Jump to content

Etifoxine

From Wikipedia, the free encyclopedia
Etifoxine
Clinical data
Trade namesStresam
Other namesÉtifoxine; Etifoxin; Etafenoxine; Etafenoxin; EFX; Hoe 36801; Hoe-36,801
AHFS/Drugs.comInternational Drug Names
Pregnancy
category
  • Not recommended[1]
Routes of
administration		Oral administration[2]
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability90%[3]
Protein binding88–95%[4]
MetabolismLiver[5]
MetabolitesSeveral (including diethyletifoxine)[5]
Elimination half-lifeEtifoxine: 6 hours[5]
Diethyletifoxine: 20 hours[5]
ExcretionMainly urine, also bile[5][2]
Identifiers
  • 6-Chloro-N-ethyl-4-methyl-4-phenyl-4H-benzo[d][1,3]oxazin-2-amine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.158.584 Edit this at Wikidata
Chemical and physical data
FormulaC17H17ClN2O
Molar mass300.79 g·mol−1
3D model (JSmol)
  • ClC1=CC=C2N=C(NCC)OC(C3=CC=CC=C3)(C)C2=C1
  • InChI=1S/C17H17ClN2O/c1-3-19-16-20-15-10-9-13(18)11-14(15)17(2,21-16)12-7-5-4-6-8-12/h4-11H,3H2,1-2H3,(H,19,20) checkY
  • Key:IBYCYJFUEJQSMK-UHFFFAOYSA-N checkY
  (verify)

Etifoxine, sold under the trade name Stresam among others, is a nonbenzodiazepine anxiolytic agent, primarily indicated for short-term management of adjustment disorder, specifically instances of situational depression accompanied by anxiety, such as stress-induced anxiety.[2][6] Administration is by mouth.[7] Side effects associated with etifoxine use include slight drowsiness, headache, skin eruptions, and allergic reactions.[2][8][9] In rare cases, etifoxine has been linked to severe skin and liver toxicity, as well as menstrual bleeding between periods.[8][1] Unlike benzodiazepines, etifoxine does not cause sedation or lack of coordination.[10][3] Etifoxine acts as a GABAA receptor positive allosteric modulator and as a ligand for translocator proteins.[10] Both mechanisms are conjectured to contribute to its anxiolytic properties.[10][3]

Etifoxine was developed in the 1960s and was introduced for medical use in France in 1979.[11] Its marketed in 53 countries worldwide, although it remains unavailable in the United States.[7][11][12] Throughout the 2010s and early 2020s, the safety profile of etifoxine was scrutinized within France and the European Union, prompted by reports of toxicity.[13][8][7] The investigation revealed that instances of toxicity were infrequent, and etifoxine was allowed to remain on the market.[13][8][7]

Medical uses

[edit]

Etifoxine has historically been used in the treatment of "psychosomatic manifestations of anxiety", for instance "autonomic dystonia, particularly with cardiovascular expression".[7][13][8][1] Subsequently, the indication for etifoxine has been more formalized as treatment of adjustment disorder (situational depression) with anxiety (ADWA) (e.g., stress-related anxiety).[7][14][3] Etifoxine has been found to reduce scores on the Hamilton Anxiety Rating Scale (HAM-A) in people with adjustment disorder with anxiety by approximately 50 to 75% after 4 weeks of treatment in clinical trials (e.g., AMETIS, ETILOR, ETIZAL, STRETI studies).[7] The medication is similarly effective or more effective than benzodiazepines like lorazepam, alprazolam, and clonazepam and more effective than buspirone for adjustment disorder with anxiety on the basis of directly comparative randomized controlled trials.[14][3][15][16][17][4] However, in the AMETIS study, both etifoxine and lorazepam failed to show greater effectiveness over placebo.[7]

The usual dosage of etifoxine (as the hydrochloride salt) is 150 to 200 mg per day in divided doses of 50 to 100 mg two to three times per day (e.g., 50 mg–50 mg–100 mg).[2][7][6][18][1][19][20] It is taken for a few days to a few weeks, but no longer than 12 weeks.[2][13][7][5]

Available forms

[edit]

Etifoxine is provided in the form of oral capsules containing 50 mg etifoxine hydrochloride.[2][1][21][22]

Contraindications

[edit]

