Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038220 (status epilepticus)
 7,272 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Primidone is a minor first-generation antiepileptic drug, little currently prescribed for this indication, but except marketing authorization, remains a first-line treatment of essential tremor. Although it is metabolized in phenyl-ethyl-malondamide and phenobarbital, active metabolites that contribute also to its action, primidone is not a prodrug and is active by itself. The rate of conversion of primidone to phenobarbital is highly variable according to the subject. Generally accepted therapeutic range for primidone is between 5 and 10 mg/L (23-46 mmol/L). The therapeutic drug monitoring (TDM) of primidone must be accompanied by the determination of phenobarbital concentrations. The level of proof of the interest of the TDM primidone was estimated to be "probably useless". Phenobarbital, a very ancient anticonvulsant, is much less used today, for the benefit of other more recent compounds. It remains prescribed in neonatology and is one of the compounds used in status epilepticus. It is a molecule with a long half-life, metabolized in p-hydroxy-phenobarbital. It is a potent inducer of CYP3A4. Several side effects, especially drowsiness, are concentration-dependent. Generally accepted therapeutic range for phenobarbital is between 10 and 40 mg/L (43 - 172 mmol/L), without considering the type of crise. The level of proof of the interest of TDM of phenobarbital was evaluated as "recommended".
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PMID:[Therapeutic drug monitoring of primidone and phenobarbital]. 2311 Aug 39

The synthesis and anticonvulsant properties of new N-Mannich bases of 3-phenyl- (9a-d), 3-(2-chlorophenyl)- (10a-d), 3-(3-chlorophenyl)- (11a-d) and 3-(4-chlorophenyl)-pyrrolidine-2,5-diones (12a-d) were described. The key synthetic strategies involve the formation of 3-substituted pyrrolidine-2,5-diones (5-8), and then aminoalkylation reaction (Mannich-type) with formaldehyde and corresponding secondary amines, which let to obtain the final compounds 9a-d, 10a-d, 11a-d and 12a-d in good yields. Initial anticonvulsant screening was performed in mice (ip) using the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizures tests. The most effective compounds in mice were tested after oral administration in rats. The acute neurological toxicity was determined applying the minimal motor impairment rotarod test. The in vivo results revealed that numerous compounds were effective especially in the MES test (model of human tonic-clonic seizures). The most active in the MES seizures in rats was 1-[(4-benzyl-1-piperidyl)methyl]-3-(2-chlorophenyl)pyrrolidine-2,5-dione (10c) which showed ED50 value of 37.64mg/kg. It should be stressed that this molecule along with 9a, 9d and 10d showed protection in the psychomotor seizure test (6-Hz), which is known as an animal model of therapy-resistant epilepsy. Furthermore compounds 9a, 9d and 10d were also tested in the pilocarpine-induced status prevention (PISP) test to assess their potential effectiveness in status epilepticus. For the most promising molecule 9d an influence on human CYP3A4 isoform of P-450 cytochrome was studied in vitro.
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PMID:Design, synthesis and anticonvulsant properties of new N-Mannich bases derived from 3-phenylpyrrolidine-2,5-diones. 2399 70