Medifoxamine
{{Short description|Withdrawn atypical antidepressant drug}}
{{Drugbox
| verifiedrevid = 444759950
| IUPAC_name = N,N-dimethyl-2,2-diphenoxyethanamine
| image = Medifoxamine.svg
| width = 200px
| tradename = Clédial, Gerdaxyl
| pregnancy_category =
| legal_status = Rx-only
| routes_of_administration = By mouth
| bioavailability = 21%{{cite journal | vauthors = Saleh S, Johnston A, Turner P | title = Absolute bioavailability and pharmacokinetics of medifoxamine in healthy humans | journal = British Journal of Clinical Pharmacology | volume = 30 | issue = 4 | pages = 621–4 | date = October 1990 | pmid = 2291875 | pmc = 1368255 | doi = 10.1111/j.1365-2125.1990.tb03823.x }}{{cite book| vauthors = Dörwald FZ |title=Lead Optimization for Medicinal Chemists: Pharmacokinetic Properties of Functional Groups and Organic Compounds|url=https://books.google.com/books?id=YTeY9ZEfNccC&pg=PA259|date=4 February 2013|publisher=John Wiley & Sons|isbn=978-3-527-64565-7|pages=259–}}
| metabolism =
| elimination_half-life = 2.8 hours (acute);
4.0 hours (chronic){{cite journal | vauthors = Gainsborough N, Nelson ML, Maskrey V, Swift CG, Jackson SH | title = The pharmacokinetics and pharmacodynamics of medifoxamine after oral administration in healthy elderly volunteers | journal = European Journal of Clinical Pharmacology | volume = 46 | issue = 2 | pages = 163–6 | year = 1994 | pmid = 8039537 | doi = 10.1007/bf00199882 | s2cid = 6978939 }}
| excretion =
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 32359-34-5
| CAS_supplemental =
16604-45-8 (fumarate)
16604-44-7 (picrate)
| ATC_prefix = N06
| ATC_suffix = AX13
| PubChem = 36109
| ChemSpiderID = 33212
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = KWU7C2A1NT
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D07341
| synonyms = Medifoxamine fumarate; N,N-Dimethyl-2,2-diphenoxyethylamine
| C=16 | H=19 | N=1 | O=2
| SMILES = CN(C)CC(OC1=CC=CC=C1)OC2=CC=CC=C2
| StdInChI = 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
| StdInChIKey = QNMGHBMGNRQPNL-UHFFFAOYSA-N
| chirality = Racemic mixture
}}
Medifoxamine, previously sold under the brand names Clédial and Gerdaxyl, is an atypical antidepressant{{cite book| vauthors = Holroyd-Leduc J, Reddy M |title=Evidence-Based Geriatric Medicine|url=https://books.google.com/books?id=VfPIUfcwrFkC&pg=PT299|date=9 March 2012|publisher=John Wiley & Sons|isbn=978-1-118-28181-9|pages=299–}} with additional anxiolytic properties{{cite book|title= Annual Reports in Medicinal Chemistry | volume = 22 |url=https://books.google.com/books?id=oJeTSJveeuAC&pg=PA323|date=2 September 1987|publisher=Academic Press|isbn=978-0-08-058366-2|pages=323–}} acting via dopaminergic and serotonergic mechanisms which was formerly marketed in France and Spain, as well as Morocco.{{cite book| vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA759|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=759–}}{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA638|date=January 2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=638–}}{{cite book| vauthors = Morton IK, Hall JM |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=mqaOMOtk61IC&pg=PA173|date=31 October 1999|publisher=Springer Science & Business Media|isbn=978-0-7514-0499-9|pages=173–}}{{cite journal | vauthors = Mitchell PB | title = Novel French antidepressants not available in the United States | journal = Psychopharmacology Bulletin | volume = 31 | issue = 3 | pages = 509–19 | year = 1995 | pmid = 8668756 }}{{cite book|title=Consolidated List of Products Whose Consumption And/or Sale Have Been Banned, Withdrawn, Severely Restricted Or Not Approved by Governments|url=https://books.google.com/books?id=leVCukUgNlsC&pg=PA135|year=2003|publisher=United Nations Publications|isbn=978-92-1-130230-1|pages=135–136}} The drug was first introduced in France sometime around 1990.{{cite journal | vauthors = Saleh S, Johnston A, Edeki T, Turner P | title = Tolerability and kinetics of intravenous medifoxamine in healthy volunteers | journal = International Clinical Psychopharmacology | volume = 5 | issue = 2 | pages = 97–102 | date = April 1990 | pmid = 2380545 | doi = 10.1097/00004850-199004000-00003 }} It was withdrawn from the market in 1999 (Morocco) and 2000 (France) following incidences of hepatotoxicity.