Medifoxamine
Chemical compound
Clinical data | |
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Trade names | Clédial, Gerdaxyl |
Other names | Medifoxamine fumarate; N , N -Dimethyl-2,2-diphenoxyethylamine |
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By mouth |
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Pharmacokinetic data | |
Bioavailability | 21% [1] [2] |
Elimination half-life |
2.8 hours (acute);
[1]
[2]
4.0 hours (chronic) [3] |
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ECHA InfoCard | 100.046.359 |
Chemical and physical data | |
Formula | C 16 H 19 N O 2 |
Molar mass | 257.333 g·mol −1 |
3D model ( JSmol ) | |
Chirality | Racemic mixture |
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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 [11] It was withdrawn from the market in 1999 (Morocco) and 2000 (France) following incidences of hepatotoxicity .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 ( IC 50 = 1,500 nM) [3] and as a weak antagonist of the 5-HT 2A and 5-HT 2C receptors (IC 50 = 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 IC 50 values of CRE-10086 for serotonin transporter , 5-HT 2A , and 5-HT 2C 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-HT 1A , 5-HT 1B , 5-HT 1D , and 5-HT 3 (>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 α 1 -adrenergic receptor relative to 5-HT 2 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 2 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 .
- 1 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 .
- 1 2 3 4 5 6 7 8 9 10 11 12 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 .
- ↑ Holroyd-Leduc J, Reddy M (9 March 2012). Evidence-Based Geriatric Medicine . John Wiley & Sons. pp. 299–. ISBN 978-1-118-28181-9 .
- ↑ Annual Reports in Medicinal Chemistry . Vol. 22. Academic Press. 2 September 1987. pp. 323–. ISBN 978-0-08-058366-2 .
- 1 2 3 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 .
- 1 2 3 Index Nominum 2000: International Drug Directory . Taylor & Francis. January 2000. pp. 638–. ISBN 978-3-88763-075-1 .
- 1 2 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 .
- 1 2 Mitchell PB (1995). "Novel French antidepressants not available in the United States". Psychopharmacology Bulletin . 31 (3): 509–19. PMID 8668756 .
- 1 2 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 .
- ↑ 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 .
- ↑ 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 .
- ↑ Papakostas GI, Fava M (2010). Pharmacotherapy for Depression and Treatment-resistant Depression . World Scientific. pp. 88–. ISBN 978-981-4287-59-3 .
- 1 2 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 .
- ↑ 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 .
- ↑ 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 .
- ↑ 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 .
- 1 2 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 .
- 1 2 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 .
- ↑ ANNUAL REPORTS IN MED CHEMISTRY V20 PPR . Academic Press. 11 September 1985. pp. 35–. ISBN 978-0-08-058364-8 .
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