Etifoxine is contraindicated in people with circulatory shock, severe liver impairment, severe kidney impairment, myasthenia gravis, galactosemia (due to lactose in the drug formulation), severe respiratory failure, and hypersensitivity (allergy) to etifoxine.[2][5] The medication is not recommended in children or adolescents under the age of 18[5] and is not recommended during pregnancy and breastfeeding due to insufficient data.[2][1] Caution is warranted with regard to combining etifoxine and other central depressants such as benzodiazepines, central analgesics, antipsychotics, sedative antihistamines, and alcohol.[2][1]

Side effects

[edit]

Side effects of etifoxine include slight drowsiness and headache.[2][9] Rarely, etifoxine can cause benign skin eruptions or rashes and allergic reactions such as hives and angioedema.[2][8][1] Etifoxine shows less adverse effects of anterograde amnesia, sedation, impaired psychomotor performance, and withdrawal syndromes than those of benzodiazepines.[5] No cases of misuse or dependence with etifoxine were identified in a French pharmacovigilance survey, which is also in contrast to benzodiazepines.[8]

Etifoxine has been associated rarely with cases of severe dermal toxicity and liver toxicity.[8][23] Skin and subcutaneous disorders are the most frequently reported, but these generally resolve after drug cessation.[3] 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 (liver) problems were very rare.[13]

Pharmacology

[edit]

Pharmacodynamics

[edit]

Unlike benzodiazepines, etifoxine may produce its anxiolytic effects through a dual mechanism, by directly binding to GABAA receptors and (purportedly, exact binding site undetermined) to the mitochondrial translocator protein (TSPO). This results in stimulation of the biosynthesis of endogenous neurosteroids, for instance allopregnanolone, a highly potent GABAA receptor positive allosteric modulator.[24]

At GABAA receptors etifoxine binds at the α+β− interface and preferentially potentiates α2β3γ2 and α3β3γ2 receptor types.[25] This direct allosteric potentiation can only be observed at relatively high concentrations (starting at >1 mM) and is perhaps not physiologically relevant at normal human doses.[26] This is different from benzodiazepines and etifoxine can be used alongside benzodiazepines to potentiate their effects without competing for binding sites;[27] however, it also means that the direct effects of etifoxine are not reversed by the benzodiazepine antagonist flumazenil.[28]

Pharmacokinetics

[edit]

Etifoxine is taken via oral administration.[2][5] It is rapidly absorbed from the gastrointestinal tract.[5] It is well-absorbed, with a bioavailability of 90%.[2][3] The time to peak levels of etifoxine is 2 to 3 hours.[5] The plasma protein binding of etifoxine is 88 to 95%.[4] It does not bind to blood cells.[2] The drug is known to cross the placental barrier.[2] Etifoxine is metabolized in the liver into several metabolites.[5] One of these metabolites, diethyletifoxine, is pharmacologically active.[5] The elimination half-life of etifoxine is 6 hours and of diethyletifoxine is almost 20 hours.[5] Etifoxine is eliminated in three phases.[2] The drug is excreted mainly in urine in the form of metabolites.[5] It is also excreted in bile.[5] Only small amounts are excreted unchanged.[5]

Chemistry

[edit]

Etifoxine is a nonbenzodiazepine—that is, it is similarly a GABAA receptor positive allosteric modulator but its chemical structure is distinct from that of benzodiazepines.[3][29] Instead, it is a benzoxazine derivative.[3]

Etifoxine and chlordiazepoxide skeletal formulae with similarities highlighted in orange.

Etifoxine is used pharmaceutically as the hydrochloride salt.[30][31]

(S)-Etifoxine, the (S) enantiomer of etifoxine, was under development by Anvyl Pharmaceuticals for the treatment of neuropathic pain, but development was discontinued.[32] A deuterated form of etifoxine with improved pharmacokinetics known as deuterated etifoxine (GRX-917) is under development by GABA Therapeutics for the treatment anxiety and mood disorders.[33][34][24][35]

History

[edit]

Etifoxine was developed by Hoechst in the 1960s.[11][36] It was introduced for medical use in France in 1979.[11] Since at least 2000, etifoxine has been marketed by the French pharmaceutical company Biocodex.[31][29][37][19] Following reports of post-marketing toxicity, the safety of etifoxine was reassessed by the French government[13][8] and the European Medicines Agency (EMA).[38][39] In January 2022, the EMA "finalized its review of Stresam and concluded that the medicine can continue to be used for the treatment of anxiety disorders, but it must not be used in patients who previously had severe skin reactions or severe liver problems after taking etifoxine."[38][39]

Society and culture

[edit]

Names

[edit]