{{cite journal | vauthors = Dumortier G, Cabaret W, Stamatiadis L, Saba G, Benadhira R, Rocamora JF, Aubriot-Delmas B, Glikman J, Januel D | display-authors = 6 | title = [Hepatic tolerance of atypical antipsychotic drugs] | language = fr | journal = L'Encéphale | volume = 28 | issue = 6 Pt 1 | pages = 542–51 | year = 2002 | pmid = 12506267 }}{{cite book| vauthors = Papakostas GI, Fava M |title=Pharmacotherapy for Depression and Treatment-resistant Depression|url=https://books.google.com/books?id=zigp-66vq0MC&pg=PA88|year=2010|publisher=World Scientific|isbn=978-981-4287-59-3|pages=88–}}
{{TOC limit|3}}
Pharmacology
=Pharmacodynamics=
Medifoxamine has been found to act preferentially as a relatively weak dopamine reuptake inhibitor,{{cite journal | vauthors = Saleh S, Turner P | title = Ocular hypotensive effects of medifoxamine | journal = British Journal of Clinical Pharmacology | volume = 34 | issue = 3 | pages = 269–71 | date = September 1992 | pmid = 1389953 | pmc = 1381400 | doi = 10.1111/j.1365-2125.1992.tb04136.x }}{{cite journal| vauthors = Vaugeois JM, Pouhé D, Lemonnier F, Costentin J |title=Neurochemical and behavioral evidence for a central indirect dopaminergic agonist activity of the antidepressant medifoxamine in mice|journal=European Neuropsychopharmacology|volume=4|issue=3|year=1994|pages=323–324|issn=0924-977X|doi=10.1016/0924-977X(94)90140-6|s2cid=54309929}}{{cite journal | vauthors = Berk M | title = Depression therapy: Future prospects | journal = International Journal of Psychiatry in Clinical Practice | volume = 4 | issue = 4 | pages = 281–6 | year = 2000 | pmid = 24926578 | doi = 10.1080/13651500050517830 | s2cid = 41078092 }} but also as an even weaker serotonin reuptake inhibitor (IC50 = 1,500 nM) 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).{{cite journal | vauthors = Martin P, Lemonnier F | title = [The role of type 2 serotonin receptors, 5-HT2A and 5-HT2C, in depressive disorders: effect of medifoxamine] | language = fr | journal = L'Encéphale | volume = 20 | issue = 4 | pages = 427–35 | year = 1994 | pmid = 7988407 }}{{cite journal | vauthors = Olié JP, Galinowski A, Lehert P, Lemonnier F, Lôo H | title = [Randomized double-blind comparative study of the efficacy and tolerance of medifoxamine and imipramine in depressed patients] | language = fr | journal = L'Encéphale | volume = 19 | issue = 4 | pages = 333–40 | year = 1993 | pmid = 8275921 }} 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). 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. Medifoxamine and its metabolites lack affinity for other serotonin receptors including 5-HT1A, 5-HT1B, 5-HT1D, and 5-HT3 (>10,000 nM). 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.
==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),{{cite journal| vauthors = Randhawa MA, Hedges A, Johnston A, Turner P |title=A psychopharmacological study to assess anti-muscarinic and central nervous effects of medifoxamine in normal volunteers|journal=Human Psychopharmacology: Clinical and Experimental|volume=3|issue=3|year=1988|pages=195–200|issn=0885-6222|doi=10.1002/hup.470030307|s2cid=145601579}} 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).{{cite book|title=ANNUAL REPORTS IN MED CHEMISTRY V20 PPR|url=https://books.google.com/books?id=j-3Cd_SWIksC&pg=PA35|date=11 September 1985|publisher=Academic Press|isbn=978-0-08-058364-8|pages=35–}} Studies in mice revealed that the drug does not possess any sedative or locomotor stimulant effects. 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. Double-blind controlled clinical studies have found it to have similar effectiveness to imipramine, clomipramine, and maprotiline in the treatment of depression.
Society and culture
=Generic names=
Medifoxamine is the generic name of the drug and its {{abbrlink|INN|International Nonproprietary Name}} while médifoxamine is its {{abbrlink|DCF|Dénomination Commune Française}}.
=Brand names=
References
{{Reflist|30em}}
{{Antidepressants}}
{{Monoamine reuptake inhibitors}}
{{Serotonin receptor modulators}}
Category:Dimethylamino compounds