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)

The effects of cholinergic drugs proposed for treatment of cognitive impairment in normal aging and dementia on divided attention have been little studied in non-human primates. We tested the hypothesis that cholinergic drugs improve spatial divided attention in primates via a computer task requiring simultaneous tracking of two visual targets in three young and two aged healthy bonnet macaques. Task accuracy (number of correct responses) and reaction time (RT) were measured 2 h after administration of either the m1 agonist +/- -cis-2-methyl-spiro(1,3-oxathiolane-5,3')quinuclidine (AF102B; 0.1-2.1 mg/kg IM) or the cholinesterase inhibitor 9-amino-1,2,3,4-tetrahydroamino-acridine (THA; 0.5-2.0 mg/kg orally). Accuracy increased for four of five monkeys at appropriate doses of one or both cholinomimetics, accompanied in two monkeys by a drop in RT. Responses were less uniform to THA than to AF102B. For the five-monkey group at Best dose, accuracy increased 34% (THA) or 43% (AF102B) above baseline (P<0.05 for both drugs), respectively, with no significant change in RT and with minimal untoward effects. Cholinotherapy may improve divided attention in young and aged healthy primates.
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PMID:Divided attention-enhancing effects of AF102B and THA in aging monkeys. 1032 74

Donepezil (donepezil hydrochloride, E-2020, Aricept, Eisai), launched in March 1997, was the first drug to be marketed for the symptomatic treatment of Alzheimer's disease (AD) in the UK. It had been launched a year earlier in the US where clinicians had already had experience of tacrine (THA). Donepezil is a piperidine based, potent, specific, non-competitive and reversible inhibitor of acetylcholinesterase (AChE). It is structurally dissimilar from other established cholinesterase inhibitors, namely THA (an acridine compound) and the carbamates, physostigmine and rivastigmine and has a pharmacokinetic and tolerability profile distinct from these agents. Experimentally, donepezil inhibits AChE activity in human erythrocytes and increases extracellular acetylcholine levels in the cerebral cortex and the hippocampus of the rat. Pharmacologically, donepezil has a half-life of approximately 70 h lending itself to once daily administration. The most common adverse events reported in clinical trials have been gastrointestinal, typically nausea, vomiting, diarrhoea and constipation. Headache, dizziness and sleep disturbance have also been reported; there has been no evidence of hepatotoxicity. Clinically a number of placebo-controlled trials have shown that donepezil 5 or 10 mg daily was associated with significant improvements in cognitive function, as assessed by the Alzheimer's disease Assessment Scale-cognitive subscale (ADAS cog) after 12 or 24 weeks treatment. Significant improvements in global function and activities of daily living have also been demonstrated after 24 weeks treatment compared with placebo in patients with mild to moderate AD. Donepezil was the first rational treatment available in the UK for this disabling condition and as such received considerable attention. Much of the original attention was negative, ostensibly based on the scientific view that there was not enough published evidence to justify widespread use, but this was driven by concerns about the potentially high drug costs if all patients with AD were eligible to receive it. Considerable data have now been produced from Phase II, III and post-marketing surveillance. This drug evaluation will review the basic pharmacology of donepezil and place it in context with the trial data and the author's clinical experience with the drug.
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PMID:The pharmacology of donepezil: a new treatment of Alzheimer's disease. 1124 55

Earlier studies of cognitive event-related brain potentials (ERPs) reporting diminished amplitudes and delayed latencies of the P300 potential in dementia of the Alzheimer type (DAT), together with independent findings of the P300- and performance-enhancing properties of nicotine in normal adults, stimulated this study to explore the single-dose effects of nicotine on auditory and visual P300s in DAT. Thirteen patients, 6 currently receiving treatment with the cholinesterase inhibitor tacrine (tetrahydroaminoacridine; THA) and the remaining being medication free, were administered 2 mg of nicotine polacrilex under double-blind, randomized, placebo-controlled conditions. Prior to nicotine administration, THA-treated patients exhibited shorter auditory P300 latencies than non-treated patients. Acutely administered nicotine failed to alter auditory P300, but increased the amplitudes of visual P300s in both DAT patient groups. Neither THA treatment nor single-dose nicotine altered behavioural performance in the visual and auditory task paradigms. The results are discussed in relation to nicotinic cholinergic, attentional and cognitive processes in DAT.
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PMID:Effects of acute nicotine administration on cognitive event-related potentials in tacrine-treated and non-treated patients with Alzheimer's disease. 1197 67