Etifoxine is the generic name of the drug and its INNTooltip International Nonproprietary Name, BANTooltip British Approved Name, and DCFTooltip Dénomination Commune Française.[30][31] It is also known by the older and much-lesser-used synonym etafenoxine[40] and by its developmental code name Hoe 36801.[30][31] Etifoxine is marketed under the brand name Stresam.[30][31][19] It has also been marketed under the brand name Strezam, specifically in Russia.[19]

Availability

[edit]

Etifoxine has been marketed in 53 countries as of 2022.[7][11] Some of the countries in which etifoxine has been marketed include Argentina, Bulgaria, Chile, France, Luxembourg, Malta, Romania, Russia, South Africa, Thailand, and Ukraine.[19][13][7][31] Etifoxine is not approved for use by the United States Food and Drug Administration (FDA) or the European Medicines Agency (EMA) of the European Union, and hence is not marketed in these regions.[11][7] However, etifoxine is marketed in five European Union member states (France, Bulgaria, Luxembourg, Malta, Romania).[13][7]

See also

[edit]

References

[edit]
  1. ^ a b c d e f g h Afect (1 May 2011). Traité de chimie thérapeutique Volume 7: Médicaments actifs sur le système nerveux central. Lavoisier. pp. 500–. ISBN 978-2-7430-1373-8. OCLC 758328876. 5.2. Propriétés pharmacologiques. [...] 5.2.2. Étifoxine. Utilisé dans les manifestations psychosomatiques de l'anxiété, telles que les dystonies neurovégétatives (Stresam, gélules à 50 mg). La posologie usuelle est de 150 à 200 mg/j. 5.4. Effets indésirables. [...] 5.4.2. Étifoxine. Légère somnolence en début de traitement, éruptions cutanées rares. 5.5. Contre-indications et précautions d'emploi. [...] 5.5.2. Étifoxine. Précaution lors d'association avec les dépresseurs centraux (benzodiazepines, analgesiques centraux, neuroleptiques, antihistaminiques H1 sédatifs, etc.). L'alcool potentialise l'effet sédatif de l'étifoxine. Ce produit est déconseillé pendant la grossesse et en cas d'allaitement.
  2. ^ a b c d e f g h i j k l m n o p q "STRESAM®, capsule Summary of Product Characteristics" (PDF). GABA Therapeutics, Inc. July 2010. Archived from the original (PDF) on 24 October 2021.
  3. ^ a b c d e f g h i Nuss P, Ferreri F, Bourin M (2019). "An update on the anxiolytic and neuroprotective properties of etifoxine: from brain GABA modulation to a whole-body mode of action". Neuropsychiatr Dis Treat. 15: 1781–1795. doi:10.2147/NDT.S200568. PMC 6615018. PMID 31308671.
  4. ^ a b c Vicente B, Saldivia S, Hormazabal N, Bustos C, Rubí P (November 2020). "Etifoxine is non-inferior than clonazepam for reduction of anxiety symptoms in the treatment of anxiety disorders: a randomized, double blind, non-inferiority trial". Psychopharmacology (Berl). 237 (11): 3357–3367. doi:10.1007/s00213-020-05617-6. PMID 33009629. S2CID 222165607.
  5. ^ a b c d e f g h i j k l m n o p q r Choi YM, Kim KH (January 2015). "Etifoxine for pain patients with anxiety". Korean J Pain. 28 (1): 4–10. doi:10.3344/kjp.2015.28.1.4. PMC 4293506. PMID 25589941.
  6. ^ a b Besnier N, Blin O (January 2008). "Étifoxine : études cliniques récentes" [Etifoxine: recent clinical studies]. L'Encéphale (in French). 34 (Suppl 1 (Etifoxine : un nouveau regard sur le récepteur GABA et l'anxiété)): S9–S14. doi:10.1016/S0013-7006(08)71386-1. ISSN 0013-7006.
  7. ^ a b c d e f g h i j k l m n "INN/active substance: etifoxine Assessment report" (PDF). European Medicines Agency. 27 January 2022. Archived from the original (PDF) on 7 February 2023.
  8. ^ a b c d e f g h i Cottin J, Gouraud A, Jean-Pastor MJ, Dautriche AD, Boulay C, Geniaux H, Auffret M, Bernard N, Descotes J, Vial T (April 2016). "Safety profile of etifoxine: A French pharmacovigilance survey". Fundam Clin Pharmacol. 30 (2): 147–52. doi:10.1111/fcp.12169. PMID 26588183. S2CID 7599622.
