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)

The recent finding that ifenprodil binds with high affinity to sigma sites suggests that other sigma agents may have ifenprodil-like cerebroprotectant and functional N-methyl-D-aspartate (NMDA) antagonist effects. The present study, compared the in vivo effects of ifenprodil and the sigma agents, BMY 14802, caramiphen and haloperidol, in three tests sensitive to NMDA antagonists and purported cerebroprotectant drugs. When administered at or below the rotorod TD50 dose, all four compounds significantly increased survival time in an hypoxic environment (4% O2 in nitrogen). Caramiphen and ifenprodil (ED50 = 52 and 61 mg/kg, respectively) also blocked maximal electroshock-induced seizures, whereas BMY 14802 and haloperidol were ineffective. Finally, caramiphen (ED50 = 95 mg/kg) antagonized seizures and lethality induced by administration of NMDA (250 mg/kg, IP). BMY 14802, haloperidol and ifenprodil only partially antagonized NMDA-induced seizures, but did enhance the anticonvulsant potency of the noncompetitive NMDA antagonist, MK-801. Together, these findings suggest that sigma agents may have cerebroprotective effects.
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PMID:Possible cerebroprotective and in vivo NMDA antagonist activities of sigma agents. 164 68

The levels of prostaglandin F1 (6-keto-PGF1 alpha), thromboxane B2 (11-dehydro-TxB2), and peptidoleukotriene C4 (LTC4) were measured (acetylcholinesterase immunoassay) in the frontal cortex (FC) and the striatum (SA) of the rat brain to study the possible role of eicosanoids in seizures induced by hyperbaric oxygen (HBO). The rats were exposed to (1) hyperbaric oxygen (HBO, 6 ATA O2) up to the first seizure (2) compressed air (6 ATA air, i.e., approximately equal to 1.25 ATA O2) or (3) atmospheric pressure (1 ATA air, i.e., 0.21 ATA O2); there was no seizure in groups 2 and 3. Transition from 6 ATA to atmospheric pressure was obtained in 15 min; the rats were then decapitated and their heads frozen in liquid nitrogen before extraction and analysis of prostanoids. Whatever the conditions, cortical levels of 6-keto-PGF1 alpha and 11-dehydro-Tx B2 are higher than striatal levels; considering the same area, 11-dehydro-Tx B2 and LTC4 concentrations were not significantly different whatever the condition, but there is a trend for lower 6-keto-PGF1 alpha levels in FC after HBO seizure. Biochemical mechanisms are discussed. Eicosanoids do not seem to play a major role in HBO seizures, although some modifications of their metabolism may take place.
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PMID:The influence of one hyperbaric oxygen-induced seizure on brain eicosanoid content. 177 30

Exposure to X rays (20 impulses of 4 Hz frequency, total dose 0.6-1.1 mGy) increased the epileptic activity of a focal area, which was produced in the visual cortex of rabbit brain by freezing with liquid nitrogen, and by stimulating with flashes of light at frequencies of 5-6 Hz. The number of seizure complexes during photostimulation for 5 s increased by 80% compared with the initial level, and this effect continued for 15 min. In control animals (with no epileptic foci), a decrease was observed in the main frequencies of the delta rhythm and the theta rhythm (by 90% and by 10%, respectively) over the cortex as a whole. In rabbits with experimental epilepsy, the delta rhythm decreased only in the frontal lobes and in the lateral geniculate body (by 30%), whereas the theta rhythm decreased only in the visual cortex (by 10%). Possible mechanisms for these effects are discussed.
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PMID:The effect of exposure to impulse X rays on normal and epileptic activity in rabbit brain. 179 42

Potent anticonvulsant activity has been reported for (R,S)-2-acetamido-N-benzyl-2-methylacetamide (2a). Select alpha-heteroatom substituted derivatives of 2a have been prepared (26 examples) in which the alpha-methyl group has been replaced by nitrogen (3a-q), oxygen (3r-u), and sulfur (3v-z) containing moieties. The functionalized amino acid derivatives were evaluated in the maximal electroshock seizure (MES) and horizontal screen (tox) tests in mice. The most active compounds were (R,S)-2-acetamido-N-benzyl-2-(methoxyamino)acetamide (31), and (R,S)-2-acetamido-N-benzyl-2-(methoxymethylamino)acetamide (3n). After ip administration, the MES ED50 values for 31 (6.2 mg/kg) and 3n (6.7 mg/kg) compared favorably with phenytoin (9.50 mg/kg).
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PMID:Preparation and anticonvulsant activity of a series of functionalized alpha-heteroatom-substituted amino acids. 187 41

