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)

In a previous pharmacokinetic study in Alzheimer patients great inter-individual variation and low oral bioavailability of the cholinesterase inhibitor tacrine (tetrahydroaminoacridine, THA) were found. In the present investigation oral and rectal administration of tacrine were compared with the aim to find a route for improved bioavailability through diminished first-pass metabolism in the liver. Eight patients suffering from Alzheimer's dementia were given tacrine by oral (25 and 50 mg b.i.d.) and rectal (12.5 and 25 mg b.i.d.) routes for 1 week with 4-6 weeks washout in between. Drug hydroxylation capacity in the patients was determined using the debrisoquine test. Levels of tacrine in plasma and cerebrospinal fluid (CSF) were determined and the cognitive performance was examined by the Mini-Mental State Examination (MMSE) and the Alzheimer Deficit Assessment Scale (ADAS). Tacrine was well tolerated in all but one patient, a slow hydroxylator, who developed an aplastic anemia. MMSE and ADAS scores did not significantly change, except for word recall which was improved on tacrine when given by the rectal route. Pharmacokinetic analysis of the two administration routes revealed that the drug dose may be reduced by almost 50% when given rectally compared to orally. Concentrations of tacrine in the CSF were significantly lower and correlated linearly with the concentrations in plasma.
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PMID:Tacrine in Alzheimer's disease: pharmacokinetic and clinical comparison of oral and rectal administration. 786 48

Brain imaging techniques will in the future play an important role in the assessment of patients with neurogenerative disorders such as Alzheimer's disease (AD). An early diagnosis of AD is today hampered by lack of reliable diagnostic markers. Positron emission tomography (PET) permits the quantification and three-dimensional imaging of physiological variables. This provides the clinician with a non-invasive imaging technique which allows in vivo quantification of physiological processes in AD underlying dysfunction of cognition. PET studies regarding changes in cerebral blood flow and metabolism are rather consistent at least in moderate/advanced cases of AD. How early in the progress of the disease deficits in these parameters can be observed is still an open question. Longitudinal studies will here be important and especially in individuals with a family history of AD. Since deficits in cholinergic neurotransmission have been measured in autopsy AD brains attempts have also been made to visualized cholinergic activity in vivo. Nicotinic and muscarinic receptors have been visualized in normal and AD brains. A reduced uptake and binding of [11C]nicotine in the temporal and frontal cortices have been measured in AD patients by PET. Few treatment studies in AD have been evaluated by PET. Long-term treatment with the cholinesterase inhibitor tacrine increase the uptake of [11C]nicotine. Significant reduction in uptake between the two enantiomers (S)(-) and (R)(+)-[11C]nicotine has been observed compatible with a restoration of nicotinic receptors. Tacrine also significantly increased the glucose metabolism. PET studies indicate that long-term tacrine treatment in AD patients with mild dementia improves functional activities in brain. When an AD patient with moderate dementia was treated with nerve growth factor (NGF) PET studies revealed increase in cortical blood flow and nicotinic receptors. PET studies will in the future play an important role in the evaluation of new therapeutic drug strategies in AD.
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PMID:Clinical studies in Alzheimer patients with positron emission tomography. 790 47

Tacrine, a cholinesterase inhibitor, has beneficial effects on cognition and global status in patients with Alzheimer's disease. These effects have been demonstrated in clinical trials by double-blind comparisons with placebo. Tacrine dosages have been studied in 5 protocols that used either enrichment or parallel designs. We have used a population pharmacodynamic model to describe the response to tacrine and placebo in the 3 trials that used the enrichment design. The time-course of the response and its relation to tacrine dosage obtained from the enrichment design analysis were used to define the parallel design. The effects of tacrine on cognition and global status was estimated separately from each trial. Analysis of the 2 trials using the parallel design confirmed the predictions from the enrichment design. By combining the data from all 5 trials it was possible to show that tacrine potency was similar in all studies, but that the placebo response was different in some. The effect of tacrine was linearly proportional to dosage from 40 to 160 mg per day. One of the enrichment design trials included a sub-group treated with lecithin, a choline precursor. The potency of lecithin was equivalent to about 40 mg per day of tacrine. Using the combined data from all 5 trials it was possible to distinguish a responder population, approximately one-third of all patients, with a 4-fold greater effect compared with poor responders. Tacrine has beneficial effects on cognitive status in patients with Alzheimer's disease. Lecithin has a small additional benefit independent of tacrine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effect of tacrine and lecithin in Alzheimer's disease. A population pharmacodynamic analysis of five clinical trials. 798 19

