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

An experimental study of pyracetam (2-pyrrolidonacetamide) showed it capable to mitigate some behavioral and toxic manifestations of the action exerted by alcohol in tests on mice and rats, such as those of the "open field", "conflict situation", "rotating rod" and righting reflex. Pyracetam also attenuated some toxic symptoms of acetaldehyde in mice. It shortened the duration of coma, lessened the intensity of convulsive seizures, but it had no influence on the lethal effect of acetaldehyde. The type of the relation between doses and effects suggests the observed antagonism to be of a nonspecific nature.
 ...
PMID:[Effect of piracetam on some manifestations of the effects of ethanol and acetaldehyde]. 57 May 15

Withdrawal seizure prone (WSP) and withdrawal seizure resistant (WRS) mice were genetically selected to express severe or mild handling-induced convulsions (HIC), respectively, after cessation of chronic ethanol (EtOH) vapor inhalation. The studies reported here tested WSP and WSR mice to determine whether elevated HIC were seen after administration of acute doses of several drugs that depress central nervous system activity. The drugs tested were EtOH, pentobarbital, t-butanol, acetaldehyde, and diazepam. All drugs initially suppressed HIC in WSP mice. This suppression was followed by an exacerbation of HIC, suggestive of a state of rebound central nervous system hyperexcitability during acute withdrawal. Susceptibility to acute withdrawal seizures was clearly under genetic control, since WSR mice did not display acute withdrawal HIC to any appreciable extent. Acute EtOH withdrawal seizures did not require testing WSP mice repeatedly, as they could be seen upon a single HIC test 8 hr after EtOH injection. Results with acetaldehyde and t-butanol suggest that the formation of acetaldehyde may be sufficient, but is not necessary for the elicitation of acute EtOH withdrawal. Earlier studies had found that WSP mice displayed more severe withdrawal HIC than WSR mice after chronic treatment with t-butanol, phenobarbital, nitrous oxide, or diazepam. The genetic predisposition to chronic EtOH withdrawal HIC in WSP mice generalized to all central nervous system depressants acutely tested, suggesting that acute and chronic withdrawal to all these drugs is largely under the control of a common group of genes.
 ...
PMID:Acute dependence on depressant drugs is determined by common genes in mice. 203 13

The results of 373 EEG investigations were analysed. They were obtained in a period of 4 years in 222 workers with occupational exposure to metallic mercury in the synthesis of acetaldehyde and salt electrolysis. Abnormal or borderline abnormal results were found in 13% of them. Results were compared in groups differing in age, duration of occupation, working post and Hg excretion with urine. Significantly greater frequency of increased Hg absorption was found in the group with abnormal records. The authors stressed the following morphological features of EEG in those exposed to Hg: tendency for seizure activity, loss of ability of following of rhythmic flashes, unchanged frequency of background activity despite increasing degree of other abnormalities, absence of low-voltage tracings, persistence of abnormalities in the records after loss of contact with mercury.
 ...
PMID:[Value of electroencephalographic studies for the evaluation of the neurotoxic effect of metallic mercury]. 326 31

The L-isomer of 4-amino-3- isoxazolidinone (L-cycloserine), a potent transaminase inhibitor, was tested for its anticonvulsant action. Intraperitoneal injection of 25 mg kg-1 protects the inbred epileptic mouse (DBA/2J) from convulsions. The drug exerts its protective influence 3 h after administration, and its effect subsides gradually thereafter. A normal mouse (CBA/Ca) can be made prone to sound-induced epilepsy by enhancing its cerebral concentrations of Zn2+ and pyridoxal-5'-phosphate (PLP). Prior administration of 25-50 mg kg-1 L-cycloserine counteracts the convulsive effects of these substances. The pretreated animal is resistant to seizures. The concentrations of glutamate and aspartate in the inferior colliculus of the treated animal are diminished, whereas the concentration of gamma-aminobutyrate is enhanced. The time course of the changes in the amino acid concentrations broadly mirrors the changes in seizure susceptibility following the treatment. Proton nuclear magnetic resonance spectra of a mixture containing equimolar concentrations of L-cycloserine, PLP, and ZnSO4 were obtained. From the resonance peaks of such an adduct, we have ascertained that a molecule of L-cycloserine forms an irreversible Schiff base with the 4-aldehyde group of PLP, and this adduct is stabilized by a zinc ion. The significance of this finding for the anticonvulsant action of the drug is discussed.
 ...
PMID:L-cycloserine: a potent anticonvulsant. 672 95

