Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In mice chronically treated with ethanol (in a liquid diet containing 6% ethanol ad libitum for 2 weeks), brain tryptophan hydroxylase (TPH) activity was increased (by 30-45% in whole brain), while brain tyrosine hydroxylase activity remained unchanged. Such chronic ethanol treatment also induced susceptibility to audiogenic seizures during withdrawal (60% incidence). When ethanol treatment was given to adrenalectomized (Adx) mice, the increase of brain TPH activity and the development of withdrawal audiogenic seizures were both prevented. In Adx mice receiving daily injections of corticosterone (0.5 mg/mouse), the ethanol-induced increase of brain TPH activity and the occurrence of withdrawal audiogenic seizures were both restored. Similarly, the ethanol-induced increase of liver alcohol dehydrogenase activity (by 60%) was prevented in Adx mice and restored by corticosterone replacement. It was noted that in all three cases replacement with such large doses of the corticoid did not enhance the ethanol effects, but merely restored the effects to the levels observed in intact mice. Apparently, glucocorticoids are required in a permissive role in order for the ethanol effects to occur.
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PMID:The permissive role of glucocorticoids in the development of ethanol dependence and tolerance. 2 Oct 65

4-Methylpyrazole (4 MP) is a strong inhibitor of alcohol dehydrogenase. Its use in acute ethylene glycol (EG) or methanol intoxication has been suggested in experimental studies about its efficacy and safety. We report three cases of accidental intoxication with ethylene glycol in man treated orally with 20 mg/kg/day of 4 MP. The treatment was maintained until plasma EG concentrations became unmeasurable. The patients were admitted early during the course of the poisoning. Their neurological status was good. A slight metabolic acidosis observed in two cases was easily corrected and did not recur. Renal function remained normal in all cases. No patient underwent hemodialysis. On admission plasma EG concentrations were 24.2 mmol/l, 13 mmol/l and 9.7 mmol/l respectively. Plasma EG half-lives were 14.5, 11.5 and 14.75 hours respectively. Plasma oxalate concentrations and the rate of urine oxalate elimination, determined in two patients, were high on admission but quickly returned to normal. Concerning possible side effects of 4 MP, a skin rash was observed in one patient and a possible eosinophilia in the others. These three cases suggest that 4 MP may decrease the metabolic consequences of EG poisoning in man and may be of therapeutic value when administered early during the course of the intoxication before coma, seizures and organic renal failure have occurred.
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PMID:4-Methylpyrazole may be an alternative to ethanol therapy for ethylene glycol intoxication in man. 357 22

We are engaged in a selective breeding program developing lines of mice which differ in severity of withdrawal convulsions after ethanol treatment. Withdrawal seizure prone (WSP) mice show greater handling-induced convulsion scores than withdrawal seizure resistant (WSR) mice after 3 days of ethanol intoxication. In the present experiments, we sought to characterize these mice further as a model of genetic susceptibility to ethanol dependence and withdrawal. During withdrawal after chronic treatment with ethanol, WSP mice displayed more severe handling-induced convulsions and tremor than WSR mice, and tended to show greater reduction of exploratory activity. WSP and WSR mice did not differ in ethanol metabolism after acute treatment with ethanol alone or after chronic treatment with ethanol and pyrazole, an alcohol dehydrogenase inhibitor. Six to 10 hr after an acute injection of ethanol, WSP and WSR mice showed elevated handling-induced convulsions. This elevation was more pronounced in WSP mice than in WSR mice. WSP mice also showed slightly more severe convulsions than WSR mice when treated with saline or pyrazole alone. In summary, WSP and WSR mice treated with identical doses of ethanol differ in several symptoms of withdrawal, whereas not differing in ethanol metabolism. These mice constitute a useful population in which to study the molecular mechanisms of ethanol dependence and withdrawal.
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PMID:Ethanol withdrawal in mice bred to be genetically prone or resistant to ethanol withdrawal seizures. 372 96

The exposure in humans to ethanol or barbiturates during prenatal or neonatal development is common. There are indications that the magnitude of the resulting symptoms may be genetically determined. In the present article, an animal model was established for the study of the genetic determination of the neurosensitivity to ethanol and barbiturates administered during prenatal and/or neonatal development. Inbred C57BL/10 (C57) and DBA/1 (DBA) mice were employed in the ethanol studies and these strains and the outbred HS/Ibg (HS) were used in the barbiturate studies. Early ethanol administration induced a long lasting increase in the susceptibility to audiogenic seizures in both strains but to a greater degree in C57. Neuropharmacological studies implicated the serotonergic but not the noradrenergic system as mediating the early ethanol induced changes in audiogenic seizures. Open field activity was decreased but only in C57. Male agonistic behavior and predatory behavior were greatly reduced by early ethanol administration but mainly in DBA. Long term induction of the activity of the hepatic enzymes, alcohol dehydrogenase and microsomal ethanol oxidizing system, occurred in both strains after early exposure to ethanol. After early exposure to phenobarbital HS mice had long lasting increases in the susceptibility to audiogenic seizures and in the hippocampus related behaviors, spontaneous alternations and eight arm maze performance. The hepatic microsomal drug oxidizing system was induced in adult HS mice with early phenobarbital (PhB) exposure. Early PhB exposure also caused long term decreased sensitivity to ethanol narcosis and an accelerated acquisition to barbiturate tolerance, possibly mediated via a change in the sensitivity of the post synaptic dopamine receptors. Changes in the PhB treated offspring also included a reduction in the levels thyroid hormone. Early exposure to PhB resulted in a long term deficit in the area of brain layers, number of neurons, dendritic spines and the ultrastructure. Strain comparison suggested that DBA was less neurosensitive to early PhB administration than both HS and C57. It was concluded that genotype-environment interaction exists in the effect of drugs on the developing CNS.
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PMID:Genetic factors in drug neuroteratogenicity. 635 25

