Medifoxamine

Medifoxamine, previously sold under the brand names Clédial and Gerdaxyl, is an atypical antidepressant[4] with additional anxiolytic properties[5] acting via dopaminergic and serotonergic mechanisms which was formerly marketed in France and Spain, as well as Morocco.[6][7][8][9][10] The drug was first introduced in France sometime around 1990.[11] It was withdrawn from the market in 1999 (Morocco) and 2000 (France) following incidences of hepatotoxicity.[10][12][13]

Medifoxamine
Clinical data
Trade namesClédial, Gerdaxyl
Other namesMedifoxamine fumarate; N,N-Dimethyl-2,2-diphenoxyethylamine
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability21%[1][2]
Elimination half-life2.8 hours (acute);[1][2]
4.0 hours (chronic)[3]
Identifiers
IUPAC name
  • N,N-dimethyl-2,2-diphenoxyethanamine
CAS Number
  • 32359-34-5 Y
    16604-45-8 (fumarate)
    16604-44-7 (picrate)
PubChem CID
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
ECHA InfoCard100.046.359
Chemical and physical data
FormulaC16H19NO2
Molar mass257.333 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
SMILES
  • CN(C)CC(OC1=CC=CC=C1)OC2=CC=CC=C2
InChI
  • InChI=1S/C16H19NO2/c1-17(2)13-16(18-14-9-5-3-6-10-14)19-15-11-7-4-8-12-15/h3-12,16H,13H2,1-2H3
  • Key:QNMGHBMGNRQPNL-UHFFFAOYSA-N
  (verify)

Pharmacology

Pharmacodynamics

Medifoxamine has been found to act preferentially as a relatively weak dopamine reuptake inhibitor,[3][14][15][16] but also as an even weaker serotonin reuptake inhibitor (IC50 = 1,500 nM)[3] and as a weak antagonist of the 5-HT2A and 5-HT2C receptors (IC50 = 950 and 980, respectively; notably greater affinity relative to amitriptyline and imipramine).[3][17][18] It is known to produce two active metabolites during first-pass metabolism in the liver, CRE-10086 (N-methyl-2,2-diphenoxyethylamine) and CRE-10357 (N,N-dimethyl-2-hydroxyphenoxy-2-phenoxyethylamine).[3] The IC50 values of CRE-10086 for serotonin transporter, 5-HT2A, and 5-HT2C binding are 450 nM, 330 nM, and 700 nM, respectively, while those of CRE-10357 are 660 nM, 1,600 nM, and 6,300  M.[3] Medifoxamine and its metabolites lack affinity for other serotonin receptors including 5-HT1A, 5-HT1B, 5-HT1D, and 5-HT3 (>10,000 nM).[3] As medifoxamine is metabolized extensively in the liver during first-pass metabolism, and as these metabolites have as much as 3-fold greater activity relative to medifoxamine, it is likely that they contribute significantly to the pharmacology of the parent drug.[3]

Effectiveness and tolerability

Unlike many tricyclic antidepressants, medifoxamine lacks anticholinergic and alpha blocker properties (very low affinity for the muscarinic acetylcholine receptors and 10-fold lower affinity for the α1-adrenergic receptor relative to 5-HT2 binding sites),[3][14][19] and is also apparently inactive as a norepinephrine reuptake inhibitor (although the same source stating this also states that it is inactive as a serotonin reuptake inhibitor, which was subsequently found not to be the case).[20] Studies in mice revealed that the drug does not possess any sedative or locomotor stimulant effects.[3] In accordance with all of the preceding, medifoxamine was found to be well tolerated at dosages of 100–300 mg per day in clinical trials.[3] Double-blind controlled clinical studies have found it to have similar effectiveness to imipramine, clomipramine, and maprotiline in the treatment of depression.[3][9][18][19]

Society and culture

Generic names

Medifoxamine is the generic name of the drug and its INN while médifoxamine is its DCF.[6][7][8]

Brand names

Medifoxamine was marketed under the brand names Clédial and Gerdaxyl.[6][7]

