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)

The effects of nefiracetam (DM-9384, CAS 77191-36-7) on the learning behavior and cholinergic and GABAergic neuronal transmitter systems of rats with experimentally-induced cerebral embolism were investigated. Cerebral embolisms were induced in male Wistar rats by injection of 800 microspheres 50 microns in diameter via the left internal carotid artery under 2% halothane anesthesia. Daily oral administration of nefiracetam (30 mg/kg/d) was started 9 days after embolization. Nefiracetam caused significant (p < 0.05) improvement of deficits in the learning of both water maze and passive avoidance tasks beginning 22 days after embolization of the rats. The drug also significantly restored decreases in cortical choline acetyltransferase (p < 0.05) and hippocampal glutamic acid decarboxylase activities (p < 0.01) in the embolized cerebral hemisphere and significantly increased cortical choline acetyltransferase (p < 0.05) and acetylcholinesterase activities (p < 0.05) in the contralateral cerebral hemisphere 21 days after embolization. These results demonstrate that nefiracetam improves cognitive dysfunction in the late phase in embolized rats and suggest that the effect is at least partly due to the increase in glutamic acid decarboxylase, choline acetyltranseferase and acetylcholinesterase activities.
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PMID:Effects of the new cognition-enhancing agent nefiracetam in rats with cerebral embolism. 149 38

Between January, 1986 and September, 1988, the Taiwan National Poison Center recorded 97 telephone consultations (49 male, 48 female) on cases of ingestion of glyphosate-surfactant herbicide concentrate containing the isopropylamine salt of glyphosate (N-phosphonomethyl glycine, CAS 1071-83-6) and a non-ionic tallow amine surfactant. Eleven of the cases resulted in fatalities, all among those attempting suicide. The average amount ingested by survivors was 120 +/- 112 mL and by nonsurvivors was 263 +/- 100 mL (p less than or equal to 0.0001). The average age of survivors was 35 +/- 15 years compared to 54 +/- 11 years for fatalities (p less than or equal to 0.0002). Irritation of the oral mucous membrane and gastrointestinal tract was the most frequently reported effect. Other effects recorded were pulmonary dysfunction, oliguria, metabolic acidosis, hypotension, leukocytosis and fever. Fourteen patients received either atropine or pralidoxime plus atropine despite the fact that glyphosate does not inhibit acetylcholinesterase. Thirteen percent of patients received a urine test for paraquat or treatment customarily used for paraquat ingestion, possibly reflecting similar initial presentations following ingestion of these two herbicides. Laboratory differentiation is essential if any doubt exists about which herbicide was ingested. Patients ingesting large volumes of concentrated glyphosate-surfactant herbicide formulations require close observation and supportive treatment.
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PMID:Taiwan National Poison Center survey of glyphosate--surfactant herbicide ingestions. 200 70

One hour after suicidal ingestion of about 20 mL of a 38% solution of bromofosmethyl, CAS: 2104-96-3 (bromophos), a 52 year-old female was admitted to the hospital with extreme miosis, hypersalivation, hyperperistalsis and muscular fibrillation. Gastric lavage was performed and activated charcoal administered. Cholinergic symptoms were antagonized by repeated doses of 0.5 mg atropine. Because of the high dose of bromophos, hemoperfusion was performed with amberlite XAD4. The bromophos clearance during hemoperfusion was 95 mL/min (flow 200 mL/min). The patient received two doses of 500 mg obidoxime for recurrent muscular fibrillation. The further clinical course was uneventful. On day 4, the patient was transferred to a psychiatric ward because of persistent suicidality. In contrast to poisoning by most organophosphates, red blood cell acetyl cholinesterase was only minimally depressed but the plasma butyryl cholinesterase was initially decreased and normalized within a few days. The records of 25 patients reported to our Poison Control Center with ingestion of more than 1 g bromophos were also evaluated. The most frequent symptoms were miosis, hyperperistalsis, hypersalivation, agitation, nausea/vomiting and convulsions. Nine of the patients had no symptoms. Bromophos is relatively less toxic than its phosphate derivative, parathion.
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PMID:Acute poisoning with bromofosmethyl (bromophos). 205 7

