Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0014544 (epilepsy)
 64,704 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pregnant Sprague-Dawley CD rats were administered 0, 100, or 200 mg/kg of phenytoin on days E7-18. Litters were reduced to 12, balancing for sex. Mean (+/- S.E.) maternal serum concentrations of total phenytoin 1 hr after dosing on E18 were 15.1 +/- 3.1 and 20.9 +/- 4.3 micrograms/ml in the PHT-100 and PHT-200 groups, respectively. Determinations of unbound concentrations revealed the drug to be 89% serum protein bound in both phenytoin groups. Maternal phenytoin concentrations in rats are, therefore, comparable to those seen therapeutically in humans with epilepsy. The PHT-200 group had elevated early postnatal mortality, while the PHT-100 group did not differ from controls. Phenytoin induced the typical dose-dependent increase in preweaning square-field locomotor activity. When this effect was compared to a new circular open field it was found that this device clearly distinguished phenytoin's effects. Phenytoin offspring also showed the typical dose-dependent abnormal circling behavior. Phenytoin offspring exhibited large dose-dependent increases in errors in a complex water maze, an effect which persisted even when rats exhibiting abnormal circling were excluded from the analyses. Offspring were also assessed for ability to locate a hidden vs. visible platform in an open swimming tank. Controls and PHT-100 offspring showed large improvements in performance when the hidden platform was made visible, but the PHT-200 offspring did not. Finally, offspring were assessed for working memory in an appetitive radial-arm maze. Both phenytoin groups exhibited impaired performance as measured by the number of reinforcements obtained in the first 8 arms visited.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dose-response effects of prenatal phenytoin exposure in rats: effects on early locomotion, maze learning, and memory as a function of phenytoin-induced circling behavior. 233 67

Details of the molecular interactions between human immunodeficiency virus (HIV-1) and its host cell during the infection process are not entirely clear. Building on recent reports by Lehr and Zimmer (1986, DMW 111, 1001-1002) that the membrane-reactive, anti-epileptic drug diphenylhydantoin (dilantin or phenytoin) (PHT) inhibited binding of HIV to lymphocytes, we hypothesized that understanding the relevant effects of this drug on cells may shed light on aspects of HIV-1 infection. We found that PHT inhibited, in a dose-dependent manner, de novo infection of various T-cell lines as well as a monocytic cell line. Moderate inhibition of HIV-1 infection was observed with drug concentrations that are therapeutic in vivo for epilepsy (approximately 20 micrograms/ml), and no concentrations used induced deleterious effects on cell growth or viability. Surprisingly, treatment of chronically infected H9 cells reduced HIV p24 expression within 1-6 weeks according to dose. This apparent induction into latency was not inhibited by cotreatment of the chronically infected cells with 5-azacytidine, which indicated that PHT was not inducing latency by induction of methylation of the viral DNA. Flow cytometric analysis demonstrated that PHT did not significantly reduce cell-surface expression of CD4. The possibility remained that the drug inhibited HIV infection due to its known effects on calcium-dependent cellular processes. Subsequent measurements of intracellular calcium demonstrated that an increase of [Ca2+]i occurred at least 24 hr postinfection, prior to synthesis of detectable viral structural protein p24, and that this virus-induced increase in [Ca2+]i was not due to binding of HIV to the cell. This HIV-induced rise in [Ca2+]i was significantly inhibited by PHT. PHT demonstrated variable inhibitory effects on infection of normal PHA-stimulated PBLs cultured in vitro, but it was synergistic to low-dose AZT (0.01 microgram/ml) in inhibiting infection of cell lines. Because of the known inhibitory effects of PHT on calcium-dependent biochemical processes in the cell, inhibition of HIV-1 infection by PHT suggests that calcium may play a role in HIV infection and maintenance. The drug may also be a candidate therapy for individuals infected with HIV.
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PMID:Inhibition of human immunodeficiency virus (HIV-1) infection by diphenylhydantoin (dilantin) implicates role of cellular calcium in virus life cycle. 257 18

