Medifoxamine, previously sold under the brand names Clédial and Gerdaxyl, is an

atypical antidepressant An atypical antidepressant is any antidepressant medication that acts in a manner that is different from that of most other antidepressants. Atypical antidepressants include agomelatine, bupropion, iprindole, mianserin, mirtazapine, nefazod ...

with additional

anxiolytic An anxiolytic (; also antipanic or antianxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxiet ...

properties acting via dopaminergic and

serotonergic Serotonergic () or serotoninergic () means "pertaining to or affecting serotonin". Serotonin is a neurotransmitter. A synapse is serotonergic if it uses serotonin as its neurotransmitter. A serotonergic neuron ''produces'' serotonin. A substance is ...

mechanisms which was formerly marketed in

France France (), officially the French Republic ( ), is a country primarily located in Western Europe. It also comprises of overseas regions and territories in the Americas and the Atlantic, Pacific and Indian Oceans. Its metropolitan area ...

and

Spain , image_flag = Bandera de España.svg , image_coat = Escudo de España (mazonado).svg , national_motto = ''Plus ultra'' (Latin)(English: "Further Beyond") , national_anthem = (English: "Royal March") , i ...

, as well as

Morocco Morocco (),, ) officially the Kingdom of Morocco, is the westernmost country in the Maghreb region of North Africa. It overlooks the Mediterranean Sea to the north and the Atlantic Ocean to the west, and has land borders with Algeria t ...

. The drug was first introduced in France sometime around 1990. It was withdrawn from the market in 1999 (Morocco) and 2000 (France) following incidences of

hepatotoxicity Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn fr ...

Pharmacology

Pharmacodynamics

Medifoxamine has been found to act preferentially as a relatively weak

dopamine reuptake inhibitor A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dop ...

, but also as an even weaker

serotonin reuptake inhibitor A serotonin reuptake inhibitor (SRI) is a type of drug which acts as a reuptake inhibitor of the neurotransmitter serotonin (5-hydroxytryptamine, or 5-HT) by blocking the action of the serotonin transporter (SERT). This in turn leads to incre ...

( IC₅₀ = 1,500 nM) and as a weak antagonist of the 5-HT_2A and 5-HT_2C receptors (IC₅₀ = 950 and 980, respectively; notably greater affinity relative to

amitriptyline Amitriptyline, sold under the brand name Elavil among others, is a tricyclic antidepressant primarily used to treat cyclic vomiting syndrome (CVS), major depressive disorder and a variety of pain syndromes from neuropathic pain to fibromyalgi ...

and imipramine). It is known to produce two active metabolites during

first-pass metabolism The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the system ...

in the

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

, 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 The serotonin transporter (SERT or 5-HTT) also known as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 is a protein that in humans is encoded by the SLC6A4 gene. SERT is a type of monoamine transporter protein tha ...

, 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. Medifoxamine and its metabolites lack affinity for other serotonin receptors including 5-HT_1A, 5-HT_1B, 5-HT_1D, 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 antidepressant Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants, which is important for the management of depression. They are second-line drugs next to SSRIs. TCAs were discovered in the early 1950s and wer ...

s, medifoxamine lacks

anticholinergic Anticholinergics (anticholinergic agents) are substances that block the action of the neurotransmitter called acetylcholine (ACh) at synapses in the central and peripheral nervous system. These agents inhibit the parasympathetic nervous sys ...

and alpha blocker properties (very low affinity for the

muscarinic acetylcholine receptor Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end-rec ...

s and 10-fold lower affinity for the α₁-adrenergic receptor relative to 5-HT₂ binding sites), and is also apparently inactive as a

norepinephrine reuptake inhibitor A norepinephrine reuptake inhibitor (NRI, NERI) or noradrenaline reuptake inhibitor or adrenergic reuptake inhibitor (ARI), is a type of drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and epin ...

(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). 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 trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...

Double-blind In a blind or blinded experiment, information which may influence the participants of the experiment is withheld until after the experiment is complete. Good blinding can reduce or eliminate experimental biases that arise from a participants' expec ...

controlled clinical studies have found it to have similar effectiveness to imipramine, clomipramine, and

maprotiline Maprotiline, sold under the brand name Ludiomil among others, is a tetracyclic antidepressant (TeCA) that is used in the treatment of depression. It may alternatively be classified as a tricyclic antidepressant (TCA), specifically a secondary am ...

in the treatment of depression.

Society and culture

Generic names

''Medifoxamine'' is the generic name of the drug and its while ''médifoxamine'' is its .

Brand names

Medifoxamine was marketed under the brand names Clédial and Gerdaxyl.

References

{{Serotonin receptor modulators 5-HT2A antagonists 5-HT2C antagonists Dimethylamino compounds Anxiolytics Antidepressants Hepatotoxins Phenol ethers Serotonin–dopamine reuptake inhibitors Withdrawn drugs