We examined the effects of tacrine (9-amino-1,2,3,4-tetrahydroacridine) on endogenous acetylcholine (ACh) release from rat hippocampal slices. Tacrine (more than 1 microM) increased the measurable amount of basal ACh release. On the other hand, in the presence of physostigmine (50 microM; under this condition, cholinesterase activity was inhibited), tacrine did not enhance the basal ACh release. Tacrine at more than 100 microM increased the submaximal electrical stimulation-evoked release of ACh in both the absence and presence of physostigmine (50 microM). This effect of tacrine was abolished by a combination of atropine (100 mM) and physostigmine. These results indicate that a high-dose of tacrine increases cholinergic neurotransmission not only by inhibition of cholinesterase but also by increasing ACh release through an atropine-like effect, perhaps by blockade of part of the process of muscarinic autoinhibition.
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PMID:Tacrine increases stimulation-evoked acetylcholine release from rat hippocampal slices. 799 Feb 71

1. The acetylcholinesterase inhibitors physostigmine, neostigmine, tetrahydroaminoacridine (tacrine; THA) and diisopropylfluorophosphate (DFP) were tested for possible direct nicotinic actions in rat striatal synaptosomes preloaded with [3H]-dopamine. In this preparation, nicotinic cholinoceptor activation evoked [3H]-dopamine release. 2. Antagonist activity was examined by giving a brief nicotine (1 microM) challenge after 30 min superfusion with an acetylcholinesterase (AChE) inhibitor (0.3-300 microM). Physostigmine, neostigmine and tacrine produced a concentration-dependent blockade. Physostigmine and tacrine were particularly potent (IC50S approx. 10 microM and 1 microM, respectively). DFP reduced nicotinic responses only at the highest concentration tested (300 microM). 3. Nicotinic blockade produced by superfusion with physostigmine (30 microM) was insurmountable when tested against nicotine (0.1-100 microM). 4. Physostigmine (30 microM) also reduced responses to the nicotinic agonists 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) and cytisine, but did not alter responses to high K+ or (+)-amphetamine. A higher concentration of physostigmine (300 microM) completely blocked responses to nicotine, somewhat reduced responses to amphetamine, and did not alter responses to high K+. Tacrine (3 microM) reduced responses to nicotine and to high K+ but did not affect responses to amphetamine. 5. Physostigmine (0.3-300 microM), given as a brief pulse, did not produce a nicotinic agonist-like effect. 6. Physostigmine, neostigmine, tacrine and DFP (all at 30 microM) each produced near-total (> 96%) inhibition of AChE activity. However, DFP at a concentration (60 microM) that produced a degree of AChE inhibition equal to that of physostigmine 30 microM, did not significantly reduce nicotine-induced dopamine release. 7. It thus appears that physostigmine blocks CNS nicotinic receptors in an insurmountable and pharmacologically selective manner, independent of its ability to inhibit acetylcholinesterase. Tacrine reduced nicotinic responses, quite possibly by an indirect mechanism. The possibility of direct or indirect blockade of nicotinic receptor-mediated actions may complicate the interpretation of preclinical studies that have employed physostigmine and tacrine.
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PMID:Blockade of nicotinic responses by physostigmine, tacrine and other cholinesterase inhibitors in rat striatum. 801 48

This article has discussed various possible pharmacologic approaches to Alzheimer's disease. Despite generally encouraging results, no agent to date has proved to be dramatically effective. At present, treatment options are limited for the clinicians. Tacrine is available on the market. In the doses recommended, efficacy is modest, and side effects require vigilance in monitoring. Other cholinesterase inhibitors may be approved for clinical use in the near future but are likely to have similar modest clinical effects. L-deprenyl is marketed for Parkinson's disease but has not been adequately tested for efficacy in Alzheimer's disease. Newer drugs in earlier stages of development are generally intended to affect cholinergic systems in various other ways. The effects of these drugs on behavioral symptoms, in severe dementia, and in non-Alzheimer's dementia have not been adequately assessed. In the absence of known cause, and in the face of uncertainty regarding pathophysiology, efforts in the near future will focus on encouraging theoretical leads, sensible empiric trials, and symptomatic treatment research. Although public anticipation will be raised over each announced "breakthrough," only results from carefully conducted trials should be accepted.
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PMID:Emerging drugs for Alzheimer's disease. Mechanisms of action and prospects for cognitive enhancing medications. 802 37

