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Overview of the Biotransformation of Antiepileptic Drugs
Published in Carl L. Faingold, Gerhard H. Fromm, Drugs for Control of Epilepsy:, 2019
Ethotoin has two important biotransformation pathways. The first is N-deethylation by liver oxidative enzymes to form 5-phenylhydantoin, which undergoes ring opening by di-hydropyrimidinase to yield 2-phenylhydantoic acid. Only the R-form of N-dealkylated ethotoin will serve as a substrate for dihydropyrimidinase. The second route of metabolism is hydroxylation of the phenyl ring. An epoxide intermediate is probably formed as in the case with phenytoin and mephenytoin. The major hydroxylated metabolite is 3-ethyl-5-(4-hy-droxyphenyl)hydantoin, the para-substituted product. Several other hydroxylated metabolites have been found, but they are not present in significant quantities. Elimination of all the hydroxylated products is by conjugation with glucuronic acid. No metabolites of ethotoin appear to have any anticonvulsant effects.
Recent developments on triazole nucleus in anticonvulsant compounds: a review
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Since the discovery of the first anticonvulsant bromide in 1857, a large number of anticonvulsants were developed and approved for epilepsy treatment: phenobarbital, phenytoin, primidone, methsuximide, methazolamide, ethotoin, diazepam, trimethadione, sodium valproate, clonazepam, clobazam, carbamazepine, acetazolamide, valproic acid, felbamate, fosphenytoin, gabapentin, lamotrigine, lacosamide, levetiracetam, oxcarbazepine, stiripentol, vigabatrin, zonisamide, rufinamide, retigabine, and so on10–12. For patients with epilepsy, a single medication is recommended initially13. But there are about half of seizures could not be controlled by using a single medication (monotherapy), then polytherapy with multiple anticonvulsants is recommended14. Unfortunately, about 30% of people continue to have seizures despite anticonvulsants treatment15, and the side effects of anticonvulsant agents follow up. Until now, the existing drugs are far from ideal, being consistently effective in fewer than 70% of patients and tending to produce a variety of side-effects in more than 50% of patients8. Toxicity, intolerance, and a lack of efficacy represent the limitations of the available anticonvulsants, which stimulated the continual attempts for discovery of new anticonvulsants.
Approaches for the discovery of drugs that target K Na 1.1 channels in KCNT1-associated epilepsy
Published in Expert Opinion on Drug Discovery, 2022
Barbara Miziak, Stanisław J Czuczwar
Yoshitomi et al. [107] studied the effects of quinidine in 4 pediatric patients with KCNT1 mutations. In the first patient (age 20 months), the first focal seizures comprising asymmetric tonic posturing with eye deviation appeared in the first month of life. Based on the symptoms and EEG picture, EIMFS was diagnosed and WES revealed a de novo heterozygous mutation in KCNT1 (c.1283 G > A: p.Arg428Gln). Therapy with antiepileptic drugs had no effect. At the age of 9 months, quinidine therapy (starting dose 2 mg/kg/d) was started as an additional treatment alongside levetiracetam and potassium bromide. At 6 months, no improvement was observed despite a gradual increase in the dose of the drug – first to 114 mg/kg/d and then to 126 mg/kg/d. The last dose of quinidine caused severe cardiac arrhythmia (ventricular tachycardia) and an increase in focal tonic seizures. The arrhythmia resolved when the quinidine dose was reduced to 73 mg/kg/d, and a 62.4% reduction in seizure frequency was observed over the next 3 months. Another patient (3 years old) had seizures comprised asymmetrical tonic convulsions with cyanosis, eye deviation, and oral automatism since 2 months of age. Similar to the above case, EIMFS was diagnosed and WES revealed a de novo heterozygous mutation in KCNT1 (c.2800 G > A; p.Ala934Thr). Treatment with quinidine (in combination with phenobarbital and potassium bromide) was started at 2 mg/kg/d and subsequently increased to 60 − 100 mg/kg/d. During the first 3 months, epileptic seizures were reduced by 48.1%, but electrocardiographic (ECG) changes (QT prolongation) were also observed at high doses. Similarly, another patient (21 months, preterm) with a diagnosis of EIMFS (de novo mutation in KCNT1 (c.862 G > A; p.Gly288Ser) who did not respond to antiepileptic drugs. Quinidine was administered at 14 months of age at a dose of 17 mg/kg/d (as add-on therapy) and gradually increased to 74.5 mg/kg, but at the highest dose ECG abnormalities appeared – in the form of wide QRS complex. The ECG abnormalities resolved when the dose was reduced to 70.7 mg/kg/d. Despite using the highest possible dose of quinidine, no neurological improvement of the patient was observed. The last patient (9 years) in this study group had suppression-burst seizures and was diagnosed with focal epilepsy (de novo heterozygous missense mutation in KCNT1 (c.1420C>T; p.Arg474Cys). Antiepileptic drugs, methyl prednisolone pulse therapy, and the ketogenic diet were ineffective. At 7 years of age, quinidine therapy was started at 21 mg/kg/d (in combination with clobazam and ethotoin) and gradually increased to 85 mg/kg/d. Within 3 months of treatment, a slight improvement was observed with a mean seizure frequency reduction of 23.1% [107].