In Experiment 1, twelve Sprague-Dawley rats were trained in a two-choice food-reinforced drug discrimination task (10-min sessions) using the state-dependent interoceptive stimulus attributes of ethanol's (ETOH) delayed or rebound effects (EDE) versus "normal" basal homeostasis. Rats were injected with either 4 g/kg ETOH or equivalent volumes of saline (SAL) 18 hr before the sessions. Each rat was injected with an additional 1 ml/kg injection of SAL 15 min before the sessions. EDE training sessions were always followed by a "day off." SAL sessions were conducted between 36-96 hr after an EDE training session. Rats demonstrated > 90% discriminative accuracy. Test sessions showed a time-dependent, cyclic, return from the experimental "hangover" state to the "normal" state, by 48 hr. The acute (immediate) effects of ETOH and chlordiazepoxide (0.75 g/kg or 0.18 mg/kg, respectively; @15 min) did not cross-generalize with the "hangover" state. Both these low-dose ETOH and chlordiazepoxide pretreatments blocked the stimulus attributes of "hangover." All subjects responded on the EDE-appropriate lever at 5.6 mg/kg pentylenetetrazole and exhibited an increase in susceptibility to clonic seizures. In Experiment 2 blood alcohol concentration kinetics functions were quantified in three groups (n = 8/group) of age-matched cohorts to Experiment 1 subjects (2, 3, and 4 g/kg ETOH) using a head-space gas chromatographic technique. The training stimulus state associated with 4 g/kg, at 18 hr postinjection intervals, in Experiment 1, did not produce any chromatogram peaks for ETOH or any its active metabolite (acetaldehyde, acetone, nor methanol).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:State-dependent stimulus control: cueing attributes of ethanol "hangover" in rats. 811 33

We have explored the structure-activity relationship (SAR) surrounding the clinically efficacious antiepileptic drug topiramate (1), a unique sugar sulfamate anticonvulsant that was discovered in our laboratories. Systematic structural modification of the parent compound was directed to identifying potent anticonvulsants with a long duration of action and a favorable neurotoxicity index. In this context, we have probed the pharmacological importance of several molecular features: (1) the sulfamate group (6-8, 22-25, 27, 84), (2) the linker between the sulfamate group and the pyran ring (9, 10, 21a,b), (3) the substituents on the 2,3- (58-60, 85, 86) and 4, 5-fused (30-38, 43, 45-47, 52, 53) 1,3-dioxolane rings, (4) the constitution of the 4,5-fused 1,3-dioxolane ring (2, 54, 55, 63-68, 76, 77, 80, 83a-r, 84-87, 90a, 91a, 93a), (5) the ring oxygen atoms (95, 96, 100-102, 104, 105), and (6) the absolute stereochemistry (106 and 107). We established the C1 configuration as R for the predominant alcohol diastereomer from the highly selective addition of methylmagnesium bromide to aldehyde 15 (16:1 ratio) by single-crystal X-ray analysis of the major diastereomer of sulfamate 21a. Details for the stereoselective syntheses of the hydrindane carbocyclic analogues 95, 96, 100, and 104 are presented. We also report the synthesis of cyclic imidosulfites 90a and 93a, and imidosulfate 91a, which are rare examples in the class of such five-membered-ring sulfur species. Imidosulfite 93a required the preparation and use of the novel sulfur dichloride reagent, BocN=SCl2. Our SAR investigation led to the impressive 4,5-cyclic sulfate analogue 2 (RWJ-37947), which exhibits potent anticonvulsant activity in the maximal electroshock seizure (MES) test (ca. 8 times greater than 1 in mice at 4 h, ED50 = 6.3 mg/kg; ca. 15 times greater than 1 in rats at 8 h, ED50 = 1.0 mg/kg) with a long duration of action (>24 h in mice and rats, po) and very low neurotoxicity (TD50 value of >1000 mg/kg at 2 h, po in mice). Cyclic sulfate 2, like topiramate and phenytoin, did not interfere with seizures induced by pentylenetetrazole, bicucculine, picrotoxin, and strychnine; also, 2 was not active in diverse in vitro receptor binding and uptake assays. However, 2 turned out to be a potent inhibitor of carbonic anhydrase from different rat tissue sources (e. g., IC50 of 84 nM for the blood enzyme and 21 nM for the brain enzyme). An examination of several analogues of 2 (83a-r, 85-87, 90a, 91a, 93a) indicated that potent anticonvulsant activity is associated with relatively small alkyl substituents on nitrogen (Me/H, 83a; Me/Me, 83m; Et/H, 83b; allyl/H, 83e; c-Pr/H, 83j; c-Bu/H, 83k) and with limited changes in the cyclic sulfate group, such as 4,5-cyclic sulfite 87a/b. The potent anticonvulsants 83a and 83j had greatly diminished carbonic anhydrase inhibitory activity; thus, inhibition of this enzyme may not be a significant factor in the anticonvulsant activity. The alpha-L-sorbopyranoses 67, 68, and 80, which mainly possess a skew conformation (ref 29), were nearly twice as potent as topiramate (1). The L-fructose enantiomers of 1 (106) and 2 (107), synthesized from L-sorbose, were found to have moderate anticonvulsant activity, with eudysmic ratios (MES ED50 in mice at 4 h, po) of 1:106 = 1.5 and 2:107 = 3.5. The log P values for 1 and 2 were determined experimentally to be 0.53 and 0.42, respectively, which are less than the optimal 2.0 for CNS active agents. However, analogues with more favorable calculated log P (clogP) values, in conjunction with just minor steric perturbation according to the developed SAR profile, such as 47 (clogP = 2.09), 83m (1.93), and 86 (1.50), did not display improved potency: 47 is less potent than 1, 83m is equipotent with 2, and 86 is less potent than 2. Although the measured log P value for diethyl analogue 31 is 1.52, this did not translate into enhanced potency relative to 1. (ABSTRACT TRUNCATED)
 ...
PMID:Structure-activity studies on anticonvulsant sugar sulfamates related to topiramate. Enhanced potency with cyclic sulfate derivatives. 954 21