THA (Tacrine) is an anticholinesterase drug reported to alleviate cognitive deficit in Alzheimer's disease. We have used rat isolated superior cervical sympathetic ganglia as a model mammalian cholinergic neural system to study effects of THA on cholinergic synaptic transmission and postsynaptic membrane currents. At 0.1 - 3 microM, THA augmented the postsynaptic depolarizations and inward clamp currents produced by acetylcholine but not by the cholinesterase-resistant analogue, DMPP. Higher concentrations depressed these responses to both acetylcholine and DMPP, and reduced the acetylcholine-induced increase in membrane current noise. At 1 microM, THA did not affect the amplitude or time-course of fast (nicotinic) excitatory postsynaptic currents (epscs) evoked by single orthodromic volleys, but higher concentrations induced a biphasic epsc decay. In contrast, low concentrations of THA (1 - 3 microM) greatly augmented and prolonged the muscarinic slow epsc evoked by repetitive orthodromic volleys: this effect was blocked by 1 microM atropine. Concentrations above 0.1 mM produced a membrane depolarization and inhibited a variety of membrane ionic currents, including voltage-gated Ca current and subsequent Ca-activated K currents, and voltage-gated M- and A-type K currents. It is concluded that the principal effect of THA is to inhibit cholinesterase, and that the main consequence of this is to augment and prolong the muscarinic slow epsc. In contrast, the nicotinic fast epsc is not increased but instead may be reduced through a nicotinic channel-blocking action. Although THA could also block several other ion channels the concentrations required were too high to contribute significantly to its principal pharmacological actions on ganglionic transmission.
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PMID:Some Actions of 9-Amino-1,2,3,4-Tetrahydroacridine (THA) on Cholinergic Transmission and Membrane Currents in Rat Sympathetic Ganglia. 1210 73

A new family of tacrine (THA) analogues (7-9, 12), containing the azaheterocyclic pyrazolo[4,3-d]pyridine or pyrazolo[3,4-b][1,8]naphthyridine systems as isosteres of the quinoline ring of THA, has been synthesized. The compounds were tested in rat brain cholinesterases using Ellman's method, and all were fully efficacious in inhibiting the enzymes. Compounds 9 and 12b were the most potent against acetylcholinesterase (AChE), showing IC(50) of 6.0 and 6.4 microM, and were less active against rat brain butyrylcholinesterase, showing selectivity indexes of 5.3 and 20.9, respectively. Compounds 7-9 and 12 were also tested for their acute neurotoxicity in vitro, using cultured rat cortical cells. Compounds 7 and 8 were not significantly toxic; 9 was toxic at 500 microM, but not at 100 microM. The naphthyridine derivatives 12a and 12b showed a significant concentration-dependent neurotoxicity, being able to kill most cells at 500 microM. Molecular dynamic simulation using the X-ray crystal structure of AChE from Torpedo californica was used to explain the possible binding mode of these new THA isosteres.
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PMID:Design, synthesis, and pharmacological profile of novel fused pyrazolo[4,3-d]pyridine and pyrazolo[3,4-b][1,8]naphthyridine isosteres: a new class of potent and selective acetylcholinesterase inhibitors. 1264 25

Distractibility in primates may be influenced by central cholinergic systems. Two cholinomimetics, the m-1 muscarinic agonist (+/-)-cis-2-methyl-spiro(1,3-oxathiolane-5,3')quinuclidine (AF102B, civemeline) and the cholinesterase inhibitor tetrahydroaminoacridine (THA, tacrine), were compared to vehicle controls for effects on distractibility in an automated visuospatial attention task. The task required visual pursuit of a moving target amongst distractor stimuli that acted to impair performance and was executed by seven healthy adult bonnet macaque monkeys. Task accuracy and reaction time were measured 1.5 h after systemic administration of each substance. For the seven-subject group at individually titrated best doses, accuracy increased significantly relative to vehicle for both drugs. Reaction time at best dose decreased for both drugs, but not significantly. Muscarinic agonists and cholinesterase inhibitors may reduce distractibility in primates.
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PMID:Reduction in distractibility with AF102B and THA in the macaque. 1459 82

