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)

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

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

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

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

Long-lasting effects of inhalation exposure to p-cymene (p-isopropyl-toluene; CAS No. 99-87-6) on regional and subcellular brain neurochemistry were studied. Male Long-Evans rats were exposed to 0, 50, or 250 p.p.m. p-cymene 6 hr/day, 5 days/week for four weeks followed by an exposure-free period of 8 weeks. Synaptosomes were isolated from whole brain minus cerebellum and used as an ex situ model for in situ conditions at the level of the presynaptic nerve terminal. There was no persistent effect on wet weight (regional) or regional noradrenaline (NA), dopamine (DA), or 5-hydroxytryptamine (5-HT) concentrations owing to exposure. Yield of synaptosomal protein was statistically significantly reduced in an exposure concentration-related manner (Control: 16.6 +/- 3.1; 50 p.p.m.: 9.2 +/- 2.1; 250 p.p.m.: 8.6 +/- 1.7 mg protein/g tissue, mean +/- I.S.D.). Synaptosomal NA and DA concentrations and acethycholinesterase, butyrylcholinesterase, and lactate dehydrogenase activities were statistically significantly increased when expressed relative to synaptosomal protein. It is hypothesized that a reduced density and number of synapses in situ are functionally compensated for by increased NA and DA release from noradrenergic and dopaminergic presynaptic nerve terminals. The applicability of the synaptosome as an ex situ neurochemical research model for the presynaptic CNS nerve terminal in situ for the study of solvent neurotoxicity in rats was further supported.
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PMID:Four weeks' inhalation exposure of rats to p-cymene affects regional and synaptosomal neurochemistry. 893 54

The effect of chronic treatment with the non-selective beta-blocker oxprenolol (CAS 6452-71-7) administered orally in two different doses (15 or 30 mg/kg/day for 6, 10 and 12 weeks) on plasma cholinesterase (PChE) activity and on the plasma level of triglyceride and total cholesterol were studied in normal rats. In all treated groups a significant increase (approximately 27-51%) of PChE activity was obtained (p < 0.05 vs. control group). The plasma concentration of total cholesterol was significantly increased as well (21-48%, p < 0.05 vs. control) but oxprenolol exerted no significant effect on plasma triglyceride levels. The increase of enzyme activity and total cholesterol were not time- or dose-dependent. According to these results which showed a direct relationship between PChE activity and total cholesterol it is supposed that the increase of enzyme activity is initially due to the action of oxprenolol on total cholesterol metabolism but that it does not have a direct effect on the enzyme. The results contribute to the hypothesis that PChE plays a role in lipoprotein metabolism although this has not yet been proven.
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PMID:Effects of oxprenolol treatment on pseudocholinesterase and lipids in rats. 929 76

In adverse drug reactions, effects accounted for by the pharmacological profile of the drug may be distinguished from sometimes bizarre, unpredictable events ("idiosyncrasies"). In the majority of cases, the latter are due to reactive intermediates formed by members of the cytochrome P450 family of enzymes. These products are usually formed at very low quantities. However, genetic disposition (e.g. by enhanced expression of the catalyzing enzyme or failure of protective factors such as glutathione) or certain external conditions (for example comedication of inducers of drug metabolism) may lead to toxic intermediates being available at relevant quantities. Once generated, these metabolites will react with macromolecules and finally cause cell necrosis. Necrosis may result from direct damage to functions essential to the cell or be secondary to harmful immune reactions activated by recognition of the new structures as neoantigens. As the principal site of drug metabolism, the liver is most frequently affected by idiosyncratic reactions, which often enough are recognized only after large numbers of patients have been treated. The idiosyncratic potential of a drug relates to its chemical structure rather than its pharmacological mechanism. Risks are evident if biotransformation yields products with chemical substructures such as quinones, phenoles, acyl halides, aromatic and hydroxyl amines. There are numerous cases of precursor drugs with idiosyncratic potential that have been replaced or marginalized by agents with more favorable chemical properties. Examples include beta 1-preferential beta-adrenoceptor antagonists (toxic precursor: practolol) and the choline esterase inhibitors used in treatment of Alzheimer's disease. In the latter group, tacrine (CAS 321-64-2) gives rise to high liver enzyme levels in about 30% of the patients, an effect not shared with more recent, chemically different entities. A similar case can be made for the insulin sensitizer troglitazone (CAS 97322-87-7) (marketed, now withdrawn in the USA) and its successors rosiglitazone (CAS 122320-73-4) and pioglitazone (CAS 111025-46-8). Due to its different chemical structure, only troglitazone can be transformed into a reactive quinone metabolite, a process that may be accelerated by the drug inducing its own metabolism. In agreement with this view, there is no evidence of specific hepatic toxicity with the two successor drugs. Ongoing progress in molecular toxicology may aid in minimizing idiosyncratic hazards already at early stages of drug development.
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PMID:From toxic precursors to safe drugs. Mechanisms and relevance of idiosyncratic drug reactions. 1210 41

