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 this study, some new 4-aryl-4-imidazoline-2-one derivatives have been prepared by the reaction of potassium cyanate with some aminoethanone hydrochlorides. The structure of these compounds have been confirmed by UV, IR, 1H-NMR and elementary analysis. Their anticonvulsant activities were determined by maximal electroshock (MES) and subcutaneous metrazol (ScMet) tests according to the ADD (Antiepileptic Drug Development) programme Phase I. Neurotoxicity of the compounds was evaluated by rotarod test. While 2 of the compounds showed protection against ScMet induced seizures at 30 and 300 mg/kg dose levels, 3 of the compounds showed neurotoxicity.
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PMID:Synthesis and anticonvulsant activity of some new 4-aryl-4-imidazoline-2-one derivatives. 153 Jun 69

Studies conducted by Fisons Pharmaceuticals and the Antiepileptic Drug Development Program (ADD Program) of the Epilepsy Branch (NINDS, NIH) revealed that 'remacemide' (FPL 12924, formerly PR 934-423) was effective orally in the prevention of maximal electroshock seizures (MES) in rats. In this context (-)stereoisomer (FPL 14145) was of equal potency to the racemate (remacemide), while the (+)stereoisomer (FPL 14144) was 54% less potent. With respect to neurotoxicity, remacemide and its enantiomers possessed more favorable therapeutic indices than phenobarbital and valproate and less favorable indices than phenytoin and carbamazepine. The duration of protection of rats in the MES test at the ED50 or 3 x ED50 of remacemide and the (+)isomer was better or on par with the best reference compounds, phenytoin and phenobarbital. After subchronic administration of either the ED50 or the ED97 of remacemide, no tolerance developed in the hexobarbital sleep test, however, the activities of 3 hepatic microsomal enzymes were elevated. In naive rats high doses of remacemide or its (-)isomer and low doses of phenobarbital caused an increase in spontaneous motor activity. Alternatively, motor activity was depressed subsequent to high doses of phenobarbital and phenytoin. Remacemide was inactive against pentylenetetrazol and 'kindling' seizures. It was without effect in 5 electrophysiological tests (evoked responses, recurrent inhibition, long-term potentiation, penicillin-induced discharge rate and veratridine-induced depolarization) employing the in vitro hippocampal slice technique. Moreover, remacemide failed to demonstrate potent binding in vitro to neuronal L-glutamate, gamma-amino-butyrate A, adenosine A1, benzodiazepine, N-methyl-D-aspartate (strychnine-insensitive glycine and ion channel subsites) or muscarinic receptors. In conclusion, remacemide specifically prevents seizures elicited by MES, an action predicting utility in patients with generalized tonic/clonic convulsions.
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PMID:Preclinical profile of the anticonvulsant remacemide and its enantiomers in the rat. 166 Mar 99

ADD 94057, a metabolite of fluzinamide, manufactured by the A. H. Robins Company, blocks chemically- and electrically-induced seizures in animals. The primary objective of this open add-on study was to evaluate patient tolerability of ADD 94057 at ascending target plasma concentrations. Nine subjects with medically refractory seizures were receiving phenytoin (PHT, 3), carbamazepine (CBZ, 3), or both (3). A pharmacokinetic profile after a single oral 400-mg dose of ADD 94057 was used to calculate ADD 94057 dosages. After a 4-week baseline period, patients were treated for 4 weeks with weekly ADD 94057 dosage escalations. Two patients completed the study at their assigned highest dosage level; the other patients finished the study at lower dosages. The patients receiving PHT (but not CBZ) tolerated higher plasma concentrations of ADD 94057 than did patients receiving CBZ, alone or in combination with PHT. Adverse experiences included headache, ataxia, blurred vision, diplopia, dizziness, lightheadedness, and mild confusion. Eight of nine patients had reductions in seizure frequency from baseline.
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PMID:Pharmacokinetic and dose tolerability study of ADD 94057 in comedicated patients with partial seizures. 173 43

