User:Fvasconcellos/Retigabine

Retigabine (INN) or ezogabine (USAN), codenamed D-23129, is an anticonvulsant being investigated as a possible treatment for partial epilepsies. , several Phase III clinical trials are underway for this indication, and retigabine is being reviewed for approval by the United States Food and Drug Administration and the European Medicines Agency. The drug is being developed by Valeant Pharmaceuticals and GlaxoSmithKline.

Retigabine works primarily as a potassium channel opener—that is, by activating a certain family of voltage-gated potassium channels in the brain. This mechanism of action is unique among antiepileptic drugs, and may hold promise for the treatment of other neurologic conditions, including migraine and neuropathic pain; a Phase II trial to assess the safety and efficacy of retigabine for treating postherpetic neuralgia is ongoing.

History
Among the newer anticonvulsants, retigabine was one of the most widely studied in the preclinical setting: it was the subject of over 100 published studies before clinical trials began. In preclinical tests, it was found to have a very broad spectrum of activity—being effective in nearly all the animal models of seizures and epilepsy used: retigabine suppresses seizures induced by electroshock, electrical kindling of the amygdala, pentylenetetrazol, kainate, NMDA, and picrotoxin. Researchers hoped this wide-ranging activity would translate to studies in humans as well.

Preclinical testing
Several animal studies have suggested that, like many antiepileptic drugs, retigabine may act as a mood stabilizer.

Clinical trials
In a double-blind, randomized, placebo-controlled Phase II clinical trial, retigabine was added to the treatment regimen of 399 participants with partial seizures that were refractory to therapy with other antiepileptic drugs. The frequency with which seizures occurred was significantly reduced (by 23 to 35%) in participants receiving retigabine, and approximately one fourth to one third of participants had their seizure frequency reduced by more than 50%. Higher doses were associated with a greater response to treatment.

Adverse effects
The adverse effects found in the Phase II trial mainly affected the central nervous system, and appeared to be dose-related. The most common adverse effects were drowsiness, dizziness and vertigo, confusion, and slurred speech. Less common side effects included tremor, memory loss, gait disturbances, and double vision.

Pharmacokinetics
Retigabine is quickly absorbed, and reaches maximum plasma concentrations in 1.5 hours after a single oral dose. It has a moderately high oral bioavailability (50–60%), a high volume of distribution (6.2 L/kg), and a terminal half-life of 8 to 11 hours. Retigabine appears to require thrice-daily dosing due to its short half-life.

Retigabine is metabolized in the liver, by N-glucuronidation and acetylation. The cytochrome P450 system is not involved. Retigabine and its metabolites are excreted by the kidneys.

Mechanism of action
Retigabine acts as a neuronal KCNQ/Kv7 potassium channel opener, a mechanism of action markedly different from than of any current anticonvulsants. This mechanism of action is similar to that of flupirtine, which is used mainly for its analgesic properties.

Interactions
Retigabine appears to be free of drug interactions with most commonly used anticonvulsants. It may increase metabolism of lamotrigine (Lamictal), whereas phenytoin (Dilantin) and carbamazepine (CBZ, Tegretol) increase the clearance of retigabine.