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 effect of anticonvulsants on pentylenetetrazol (PTZ)-induced EEG power spectrum changes was examined. When the minimum dose of PTZ (15 mg/kg) was administered intravenously twice, with an interval of 80 min, a clear EEG power spectrum change was observed after the second PTZ administration, irrespective of whether or not the first PTZ administration evoked marked EEG changes. We defined the values F/N, S/N and S/F. The value F/N, obtained by dividing the power spectrum area after the first PTZ administration by the normal power spectrum area, was 1.06 +/- 0.05 (mean +/- S.E.). The value S/N, obtained by dividing the power spectrum area after the second PTZ administration by the normal power spectrum area, was 2.00 +/- 0.21. The value S/F, obtained by dividing S/N by F/N, was 1.86 +/- 0.16. The S/F value was almost constant regardless of whether or not the first PTZ administration could evoke marked EEG changes. The effect of anticonvulsants was examined by S/F value changes, and 100 mg/kg of PHT completely inhibited the double PTZ effect. Phenobarbital, ethosuximide and sodium valproate also inhibited the double PTZ effect. Using the S/F value of the EEG power spectrum with minimum dose double PTZ administration, quantitative evaluation is possible for anticonvulsant drugs.
Epilepsy Res 1987 Sep
PMID:Effect of anticonvulsants on pentylenetetrazol-induced power spectrum changes in electroencephalograms in rats. 284 95

Safety and efficacy studies of new antiepileptic drugs require strict adherence to prescribed dosage regimens. Therefore, they provide a unique opportunity to investigate the variability in serum concentrations that are seen in a compliant group of motivated patients. Phenytoin and carbamazepine serum concentrations from two safety and efficacy trials were evaluated for coefficient of variation, difference from baseline concentration, and percent difference. Coefficient of variation for phenytoin was usually less than 20% and was not influenced by baseline serum concentration or frequency of administration. There was no relationship between serum concentration and frequency of administration on carbamazepine coefficient of variation which was less than 25% in most cases. Most PHT differences from baseline were within 5 micrograms/ml, whereas most CBZ differences were within 2 micrograms/ml. Most PHT concentrations were within 30% of each other whereas most CBZ concentrations were within 40% of each other. Data from this study provide information regarding the variability of phenytoin and carbamazepine concentrations under ideal conditions and can be used to set limits for fluctuations of concomitant antiepileptic drugs in safety and efficacy trials or ideal patient care settings.
Epilepsy Res Suppl 1988
PMID:Compliant populations: variability in serum concentrations. 307 93

The main objective of this study was to determine whether stripentol (STP) alleviates side-effects commonly observed in treated epileptic patients, since preliminary data suggested a positive psychotropic effect. A secondary objective was an evaluation of drug efficacy. Eleven patients with either a drug-resistant epilepsy or toxic effects of AEDs completed the study. Ten had symptomatic partial epilepsies and one an idiopathic generalized epilepsy. STP was added to the baseline therapy (1 or 2 AEDs) and the dose of the baseline AEDs was reduced to maintain plasma levels unchanged (mean reduction: PB 26%, PHT: 49%, CBZ: 38%). Several motor, perceptual and attention tasks and the Washington Psychosocial Seizure Inventory were performed before and after STP administration. Seizure frequency and clinical side-effects were evaluated during a baseline period and after two months of constant therapy. Effects of repeated administration of the neuropsychological battery were assessed by administration of the battery on two occasions at 12-week interval to a randomized subgroup of patients. No practice effect was observed. A trend of improvement (p less than 0.05) in the performance of two tasks requiring sustained attention was noted. Previous side-effects (mainly drowsiness) decreased or disappeared in 7 of 9 patients who became more alert. Six of the nine uncontrolled patients experienced a decrease in seizure frequency equal to or larger than 50 per cent.
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PMID:[Neurophysiological and therapeutic evaluation of stiripentol in epilepsy. Preliminary results]. 336 91

