Окскарбазепин

Oxcarbazepine is a new antiepileptic carbamazepine derivative, reportedly better tolerated than carbamazepine. It appears to be most effective in partial epilepsy with complex seizures.

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Oxcarbazepine is a sodium channel protein inhibitor. It is an anticonvulsant and mood-stab.

ChEBI: A dibenzoazepine derivative, having a carbamoyl group at the ring nitrogen, substituted with an oxo group at C-4 of the azepeine ring which is also hydrogenated at C-4 and C-5. It is a anticholinergic anticonvulsant and mood stabilizing drug, used primaril in the treatment of epilepsy.

Oxcarbazepine is chemically and pharmacologically closely related to carbamazepine, but it has much less capacity to induce drug-metabolizing enzymes. This property decreases the problems associated with drug interactions when oxcarbazepine is used in combination with other drugs. The clinical uses and adverse effect profile of oxcarbazepine appear to be similar to those of carbamazepine.

Oxcarbazepine, marketed under the trade name Trileptal^?, is an anticonvulsant developed and prescribed for treatment of epilepsy. In recent years, Oxcarbazepine has shown efficacy in treatment of mood disorders. This certified solution standard is suitable as starting material for the preparation of calibrators and controls in oxcarbazepine testing by GC/MS or LC-MS/MS.

Anticonvulsant; protects mice and rats against generalized tonic-clonic seizures induced by electroshock. Thought to act via inhibition of sodium channel activity.

Although oxcarbazepine is less potent that CBZ, its mechanism of action is similar. The majority of the pharmacological activity for oxcarbazepine is attributed to its primary metabolite, 10-monohydroxycarbazepine (MHD), the plasma levels of which may be ninefold higher than those for CBZ. Both oxcarbazepine and MHD produce a blockade of voltagedependent sodium channels, thus decreasing repetitive firing and spread of electrical activity. An additional action on calcium and potassium channels may contribute to the therapeutic effect. Like carbamazepine, oxcarbazepine may worsen juvenile myoclonic or absence seizures.

Oxcarbazepine is completely absorbed, and food has no effect on its absorption. Unlike CBZ, it does not cause autoinduction of its own metabolism. The metabolism of oxcarbazepine is different from that of CBZ. Oxcarbazepine is reduced by cytosolic enzymes to MHD before its O-glucuronidation. More than 95% of its oral dose is excreted as conjugated metabolites, with approximately 4% of the drug converted to inactive 10,11-dihydroxy CBZ. Unlike CBZ, no epoxide nor aromatic hydroxylation metabolites are formed. The half-life is 2 hours for oxcarbazepine and 9 hours for the active 10-monohydroxy metabolite. In patients with impaired renal function, the half-life for MHD is prolonged to 19 hours, with a doubling in its area under the plasma concentration curve. Peak plasma concentration following an oral dose occurs at approximately 4.5 hours.
Oxcarbazepine induces CYP3A4/5 and UTP, and it also inhibits CYP2C19, producing significant effects on the plasma concentration of other drugs. Therefore, oxcarbazepine decreases felodipine bioavailability and lowers plasma levels for lamotrigine, CBZ, CBZ epoxide, calcium channel blockers, and oral contraceptives. Oxcarbazepine increases plasma levels of phenobarbital and phenytoin. Unlike carbamazepine, oxcarbazepine has no effect on plasma levels of risperidone or olanzepine. The plasma levels for oxcarbazepine or MHD are decreased by CBZ, phenobarbital, phenytoin, valproate, and verapamil. Serum MHD may decrease during pregnancy but increase following delivery. Oxcarbazepine clearance is decreased in renal impairment and the elderly. In children, a higher dose/kg for oxcarbazepine than in adults is required to obtain an effective plasma concentration.

Oxcarbazepine (Trileptal?) is the 10-keto analogue of carbamazepine. It is indicated as monotherapy or adjunctive therapy for partial seizures in adults with epilepsy, as monotherapy for the treatment of partial seizures in children 4 years of age or older, and as adjunct therapy in children 2 to 4 years of age.

Patients with hypersensitivity reactions to carbamazepine can be expected to show cross-sensitivity (e.g., rash) or related problems to oxcarbazepine. The improved toxicity profile for oxcarbazepine when compared to CBZ may result from absence of the epoxide or CBZ-iminoquinone metabolites. The most common side effects are headache, dizziness, nystagmus, blurred vision, somnolence, nausea, ataxia, and fatigue. The incidence of adverse effects has been related to elevated serum MHD concentrations. Adverse effects on cognitive status, hyponatremia, and serious dermatological reactions have been reported, as has hyponatremia.

Oxcarbazepine can be obtained in two different ways.
1) Reaction of 10-methoxy-5H-dibenz[b,f]azepine (1) with phosgene gives the 5- chlorocarbonyl compound, treatment with NH3 affords 10-methoxy-5H-dibenz[b,f ]azepine-5-carboxamide (2), which is hydrolyzed with diluted HCl to oxcarbazepine.
2) Nitration of 5-cyano-5H-dibenz[b,f ]azepine (3) with NaNO3 in acetic anhydride/acetic acid gives 5-cyano-10-nitro-5H-dibenz[b,f ]azepine (4), which is treated with BF3 and powdered iron in acetic acid.