The effect of fasting, atropine, and poisoning by an organophosphate anticholinesterase soman (pinacolyl methylphosphonofluoridate) on the pharmacokinetics of the acetylcholinesterase oxime reactivator HI-6 (CAS Reg. No. 34433-31-3; 1-[(4-(aminocarbonyl)pyridinio)methoxy)methyl)-2-(hydroxy imino)methyl) pyridinium dichloride) was investigated. Pharmacokinetic parameters (elimination half-life, volume of distribution, clearance rate) were determined for the following groups: (1) a 20 and 50 mg kg-1 dose of HI-6; (2) a 50 mg kg-1 dose of HI-6 after fasting for 18 h (water ad lib); (3) a 50 mg kg-1 dose of HI-6 at 0, 4, and 24 h after atropine (17.4 mg kg-1, i.p.) and soman (287 micrograms kg-1, s.c.); and (4) a 50 mg kg-1 dose of HI-6 at 0 and 4 h after soman (100 micrograms kg-1, s.c.). Fasting increased significantly (p less than 0.05) the elimination of half-life (t1/2) and tended to increase the volume of distribution (Vd) and decrease the clearance rate (CL). Following soman (287 micrograms kg-1) poisoning the t1/2 of HI-6 increased from 8.6 min to 21.6 min and the Vd increased to 0.731 kg-1. At the lower soman dose (100 micrograms kg-1) no significant effect on HI-6 pharmacokinetics was found. Atropine (17.4 mg kg-1: i.p.) pretreatment increased the t1/2 and CL while having no effect on the Vd. By 24 h the pharmacokinetic parameters of HI-6 in the various treatment groups were not significantly different from the control group. The changes in the pharmacokinetics of HI-6 following soman and atropine are probably the result of haemodynamic changes.
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PMID:Effect of poisoning by soman (pinacolyl methylphosphonofluoridate) on the serum half-life of the cholinesterase reactivator HI-6 in mice. 337 Mar 6

Oxamyl (methylN',N'-dimethyl-N-[(methylcarbamoyl)oxy]-1-thiooxam imidate; CAS 23135-22-0) was tested for oral toxicity in the rat and dog (90-day and 2-year feeding studies) and in the mouse (2-year feeding study). Teratogenic potential was evaluated in the rat and rabbit and functional reproductive capacity was studied in the rat in a one- and a three-generation reproduction study. Rats fed a diet containing oxamyl at 500 ppm showed clinical signs of cholinesterase inhibition and body weight loss within 2 days. Feeding of either 100 or 150 ppm oxamyl for 90 days produced a reduced rate of weight gain without other signs of response, and no effects were detected at 50 ppm. An oxamyl feeding period of 2 years also showed depressed body weight gains in rats fed either 100 or 150 ppm. Cholinesterase activity was depressed only during the first week of feeding and only in the 150-ppm group. All other indices of response, including the type and distribution of tumors, were similar in the test and control rats and it was concluded that the no-observed-effect level was 50 ppm (equivalent to approximately 5 mg/kg). Mice fed oxamyl at 100 ppm for 6 weeks showed signs of cholinesterase inhibition and some mortalities, so the dietary concentration was reduced to 75 ppm in the 2-year study. Body weights of mice fed oxamyl at 50 or 75 ppm were lower than controls during the first 6 months of the study. No other signs of a toxic response to oxamyl were seen in mice and a no-observed-effect level of 25 ppm (approximately 2.5 mg/kg) was assigned to this compound. No evidence of a tumorigenic response was obtained. Dogs fed oxamyl at 150 ppm for 2 years showed marginal increases in serum alkaline phosphatase activity and cholesterol concentration but no tissue pathology was seen. No evidence of cholinesterase inhibition was seen. It was concluded that the no-observed-effect level for oxamyl in the dog was 100 ppm (approximately 2.5 mg/kg). In the one- and three-generation reproduction studies, litter sizes were somewhat lower in rats fed oxamyl at 100 or 150 ppm oxamyl with normal values seen at 50 ppm. Weanling body weights were normal in rats in the 50-ppm group for three generations but were reduced in the one-generation study. Pup body weights were lower in rats in both the 100- or 150-ppm groups.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Chronic toxicity, reproductive, and teratogenic studies with oxamyl. 373 61

