in the brain and dual inhibition may lead to greater, broader efficacy, as well as a greater potential for disease modification. However, potent and rapid elevation in levels of ACh may also induce more acute tolerability problems, such as nausea and vomiting. Only rivastigmine appears to show brain region-selectivity, particularly for regions involved in attention and behaviour and that are known to degenerate during the progression of various dementia types. This selectivity is due to preferential inhibition of the G1 form of AChE and, probably, also BuChE. Cholinesterase inhibitors that lack preferential selectivity for particular isoforms may provide less targeted actions. This may explain the relatively higher incidences of certain peripheral side effects observed during maintenance treatment with some of these drugs. All cholinesterase inhibitors interact via ACh, additionally available due to enzyme inhibition, with nicotinic and muscarinic receptors (nAChRs and mAChRs). Allosteric modulation of a presynaptic nAChR has been shown in vitro with many of these agents, and it has been proposed, but not demonstrated, that this may result in an increased release and potentiation of ACh in the brain. The clinical relevance of this mechanism is unknown. The rapidly reversible actions of donepezil, tacrine and galantamine may lead to tolerance due to their ability to upregulate target enzyme activities; however upregulation is not seen with the slowly reversible (pseudo-irreversible) inhibitor rivastigmine. Available clinical data support the hypothesis that potent, slowly reversible inhibitors of AChE and BuChE targeted to the G1 isoforms may lead to greater, broader and more sustained benefits. However, further investigation of the cholinesterase inhibitors to elucidate more definitely the clinical consequences of their differing pharmacological properties is required.
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PMID:Evidence that the clinical effects of cholinesterase inhibitors are related to potency and targeting of action. 1213 68

Dementia of Alzheimer's type (DAT), together with vascular dementia, is the most important indication for Ginkgo biloba extract (EGb). The therapeutic efficacy of this extract is founded on neuroprotective, metabolic and rheological effects. In addition to these mechanisms--which also form the basis of the activity of the older synthetic nootropics--the hypothesis that DAT is due to a "cholinergic deficit" at central synapses has led, over the last decade, to the development of a new group of drugs for this indication, the cholinesterase (ChE) inhibitors. Thus nowadays, EGb is competing, on the synthetic side, with the ChE inhibitors tacrine, donepezil, rivastigmine and galantamine. No direct comparative trials have been undertaken, but long-term studies lasting 24-56 weeks to demonstrate efficacy have been carried out with both groups of substances in accordance with current EU guidelines. To date, only one psychometric scale has gained general acceptance as the primary criterion of efficacy, namely the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), whose scores range from 0 to 70 (the lower the better). The initial scores of patients in the trials were between 20 and 30; the improvements after 6 months treatment (less those seen with placebo) were about 2 points under Ginkgo extract and 2 to 4 points with the ChE inhibitors. However, the relatively small differences are called into question by the occurrence of drug-specific side effects with the ChE inhibitors. Unlike the treatment with EGb, up to 90% of the patients given the ChE inhibitors developed nausea and vomiting, so there is a suspicion that methodological reasons in the sense of an "unblinding" of the treatment groups caused the apparent superiority in the intensity of the effect. In addition, the benefits of treatment were rapidly reversed after ending administration of ChE inhibitors, which did not occur to the same extent with EGb. Adverse drug reactions are more than 10 times more common with the ChE inhibitors and the treatment costs about five times higher than with EGb. Given the limited therapeutic options for DAT, treatment with EGb still appears to be the method of choice compared to the ChE inhibitors.
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PMID:Ginkgo extract or cholinesterase inhibitors in patients with dementia: what clinical trials and guidelines fail to consider. 1280 48

The dual cholinesterase inhibitor rivastigmine is approved in capsule form in many countries for the symptomatic treatment of dementia associated with Alzheimer disease (AD) and Parkinson disease (PD). All orally administered cholinesterase inhibitors are associated with central cholinergic gastrointestinal side effects, particularly during the titration phase, which are believed to be caused by a rapid increase in brain acetylcholine levels after effective inhibition of the target enzymes. A recently developed rivastigmine transdermal patch may have the potential to reduce such side effects. Pharmacokinetic studies have shown that transdermal administration of rivastigmine prolongs t(max), lowers C(max), and reduces fluctuations in plasma concentration. The 10-cm(2) rivastigmine patch provides comparable exposure (area under the curve, AUC) to the highest capsule dose (6-mg BID) and may be the target maintenance dose for most patients, delivering optimal rivastigmine exposure to produce a therapeutic effect. The potential of a patch to improve the tolerability of rivastigmine (e.g., nausea and vomiting) while permitting similar exposure to the highest doses of capsules may, in turn, lead to improved efficacy and compliance.
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PMID:Pharmacokinetic rationale for the rivastigmine patch. 1764 18

Inhibitors of acetylcholinesterase provide a modest symptomatic benefit for a majority of patients with Alzheimer's disease. Cholinergic "secondary" effects are variable, but sometimes quite invalidating. Nausea and vomiting appear to be linked to peak plasma concentration of the drug. A transdermal patch of rivastigmine is available that allows to obtain a lower peak of concentration, less gastro-intestinal side effects, and an efficacy similar to the oral capsules of rivastigmine.
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PMID:[A transdermal patch of rivastigmine (Exelon)]. 1905 14


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