We assessed the effects of chronic treatment with haloperidol (0.5-2 mg/kg/day, p.o., 17 days) and methamphetamine (1-2 mg/kg/day, p.o., 17 days; 4 mg/kg/day, p.o. 9 days) on hippocampal kindled seizures using a kindling procedure with low-frequency (about 3 Hz) electrical stimulation in cats. The number of stimulating pulses required to trigger epileptic afterdischarge (pulse-number threshold, PNT) was considered an indicator of seizure threshold. Haloperidol, 0.5 and 1.0 mg/kg, reduced the duration of epileptic afterdischarge (afterdischarge duration, ADD) without affecting PNT, and 2.0 mg/kg strongly reduced PNT and ADD. Methamphetamine, 2.0 mg/kg, reduced PNT and ADD, and 4.0 mg/kg preferentially reduced PNT. The effects of the two drugs on hippocampal kindled seizures were found to be partially opposite to those on amygdala kindled seizures, suggesting the different response of these limbic structures to dopamine receptor manipulation.
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PMID:Effects of chronic treatment with haloperidol and methamphetamine on hippocampal kindled seizures in the cat. 186 21

The pharmacokinetic and pharmacodynamic properties of the spiro carboxylic acid, spiro[4.6]undecane-2-carboxylic acid (SUCA, ADD 93024), were investigated in rats and compared with those of the standard anticonvulsant carboxylic acid, valproate (VPA). The clearance of SUCA was dose-dependent, although the observed nonlinearity did not appear to be due to classical saturable elimination. The change in clearance across doses was consistent with end-product inhibition or cosubstrate depletion. The volume of distribution of the spiro compound also evidenced nonlinearity, possibly due to concentration-dependent binding to serum proteins. In contrast, the dose-dependent clearance displayed by VPA was composed of both saturable and nonsaturable components. Furthermore, the disposition of VPA was characterized by a significant enterohepatic recirculation, whereas no such recirculatory process was apparent for SUCA. Both compounds afforded significant protection from pentylenetetrazol (PTZ)-induced seizures, and the time course of anticonvulsant effect did not correspond to that of drug concentrations in serum for either anticonvulsant. The apparent dissociation between the pharmacokinetics and pharmacodynamics of VPA may be a function of the mechanism of antiepileptic action and not due to the presence of active metabolites of the drug.
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PMID:Pharmacokinetics and pharmacodynamics of valproate analogues in rats. I. Spiro[4.6]undecane-2-carboxylic acid. 211 71

The anticonvulsant and toxic properties of 4-chlorobenzenesulfonamide (ADD 55051) were compared with phenytoin (PHT), phenobarbital (PB), ethosuximide (ESM), and valproate (VPA). These compounds were evaluated in mice and rats using well-standardized anti-convulsant test procedures. The results indicate that ADD 55051 is a very effective anticonvulsant in the maximal electroshock seizure (MES) model in mice after either intraperitoneal (i.p.) or oral administration and in rats after oral administration. In mice treated i.p. or orally, ADD 55051 was also effective in preventing seizures induced by pentylenetetrazol (PTZ). The toxicity of ADD 55051 after oral administration was quite low, yielding high TD50 values in both mice and rats and producing a very high protective index (PI = TD50/ED50) in both species as compared with the prototype antiepileptic drugs (AEDs).
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PMID:Comparative anticonvulsant activity of 4-chlorobenzenesulfonamide and prototype antiepileptic drugs in rodents. 211 72

Acute effects of 4 anticonvulsants on hippocampal kindled seizures induced with about 3 Hz electrical stimulations were assessed in cats. The number of stimulating pulses required for the triggering of epileptic afterdischarge (pulse-number threshold, PNT) was used as the indicator for the seizure threshold. Duration of afterdischarge (ADD), ictal and interictal behaviors and serum drug levels were also recorded. PB produced a PNT-increase more prominently than an ADD-decrease with seizure stage regression. PHT produced only a proconvulsive effect by decreasing PNT. CBZ also produced a proconvulsive effect by decreasing PNT at a low dose, and decreased PNT and ADD simultaneously at a high dose. Conversely VPA increased PNT and ADD simultaneously. These results were discussed comparing mainly with a previous study of amygdala-generating seizures.
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PMID:Effects of anticonvulsants on hippocampus-generating seizures. 233 44