The distribution of diphenylhydantoin (PHT) (40 mg/kg i.p.) in the brain was investigated in cats with convulsive generalized (group 1) and focal penicillin-induced status epilepticus (group 2), and in controls. A significant increase in the amount of PHT entering the brain during the convulsive status was found, with peak brain levels at 45 min (12 +/- 3.2 micrograms/g vs. 6.0 +/- 0.8 in normal cats, P less than 0.05). In the focal status brain concentrations of PHT reached levels intermediate between controls and group 1 cats. At 15 min, elevated blood levels of the drug were paralleled by increased concentrations in the brain, whereas at 30 and 45 min other factors, such as changes in cerebral blood flow, cerebral pH, vascular resistance, metabolic derangement and blood-brain barrier disruption were presumably responsible for the altered brain PHT uptake. The relevance of these data to clinical practice is discussed, in relation to the treatment of human status epilepticus and the potentially neurotoxic effects of the drug.
Epilepsy Res 1987 May
PMID:Distribution of diphenylhydantoin in the brain during experimental status epilepticus of the cat. 350 95

The analysis of clinical features of groups of patients with frequent and rare epileptic seizures showed that the mean age of the first seizure, the mean age at the time of examination, and the mean duration of the disease were not significantly different in both studied groups. In the group with frequent seizures a significantly more frequent presence of features indicating serious organic brain damage was found (more frequent occurrence of known aetiological factors, more cases of posttraumatic epilepsy, psychic and neurological abnormalities). In group C changes in the background activity in EEG were also more frequent. The analysis of pharmacological treatment showed a more frequent application of polytherapy in group C. On the other hand, the mean levels of antiepileptic drugs in the serum and the mean doses of these drugs for kg of body mass were not significantly different in both groups. In about 40% of patients in both groups the prescribed drugs failed to reach the levels generally regarded as therapeutic (slightly more frequently in the group with rare seizures). This was true mainly of PHT since about 81% of patients in both groups failed to reach the therapeutic level of the drug (10 ug/ml). The likely causes of this fact were: too low doses prescribed (55% of the patients were given doses below the generally recommended), lower bioavailability of PHT (27% of patients had no therapeutic level of the drug in the serum, despite doses exceeding 5 mg/kg); or drug interaction. This requires elucidation in further studies.
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PMID:[Characteristics of the clinical features and pharmacological treatment of epileptics with frequent seizures]. 371 70

There have been several reports of the isolated occurrence of raised serum gamma GT levels in the course of long-term anticonvulsive treatment. The findings concerning the correlation between this elevation of gamma GT and various dimensions of epilepsy or treatment regimens are equivocal. In a retrospective study of 158 epileptics, the mean values of the serum gamma GT level have been grouped according to anticonvulsive regimen and compared with one another, as well as correlated to the serum concentration of the antiepileptic drug. An elevation of serum gamma GT was found in 103 patients. Among the different subgroups the mean value for serum gamma GT was raised in cases under treatment with PHT, PB or PRM. No such elevation was found in cases under monotherapy with CBZ or VPR. The elevation of serum gamma GT is considered to reflect hepatic enzyme induction rather than hepatic impairment.
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PMID:[Rise in gamma-GT during anticonvulsive therapy]. 613 95

(1) The concentrations of various anticonvulsants (PB, PHT, CBZ, VPA) were measured in brain specimens from 7 patients who had undergone neurosurgery for a therapy resistant epilepsy of tumoral origin (astrocytoma) in 6 cases, glioblastoma in 1 case). (2) Great interindividual variability of the mean brain/plasma concentration ratios was observed for PB in 5 patients (range: 0.4-1.0). A mean brain/plasma ratio of 1.0 was recorded for PHT and CBZ (one patient each). (3) In the different tissue specimens (7-14) from the same patient AED concentrations varied greatly, even in neighboring areas. (4) Intraindividual variations were more marked in the present group of patients than in previously studied non-tumoral epileptics. (5) No correlation was found between the localization of the lesions and the variations in AED concentrations. (6) Brain AED concentration appeared to be higher in the few samples of non-tumoral tissue and lower in the 'epileptogenic' areas as defined by stereo-EEG seconding. (7) On the basis of these data, the hypothesis can be formulated that the therapy resistance of these patients may be at least partly explained by the presence of low AED concentration (even in presence of 'therapeutic' AED plasma levels) in the epileptogenic areas.
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PMID:[Cerebral concentrations of anticonvulsants in patients with epilepsy of tumoral origin (author's transl)]. 704 45


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