  9. ^ a b Deplanque D, Machuron F, Waucquier N, Jozefowicz E, Duhem S, Somers S, Colin O, Duhamel A, Bordet R (August 2018). "Etifoxine impairs neither alertness nor cognitive functions of the elderly: A randomized, double-blind, placebo-controlled crossover study". Eur Neuropsychopharmacol. 28 (8): 925–932. doi:10.1016/j.euroneuro.2018.05.011. PMID 30135030. S2CID 52066957.
  10. ^ a b c Poisbeau P, Gazzo G, Calvel L (2018). "Anxiolytics targeting GABAA receptors: Insights on etifoxine". World J Biol Psychiatry. 19 (sup1): S36–S45. doi:10.1080/15622975.2018.1468030. PMID 30204559. S2CID 52191153.
  11. ^ a b c d e f Sartori SB, Singewald N (December 2019). "Novel pharmacological targets in drug development for the treatment of anxiety and anxiety-related disorders". Pharmacol Ther. 204: 107402. doi:10.1016/j.pharmthera.2019.107402. PMID 31470029. S2CID 201785150.
  12. ^ "Hermitage Man Sentenced for Importing and Selling Drugs Not Approved by FDA". www.justice.gov. 2019-10-07. Retrieved 2022-05-12.
  13. ^ a b c d e f g h "COMMISSION NATIONALE DE PHARMACOVIGILANCE Compte rendu de la réunion du mardi 26 juin 2012" (PDF) (in French). Archived from the original (PDF) on 2021-03-09.
  14. ^ a b Stein DJ (2018). "Pharmacotherapy of adjustment disorder: A review". World J Biol Psychiatry. 19 (sup1): S46–S52. doi:10.1080/15622975.2018.1492736. PMID 30204560. S2CID 52187107.
  15. ^ Servant D, Graziani PL, Moyse D, Parquet PJ (1998). "Traitement du trouble de l'adaptation avec anxiété: évaluation de l'efficacité et de la tolérance de l'étifoxine par un essai en double aveugle contre produit de référence" [Treatment of adjustment disorder with anxiety: efficacy and tolerance of etifoxine in a double-blind controlled study]. Encephale (in French). 24 (6): 569–74. PMID 9949940.
  16. ^ Nguyen N, Fakra E, Pradel V, Jouve E, Alquier C, Le Guern ME, Micallef J, Blin O (April 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". Hum Psychopharmacol. 21 (3): 139–49. doi:10.1002/hup.757. PMID 16625522. S2CID 25940120.
  17. ^ Stein DJ (January 2015). "Etifoxine versus alprazolam for the treatment of adjustment disorder with anxiety: a randomized controlled trial". Adv Ther. 32 (1): 57–68. doi:10.1007/s12325-015-0176-6. PMC 4311065. PMID 25620535.
  18. ^ Spadone C, Glikman M (April 2008). "L'étifoxine: un nouveau regard sur le récepteur GABA et l'anxiété" [Etifoxine: a new look at the GABA receptor and anxiety]. Encephale (in French). 34 Spec No 1: 1–11. doi:10.1016/S0013-7006(08)70553-0. ISSN 0013-7006. PMID 18826172.
  19. ^ a b c d e "Micromedex Products: Please Login".
  20. ^ Micallef J, Soubrouillard C, Guet F, Le Guern ME, Alquier C, Bruguerolle B, Blin O (June 2001). "A double blind parallel group placebo controlled comparison of sedative and mnesic effects of etifoxine and lorazepam in healthy subjects [corrected]". Fundam Clin Pharmacol. 15 (3): 209–16. doi:10.1046/j.1472-8206.2001.00025.x. PMID 11468032. S2CID 73049654.
  21. ^ Concours Médical, Volume 123, Issues 34-40. 2001. p. 2361. OCLC 1564649. STRESAM gélule . COMPOSITION - Etifoxine chlorhydrate , 50 mg par gélule . Excipients q.s.p. 1 géluie de 200 mg . INDICATIONS THÉRAPEUTIQUES - Manifestations psychosomatiques de l'anxiété telles que dystonies neurovégétatives [...]
  22. ^ Gazengel JM, Orecchioni AM (15 April 2013). Le préparateur en pharmacie - Guide théorique et pratique (2e ed.). Lavoisier. pp. 820–. ISBN 978-2-7430-6371-9. OCLC 1005722892. L'étifoxine (Stresam®, gél 50 mg, liste I) a son indication dans les manifestations psychosomatiques de l'anxiété telles que dystonies neurovégétatives, notamment à expression cardiovasculaire.
