Etifoxine

Last updated
Etifoxine
Etifoxine.svg
Etifoxine ball-and-stick.png
Clinical data
Trade names Stresam
Other namesÉtifoxine; Etifoxin; Etafenoxine; Etafenoxin; EFX; Hoe 36801; Hoe-36,801
AHFS/Drugs.com International Drug Names
Pregnancy
category
  • Not recommended [1]
Routes of
administration 		Oral administration [2]
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 90% [3]
Protein binding 88–95% [4]
Metabolism Liver [5]
Metabolites Several (including diethyletifoxine) [5]
Elimination half-life Etifoxine: 6 hours [5]
Diethyletifoxine: 20 hours [5]
Excretion Mainly urine, also bile [5] [2]
Identifiers
  • 6-Chloro-N-ethyl-4-methyl-4-phenyl-4H-benzo[d][1,3]oxazin-2-amine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
ECHA InfoCard 100.158.584 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C17H17ClN2O
Molar mass 300.79 g·mol−1
3D model (JSmol)
  • ClC1=CC=C2N=C(NCC)OC(C3=CC=CC=C3)(C)C2=C1
  • InChI=1S/C17H17ClN2O/c1-3-19-16-20-15-10-9-13(18)11-14(15)17(2,21-16)12-7-5-4-6-8-12/h4-11H,3H2,1-2H3,(H,19,20) Yes check.svgY
  • Key:IBYCYJFUEJQSMK-UHFFFAOYSA-N Yes check.svgY
   (verify)

Etifoxine, sold under the trade name Stresam among others, is a nonbenzodiazepine anxiolytic agent, primarily indicated for short-term management of adjustment disorder, specifically instances of situational depression accompanied by anxiety, such as stress-induced anxiety. [2] [6] Administration is by mouth. [7] Side effects associated with etifoxine use include slight drowsiness, headache, skin eruptions, and allergic reactions. [2] [8] [9] In rare cases, etifoxine has been linked to severe skin and liver toxicity, as well as menstrual bleeding between periods. [8] [1] Unlike benzodiazepines, etifoxine does not cause sedation or lack of coordination. [10] [3] Etifoxine acts as a GABAA receptor positive allosteric modulator and as a ligand for translocator proteins. [10] Both mechanisms are conjectured to contribute to its anxiolytic properties. [10] [3]

Contents

Etifoxine was developed in the 1960s and was introduced for medical use in France in 1979. [11] Its marketed in 53 countries worldwide, although it remains unavailable in the United States. [7] [11] [12] Throughout the 2010s and early 2020s, the safety profile of etifoxine was scrutinized within France and the European Union, prompted by reports of toxicity. [13] [8] [7] The investigation revealed that instances of toxicity were infrequent, and etifoxine was allowed to remain on the market. [13] [8] [7]

Medical uses

Etifoxine has historically been used in the treatment of "psychosomatic manifestations of anxiety", for instance "autonomic dystonia, particularly with cardiovascular expression". [7] [13] [8] [1] Subsequently, the indication for etifoxine has been more formalized as treatment of adjustment disorder (situational depression) with anxiety (ADWA) (e.g., stress-related anxiety). [7] [14] [3] Etifoxine has been found to reduce scores on the Hamilton Anxiety Rating Scale (HAM-A) in people with adjustment disorder with anxiety by approximately 50 to 75% after 4 weeks of treatment in clinical trials (e.g., AMETIS, ETILOR, ETIZAL, STRETI studies). [7] The medication is similarly effective or more effective than benzodiazepines like lorazepam, alprazolam, and clonazepam and more effective than buspirone for adjustment disorder with anxiety on the basis of directly comparative randomized controlled trials. [14] [3] [15] [16] [17] [4] However, in the AMETIS study, both etifoxine and lorazepam failed to show greater effectiveness over placebo. [7]

The usual dosage of etifoxine (as the hydrochloride salt) is 150 to 200 mg per day in divided doses of 50 to 100 mg two to three times per day (e.g., 50 mg–50 mg–100 mg). [2] [7] [6] [18] [1] [19] [20] It is taken for a few days to a few weeks, but no longer than 12 weeks. [2] [13] [7] [5]

Available forms

Etifoxine is provided in the form of oral capsules containing 50 mg etifoxine hydrochloride. [2] [1] [21] [22]

Contraindications

Etifoxine is contraindicated in people with circulatory shock, severe liver impairment, severe kidney impairment, myasthenia gravis, galactosemia (due to lactose in the drug formulation), severe respiratory failure, and hypersensitivity (allergy) to etifoxine. [2] [5] The medication is not recommended in children or adolescents under the age of 18 [5] and is not recommended during pregnancy and breastfeeding due to insufficient data. [2] [1] Caution is warranted with regard to combining etifoxine and other central depressants such as benzodiazepines, central analgesics, antipsychotics, sedative antihistamines, and alcohol. [2] [1]

Side effects

Side effects of etifoxine include slight drowsiness and headache. [2] [9] Rarely, etifoxine can cause benign skin eruptions or rashes and allergic reactions such as hives and angioedema. [2] [8] [1] Etifoxine shows less adverse effects of anterograde amnesia, sedation, impaired psychomotor performance, and withdrawal syndromes than those of benzodiazepines. [5] No cases of misuse or dependence with etifoxine were identified in a French pharmacovigilance survey, which is also in contrast to benzodiazepines. [8]

