Medifoxamine

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Medifoxamine, previously sold under the brand names Clédial and Gerdaxyl, is an atypical antidepressant[1] with additional anxiolytic properties[2] acting via dopaminergic and serotonergic mechanisms which was formerly marketed in France and Spain, as well as Morocco.[3][4][5][6][7] The drug was first introduced in France sometime around 1990.[8] It was withdrawn from the market in 1999 (Morocco) and 2000 (France) following incidences of hepatotoxicity.[7][9][10]

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Pharmacology

Pharmacodynamics

Medifoxamine has been found to act preferentially as a relatively weak dopamine reuptake inhibitor,[11][12][13][14] but also as an even weaker serotonin reuptake inhibitor (IC50 = 1,500 nM)[11] 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).[11][15][16] 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).[11] 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.[11] Medifoxamine and its metabolites lack affinity for other serotonin receptors including 5-HT1A, 5-HT1B, 5-HT1D, and 5-HT3 (>10,000 nM).[11] 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.[11]

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),[11][12][17] 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).[18] Studies in mice revealed that the drug does not possess any sedative or locomotor stimulant effects.[11] 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.[11] Double-blind controlled clinical studies have found it to have similar effectiveness to imipramine, clomipramine, and maprotiline in the treatment of depression.[11][6][16][17]

Society and culture

Generic names

Medifoxamine is the generic name of the drug and its INNTooltip International Nonproprietary Name while médifoxamine is its DCFTooltip Dénomination Commune Française.[3][4][5]

Brand names

Medifoxamine was marketed under the brand names Clédial and Gerdaxyl.[3][4]

References

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