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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Chemical and physical data | |
Formula | C16H18FN3O2 |
Molar mass | 303.331 g/mol g·mol−1 |
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Retigabine (INN) or ezogabine (USAN), codenamed D-23129, is an anticonvulsant being investigated as a possible treatment for partial epilepsies. As of July 2010[update], 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.[2] 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.[3][4][5] 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
[edit]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.[6] Researchers hoped this wide-ranging activity would translate to studies in humans as well.[7]
Preclinical testing
[edit]Several animal studies have suggested that, like many antiepileptic drugs, retigabine may act as a mood stabilizer.[8][9][10]
Clinical trials
[edit]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.[11][7][12]
Adverse effects
[edit]The adverse effects found in the Phase II trial mainly affected the central nervous system, and appeared to be dose-related.[7] The most common adverse effects were drowsiness, dizziness and vertigo, confusion, and slurred speech.[12] Less common side effects included tremor, memory loss, gait disturbances, and double vision.[11]
Pharmacokinetics
[edit]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.[13] Retigabine appears to require thrice-daily dosing due to its short half-life.[12][7]
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.[13]
Mechanism of action
[edit]Retigabine acts as a neuronal KCNQ/Kv7 potassium channel opener, a mechanism of action markedly different from than of any current anticonvulsants.[3][4][14] This mechanism of action is similar to that of flupirtine,[15] which is used mainly for its analgesic properties.
Interactions
[edit]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.[13]
References
[edit]- ^ 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. doi:10.1177/00912700222011210. PMID 11831540. S2CID 5568963.
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ignored (help)CS1 maint: multiple names: authors list (link) - ^ "Retigabine New Drug Application".
- ^ a b Rundfeldt C (1997). "The new anticonvulsant retigabine (D-23129) acts as an opener of K+ channels in neuronal cells". European Journal of Pharmacology. 336 (2–3): 243–9. doi:10.1016/S0014-2999(97)01249-1. PMID 9384239.
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: Unknown parameter|month=
ignored (help) - ^ a b Main MJ, Cryan JE, Dupere JR, Cox B, Clare JJ, Burbidge SA (2000). "Modulation of KCNQ2/3 potassium channels by the novel anticonvulsant retigabine". Molecular Pharmacology. 58 (2): 253–62. doi:10.1124/mol.58.2.253. PMID 10908292.
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ignored (help)CS1 maint: multiple names: authors list (link) - ^ Rogawski MA, Bazil CW. New molecular targets for antiepileptic drugs: α2δ, SV2A, and Kv7/KCNQ/M potassium channels. Curr Neurol Neurosci Rep. 2008 Jul;8(4):345-52 PMID 18590620.
- ^ Rogawski MA (2006). "Diverse mechanisms of antiepileptic drugs in the development pipeline". Epilepsy Research. 69 (3): 273–94. doi:10.1016/j.eplepsyres.2006.02.004. PMC 1562526. PMID 16621450.
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ignored (help) - ^ a b c d 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.
- ^ Dencker D, Dias R, Pedersen ML, Husum H (2008). "Effect of the new antiepileptic drug retigabine in a rodent model of mania". Epilepsy Behav. 12 (1): 49–53. doi:10.1016/j.yebeh.2007.09.023. PMID 18086455. S2CID 45545956.
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ignored (help)CS1 maint: multiple names: authors list (link) - ^ Redrobe JP, Nielsen AN (2009). "Effects of neuronal Kv7 potassium channel activators on hyperactivity in a rodent model of mania". Behav. Brain Res. 198 (2): 481–5. doi:10.1016/j.bbr.2008.12.027. PMID 19162078. S2CID 26795771.
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ignored (help) - ^ Dencker D, Husum H (2010). "Antimanic efficacy of retigabine in a proposed mouse model of bipolar disorder". Behav. Brain Res. 207 (1): 78–83. doi:10.1016/j.bbr.2009.09.040. PMID 19815032. S2CID 24271508.
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ignored (help) - ^ 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. S2CID 24574886.
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ignored (help)CS1 maint: multiple names: authors list (link) - ^ a b c Plosker GL, Scott LJ (2006). "Retigabine: in partial seizures". CNS Drugs. 20 (7): 601–8, discussion 609–10. doi:10.2165/00023210-200620070-00005. 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. doi:10.1016/s1734-1140(09)70024-6. PMID 19443931.
- ^ Rogawski MA, Bazil CW. New molecular targets for antiepileptic drugs: α2δ, SV2A, and Kv7/KCNQ/M potassium channels. Curr Neurol Neurosci Rep. 2008 Jul;8(4):345-52 PMID 18590620.
- ^ Brown, DA; Passmore, GM (2009). "Neural KCNQ (Kv7) channels". British Journal of Pharmacology. 156 (8): 1185–95. doi:10.1111/j.1476-5381.2009.00111.x. PMC 2697739. PMID 19298256.
Further reading
[edit]- 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. doi:10.1111/j.1527-3458.2005.tb00033.x. PMC 6741764. 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.
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