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Medifoxamine

From Wikipedia, the free encyclopedia
Withdrawn atypical antidepressant drug
Pharmaceutical compound
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]
Eliminationhalf-life2.8 hours (acute);[1][2]
4.0 hours (chronic)[3]
Identifiers
  • N,N-dimethyl-2,2-diphenoxyethanamine
CAS Number
PubChemCID
ChemSpider
UNII
KEGG
CompTox Dashboard(EPA)
ECHA InfoCard100.046.359Edit this at Wikidata
Chemical and physical data
FormulaC16H19NO2
Molar mass257.333 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
  • CN(C)CC(OC1=CC=CC=C1)OC2=CC=CC=C2
  • 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)

Medifoxamine, previously sold under the brand namesClédial andGerdaxyl, is anatypical antidepressant[4] with additionalanxiolytic properties[5] acting viadopaminergic andserotonergic mechanisms which was formerly marketed inFrance andSpain, as well asMorocco.[6][7][8][9][10] The drug was first introduced in France sometime around 1990.[11] It waswithdrawn from the market in 1999 (Morocco) and 2000 (France) following incidences ofhepatotoxicity.[10][12][13]

Pharmacology

[edit]

Pharmacodynamics

[edit]

Medifoxamine has been found to act preferentially as a relatively weakdopamine reuptake inhibitor,[3][14][15][16] but also as an even weakerserotonin reuptake inhibitor (IC50 = 1,500 nM)[3] and as a weakantagonist of the5-HT2A and5-HT2C receptors (IC50 = 950 and 980, respectively; notably greateraffinity relative toamitriptyline andimipramine).[3][17][18] It is known to produce twoactive metabolites duringfirst-pass metabolism in theliver,CRE-10086 (N-methyl-2,2-diphenoxyethylamine) andCRE-10357 (N,N-dimethyl-2-hydroxyphenoxy-2-phenoxyethylamine).[3] The IC50 values of CRE-10086 forserotonin 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 otherserotonin receptors including5-HT1A,5-HT1B,5-HT1D, and5-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 thepharmacology of the parent drug.[3]

Effectiveness and tolerability

[edit]

Unlike manytricyclic antidepressants, medifoxamine lacksanticholinergic andalpha blocker properties (very low affinity for themuscarinic acetylcholine receptors and 10-fold lower affinity for theα1-adrenergic receptor relative to 5-HT2 binding sites),[3][14][19] and is also apparently inactive as anorepinephrine 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 anysedative orlocomotor stimulant effects.[3] In accordance with all of the preceding, medifoxamine was found to bewell tolerated at dosages of 100–300 mg per day inclinical trials.[3]Double-blindcontrolledclinical studies have found it to have similar effectiveness to imipramine,clomipramine, andmaprotiline in the treatment ofdepression.[3][9][18][19]

Society and culture

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Generic names

[edit]

Medifoxamine is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name whilemédifoxamine is itsDCFTooltip Dénomination Commune Française.[6][7][8]

Brand names

[edit]

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

References

[edit]
  1. ^abSaleh 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. ^abDörwald 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. ^abcdefghijklGainsborough 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. ^abcElks 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. ^abcIndex Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 638–.ISBN 978-3-88763-075-1.
  8. ^abMorton 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. ^abMitchell PB (1995). "Novel French antidepressants not available in the United States".Psychopharmacology Bulletin.31 (3):509–19.PMID 8668756.
  10. ^abConsolidated 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. ^abSaleh 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. ^abOlié 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. ^abRandhawa 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.
SSRIsTooltip Selective serotonin reuptake inhibitors
SNRIsTooltip Serotonin–norepinephrine reuptake inhibitors
NRIsTooltip Norepinephrine reuptake inhibitors
NDRIsTooltip Norepinephrine–dopamine reuptake inhibitors
NaSSAsTooltip Noradrenergic and specific serotonergic antidepressants
SARIsTooltip Serotonin antagonist and reuptake inhibitors
SMSTooltip Serotonin modulator and stimulators
Others
TCAsTooltip Tricyclic antidepressants
TeCAsTooltip Tetracyclic antidepressants
Others
Non-selective
MAOATooltip Monoamine oxidase A-selective
MAOBTooltip Monoamine oxidase B-selective
Miscellaneous
DATTooltip Dopamine transporter
(DRIsTooltip Dopamine reuptake inhibitors)
NETTooltip Norepinephrine transporter
(NRIsTooltip Norepinephrine reuptake inhibitors)
SERTTooltip Serotonin transporter
(SRIsTooltip Serotonin reuptake inhibitors)
VMATsTooltip Vesicular monoamine transporters
Others
5-HT1
5-HT1A
5-HT1B
5-HT1D
5-HT1E
5-HT1F
5-HT2
5-HT2A
5-HT2B
5-HT2C
5-HT3–7
5-HT3
5-HT4
5-HT5A
5-HT6
5-HT7
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