Inhibition of acetylcholinesterase (AChE) in the whole brain, cerebellum, pons, frontal cortex, basal ganglia and medulla oblongata of rat brain by physostigmine (CAS 57-47-6) in vitro was studied. Constants characterizing this inhibition namely: binding constant (KI) and bimolecular rate constant (K'2) were determined. The highest values of K'2 were obtained in the cases of pons and medulla oblongata, the parts responsible for the respiratory and vital centers. The difference in the inhibition of AChE in the different parts of the brain could be due to the difference in the grey and white matters contents in these parts.
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PMID:Effect of physostigmine on cholinesterase activity in different parts of rat brain. 764 66

Loss of cholinergic function in the neocortex and hippocampus arising from death or atrophy of basal forebrain cholinergic neurons is a consistent feature of the Alzheimer brain at autopsy or biopsy. Replacement of lost cholinergic function, therefore, may be of therapeutic benefit to the Alzheimer's (AD) patients. This can be accomplished by enhancing endogenous levels of acetylcholine (ACh) through inhibition of its degradation by acetylcholinesterase on by directly mimicking its actions at postsynaptic muscarinic receptors. Initial efforts focused on inhibition of cholinesterase activity with tacrine (1,2,3,4-tetrahydroaminoacridine monochloride, CAS 1684-40-8, THA, Cognex). Tacrine is a mixed, reversible inhibitor of cholinesterase activity that binds near but not to the catalytically active serine in the active site of the enzyme. Through this action tacrine indirectly elevates ACh levels in the brains of animals and improves cognitive performance in rodents and monkeys. More importantly, tacrine has been shown to significantly improve several measures of cognitive performance in probable AD patients in well-controlled clinical trials, although not all patients respond to this agent. CI-979 ((E)-1,2,5,6-tetrahydro-1-methyl-3-pyridine-carboxyaldehyde-O-meth yl oxime, CAS 139886-04-7) is a non-subtype selective, partial muscarinic agonist that enhances cognitive performance and increases central cholinergic activity in rodents at doses below those required to increase peripheral cholinergic tone. In normal healthy volunteers, CI-979 is well tolerated at single and multiple doses (q 6 h) up to 1.0 mg. In normal healthy volunteers, CI-979 is well tolerated at single and multiple doses (q 6 h) up to 1.0 mg. Expected signs of mild to moderate peripheral cholinergic stimulation were noted at 0.5 to 1.0 mg doses (q 6 h).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cholinergic therapies for Alzheimer's disease. Palliative or disease altering? 776 38

MDL 73,745 (2,2,2-trifluoro-1-(3-trimethylsilylphenyl) ethanone, CAS 132236(18-1) is a novel tight-binding inhibitor of acetylcholinesterase (AChE), which is in development as a potential therapeutic compound in the symptomatic treatment of Alzheimer's disease. Pharmacokinetics and pharmacodynamics of the compound were studied in the dog after single intravenous (i.v. 2 mg/kg), oral p.o. 10 mg/kg) and sub-cutaneous (s.c., 10 mg/kg) administrations of [14C]-MDL 73,745. Plasma concentrations of total radioactivity were much higher than those of parent drug after i.v., p.o. and s.c. administration, indicating extensive metabolism of the compound, although this was less after, s.c. administration than after p.o. administration. The bioavailability (F) was 34% after s.c. administration, compared with 4% after p.o. administration. The low bioavailability after p.o. administration was not due to poor drug absorption, as over 64% of the dose was absorbed. Pharmacokinetic parameters, calculated after i.v. administration, showed a terminal elimination half-life of 24 h, total body plasma clearance of around 70 ml/min/kg and apparent volume of distribution of 150 l/kg. AChE activity was almost 100% inhibited after i.v. administration, and over 80% inhibited 1 h after p.o. administration. In both cases, AChE activity returned to baseline levels by 12 h. AChE was around 80% inhibited 4 h after s.c. administration, and did not return to baseline levels until 36 h after drug administration. A combined pharmacokinetic-pharmacodynamic (PK-PD) effect model demonstrated that the extent of AChE inhibition could be correlated with plasma levels of the parent compound. As s.c. administration increased F, and led to longer AChE inhibition, transdermal (t.d.) delivery was assessed in the same animals. Patches, corresponding to a dose of 50 mg/kg, were applied to the shaved lateral abdominal skin for a period of 96 h. Sustained plasma concentrations of the parent drug were observed over the 96 h period of t.d. application. Mean (+/- SD) maximum plasma concentrations (Cmax) of 26.9 +/- 4.3 ng/ml were found 3.7 +/- 2.5 h after t.d. patch application und F was around 13%. AChE inhibition reached a maximum of 72% at 6 h after t.d. application and was still 35% at 96 h. The rate of release from the delivery system, per unit surface area, (ko) was calculated to be 7.7 micrograms/cm2. Transdermal delivery of MDL 73,745 thus decreased the important hepatic first-pass effect, and led to sustained plasma concentrations of drug, thus avoiding peaks and troughs which could lead to side-effects or poor efficacy.
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PMID:Pharmacokinetics and pharmacodynamics of the acetylcholinesterase inhibitor 2,2,2-trifluoro-1-(3-trimethylsilylphenyl) ethanone in dog. Potential for transdermal patch delivery. 859 78