Withdrawal Seizure-Prone (WSP) and -Resistant (WSR) mice have been bidirectionally selected for severity of handling-induced convulsions (HIC) following withdrawal from 72 hr of chronic ethanol vapor inhalation. During selection, daily injections of the alcohol dehydrogenase inhibitor, pyrazole, were used to enhance and stabilize blood ethanol concentrations (BEC). After 26 generations of selection, WSR mice show lower withdrawal BEC than WSP mice exposed to the same ethanol vapor concentrations. Because it is desirable to compare mice maintained at the same BEC to assess correlated responses to selection, this has necessitated exposing WSR mice to higher ethanol vapor concentrations than WSP mice to achieve matched chronic BEC. The experiments reported herein demonstrate two methods for producing matched withdrawal BEC: (1) by exposing mice to the same ethanol vapor concentration and varying the pyrazole dose; and (2) by administering only ethanol at different vapor concentrations and selecting some mice with approximately the same BEC. When exposed to the same ethanol vapor concentration, WSR mice given 1.0 mmol/kg pyrazole had withdrawal BEC equivalent to WSP mice given 0.75 mmol/kg pyrazole. However, WSP mice had much more severe withdrawal HIC than WSR mice. WSP and WSR mice metabolized ethanol at the same rate following withdrawal. The basis for the differential effectiveness of pyrazole is unknown. We also exposed mice to higher ethanol vapor concentrations in the absence of pyrazole. By exposing WSR mice to higher concentrations than WSP, roughly equivalent BEC on withdrawal was achieved. Because BEC are more variable in the absence of pyrazole, it was necessary to select animals of each genotype to achieve relatively matched BEC.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Indexing withdrawal in mice: matching genotypes for exposure in studies using ethanol vapor inhalation. 794 52

Experiments were carried out in which a nutritionally balanced liquid diet previously used in this laboratory was modified as to total calorie content and high or low carbohydrate and fat concentration. Ethanol was added at 4.5% and 6.2% of diet weight and provided either 27% or 34-37% of total calories depending upon the changes in nutrient content. Measurements included 8-day food/calorie and ethanol consumption, plasma ethanol level, liver alcohol dehydrogenase (ADH) activity, and rate of audiogenic-induced withdrawal seizures. The original liquid diet with 4.5% ethanol was consumed in significantly lesser amounts than the alcohol-free diet, and essentially no body weight gain occurred, regardless if the major nonalcohol, nonprotein calorie source was fat or carbohydrate. When the calorie content of the diet was boosted through the addition of extra carbohydrate or fat (at the expense of water), appreciable weight gain was noted; in the case of the higher calorie diet boosted with more carbohydrate (maltodextrin) calories, growth was similar to that observed on the alcohol-free control diet. On this latter diet ethanol calories appeared to be utilized close to their theoretical value of 7 kcal/g. Blood alcohol levels were significantly higher on the lower calorie diets and were lowest on the high-calorie, high-carbohydrate, 4.5% ethanol diet. This diet also allowed for the lowest rate of withdrawal seizures despite an ethanol intake that was as high as on the lower calorie diets. Essentially, no differences were noted among ADH activities for the dietary treatments studied and thus, did not explain the differences observed among blood ethanol levels. When the alcohol concentration in the high-carbohydrate, high-calorie diet was raised to 6.2% from 4.5% to provide 34% of total calories, the rats responded by decreasing their food (and alcohol) intake to the same level as did the animals receiving a much lower calorie diet, but with 37% of caloric alcohol content. This suggests that at a diet alcohol concentration of 34-37%, one or more nutrient metabolites become limiting in the utilization of ethanol, resulting in food intake adjustments that maintain similar amounts of alcohol consumption.
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PMID:Diet composition, alcohol utilization, and dependence. 881 56

