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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dose-response curves for the prototypical anticonvulsants phenytoin (PHT) and carbamazepine (CBZ), and a novel anticonvulsant, ameltolide (LY201116), were determined with and without pretreatment with the selective serotonin-uptake inhibitor fluoxetine by maximal electroshock seizure (MES) test in mice. Fluoxetine (2.5, 5, and 10 mg/kg intraperitoneally, i.p.) produced a dose-related decrease in the ED50 values for the anticonvulsants (i.p. administration) to protect against MES-induced tonic-extensor seizures. Fluoxetine (10 mg/kg i.p.) also decreased the intravenous (i.v.) ED50 doses of the three anticonvulsants by a factor of approximately 2. These data suggest that fluoxetine, through its selective inhibition of serotonergic reuptake, may have beneficial advantages as compared with common antidepressant drugs in treatment of depressed patients with epilepsy and may also enhance the seizure control of prototypical anticonvulsants in treatment of epilepsy.
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PMID:Fluoxetine, a selective serotonin-uptake inhibitor, enhances the anticonvulsant effects of phenytoin, carbamazepine, and ameltolide (LY201116). 153 97

Ameltolide, a novel anticonvulsant agent, has been shown in animal models to be effective in controlling seizures. The developmental toxicity of ameltolide was evaluated in two species. Naturally mated rats and rabbits were dosed once daily by gavage on gestation days (GD) 6-17 and 6-18, respectively. Rats were given doses of 0, 10, 25, or 50 mg/kg; rabbits were given 0, 25, 50, or 100 mg/kg. Laparotomy was performed on rats on GD 20 and on rabbits on GD 28. In rats, maternal toxicity was indicated at the 25- and 50-mg/kg dose levels by depressed body weight gain. Fetal body weight was depressed at the 50-mg/kg dose level. Fetal viability and morphology were not affected. The no-observed effect levels (NOEL) for adult and developmental toxicity in the rat were 10 and 25 mg/kg, respectively. In rabbits, maternal toxicity was indicated by a net loss in body weight at the 50- and 100-mg/kg dose levels. Fetal viability and body weight were depressed at the 100 mg/kg dose level. Shortened digits occurred on the right forepaw of one fetus at the 50-mg/kg dose level (in conjunction with severe maternal toxicity) and on the hindpaws of two fetuses from separate litters at the 100-mg/kg dose level. Incomplete ossification of the phalanges occurred on the forepaws of nine fetuses from four litters at the 100-mg/kg dose level. Ameltolide was weakly teratogenic in the rabbit. The NOEL for adult and developmental toxicity in the rabbit was 25 mg/kg.
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PMID:Ameltolide. I: Developmental toxicology studies of a novel anticonvulsant. 195 61

In mice, the diethylglycineamide analogue of LY201116, DEGA (N-(2,6-dimethylphenyl)-4-[[(diethylamino)acetyl]amino]benzamide), is metabolized by consecutive N-deethylations for form MEGA and GA; the monoethylglycineamide and glycineamide analogues of LY201116, respectively. All of these compounds are in turn hydrolyzed to form LY201116 [4-amino-N-(2,6-dimethylphenyl)benzamide]. LY201116 is N-acetylated to form the N-acetyl metabolite, NAC. NAC is also deacetylated to reform LY201116. All of the above compounds inhibit maximal electroshock-induced seizures (MES) in mice. After oral administration, the potencies of these compounds were similar at their time of peak anticonvulsant effect. However, the MES ED50 values for the above compounds 5 min after iv dosing were 43, 13, 2, and 0.5 mg/kg for DEGA, MEGA, GA, and LY201116, respectively. Similar plasma levels of LY201116 were produced in mice 5 min after iv dosing with the respective ED50 values of the above compounds, which suggested that all of the compounds produced their anticonvulsant effects via LY201116. The in vivo metabolism of DEGA and MEGA but not GA to LY201116 was inhibited by the acylamidase inhibitor bis-(p-nitrophenyl) phosphate (BNPP). Mice predosed with BNPP were not protected by DEGA and MEGA from MES-induced seizures and the plasma samples contained little or no LY201116. The metabolism of GA to LY201116 was not inhibited by BNPP, and GA was an active anticonvulsant in BNPP-pretreated mice. The apparent iv potency of DEGA increased dramatically with time after dosing, again suggesting time-dependent, metabolically mediated liberation of the more potent anticonvulsant LY201116.
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PMID:Metabolism of the prodrug DEGA (N-(2,6-dimethylphenyl)-4-[[(diethylamino)acetyl]amino]benzamide) to the potent anticonvulsant LY201116 in mice. Effect of bis-(p-nitrophenyl)phosphate. 290 94

LY201116 [4-amino-N-(2,6-dimethylphenyl)benzamide], an effective anticonvulsant in several animal models, is rapidly metabolized by N-acetylation in rats, mice and monkeys. In an attempt to preclude metabolic N-acetylation sterically, we investigated LY201409, an analogue possessing two methyl groups ortho to the 4-amino substituent. This structural modification successfully altered the metabolic pathway, and LY201409 displayed potent anticonvulsant activity. LY201409 antagonized maximal electroshock (MES)-induced seizures with ED50 values of 16.2 and 4.2 mg/kg after oral administration to mice and rats, respectively. The compound did not effectively antagonize seizures induced by a variety of chemical convulsants in rats, but did block pentylenetetrazol-induced seizures in mice. Thus, among the classic anticonvulsants, the profile of phenytoin most closely resembles that of LY201409. Studies conducted with the rotorod and horizontal screen assays in mice and behavioral studies in rats suggested that doses of LY201409 that produced CNS side-effects such as sedation or ataxia were well separated from the anti-MES doses. LY201409 was a potent, dose-dependent potentiator of hexobarbital-induced sleeping time in mice. Oral administration of 6.0 mg/kg led to a 372% increase in sleep time relative to control values. Although LY201409 is a potent and effective anticonvulsant, it is also one of the most potent potentiators of hexobarbital-induced sleep time yet described.
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PMID:Pharmacology of LY201409, a potent benzamide anticonvulsant. 319 92

The anticonvulsant ameltolide (LY201116) is a novel potential therapy for the treatment of canine epilepsy. Eight dogs were administered five different oral doses of ameltolide and clinical scoring of the maximal electroshock (MES) induced seizures at 3 and 24 h postdosing were determined in two separate crossover design studies. Plasma ameltolide concentrations were determined at the time of seizures in all dogs and complete plasma concentration-time profiles were also determined in a separate study. A nonlinear mixed effects PK/PD model was fit to the resulting data. A one compartment open model with first order absorption was determined to best fit the ameltolide pharmacokinetics. An effect compartment with a cumulative logistic regression equation was used to establish the PK/PD relationship. The mean bioavailability normalized volume of distribution and the elimination half-life were estimated at 1.20 L/kg and 5.46 h, respectively. The fitted model estimated that from 2 to 15 h following a single 3 mg/kg oral ameltolide dose the mean probability of obtaining a 1 unit reduction in the seizure clinical score severity was greater than 0.80. The utilized PK/PD analysis combined with the canine MES model allowed for the rapid and efficient determination of the plasma ameltolide concentration-anticonvulsant relationship preclinically in dogs.
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PMID:Nonlinear mixed effects pharmacokinetic/pharmacodynamic analysis of the anticonvulsant ameltolide (LY201116) in a canine seizure model. 1900 Feb 80