The anticonvulsant potential of a series of N-phenylphthalimide derivatives has been screened in subcutaneous pentylenetetrazole seizure (scPTZ) and maximal electroshock seizure (MES) tests. Intraperitoneal 4-amino-N-phenylphthalimides were the most potent agents against MES in mice. Referring to the N-(2,6-dimethyl-phenyl)phthalimide structure, the order of anticonvulsant activity appears to correspond to the phthalimide ring substitution pattern of 4-amino > 4-nitro > 4-methyl; H > 3-nitro; 3-amino. The 4-amino-N-(2-methylphenyl)-phthalimide displays an anti-MES ED50 of 47.61 mumol/kg with a protective index (PI) of 4.2. Oral administration to rats of the compounds found to be active in mice showed that the 4-amino-N-(2,6-dimethylphenyl)phthalimide is the most potent anti-MES agent in rats, exhibiting an ED50 of 25.2 mumol/kg and a PI greater than 75. Regarding the nature of the 2 and 6 substituents of the N-phenyl ring, the anticonvulsant efficiencies may be ordered as follows: 2,6-dimethyl > 2-methyl > 2-ethyl > 2-ethyl-6-methyl > 2,6-diethyl > unsubstituted phenyl ring. N-Phenylphthalimide derivatives seem to have great potential as candidate anticonvulsant drugs.

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We compared the anticonvulsant activity and neurotoxicity of 4-amino-N-(2,6-dimethylphenyl)phthalimide (ADD 213063) with those of phenytoin (PHT), carbamazepine (CBZ), phenobarbital (PB), ethosuximide (ESM), valproate (VPA), and felbamate (FBM). Evaluation of anticonvulsant properties performed according to well-established procedures in rats and mice showed that ADD 213063 is most effective in protecting animals against maximal electroshock seizures (MES). This anti-MES activity is achieved with nontoxic doses, with the optimal effect recorded in rats dosed orally with anti-MES ED50 and protective index (PI) values of 25.2 mumol/kg and > 75, respectively. ADD 213063 protects to a lesser extent against seizures induced by subcutaneous (s.c.) picrotoxin and subcutaneous pentylenetetrazol (PTZ) in mice dosed intraperitoneally and orally, respectively. The profile of anticonvulsant action of ADD 213063 closely parallels that of CBZ.

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We describe on a 3-year-old child referred for evaluation and therapy of a cerebral vascular accident with residual hemiplegia and partial epilepsy. Metabolic investigations initially showed normal urinary organic acids as well as normal blood and urinary amino acids. Blood carnitine fractions had been pathological and a secondary carnitine deficiency was diagnosed and treated by oral L-carnitine supplementation. During carnitine treatment, abnormal urinary acylcarnitine profiles were noticed with excessive amounts of several carnitine esters including propionylcarnitine, butyryl- and/or isobutyryl-carnitine, isovaleryl- and/or 2-methylbutyryl-carnitine, hexanoylcarnitine and octanoylcarnitine. Subsequently, an urinary organic acid profile suggestive of glutaric aciduria type II was recorded during a clinical decompensation crisis. Morphological and biochemical studies on skeletal muscle and skin fibroblasts were performed and confirmed the existence of a defect of the mitochondrial beta-oxidation pathways with lipidic myopathy, reduced palmitate and octanoate oxidation rates in cultured fibroblasts. Glutaric aciduria type II increases the list of metabolic disorders characterized by hemiplegia and other sequelae of brain ischaemia such as stroke-like episode, seizures, aphasia, ataxia and myoclonia, similar to those seen in MELAS.