The effects of a common industrial solvent, trichloroethylene (TCE), which was once used as an anesthetic agent but its in vivo mechanism is still unknown, on convulsant-induced seizures in mice were examined. Pretreatment with TCE (250-2000 mg/kg, i.p.) significantly increased pentylenetetrazol (PTZ)-, picrotoxin (PIC)-, bicuculline (BIC)-, strychnine (STY)-, 4-aminopyridine (4-AP)- and N-methyl-D-aspartate (NMDA)-induced convulsion thresholds and lethal doses. However, the increase in convulsion thresholds and lethal doses was much greater for GABAergic antagonists (PIC, BIC, and PTZ) than non-GABAergic convulsants (STY, 4AP, and NMDA) following 2000 mg/kg TCE administration. Pre-treatment of mice with disulfiram (an inhibitor of CYP 4502E1) but not 4-methyl pyrazole (an inhibitor of alcohol dehydrogenase) significantly prolonged the time required for TCE (5000 mg/kg, i.p.) to induce the loss of righting reflex. These results suggest that acute exposure to TCE differentially alters the susceptibility to chemically induced convulsions in mice. The anticonvulsive effect of TCE may be predominantly mediated by GABA(A) receptors. In addition, TCE appears to exert a direct anesthetic effect.
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PMID:Acute exposure to trichloroethylene differentially alters the susceptibility to chemoconvulsants in mice. 1131 56

A 53-year-old African-American man with relapsed non-Hodgkin's lymphoma developed seizures and respiratory arrest 2 hours after an infusion of high-dose etoposide in preparation for an autologous bone marrow transplant. Laboratory tests revealed both rapid hemolysis and severe metabolic acidosis. The patient died the following day. Based on toxicities observed, we suspect that our patient possessed an ethnic polymorphism of the enzyme alcohol dehydrogenase. Further research is required to determine the relationship between the benzyl alcohol metabolic rate and toxicity and genetic polymorphisms of alcohol dehydrogenase in African-Americans.
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PMID:Fatal hemolysis after high-dose etoposide: is benzyl alcohol to blame? 1140 Nov 89

1,4-Butanediol (1,4-BD) is the dihydroxy precursor of gamma-hydroxybutyrate (GHB), a popular recreational drug that has been banned by the United States Food and Drug Administration (FDA) and controlled as a federal schedule I drug. 1,4-BD is enzymatically converted in vivo to GHB by alcohol dehydrogenase (ADH), and overdoses can result in coma, severe respiratory depression, bradycardia, hypothermia, seizures, and death. Presently, there is no antidote. We pretreated CD-1 mice with the ADH antagonist, 4-methylpyrazole (4-MP), to determine if blocking ADH can prevent or decrease toxicity from 1,4-BD overdose. Pretreatment with 4-MP increased the Toxic Dose-50 (TD(50)) of 1,4-BD for the righting reflex from 585 mg/kg (95% CI, 484-707 mg/kg) in control mice to 5,550 mg/kg (95% CI, 5,353-5,756 mg/kg) in pretreated mice. Pretreatment with 4-MP also increased the TD(50) of 1,4-BD for the rotarod test from 163 mg/kg (95% CI, 136-196 mg/kg) in control mice to 4,900 mg/kg (95% CI, 4,812-4,989 mg/kg) in pretreated mice. Pretreatment with 4-MP significantly decreased the toxicity of 1,4-BD in CD-1 mice, presumably by inhibiting its ADH biotransformation to GHB. 4-MP warrants further investigation as a potential antidote for this increasingly abused drug.
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PMID:Pretreatment of CD-1 mice with 4-methylpyrazole blocks toxicity from the gamma-hydroxybutyrate precursor, 1,4-butanediol. 1207 36

To investigate alcohol dependency and the potential role of age of initial alcohol consumption, Long-Evans (LE) rats were fed an ethanol-containing liquid diet starting at postnatal (P) ages (days): P23-27 (juvenile), P35-45 (adolescent) or P65-97 (young adult). Severity of subsequent withdrawal symptoms was dependent on age when consumption began and on duration of alcohol consumption. Frequency of withdrawal seizures was highest for rats starting consumption as juveniles, intermediate for adolescents and lowest for adults. Normalized to body weight, alcohol consumption was significantly higher for adolescent and juvenile rats than for adults. Sprague-Dawley rats that began alcohol consumption as adolescents (P35) had a level of alcohol consumption identical to that of the adolescent LE rats but showed much lower frequency of withdrawal seizures when tested after 2, 3 and 5 weeks of alcohol consumption. Based on several indicators, the capacity of the juveniles to metabolize ethanol is equal to or exceeds that of adults. Recoveries from a single dose of ethanol (2.5 g ethanol/kg body weight) were faster for juvenile LE rats than adults. The rate of decline in blood ethanol concentration was identical for juvenile and adult rats while the corrected ethanol elimination rate was higher for juveniles. The primary isozyme of alcohol dehydrogenase (ADH) in rat liver, ADH-3, had a similar Km and higher activity in liver preparations from juveniles. In conclusion, LE rats beginning alcohol consumption as juveniles or adolescents develop a severe alcohol withdrawal syndrome that may not be attributed entirely to higher levels of consumption and was not explained by any obvious deficiencies in metabolism.
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PMID:Severity of alcohol withdrawal symptoms depends on developmental stage of Long-Evans rats. 1820 24


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