The characteristic features of Alzheimer's disease (AD) include a high density of beta-amyloid-containing plaques in the cerebral cortex and the loss of basal forebrain cholinergic neurons. Amyloid beta-protein (A beta, Mr. approximately 4.5 kDa) is derived from a family of large (Mr. approximately 110-140 kDa) beta-amyloid precursor proteins (APP) which are integral membrane glycoproteins consisting of a large extracytoplasmic domain, a transmembrane domain, and a short cytoplasmic tail. Secreted derivatives of APP lacking the cytoplasmic tail, transmembrane domain, and a small portion of the extracellular domain are generated by the proteolytic processing of full length APP by a family of proteolytic enzymes known as APP secretases. Using cell cultures, we investigated the possibility that APP processing can be regulated by a centrally active cholinesterase inhibitor, tacrine, which has recently been shown to improve memory and cognitive functions in patients with AD. We analyzed the level of APP in glial, fibroblast, pheochromocytoma (PC12), and neuroblastoma cells by immunoblotting cell lysates and conditioned media. Normal levels of secretion of soluble APP derivatives by cells into conditioned media were severely inhibited by treating cells with tacrine. A similar decrease after treatment with tacrine was observed when neuroblastoma and PC12 cells were pretreated with either growth factors, phorbol ester, or retinoic acid. To determine whether the effect of tacrine on APP levels was specific or a more general phenomenon affecting other proteins, we measured the level of heat shock protein-70 (HSP-70) and another secretory protein, protease nexin-1 (PN-1). Tacrine treatment did not alter the level of HSP-70 in cell extracts and tacrine affected mildly the secretion of PN-1. Thus, the processing of HSP and PN-1, unlike APP, was not severely affected by treating cells with tacrine. Our results suggest that tacrine may inhibit an acetylcholinesterase-associated proteolytic activity involved in the secretion of APP, which results in less secretion of soluble APP into the conditioned media from tacrine treated cells. These results demonstrate that tacrine regulates APP secretion in cell cultures and suggest the possibility that tacrine therapy of Alzheimer's disease may, in the longer term, have effects on the process of A beta deposition.
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PMID:Tacrine alters the secretion of the beta-amyloid precursor protein in cell lines. 804 78

Tacrine, a centrally acting cholinesterase inhibitor, may improve cognitive and functional status in patients with mild to moderate Alzheimer's disease. In recent controlled trials, patients have shown improvement in cognitive assessment scores, but the clinical significance of such benefits remains unclear. Appropriate diagnostic evaluation is necessary to prevent inappropriate treatment in patients with non-Alzheimer's dementia. Hepatotoxicity and gastrointestinal symptoms are common adverse effects of tacrine, and frequent monitoring of liver function is required.
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PMID:Tacrine therapy for the dementia of Alzheimer's disease. 807 12

Tacrine (THA) was evaluated in vitro and in vivo as a pretreatment for nerve agent intoxication. In vitro experiments showed that the primary effect of THA was direct inhibition of purified fetal bovine serum acetylcholinesterase (AChE) with a slight effect on slowing the aging rate of nerve agent-inhibited AChE. THA produced significant behavioral effects at doses above 1.7 mg/kg, i.m., in the mouse and 3.4 mg/kg, i.m., in the guinea pig. At the no observable effect level (NOEL) for mice (1.7 mg/kg), THA was effective (P < or = 0.05) in reducing tabun- and soman-, but not sarin-induced lethality in mice. Experiments in the guinea pig showed that at the NOEL (3.4 mg/kg, i.m.) THA was not effective in decreasing lethality due to soman exposure. Since there was significant overlap between pharmacologically effective doses of THA and those which produce behavioral toxicity, THA was not considered a suitable pretreatment for nerve agent intoxication.
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PMID:Efficacy of tacrine as a nerve agent pretreatment. 816 31

The anticholinesterase properties of tetrahydroaminoacridine (THA, Tacrine), alpha-tocopheryl hemisuccinate (TS), and cholesteryl hemisuccinate (CS), given alone and in combination, were examined in vitro. Results from these studies indicate that: [1] THA is a potent inhibitor of acetylcholinesterase (AChE, IC50 of 0.40 microM) and butyrylcholinesterase (BChE, IC50 of 0.10 microM) with greatest inhibitory activity towards BChE; [2] TS and CS are weak inhibitors of BChE (IC50 of 100 microM and 168 microM, respectively) but potent inhibitors of ACHE (IC50 of 1.73 microM and 0.79 microM, respectively); [3] both TS and CS treatment in combination with THA significantly increased THA's anticholinesterase activity. The percentage AChE inhibition observed with this combination was often significantly greater than the sum of the individual values (synergistic). The addition of 0.5 microM CS or TS to an ACHE preparation reduced THA's IC50 value from 0.40 microM or 0.18 microM, respectively [4]; inhibition of AChE by THA, TS and CS are mixed non-competitive while THA inhibition of BChE is mixed non-competitive and TS and CS inhibition of BChE are simple non-competitive; and [5] inhibition of cholinesterases by TS and CS occurs immediately (50 to 75%), during the first 30 min of incubation (25 to 50%) and is dependent on the anionic charged portion of the molecule. In conclusion, our experimental data indicate that TS and CS are potent inhibitors of AChE activity and significantly potentiate the anticholinesterase activity of THA. Such potent and synergistic inhibition of AChE suggest that TS or CS, alone and in combination with THA, may prove beneficial in the treatment of organophosphate poisoning and Alzheimer's disease.
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PMID:Inhibition of cholinesterase activity by tetrahydroaminoacridine and the hemisuccinate esters of tocopherol and cholesterol. 818 46


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