Metaldehyde has been widely used as a main ingredient of solid fuel for making fire and slug baits in Japan. It is also marketed as a color flame tablet for party goods (ENGELFIRE). Consequently, children have been poisoned by eating such tablets which they mistook for candy. As a result, poison information center calls are increasing. According to POISINDEX, the treatment for metaldehyde poisoning consists in prevention of adsorption by activated charcoal, seizure control and airway protection. However, the optimum dose of charcoal is not established. We studied the quantitative adsorption capacity of activated charcoal for acute oral toxicity of metaldehyde in rats. In vivo toxicity and absorption tests for metaldehyde in Wister rats were done. The detoxifying effect of activated charcoal on metaldehyde toxicity and inhibition of metaldehyde absorption were investigated. Ratios used of po activated charcoal given 30 min after dosing to 400 mg metaldehyde/kg po were 5:1, 2:1, 1:1, 0.5:1. Serum metaldehyde was determined by gas chromatography in the control group (no charcoal) and the various experimental groups. Metaldehyde mortality was completely prevented at the ratio of 5:1. Gastrointestinal absorption of metaldehyde was reduced significantly by 45.3% in comparison to the control rats. There was no acetaldehyde detected in the serum of the metaldehyde-dosed rats. Metaldehyde poisoning may be prevented by early po administration of activated charcoal in a ratio of > 5:1 compared to metaldehyde. The theory that acetaldehyde is the primary toxic agent in metaldehyde poisoning should be re-evaluated.
 ...
PMID:Adsorption effects of activated charcoal on metaldehyde toxicity in rats. 994 77