To study the relationship between cAMP and epilepsy, we investigated the effects of coriaria lactone (CL) on the levels of cAMP in cerebral cortex and hippocampus. Fifty normal WC1 mice were divided into 5 groups. All groups were injected with CL (2.5 mg/kg, i.m.), except the control group which was injected with NS. The concentrations of cAMP were measured after the animals had been immersed in liquid nitrogen to die at different phases of seizure development induced by CL (before seizures, in mild seizures, during severe seizures, and after severe seizures). The results indicated that the levels of cAMP in both cerebral cortex and hippocampus were significantly increased (1.73-fold and 1.33-fold) in severe seizure, and they continuously increased (1.85-fold and 1.45-fold) after severe seizures. On the other hand, no changes of cAMP were observed in mild seizures and before seizures. These data suggested that accumulation of cAMP is probably the result of seizure activity rather than the cause of seizure.
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PMID:[Variation of cAMP in cerebral cortex and hippocampus in seizure mice induced by coriaria lactone]. 196 94

Phenytoin (DPH) is commonly used to treat seizures associated with acute head injury. Consequent to decreases in DPH protein binding in such patients, the DPH free fraction (DPHff) may increase and thereby produce symptoms compatible with DPH toxicity despite the presence of total serum concentrations within the usually accepted therapeutic range. We examined the effect of acute traumatic injury on DPH protein binding in 13 hospitalized pediatric patients. In addition to total and free DPH serum concentrations, biochemical variables including blood pH, total and direct bilirubin, serum urea nitrogen, creatinine, albumin, gamma glutamyltransferase (GGT), and free fatty acid concentrations were measured serially over 10 days. The DPHff was compared between selected time intervals in hospitalized patients and data obtained in a control population of 27 epileptic outpatients who were maintained on DPH. Additionally, a multiple regression model was used to examine for covariance between the DPHff and the respective biochemical variables in the hospitalized patients. In the study patients, the DPHff progressively increased, attaining a maximum value (8.5 +/- 0.7%) on the fifth hospital day which was significantly greater (6.4 +/- 0.7%, p less than .05) than that on day 1 and also in the control group (6.1 +/- 0.3%; p less than .01). Blood pH, serum albumin, free fatty acids, creatinine and bilirubin concentrations did not change, but GGT did increase significantly over the 10-day sampling period. A significant (r = .51, p less than .0001) linear relationship was found between the DPHff and the serum albumin concentration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phenytoin protein binding in pediatric patients with acute traumatic injury. 196 39

Iminohydantoins selectively substituted at position C-5 and their 1-carbobenzoxy derivatives have been synthesized, and their anticonvulsant activity was evaluated in mice. In general, the more lipophilic 1-carbobenzoxy iminohydantoins were more potent than the unsubstituted counterparts. Evaluation of the individual enantiomers of the chiral iminohydantoins showed that the anticonvulsant activity resided primarily in the S isomers. In this study, (S)-(+)-1-carbobenzoxy-5-isobutyl-2-iminohydantoin (9a) was the most active member. This compound was not nearly as active as phenytoin against electrically induced convulsions, but was also active against pentylenetetrazole-induced seizures, suggesting a broader clinical potential. The closest analogue of phenytoin, viz., 5,5-diphenyl-2-iminohydantoin (1), failed to show any significant activity. Methylation on N-3 or the imino nitrogen of 1 also did not provide a compound with substantial activity. 2-Thiophenytoin was not active against electroshock seizures and showed only a weak activity against pentylenetetrazole. This study suggested that the structure-activity relationship of 2-iminohydantoins was quite different from that of 2-hydantoins.
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PMID:Synthesis and anticonvulsant activity of 2-iminohydantoins. 206 25

