User:Kramoswiki/sandbox

Mesuximide (or methsuximide, methosuximide) is a succinimide anticonvulsant medication. It is sold as a racemate by Pfizer under the tradenames Petinutin (Switzerland) and Celontin (United States). The therapeutic efficacy of methosuximide is largely due to its pharmacologically active metabolite, N-desmethylmethosuximide, which has a longer half-life and attains much higher plasma levels than its parent.

History of treatments
Methsuximide was discovered in the early 1950’s primarily for the treatment of absence seizures (petit mal seizures). Methsuximide is a broader spectrum antiepileptic drug and was considered a last resort drug to treat seizure disorders in patients that are refractory to treatment with other antiepileptic drugs. However, continued clinical trials led to many off label uses for effective treatment of a broad spectrum of seizures; refractory partial complex seizures, psychomotor seizures, myoclonic seizures, mixed epilepsy and Lennox-Gastaut syndrome.

Synthesis


2-Methyl-2-phenylsuccinic acid is reacted with an excess of methylamine and water to produce methsuximide. The excess methylamine and water are distilled off under reduced pressure to yield the dimethylamine salt of the acid. The dimethylamine salt undergoes pyrolysis at 250 ˚C the product is dissolved in solvent and treated with activated charcoal. Methsuximde is precipitated with the addition of water.

Characteristics
Methsuximide has a nonpolar lipophilic moiety which allows for rapid tissue distribution. Water solubility at pH 7.0 (25˚C) is 2.8 mg/ml.

Petit mal seizures
N-desmethylmethosuximide, the active metabolite of methsuximide, dampens the low threshold calcium currents in thalamic neurons that play a role in the generation of the spike-wave discharges in petit mal epilepsy by blocking voltage-gated t-type calcium channels. N-desmethylmethosuximide and the low threshold calcium current-reducing receptor show a bimolecular interaction, which indicates co-operative binding of more than one molecule of N-desmethylmethosuximide binding to a receptor. The extent of the reduction of the low threshold calcium current is voltage dependent and most effective at the voltage threshold for initiating the current. N-desmethylmethosuximide has a lower potency but a higher efficacy when compared to a similar succinimide, ethosuximide, with a maximal effect of 100% and an Ic50 of 1100 μM compared to ethosuximide maximal effect 40% and an Ic50 of 200 μM.

Other seizure types
The structure of N-desmethylmethosuximide is very similar to phenytoin. Therefore, it is predicted that the broad spectrum anticonvulsant effects are due to its effects on sodium currents.

Pharmacokinetics
Methsuximide is administered orally and is rapidly absorbed into the small intestine and rapidly distributed throughout the body. Methsuximide crosses the blood brain barrier, which may be due to its nonpolar lipophilic properties. Dose amount and dose frequency differ for adults and children and are generally based on the serum concentration of N-desmethylmethsuximide. The average starting dose is 10 mg/kg to reach a recommended serum range for adults: 20-40 ug/mL and children: 40-50 ug/mL. Methsuximide and N-desmethylmethsuximide follow first order kinetics and there is a linear relationship between dose and steady state serum levels. Once a determined drug regimen has begun, N-desmethylmethsuximide reaches steady state in 8.1-16.8 days. Maximum plasma concentration Tmax values for N-Desmethylmethsuximide in adults is 1-4 hours and children is 2-3 hours.

The serum protein binding of methsuximide is negligible. The serum protein binding for N-desmethylmethsuximide is 45-60%. The serum concentration of N-desmethylmethsuximide is approximately 700 times more than methsuximide.

In the liver N-desmethylmethsuximide is rapidly formed by the n-demethylation of methsuximide. The half-life of methsuximide is 1.4 to 2.6 hours. The average half-life of N-desmethylmethsuximide in adults is 36-45 hours and in children 16-45 hours. N-desmethylmethsuximide is further metabolized by enzyme cytochrome P450 2C19. Other possible mechanisms of metabolism of N-desmethylmethsuximide are: microsomal enzyme induction, porphyrinogenesis and hydrolysis of the succinimide ring.

Elimination is primarily renal; methsuximide and N-desmethylmethsuximide are detected in urine.

Potential side effects
Some of the most common side effects are; nausea, abdominal discomfort, anorexia, vomiting, diarrhea, drowsiness, vertigo, diplopia, blurred vision, rash, ataxia, dizziness, hiccups, and irritability. Some of the less common side effects include; inattention, personality change, confusion, nervousness, headaches, lethargy, fearfulness, slurred speech, dysarthria, increased seizures, and photophobia. Some severe and rare side effects include; irreversible cerebellar damage, periorbital edema, porphyria, restless leg syndrome, proteinuria, microscopic hematuria, hyperemia, and death.

Methsuximide interactions with other Antiepileptic Drugs
Methsuximide increases the serum concentrations of phenobarbital and phenytoin and decreases the serum concentrations of primidone, valproic acid, levetiracetam, lamotrigine, topiramate, and oxcarbazepine. Phenytoin and phenobarbital increase the metabolism of methsuximide and therefore increase the serum ratio of N-desmethylmethsuximide to methsuximide. Serum levels of N-desmethylmethsuximide are increased by the inhibition of methsuximide metabolism by Felbamate.