The pharmacological properties of MKC-231 (2-(2-oxopyrrolidin-1-yl)-N- (2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl) acetoamide, CAS 135463-81-9) in comparison with an acetylcholinesterase (AChE) inhibitor, tacrine (CAS 1684-40-8) were studied. MKC-231(10(-10)-10(-6) moll) significantly increased high affinity choline uptake (HACU) when it was incubated with the hippocampal synaptosomes of ethylcholine mustard aziridinium ion (AF64A) treated rats, but not of normal rats. MKC-231 did not affect the AChE activity, [3H]- quinuclidinyl benzilate binding, and [3H]-pirenzepine binding. Oral administration of MKC-231 (1-10 mg/kg) significantly improved the learning deficits in the Morris' water maze of AF64A-treated rats, but it did not produce any significant side effects, like tremor, salivation or hypothermia, which were observed in rats treated with high doses of tacrine. Tacrine (0.1-3 mg/kg p.o.) failed to ameliorate the learning deficits in AF64A-treated rats. These results suggest that MKC-231 is a novel and quite unique compound, which improves the memory impairment induced by AF64A through the enhancement of HACU without any side effects at the effective doses.
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PMID:Effect of the novel high affinity choline uptake enhancer 2-(2-oxopyrrolidin-1-yl)-N-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b] quinolin-4-yl)acetoamide on deficits of water maze learning in rats. 874 80

One-month oral toxicity of (S)-10-[(S)-(8-amino-6-azaspiro[3,4] octan-6-yl)]-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de] [1,4]benzoxazine-6-carboxylic acid hemihydrate (CAS 151390-79-3, DV-7751a) a new quinolone antibacterial agent was investigated in Sprague-Dawley rats at doses of 12.5, 50, 200 and 800 mg/kg/d and in cynomolgus monkeys at 10, 30 and 100 mg/kg/d. Rats receiving 200 mg/ kg showed abnormal urine crystals, enhanced deposition of lipid in hepatocytes and exacerbation of osteochondrotic lesions in the femoral condyle. In addition, dosing at 800 mg/kg induced decrease in body weight gain and increased levels of serum alkaline phosphatase (ALP), cholinesterase, leucine aminopeptidase and total cholesterol. Monkeys receiving 100 mg/kg showed abnormal urine crystals and increases in serum glutamic oxaloacetic transaminase, glutamic pyruvic transaminase and ALP levels. The non-toxic doses of DV-7751a in rats and monkeys were 50 and 30 mg/kg, respectively, under the present experimental conditions.
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PMID:One-month oral toxicity study of the new quinolone antibacterial agent (S)-10-[(S)-(8-amino-6-azaspiro[3,4]octan-6-yl)-9-fluoro-2,3-dihydro-3- methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid hemihydrate in rats and cynomolgus monkeys. 884 43


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