  23. ^ Moch C, Rocher F, Lainé P, Lacotte J, Biour M, Gouraud A, Bernard N, Descotes J, Vial T (October 2012). "Etifoxine-induced acute hepatitis: a case series". Clin Res Hepatol Gastroenterol. 36 (5): e85–8. doi:10.1016/j.clinre.2012.04.002. PMID 22633197.
  24. ^ a b Rupprecht R, Pradhan AK, Kufner M, Brunner LM, Nothdurfter C, Wein S, Schwarzbach J, Puig X, Rupprecht C, Rammes G (December 2022). "Neurosteroids and translocator protein 18 kDa (TSPO) in depression: implications for synaptic plasticity, cognition, and treatment options". Eur Arch Psychiatry Clin Neurosci. 273 (7): 1477–1487. doi:10.1007/s00406-022-01532-3. PMID 36574032. S2CID 255205221.
  25. ^ Mattei C, Taly A, Soualah Z, Saulais O, Henrion D, Guérineau NC, Verleye M, Legros C (2019). "Involvement of the GABAA receptor α subunit in the mode of action of etifoxine" (PDF). Pharmacol. Res. 145: 104250. doi:10.1016/j.phrs.2019.04.034. PMID 31059790.
  26. ^ 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. S2CID 9892214.
  27. ^ 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.
  28. ^ 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.
  29. ^ a b Girard C, Liu S, Adams D, Lacroix C, Sinéus M, Boucher C, Papadopoulos V, Rupprecht R, Schumacher M, Groyer G (January 2012). "Axonal regeneration and neuroinflammation: roles for the translocator protein 18 kDa". J Neuroendocrinol. 24 (1): 71–81. doi:10.1111/j.1365-2826.2011.02215.x. PMID 21951109. S2CID 21312172.
  30. ^ a b c d Elks J, ed. (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 523–. ISBN 978-1-4757-2085-3. OCLC 1058412474.
  31. ^ a b c d e f Swiss Pharmaceutical Society (2000). Index Nominum 2000: International Drug Directory. Taylor & Francis. pp. 416–. ISBN 978-3-88763-075-1.
  32. ^ "S-Etifoxine - AdisInsight".
  33. ^ "Etifoxine deuterated - GABA Therapeutics - AdisInsight".
  34. ^ Rupprecht R, Wetzel CH, Dorostkar M, Herms J, Albert NL, Schwarzbach J, Schumacher M, Neumann ID (July 2022). "Translocator protein (18kDa) TSPO: a new diagnostic or therapeutic target for stress-related disorders?" (PDF). Mol Psychiatry. 27 (7): 2918–2926. doi:10.1038/s41380-022-01561-3. PMID 35444254. S2CID 248245591.
  35. ^ Witkin JM, Lippa A, Smith JL, Jin X, Ping X, Biggerstaff A, Kivell BM, Knutson DE, Sharmin D, Pandey KP, Mian MY, Cook JM, Cerne R (February 2022). "The imidazodiazepine, KRM-II-81: An example of a newly emerging generation of GABAkines for neurological and psychiatric disorders". Pharmacol Biochem Behav. 213: 173321. doi:10.1016/j.pbb.2021.173321. PMID 35041859. S2CID 245963990.
  36. ^ U.S. patent 3,725,404
  37. ^ Barresi E, Robello M, Costa B, Da Pozzo E, Baglini E, Salerno S, Da Settimo F, Martini C, Taliani S (January 2021). "An update into the medicinal chemistry of translocator protein (TSPO) ligands". Eur J Med Chem. 209: 112924. doi:10.1016/j.ejmech.2020.112924. PMID 33081988. S2CID 224823944.
  38. ^ a b "Etifoxine-containing medicinal products". European Medicines Agency. 27 January 2022. Retrieved May 12, 2022.
  39. ^ a b "EU OKs Continued Use Of Etifoxine For Anxiety Despite Toxicity Concerns". Pink Sheet Informa Pharma Intelligence. January 31, 2022. Retrieved May 12, 2022.
  40. ^ Kim T, Pae AN (November 2016). "Translocator protein (TSPO) ligands for the diagnosis or treatment of neurodegenerative diseases: a patent review (2010 - 2015; part 2)". Expert Opin Ther Pat. 26 (11): 1353–1366. doi:10.1080/13543776.2016.1230605. PMID 27599163. S2CID 21582859.

Further reading

[edit]
[edit]
Retrieved from "https://en.wikipedia.org/w/index.php?title=Etifoxine&oldid=1230446240"