Etifoxine

Etifoxine
Etifoxine.svg
Etifoxine ball-and-stick.png
Clinical data
Trade names Stresam
Synonyms Etafenoxine
AHFS/Drugs.com International Drug Names
Pregnancy
category
  • Not recommended. Crosses the placental barrier
Routes of
administration
Oral
ATC code
Legal status
Legal status
  • US: Unscheduled and not FDA approved
Pharmacokinetic data
Metabolism Hepatic (no CYP450 interactions)
Elimination half-life 2 to 6 hours (etifoxine),[1]
Excretion Renal
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C17H17ClN2O
Molar mass 300.79 g·mol−1
3D model (JSmol)
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Etifoxine (INN; also known as etafenoxine; trade name Stresam) is an anxiolytic and anticonvulsant drug[2][3] developed by Hoechst in the 1960s.[4] It is sold in approximately 40 countries for anxiety disorders, without the sedation and ataxia associated with benzodiazepine drugs.[5] It has similar anxiolytic effects to benzodiazepine drugs, but is structurally distinct and does not bind to the benzodiazepine receptor.[6] It is as effective as lorazepam as an anxiolytic, but has fewer side effects.[7] Etifoxine is not approved by the U.S. Food and Drug Administration or the European Medicines Agency.

Side effects[edit]

The most common adverse effect of etifoxine is mild drowsiness at initial dosing. It is not associated with any withdrawal syndromes or dependence.[medical citation needed] Etifoxine shows less adverse effects of anterograde amnesia, sedation, impaired psychomotor performance, and withdrawal syndromes than those of benzodiazepines.[8] A 2012 review of etifoxine by the French National Pharmacovigilance Committee determined that etifoxine was safe and continued to provide a favorable alternative to benzodiazepine anxiolytics. The committee found (for a ten-year pharmacovigilance period) that safety concerns were rare or very rare and that the incidence of idiosyncratic hepatic problems were very rare.[9]

Mechanism of action[edit]

Unlike benzodiazepines, etifoxine appears to produce its anxiolytic effects in humans by activation of translocator protein (TSPO), stimulating the production of GABAA-active neurosteroids that may act in conjunction with etifoxine’s direct activation of β2 and β3 subunit containing channels of the GABAA receptor complex (a different binding site than benzodiazepines. Direct activation occurs at high concentrations and is perhaps not physiologically relevant (starting at > 1 micromolar).[10] This is different than benzodiazepines and etifoxine can be used alongside benzodiazepines to potentiate their effects without competing for binding sites;[11] however, it also means that the direct effects of etifoxine are not reversed by the benzodiazepine antagonist flumazenil.[12]

Etifoxine has been shown to stimulate the biosynthesis of endogenous neurosteroids, namely 17-hydroxypregnenolone, dehydroepiandrosterone, progesterone, and tetrahydroprogesterone.[13] Several studies have shown that the synthesis of neurosteroids is essential to the pharmacological actions of etifoxine. Inhibitors of neurosteroid biosynthesis reverse the anxiolytic and analgesic actions of etifoxine in preclinical studies.

References[edit]

  1. ^ “Stresam PI” (PDF). Adcock Ingram. n.d. Retrieved 2008-08-30.[dead link]
  2. ^ Kruse HJ, Kuch H (1985). “Etifoxine: evaluation of its anticonvulsant profile in mice in comparison with sodium valproate, phenytoin and clobazam”. Arzneimittelforschung. 35 (1): 133–135.
  3. ^ The Merck Index, 12th Edition. 3910.
  4. ^ U.S. Patent 3,725,404
  5. ^ Girard C, Liu S, Cadepond F, Adams D, Lacroix C, Verleye M, Gillardin JM, Baulieu EE, Schumacher M, Schweizer-Groyer G (2008). “Etifoxine improves peripheral nerve regeneration and functional recovery”. Proc Natl Acad Sci U S A. 105 (51): 20505–10. Bibcode:2008PNAS..10520505G. doi:10.1073/pnas.0811201106. PMC 2629330. PMID 19075249.
  6. ^ Schlichter R, Rybalchenko V, Poisbeau P, Verleye M, Gillardin J (2000). “Modulation of GABAergic synaptic transmission by the non-benzodiazepine anxiolytic etifoxine”. Neuropharmacology. 39 (9): 1523–35. doi:10.1016/s0028-3908(99)00253-1. PMID 10854897.
  7. ^ Nguyen N, Fakra E, Pradel V, Jouve E, Alquier C, Le Guern ME, Micallef J, Blin O (2006). “Efficacy of etifoxine compared to lorazepam monotherapy in the treatment of patients with adjustment disorders with anxiety: a double-blind controlled study in general practice”. Human Psychopharmacology. 21 (3): 139–49. doi:10.1002/hup.757. PMID 16625522.
  8. ^ Choi, Y. M.; Kim, K. H. (2015). “Etifoxine for Pain Patients with Anxiety”. The Korean Journal of Pain. 28 (1): 4–10. doi:10.3344/kjp.2015.28.1.4. PMC 4293506. PMID 25589941.
  9. ^ “COMMISSION NATIONALE DE PHARMACOVIGILANCE Compte rendu de la réunion du mardi 26 juin 2012” (PDF).
  10. ^ Hamon A, Morel A, Hue B, Verleye M, Gillardin JM (2003). “The modulatory effects of etifoxine’s direct effects on GABA(A) receptors are mediated by the beta subunit”. Neuropharmacology. 45 (3): 293–303. doi:10.1016/s0028-3908(03)00187-4. PMID 12871647.
  11. ^ Kruse HJ, Kuch H (1986). “Potentiation of clobazam’s anticonvulsant activity by etifoxine, a non-benzodiazepine tranquilizer, in mice. Comparison studies with sodium valproate”. Arzneimittelforschung. 36 (9): 1320–2. PMID 3098254.
  12. ^ Verleye M, Schlichter R, Gillardin JM (1999). “Interactions of etifoxine with the chloride channel coupled to the GABA(A) receptor complex”. NeuroReport. 10 (15): 3207–10. doi:10.1097/00001756-199910190-00015. PMID 10574561.
  13. ^ do Rego, Jean Luc; Vaudry, David; Vaudry, Hubert (2015). “The Non-Benzodiazepine Anxiolytic Drug Etifoxine Causes a Rapid, Receptor-Independent Stimulation of Neurosteroid Biosynthesis”. PLoS ONE. 10 (3): e0120473. Bibcode:2015PLoSO..1020473D. doi:10.1371/journal.pone.0120473. PMC 4364751. PMID 25785994.