Phensuximide (PSX) is a 2-arylsuccinimide useful in the treatment of absence seizures. PSX is a mild urotoxicant and is structurally related to N-phenylsuccinimide (NPS) and its antifungal derivatives. Since substitution of the phenyl ring of NPS with chloro or tert-butyl groups can produce compounds with enhanced nephrotoxic potential, it was felt that similar substitutions on the phenyl ring of PSX also might produce derivatives with enhanced nephrotoxic potential. Three derivatives of PSX were prepared and tested: 2-(3-chlorophenyl)-N-methylsuccinimide (CPMS); 2-(4-tert-butylphenyl)-N-methylsuccinimide (BPMS) and 2-(3,5-dichlorophenyl)-N-methylsuccinimide (DPMS). In one set of experiments, male Fischer 344 rats were administered a single intraperitoneal (i.p.) injection of a succinimide (0.4 or 1.0 mmol kg-1) or vehicle (sesame oil, 2.5 ml kg-1) and renal function monitored at 24 and 48 h. Only minor changes in renal function were noted with the PSX derivatives. BPMS and DPMS (1.0 mmol kg-1) treatment induced mild renal tubular necrosis and thickening of the glomerular membranes. However, no significant morphological changes were noted in ureters, bladder or liver in any treatment group. In a second set of experiments, rats were pretreated with phenobarbital (75 mg kg-1 day-1, i.p., 3 days) followed by a single i.p. injection of DPMS (0.4 or 1.0 mmol kg-1) or DPMS vehicle. Renal function was monitored as before. Phenobarbital pretreatment did not markedly enhance the functional nephrotoxicity induced by DPMS (0.4 mmol), but tubular necrosis was greater than observed in non-phenobarbital-pretreated rats receiving DPMS (1.0 mmol kg-1). In addition, hepatotoxicity was observed as the appearance of numerous non-staining vacuoles in hypertrophied hepatocytes. In the phenobarbital plus DPMS (1.0 mmol kg-1) treatment group, all rats died by 48 h. Prior to death, rats exhibited increased proteinuria (+3), hematuria (+3) and blood urea nitrogen concentration. At 24 h, kidneys from rats treated with phenobarbital plus DPMS (1.0 mmol kg-1) exhibited extensive proximal tubular necrosis and numerous glomeruli with thickened membranes. Hepatotoxicity was more pronounced than with phenobarbital plus DPMS (0.4 mmol kg-1) at 48 h and urinary bladders had focal areas of erythrocytes pooling below the epithelial lining. These results demonstrate that although NPS and PSX are structural analogs, chemical substitutions that enhance the nephrotoxic potential of NPS do not have a similar effect on PSX. In addition, DPMS can induce urotoxicity in a manner similar to that observed for PSX and probably induces toxicity via one or more metabolites.
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PMID:Acute toxicity induced by 2-aryl-N-methylsuccinimides. 236 80

Ifosfamide/mesna was given to 97 patients who had malignant solid tumors diagnosed before they were 21 years of age. Patients received 1.6 g/m2 ifosfamide daily x 5, given i.v. over 15 min, followed by 400 mg/m2 i.v. mesna at 15 min and 4 and 6 h after ifosfamide. Responses were noted in patients with osteosarcoma, Ewing's sarcoma, rhabdomyosarcoma and other soft-tissue sarcomas, rhabdoid tumor, neuroblastoma, Wilms' tumor, primitive neuroectodermal tumor, retinoblastoma, germ-cell tumors, and B-cell lymphoma. Toxicity included mild to moderate nausea and vomiting, transient, reversible myelosuppression, transient elevations of serum blood urea nitrogen (BUN) and creatinine and liver enzymes, infections, and self-limiting neurotoxicity characterized by changes in mental status, motor dysfunction, cranial nerve palsy, cerebellar dysfunction, and seizures. Neurotoxic symptoms were generally seen in patients who had previously received cisplatin. Ifosfamide is an important alkylating agent that should be combined with other agents in phase II and III trials. Alternate dose schedules should also be investigated.
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PMID:Ifosfamide in pediatric malignant solid tumors. 250 57

We examined the effects of laudanosine, one of the principal metabolites of atracurium, on the electroencephalogram (EEG) in an animal model of induced epilepsy. Fourteen rabbits were anaesthetized with 4% halothane in oxygen, the trachea intubated and the lungs ventilated mechanically with 30% oxygen and 1% halothane in nitrogen. Animals were assigned randomly to receive either an infusion of laudanosine (laudanosine group, n = 7) at a rate calculated to produce plasma concentrations similar to those found following the clinical use of atracurium, or an equal volume of normal saline (control group, n = 7). To induce an epileptogenic focus, gelfoam sponges soaked in a pH-adjusted 4% cefazolin solution were applied bilaterally to the parietal cortical surface. This resulted in the production of spike and burst EEG activity in all animals. However, scoring the frequency of the spikes and bursts revealed no significant differences between the laudanosine and control groups. We conclude that, in this animal model of epilepsy, no increased incidence of seizure activity was produced by mean plasma laudanosine concentrations as great as 0.8 micrograms ml-1. These results suggest that the routine use of atracurium is unlikely to provoke seizures, even in the presence of an epileptogenic focus.
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PMID:Electroencephalographic effects of laudanosine in an animal model of epilepsy. 273 Aug 27


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