Seven cats were stimulated once a day with low-frequency electrical stimulations to assess the serial changes of development. Each animal had been implanted stereotaxically with a stimulating electrode into the left-side ventral hippocampus and with recording electrodes into the right-side ventral hippocampus, the bilateral dorsal hippocampus. We applied the stimulations at 10:00 AM, bipolarly with 2 mA-biphasic square-wave pulses (1 msec durations). The pulse-interval was set at 300 msec. If epileptic afterdischarge could not be triggered on EEG with this pulse-interval, a 100msec-interval stimulation was applied after 15 min-rest period. The number of stimulating pulses required for a triggering of afterdischarge was defined as pulse-number threshold (PNT) which was used as an indicator of the seizure-threshold. The duration of each seizure on EEG (afterdischarge duration, ADD) was also recorded and the seizure-related behaviors were classified into 5 stages as follows: 1, staring or immobility; 2 appearance of facial twitching or head nodding ; 3, tonic convulsions of the right-side fore-paw or a head turning toward the right-side; 4, generalized clonic convulsions; 5, generalized convulsions with a falling down. The kindling procedure completed within a mean of 36.5 days, and all the animals presented stage-5 seizures. At the completion of kindling, PNT was determined at 10.5 +/- 1.8 (mean +/- SE). During the kindling process PNT showed a sudden decrease in the initial part of stage-1 (within a mean of 3.8 days) and a gradual increase from stage-3 to stage-5. ADD showed a simple increasing function of the development of seizure-stage.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[A biphasic changes in the seizure-threshold in kindling seizure development induced with low-frequency electrical stimulations]. 260 45

We have recently reported some pharmacological studies using a kindling model of epilepsy induced with 1-3 HZ electrical stimulations, referred to as the low-frequency kindling. Since a previous study showed that the effects of psychotropic drugs on limbic seizures were dependent on the location of epileptic focus, we decided to study acute and chronic effects of anticonvulsants on the hippocampus generating seizures to compare with the results of a previous study of the amygdala generating seizures, which was done under the same conditions with this study. The number of stimulating pulses required for the triggering of epileptic afterdischarge (pulse-number threshold) was used as the indicator for the seizure threshold. Duration of after discharge (ADD), ictal and interictal behaviors of the subjected 7 cats, and serum drug levels were also recorded. A dose-dependent increase of serum drug levels was confirmed in each drug, and the values were well comparable with the optimal range in clinical use. In acute experiment PB 5 mg/kg p.o. produced no significant effect on PNT and ADD. PB 10 mg/kg increased PNT significantly (p less than 0.02) at 2 hrs after administration without affecting ADD, but 4 cats presented the seizure-stage regressions. PB 20 mg/kg increased PNT (p less than 0.02) and decreased ADD (p less than 0.02) with the seizure-stage regressions of all the tested cats at 2 hrs after administration, and increased PNT (p less than 0.05) without affecting ADD and seizure stage at 96 hrs after administration. PHT 5, 10, 20 mg/kg decreased PNT (p less than 0.05, 0.02, 0.02, respectively) without affecting ADD at 2 hrs after administration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Effects of phenobarbital and phenytoin on hippocampus generating seizures]. 262 37

The anticonvulsant and toxic properties of 4-amino-N-(2,6-dimethylphenyl)benzamide, (ADD 75073), were compared with phenytoin (PHT), phenobarbital (PB), ethosuximide (ESM), and valproate (VPA). These compounds were evaluated in mice and rats using well-standardized anticonvulsant test procedures. The results indicate that ADD 75073 is a very potent anticonvulsant in the maximal electroshock seizure (MES) model. The compound was effective in nontoxic doses following intraperitoneal (i.p.) administration in mice and oral administration in both mice and rats. In mice, the i.p. administration of ADD 75073 resulted in an ED50 value of 2.6 mg/kg as compared with a value of 9.5 mg/kg for phenytoin (PHT) in the same assay. Compound ADD 75073 was ineffective in nontoxic doses against all other seizure models examined in this study, and thus has a pharmacologic profile similar to that of PHT.
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PMID:Comparative anticonvulsant activity and neurotoxicity of 4-amino-N-(2,6-dimethylphenyl)benzamide and prototype antiepileptic drugs in mice and rats. 283 43


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