References
  1. Saleh S, Johnston A, Turner P (October 1990). "Absolute bioavailability and pharmacokinetics of medifoxamine in healthy humans". British Journal of Clinical Pharmacology. 30 (4): 621–4. doi:10.1111/j.1365-2125.1990.tb03823.x. PMC 1368255. PMID 2291875.
  2. Dörwald FZ (4 February 2013). Lead Optimization for Medicinal Chemists: Pharmacokinetic Properties of Functional Groups and Organic Compounds. John Wiley & Sons. pp. 259–. ISBN 978-3-527-64565-7.
  3. Gainsborough N, Nelson ML, Maskrey V, Swift CG, Jackson SH (1994). "The pharmacokinetics and pharmacodynamics of medifoxamine after oral administration in healthy elderly volunteers". European Journal of Clinical Pharmacology. 46 (2): 163–6. doi:10.1007/bf00199882. PMID 8039537. S2CID 6978939.
  4. Holroyd-Leduc J, Reddy M (9 March 2012). Evidence-Based Geriatric Medicine. John Wiley & Sons. pp. 299–. ISBN 978-1-118-28181-9.
  5. Annual Reports in Medicinal Chemistry. Vol. 22. Academic Press. 2 September 1987. pp. 323–. ISBN 978-0-08-058366-2.
  6. Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 759–. ISBN 978-1-4757-2085-3.
  7. Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 638–. ISBN 978-3-88763-075-1.
  8. Morton IK, Hall JM (31 October 1999). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 173–. ISBN 978-0-7514-0499-9.
  9. Mitchell PB (1995). "Novel French antidepressants not available in the United States". Psychopharmacology Bulletin. 31 (3): 509–19. PMID 8668756.
  10. Consolidated List of Products Whose Consumption And/or Sale Have Been Banned, Withdrawn, Severely Restricted Or Not Approved by Governments. United Nations Publications. 2003. pp. 135–136. ISBN 978-92-1-130230-1.
  11. Saleh S, Johnston A, Edeki T, Turner P (April 1990). "Tolerability and kinetics of intravenous medifoxamine in healthy volunteers". International Clinical Psychopharmacology. 5 (2): 97–102. doi:10.1097/00004850-199004000-00003. PMID 2380545.
  12. Dumortier G, Cabaret W, Stamatiadis L, Saba G, Benadhira R, Rocamora JF, et al. (2002). "[Hepatic tolerance of atypical antipsychotic drugs]". L'Encéphale (in French). 28 (6 Pt 1): 542–51. PMID 12506267.
  13. Papakostas GI, Fava M (2010). Pharmacotherapy for Depression and Treatment-resistant Depression. World Scientific. pp. 88–. ISBN 978-981-4287-59-3.
  14. Saleh S, Turner P (September 1992). "Ocular hypotensive effects of medifoxamine". British Journal of Clinical Pharmacology. 34 (3): 269–71. doi:10.1111/j.1365-2125.1992.tb04136.x. PMC 1381400. PMID 1389953.
  15. Vaugeois JM, Pouhé D, Lemonnier F, Costentin J (1994). "Neurochemical and behavioral evidence for a central indirect dopaminergic agonist activity of the antidepressant medifoxamine in mice". European Neuropsychopharmacology. 4 (3): 323–324. doi:10.1016/0924-977X(94)90140-6. ISSN 0924-977X. S2CID 54309929.
  16. Berk M (2000). "Depression therapy: Future prospects". International Journal of Psychiatry in Clinical Practice. 4 (4): 281–6. doi:10.1080/13651500050517830. PMID 24926578. S2CID 41078092.
  17. Martin P, Lemonnier F (1994). "[The role of type 2 serotonin receptors, 5-HT2A and 5-HT2C, in depressive disorders: effect of medifoxamine]". L'Encéphale (in French). 20 (4): 427–35. PMID 7988407.
  18. Olié JP, Galinowski A, Lehert P, Lemonnier F, Lôo H (1993). "[Randomized double-blind comparative study of the efficacy and tolerance of medifoxamine and imipramine in depressed patients]". L'Encéphale (in French). 19 (4): 333–40. PMID 8275921.
  19. Randhawa MA, Hedges A, Johnston A, Turner P (1988). "A psychopharmacological study to assess anti-muscarinic and central nervous effects of medifoxamine in normal volunteers". Human Psychopharmacology: Clinical and Experimental. 3 (3): 195–200. doi:10.1002/hup.470030307. ISSN 0885-6222. S2CID 145601579.
  20. ANNUAL REPORTS IN MED CHEMISTRY V20 PPR. Academic Press. 11 September 1985. pp. 35–. ISBN 978-0-08-058364-8.
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