User:Fvasconcellos/Retigabine
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| Routes of administration | Oral |
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| Pharmacokinetic data | |
| Bioavailability | 60% |
| Protein binding | 60–80% |
| Metabolism | Hepatic glucuronidation and acetylation. CYP not involved |
| Elimination half-life | 8 hours (mean)[1] |
| Excretion | Renal (84%) |
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| Formula | C16H18FN3O2 |
| Molar mass | 303.331 g/mol g·mol−1 |
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Retigabine (INN, codenamed D-23129) is an anticonvulsant being investigated as a possible treatment for partial epilepsies. As of May 2009[update], several Phase III clinical trials are underway for this indication. The drug is being developed by Valeant Pharmaceuticals and GlaxoSmithKline.
Retigabine works primarily 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 animal studies, it was found to have a very broad spectrum of activity, being effective against several types of seizures.
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.[2]
Adverse effects
The adverse effects found in the Phase II trial mainly affected the central nervous system, and appeared to be dose-related.[3] Adverse effects included drowsiness, dizziness and vertigo, confusion, slurred speech, tremor, memory loss, gait disturbances, and double vision.[2]
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.[5] Retigabine appears to require thrice-daily dosing due to its short half-life.[4][3]
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.[5]
Mechanism of action
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.[5]
References
- ^ Ferron GM, Paul J, Fruncillo R; et al. (2002). "Multiple-dose, linear, dose-proportional pharmacokinetics of retigabine in healthy volunteers". J Clin Pharmacol. 42 (2): 175–82. PMID 11831540.
{{cite journal}}: Explicit use of et al. in:|author=(help); Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ a b Porter RJ, Partiot A, Sachdeo R, Nohria V, Alves WM (2007). "Randomized, multicenter, dose-ranging trial of retigabine for partial-onset seizures". Neurology. 68 (15): 1197–204. doi:10.1212/01.wnl.0000259034.45049.00. PMID 17420403.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ a b c Ben-Menachem E (2007). "Retigabine: has the orphan found a home?". Epilepsy Curr. 7 (6): 153–4. doi:10.1111/j.1535-7511.2007.00209.x. PMC 2096728. PMID 18049722.
- ^ a b Plosker GL, Scott LJ (2006). "Retigabine: in partial seizures". CNS Drugs. 20 (7): 601–8, discussion 609–10. PMID 16800718.
- ^ a b c Łuszczki JJ (2009). "Third-generation antiepileptic drugs: mechanisms of action, pharmacokinetics and interactions" (PDF). Pharmacology Reports. 61 (2): 197–216. PMID 19443931.
Further reading
- Blackburn-Munro G, Dalby-Brown W, Mirza NR, Mikkelsen JD, Blackburn-Munro RE (2005). "Retigabine: chemical synthesis to clinical application". CNS Drug Rev. 11 (1): 1–20. PMID 15867950.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - Hempel R, Schupke H, McNeilly PJ; et al. (1999). "Metabolism of retigabine (D-23129), a novel anticonvulsant". Drug Metab Dispos. 27 (5): 613–22. PMID 10220491.
{{cite journal}}: Explicit use of et al. in:|author=(help); Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link)