Felbamate demonstrates a unique therapeutic profile and often results in seizure control when other agents fail. Its use has been associated with risks for aplastic anaemia and hepatic failure. A number of confounding factors makes the actual incidence rate for each adverse effect difficult to determine. However, certain risk factors are common in reported cases. In order to minimise the risk, at the present time, it is necessary to rely on the clinical profile of the patients reporting these adverse effects. The patient reporting aplastic anaemia is usually female, Caucasian, and an adult. The dose did not appear to be a factor and the time to onset of aplastic anaemia was less than 1 year for all patients. Concomitant medications and diseases may play an important role. Patients with reported aplastic anaemia generally had a history of a serious allergy or toxicity to other anticonvulsants and/or a background of having had a cytopenia due to other anticonvulsants, and a diagnosis or serological evidence of concomitant immune disorder. The demographics associated with hepatic failure are less well defined. Patients were also predominantly female, were equally divided among adult and paediatric patients, and had a broad range of time to presentation of hepatotoxicity following felbamate therapy. Concomitant medications again play an important role with, in this case, valproic acid (sodium valproate), phenytoin and carbamazepine being the most frequent. In 50% of the population, hepatic failure was not felt to be due to felbamate but associated with confounding factors including status epilepticus, paracetamol (acetaminophen) toxicity, hepatitis and shock liver. Initial research has failed to provide a diagnostic indicator. However, work on a potential intermediate felbamate metabolite has suggested the formation of a reactive aldehyde whose end products have been detected in the urine of felbamate treated patients. Until these data are confirmed, the medical history, clinical picture, and laboratory testing, should be used to identify patients at risk. The risks for toxicity with felbamate should be evaluated before starting treatment. In addition, liver function tests and complete blood count (CBC) prior to therapy and at clinically rational intervals should be conducted. Patients must be educated in the likely prodromal symptoms of potential marrow/liver toxicity. Felbamate is too valuable an anticonvulsant to be relegated to the therapeutic scrap heap. With monitoring, patient education, and continued research to further elucidate risk factors, felbamate can be a viable therapeutic agent for patients with epilepsy.
 ...
PMID:Felbamate in epilepsy therapy: evaluating the risks. 1048 99

We previously identified vitamin B6 deficiency in a child presenting with seizures whose primary diagnosis was the inherited disorder hyperprolinemia type II. This is an unrecognized association, which was not explained by diet or medication. We hypothesized that pyridoxal phosphate (vitamin B6 coenzyme) was de-activated by L-Delta(1)-pyrroline-5-carboxylic acid, the major intermediate that accumulates endogenously in hyperprolinemia type II. The proposed interaction has now been investigated in vitro with high resolution 1H nuclear magnetic resonance spectroscopy and mass spectrometry at a pH of 7.4 and temperature of 310 K. Three novel adducts were identified. These were the result of a Claisen condensation (or Knoevenagel type of reaction) of the activated C-4 carbon of the pyrroline ring with the aldehyde carbon of pyridoxal phosphate. The structures of the adducts were confirmed by a combination of high performance liquid chromatography, nuclear magnetic resonance, and mass spectrometry. This interaction has not been reported before. From preliminary observations, pyrroline-5-carboxylic acid also condenses with other aromatic and aliphatic aldehydes and ketones, and this may be a previously unsuspected generic addition reaction. Pyrroline-5-carboxylic acid is thus found to be a unique endogenous vitamin antagonist. Vitamin B6 de-activation may contribute to seizures in hyperprolinemia type II, which are so far unexplained, but they may be preventable with long term vitamin B6 supplementation.
 ...
PMID:Pyridoxal phosphate de-activation by pyrroline-5-carboxylic acid. Increased risk of vitamin B6 deficiency and seizures in hyperprolinemia type II. 1113 58

Metaldehyde, a cyclic tetramer of acetaldehyde, is a widely used molluscicide. Although cases with acute metaldehyde poisoning have been reported, the occurrence of severe poisoning is uncommon. To provide more information on human metaldehyde poisoning, we reviewed 15 cases of metaldehyde exposure reported to the Taiwan National Poison Control Center at the Taipei Veterans General Hospital between 1991 and 2002. While 7 patients were asymptomatic, the other 8 patients, including 4 who coingested alcohol or other poisons, exhibited toxic manifestations of abdominal pain, dizziness, nausea, irritation of oral mucosa, and seizures after oral exposure. One patient died after ingesting 12 g (or 258.6 mg/kg) of metaldehyde. Although the toxicity from metaldehyde is largely mild, the clinical course of metaldehyde poisoning may be rapidly deteriorating and fatal on rare occasions. Physicians should therefore be cautious in managing patients with metaldehyde poisoning, and vigorous supportive measures should be promptly instituted in patients who manifest severe toxicity.
 ...
PMID:Acute metaldehyde poisoning in Taiwan. 1517 91


1 2 3 Next >>