In this publication, single and repeated dose experiments in rats, mice, rabbits and dogs are reported to assess the pharmacokinetics of galantamine (CAS-1953-04-4), a tertiary alkaloid with reversible cholinesterase inhibiting and nicotinic receptor modulatory properties developed for the treatment of Alzheimer's disease in humans. Rats received single i.v. and single and repeated oral administrations of various doses, up to 160 mg/kg/day. In mice, only repeated oral administration of galantamine was investigated, up to 40 mg/kg/day. Galantamine single and repeated oral doses up to 32 mg/kg/day were administered to female pregnant rabbits. Beagle dogs received single i.v. and single and repeated oral administrations of doses up to 8 mg/kg/day. Generally, oral absorption was rapid, with maximal plasma levels reached within 2 h in all species. Absolute oral bioavailability of a gavage dose was high in rat (77%) and dog (78%). In mice and rats, the bioavailability of galantamine administered via the food was lower than of galantamine administered by gavage. Elimination half-life of galantamine was relatively large in rat and dog and smaller in mouse and rabbit. In general, galantamine displayed dose-proportional to somewhat more than dose-proportional kinetics. In rats, plasma levels were lower in females than in males, whereas in mice, females showed higher levels than males. No gender differences were observed in dogs. No relevant differences in exposure to galantamine were found in rats and dogs upon oral administration of galantamine obtained as a natural extract or from chemical synthesis. The exposure to the active metabolite norgalantamine in plasma of the different animal species was low, except in the dog where the steady-state norgalantamine exposure was approximately 75% of galantamine exposure. Galantamine plasma levels after single and repeated administration of 10 mg/kg/day in all species investigated except female rat and rabbit were much higher than mean therapeutic plasma levels of galantamine obtained in humans. The pharmacokinetic profile of galantamine after repeated oral administration in rats was most similar to the profile obtained after repeated administration of 12 mg b.i.d. in man.
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PMID:Pharmacokinetics of galantamine, a cholinesterase inhibitor, in several animal species. 1291 14

Although the physiological function of serum butyrylcholinesterase (BuChE) has not yet been clarified, there is evidence that this enzyme is involved in serum lipoprotein metabolism. It has been suggested that serum BuChE is positively correlated with LDL (low-density lipoprotein) and negatively with HDL (high-density lipoprotein) levels. The objective of this study was to determine whether the activity of BuChE changes during treatment with simvastatin (CAS 79902-63-9). The effects of simvastatin therapy on serum lipoproteins and plasma BuChE activity were studied in 15 patients with type IIa and 17 patients with type IIb hyperlipoproteinemia. Beside the expected influence on serum lipid concentration, a statistically significant decrease in BuChE activity in patients with hyperlipoproteinemia type IIa and IIb during treatment with simvastatin was not observed.
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PMID:Clinical study on the effect of simvastatin on butyrylcholinesterase activity. 1596 Apr 26

The effects of chronic treatment with oxprenolol (CAS 6452-72-7, OXP, 15 mg/ kg/ day) or glibenclamide (CAS 10238-21-8, GL, 2.5 mg/kg/day), or their combination administered for 6 and 12 weeks, on the butyrylcholinesterase (BuChE) activity in plasma and liver and on the plasma levels of triglycerides, total cholesterol and high density lipoprotein (HDL)-cholesterol were studied in normal, non-diabetic female rats. In all treated groups a significant increase of plasma BuChE activity was obtained after 6 weeks of either OXP (46 %), or GL (36 %) treatment, or of their concurrent application (24 %). After 12 weeks of treatment, the increase in enzyme activity was significant only in the OXP group. The BuChE activity in the liver was increased (between 3-25 %) in all treated groups except in one during 6 and 12 weeks of treatment. These effects of either OXP or GL, or their combination on BuChE activity in liver suggest their stimulating effects on enzyme synthesis. The changes of total plasma cholesterol in all groups were insignificant. On the other hand, HDL-cholesterol was significantly decreased in all treated groups. After 6 weeks of treatment, GL, OXP, or their combination caused a decrease in plasma HDL cholesterol by 19, 50 or 22 % respectively, when compared with the control group. After 12 weeks of GL, OXP, or GL+OXP administration, HDL-cholesterol plasma levels in treated groups were 32, 25 and 22 % lower than in the control group. Treatment with GL, OXP, or GL+OXP during 6 weeks had no significant effect on triglycerides level. However, after 12 weeks of GL, OXP, or GL+OXP administration, the triglycerides levels were significantly increased (9, 47 and 36 %) when compared with the control group. These results showed that the increase in BuChE activity might be the first sign of altered triglyceride and lipoprotein metabolism.
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PMID:Changes in butyrylcholinesterase activity and serum lipids after oxprenolol and glibenclamide treatments in non-diabetic rats. 1657 19


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