Medifoxamine

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Medifoxamine
Medifoxamine Structural Formulae.png
Systematic (IUPAC) name
N,N-Dimethyl-2,2-diphenoxyethanamine
Clinical data
Routes of
administration
Oral
Legal status
  • (Prescription only)
Pharmacokinetic data
Bioavailability 21%[1][2]
Biological half-life 2.8 ± 1.04 hours (acute);[1][2]
4.0 hours (chronic)[3]
Identifiers
CAS Number 32359-34-5 YesY
ATC code N06AX13 (WHO)
PubChem CID 36109
ChemSpider 33212
UNII KWU7C2A1NT YesY
KEGG D07341 YesY
Chemical data
Formula C16H19NO2
Molar mass 257.328 g/mol
Chirality Racemic mixture
  (verify)

Medifoxamine (INN) (brand names Clédial, Gerdaxyl) or medifoxamine fumarate, also known as N,N-dimethyl-2,2-diphenoxyethylamine, is an atypical[4] antidepressant with additional anxiolytic properties[5] acting via dopaminergic and serotonergic mechanisms that 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and Spain, as well as Morocco.[6][7][8][9][10] The drug was first introduced in France sometime around 1990.[11] It was withdrawn from the market in 1999 (Morocco) and 2000 (France) following incidences of hepatotoxicity.[10][12][13]

Pharmacology[edit]

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 = 1500 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, 1600 nM, and 6300 nM.[3] Medifoxamine and its metabolites lack affinity for other serotonin receptors including 5-HT1A, 5-HT1B, 5-HT1D, and 5-HT3 (>10000 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]

Efficacy and tolerability[edit]

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]

See also[edit]

References[edit]

  1. ^ a b Saleh, S; Johnston, A; Turner, P (1990). "Absolute bioavailability and pharmacokinetics of medifoxamine in healthy humans.". British Journal of Clinical Pharmacology 30 (4): 621–624. doi:10.1111/j.1365-2125.1990.tb03823.x. ISSN 0306-5251. 
  2. ^ a b Florencio Zaragoza Dörwald (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. ^ a b c d e f g h i j k l Gainsborough N, Nelson ML, Maskrey V, Swift CG, Jackson SH (1994). "The pharmacokinetics and pharmacodynamics of medifoxamine after oral administration in healthy elderly volunteers". Eur. J. Clin. Pharmacol. 46 (2): 163–6. PMID 8039537. 
  4. ^ Jayna Holroyd-Leduc; Madhuri Reddy (9 March 2012). Evidence-Based Geriatric Medicine. John Wiley & Sons. pp. 299–. ISBN 978-1-118-28181-9. 
  5. ^ ANNUAL REPORTS IN MED CHEMISTRY V22 PPR. Academic Press. 2 September 1987. pp. 323–. ISBN 978-0-08-058366-2. 
  6. ^ J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 759–. ISBN 978-1-4757-2085-3. 
  7. ^ Dr. Ian Morton; I.K. Morton; Judith M. Hall (31 October 1999). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 173–. ISBN 978-0-7514-0499-9. 
  8. ^ Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 638–. ISBN 978-3-88763-075-1. 
  9. ^ a b Mitchell PB (1995). "Novel French antidepressants not available in the United States". Psychopharmacol Bull 31 (3): 509–19. PMID 8668756. 
  10. ^ a b 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 (1990). "Tolerability and kinetics of intravenous medifoxamine in healthy volunteers". Int Clin Psychopharmacol 5 (2): 97–102. PMID 2380545. 
  12. ^ Dumortier G, Cabaret W, Stamatiadis L, Saba G, Benadhira R, Rocamora JF, Aubriot-Delmas B, Glikman J, Januel D (2002). "[Hepatic tolerance of atypical antipsychotic drugs]". Encephale (in French) 28 (6 Pt 1): 542–51. PMID 12506267. 
  13. ^ George I. Papakostas; Maurizio Fava (2010). Pharmacotherapy for Depression and Treatment-resistant Depression. World Scientific. pp. 88–. ISBN 978-981-4287-59-3. 
  14. ^ a b Saleh, S; Turner, P (1992). "Ocular hypotensive effects of medifoxamine.". British Journal of Clinical Pharmacology 34 (3): 269–271. doi:10.1111/j.1365-2125.1992.tb04136.x. ISSN 0306-5251. 
  15. ^ Vaugeois, J.-M.; 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. 
  16. ^ Berk, Michael (2000). "Depression therapy: Future prospects". International Journal of Psychiatry in Clinical Practice 4 (4): 281–286. doi:10.1080/13651500050517830. ISSN 1365-1501. 
  17. ^ Martin P, Lemonnier F (1994). "[The role of type 2 serotonin receptors, 5-HT2A and 5-HT2C, in depressive disorders: effect of medifoxamine]". Encephale (in French) 20 (4): 427–35. PMID 7988407. 
  18. ^ a b 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]". Encephale (in French) 19 (4): 333–40. PMID 8275921. 
  19. ^ a b Randhawa, M. A.; 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. 
  20. ^ ANNUAL REPORTS IN MED CHEMISTRY V20 PPR. Academic Press. 11 September 1985. pp. 35–. ISBN 978-0-08-058364-8.