A Treatment IND (TIND) is a mechanism available to the Food and Drug Administration (FDA) in the United States by which promising new drugs can be provided to patients with life-threatening illnesses. In many instances, the illness is life-threatening but of relatively low incidence, making the demand for the new treatment limited. However, if the disease is more prevalent and incidence is increasing, the demand for access to an experimental therapy may be substantially greater. Novel approaches and technologies would help manage recruitment of physicians, enrollment of patients and retrieval and timely analysis of data. Such was the case in the TIND for tacrine hydrochloride (Cognex), a cholinesterase inhibitor which was under development for the treatment of patients with Alzheimer's Disease (AD). There were an estimated 4 million prevalent cases of AD in the US for which no approved therapeutic option was available at the time this TIND was initiated. We anticipated that there could be a large demand by both physicians and patients to enroll in the TIND. Therefore, to meet this demand, various mechanisms were employed to allow rapid enrollment and drug shipments to the patient. In addition, physicians who participated in the TIND were able to use a telephone touch-tone data entry system for reporting data and ordering new supplies of tacrine for their patients. Serious adverse events were reported directly to trained operators and summarized on a weekly basis for reporting to the FDA. At the time the programme was terminated, nearly 2000 physicians had enrolled to participate in the TIND and nearly 10,000 patients had received tacrine under the programme. The methods employed in this study to collect clinic visit and safety data met both regulatory and good clinical practice guidelines. In summary, a large volume of data was handled rapidly and efficiently in this programme.
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PMID:Tacrine hydrochloride treatment IND: methods for rapid physician and patient enrollment and data retrieval. 1507 61

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

The auditory mismatch negativity (MMN) event-related brain potential (ERP) reflects the storage of information in acoustic sensory memory. Thirteen patients with probable Alzheimer's disease (AD), 6 receiving treatment with the cholinesterase inhibitor (ChEI) tacrine (tetrahydroaminoacridine, THA) and 7 receiving no treatment, were administered 2 mg of nicotine polacrilex and placebo. MMNs were recorded with 1- and 3-s interstimulus intervals pre- and postplacebo/nicotine administration. In nontreated patients, amplitudes were decreased from pre- to postplacebo recordings but remained stable in THA-treated patients. Comparison of pre- and postnicotine MMNs found amplitude increases with nicotine in nontreated but not THA-treated patients. MMN latencies were shortened by nicotine in both treatment groups. These exploratory findings suggest that nicotine-improved strength of acoustic sensory memory traces and speed of acoustic sensory discrimination in AD are differentially affected by chronic ChEI treatment.
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PMID:Nicotine and sensory memory in Alzheimer's disease: an event-related potential study. 1525 98

A number of studies indicate that free radicals are involved in the neurodegeneration in Alzheimer's disease (AD). The role of superoxide anion (O2*-) in neuronal cell injury induced by reactive oxygen species (ROS) was examined in PC12 cells using pyrogallol (1,2,3-benzenetrior), a donor to release O2*-. Pyrogallol induced PC12 cell death at concentrations, which evidently increased intracellular O2*-, as assessed by O2*- sensitive fluorescent precursor hydroethidine (HEt). A water extract of Curcuma longa L. (Zingiberaceae) (CLE), having O2*- scavenging activity rescued PC12 cells from pyrogallol-induced cell death. Hypoxia/reoxygenation injury of PC12 cells was also blocked by CLE. The present study was also conducted to examine the effect of CLE on H2O2 -induced toxicity in rat pheochromocytoma line PC12 by measuring cell lesion, level of lipid peroxidation and antioxidant enzyme activities. Following a 30 min exposure of the cells to H2O2 (150 microM), a marked decrease in cell survival, activities of glutathione peroxidase and catalase as well as increased production of malondialdehyde (MDA) were found. Pretreatment of the cells with CLE (0.5-10 microg/ml) prior to H2O2 exposure significantly elevated the cell survival, antioxidant enzyme activities and decreased the level of MDA. The above-mentioned neuroprotective effects are also observed with tacrine (THA, 1 microM), suggesting that the neuroprotective effects of cholinesterase inhibitor might partly contribute to the clinical efficacy in AD treatment. Further understanding of the underlying mechanism of the protective effects of these radical scavengers reducing intracellular O2*- on neuronal cell death may lead to development of new therapeutic treatments for hypoxic/ischemic brain injury.
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PMID:A water extract of Curcuma longa L. (Zingiberaceae) rescues PC12 cell death caused by pyrogallol or hypoxia/reoxygenation and attenuates hydrogen peroxide induced injury in PC12 cells. 1535 Aug 33


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