Chemistry:Medifoxamine

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Short description: Withdrawn atypical antidepressant drug
Medifoxamine
Medifoxamine.svg
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
CAS Number
  • 32359-34-5 ☑Y
    16604-45-8 (fumarate)
    16604-44-7 (picrate)
PubChem CID
ChemSpider
UNII
KEGG
Chemical and physical data
FormulaC16H19NO2
Molar mass257.333 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
  (verify)

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Spain , as well as Morocco.[6][7][8][9][10] The drug was first introduced in France sometime around 1990.[11] It was withdrawn from the market in 1999 (Morocco) and 2000 (France) following incidences of hepatotoxicity.[10][12][13]


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. ↑ 1.0 1.1 "Absolute bioavailability and pharmacokinetics of medifoxamine in healthy humans". British Journal of Clinical Pharmacology 30 (4): 621–4. October 1990. doi:10.1111/j.1365-2125.1990.tb03823.x. PMID 2291875. 
  2. ↑ 2.0 2.1 Lead Optimization for Medicinal Chemists: Pharmacokinetic Properties of Functional Groups and Organic Compounds. John Wiley & Sons. 4 February 2013. pp. 259–. ISBN 978-3-527-64565-7. https://books.google.com/books?id=YTeY9ZEfNccC&pg=PA259. 
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 "The pharmacokinetics and pharmacodynamics of medifoxamine after oral administration in healthy elderly volunteers". European Journal of Clinical Pharmacology 46 (2): 163–6. 1994. doi:10.1007/bf00199882. PMID 8039537. 
  4. ↑ Evidence-Based Geriatric Medicine. John Wiley & Sons. 9 March 2012. pp. 299–. ISBN 978-1-118-28181-9. https://books.google.com/books?id=VfPIUfcwrFkC&pg=PT299. 
  5. ↑ Annual Reports in Medicinal Chemistry. 22. Academic Press. 2 September 1987. pp. 323–. ISBN 978-0-08-058366-2. https://books.google.com/books?id=oJeTSJveeuAC&pg=PA323. 
  6. ↑ 6.0 6.1 6.2 The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. 14 November 2014. pp. 759–. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA759. 
  7. ↑ 7.0 7.1 7.2 Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 638–. ISBN 978-3-88763-075-1. https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA638. 
  8. ↑ 8.0 8.1 Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. 31 October 1999. pp. 173–. ISBN 978-0-7514-0499-9. https://books.google.com/books?id=mqaOMOtk61IC&pg=PA173. 
  9. ↑ 9.0 9.1 "Novel French antidepressants not available in the United States". Psychopharmacology Bulletin 31 (3): 509–19. 1995. PMID 8668756. 
  10. ↑ 10.0 10.1 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. https://books.google.com/books?id=leVCukUgNlsC&pg=PA135. 
  11. ↑ "Tolerability and kinetics of intravenous medifoxamine in healthy volunteers". International Clinical Psychopharmacology 5 (2): 97–102. April 1990. doi:10.1097/00004850-199004000-00003. PMID 2380545. 
  12. ↑ "[Hepatic tolerance of atypical antipsychotic drugs]" (in fr). L'Encéphale 28 (6 Pt 1): 542–51. 2002. PMID 12506267. 
  13. ↑ Pharmacotherapy for Depression and Treatment-resistant Depression. World Scientific. 2010. pp. 88–. ISBN 978-981-4287-59-3. https://books.google.com/books?id=zigp-66vq0MC&pg=PA88. 
  14. ↑ 14.0 14.1 "Ocular hypotensive effects of medifoxamine". British Journal of Clinical Pharmacology 34 (3): 269–71. September 1992. doi:10.1111/j.1365-2125.1992.tb04136.x. PMID 1389953. 
  15. ↑ "Neurochemical and behavioral evidence for a central indirect dopaminergic agonist activity of the antidepressant medifoxamine in mice". European Neuropsychopharmacology 4 (3): 323–324. 1994. doi:10.1016/0924-977X(94)90140-6. ISSN 0924-977X. 
  16. ↑ "Depression therapy: Future prospects". International Journal of Psychiatry in Clinical Practice 4 (4): 281–6. 2000. doi:10.1080/13651500050517830. PMID 24926578. 
  17. ↑ "[The role of type 2 serotonin receptors, 5-HT2A and 5-HT2C, in depressive disorders: effect of medifoxamine]" (in fr). L'Encéphale 20 (4): 427–35. 1994. PMID 7988407. 
  18. ↑ 18.0 18.1 "[Randomized double-blind comparative study of the efficacy and tolerance of medifoxamine and imipramine in depressed patients]" (in fr). L'Encéphale 19 (4): 333–40. 1993. PMID 8275921. 
  19. ↑ 19.0 19.1 "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. 1988. 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. https://books.google.com/books?id=j-3Cd_SWIksC&pg=PA35. 



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