Etifoxine has been associated rarely with cases of severe dermal toxicity and liver toxicity. [8] [23] Skin and subcutaneous disorders are the most frequently reported, but these generally resolve after drug cessation. [3] A 2012 review of etifoxine by the French National Pharmacovigilance Committee determined that etifoxine was safe and continued to provide a favorable alternative to benzodiazepine anxiolytics. The committee found (for a ten-year pharmacovigilance period) that safety concerns were rare or very rare and that the incidence of idiosyncratic hepatic (liver) problems were very rare. [13]

Pharmacology

Pharmacodynamics

Unlike benzodiazepines, etifoxine may produce its anxiolytic effects through a dual mechanism, by directly binding to GABAA receptors and (purportedly, exact binding site undetermined) to the mitochondrial translocator protein (TSPO). This results in stimulation of the biosynthesis of endogenous neurosteroids, for instance allopregnanolone, a highly potent GABAA receptor positive allosteric modulator. [24]

At GABAA receptors etifoxine binds at the α+β− interface and preferentially potentiates α2β3γ2 and α3β3γ2 receptor types. [25] This direct allosteric potentiation can only be observed at relatively high concentrations (starting at >1 mM) and is perhaps not physiologically relevant at normal human doses. [26] This is different from benzodiazepines and etifoxine can be used alongside benzodiazepines to potentiate their effects without competing for binding sites; [27] however, it also means that the direct effects of etifoxine are not reversed by the benzodiazepine antagonist flumazenil. [28]

Pharmacokinetics

Etifoxine is taken via oral administration. [2] [5] It is rapidly absorbed from the gastrointestinal tract. [5] It is well-absorbed, with a bioavailability of 90%. [2] [3] The time to peak levels of etifoxine is 2 to 3 hours. [5] The plasma protein binding of etifoxine is 88 to 95%. [4] It does not bind to blood cells. [2] The drug is known to cross the placental barrier. [2] Etifoxine is metabolized in the liver into several metabolites. [5] One of these metabolites, diethyletifoxine, is pharmacologically active. [5] The elimination half-life of etifoxine is 6 hours and of diethyletifoxine is almost 20 hours. [5] Etifoxine is eliminated in three phases. [2] The drug is excreted mainly in urine in the form of metabolites. [5] It is also excreted in bile. [5] Only small amounts are excreted unchanged. [5]

Chemistry

Etifoxine is a nonbenzodiazepine—that is, it is similarly a GABAA receptor positive allosteric modulator but its chemical structure is distinct from that of benzodiazepines. [3] [29] Instead, it is a benzoxazine derivative. [3]

Etifoxine is used pharmaceutically as the hydrochloride salt. [30] [31]

(S)-Etifoxine, the (S) enantiomer of etifoxine, was under development by Anvyl Pharmaceuticals for the treatment of neuropathic pain, but development was discontinued. [32] A deuterated form of etifoxine with improved pharmacokinetics known as deuterated etifoxine (GRX-917) is under development by GABA Therapeutics for the treatment anxiety and mood disorders. [33] [34] [24] [35]

History

Etifoxine was developed by Hoechst in the 1960s. [11] [36] It was introduced for medical use in France in 1979. [11] Since at least 2000, etifoxine has been marketed by the French pharmaceutical company Biocodex. [31] [29] [37] [19] Following reports of post-marketing toxicity, the safety of etifoxine was reassessed by the French government [13] [8] and the European Medicines Agency (EMA). [38] [39] In January 2022, the EMA "finalized its review of Stresam and concluded that the medicine can continue to be used for the treatment of anxiety disorders, but it must not be used in patients who previously had severe skin reactions or severe liver problems after taking etifoxine." [38] [39]

Society and culture

Names

Etifoxine is the generic name of the drug and its INN Tooltip International Nonproprietary Name, BAN Tooltip British Approved Name, and DCF Tooltip Dénomination Commune Française. [30] [31] It is also known by the older and much-lesser-used synonym etafenoxine [40] and by its developmental code name Hoe 36801. [30] [31] Etifoxine is marketed under the brand name Stresam. [30] [31] [19] It has also been marketed under the brand name Strezam, specifically in Russia. [19]

Availability

Etifoxine has been marketed in 53 countries as of 2022. [7] [11] Some of the countries in which etifoxine has been marketed include Argentina, Bulgaria, Chile, France, Luxembourg, Malta, Romania, Russia, South Africa, Thailand, and Ukraine. [19] [13] [7] [31] Etifoxine is not approved for use by the United States Food and Drug Administration (FDA) or the European Medicines Agency (EMA) of the European Union, and hence is not marketed in these regions. [11] [7] However, etifoxine is marketed in five European Union member states (France, Bulgaria, Luxembourg, Malta, Romania). [13] [7]

See also

Related Research Articles

An anxiolytic 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 anxiety disorders and their related psychological and physical symptoms.

<span class="mw-page-title-main">Benzodiazepine</span> Class of depressant drugs

Benzodiazepines, colloquially called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, insomnia, and seizures. The first benzodiazepine, chlordiazepoxide (Librium), was discovered accidentally by Leo Sternbach in 1955 and was made available in 1960 by Hoffmann–La Roche, who soon followed with diazepam (Valium) in 1963. By 1977, benzodiazepines were the most prescribed medications globally; the introduction of selective serotonin reuptake inhibitors (SSRIs), among other factors, decreased rates of prescription, but they remain frequently used worldwide.

GABA<sub>A</sub> receptor Ionotropic receptor and ligand-gated ion channel

The GABAA receptor (GABAAR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Accurate regulation of GABAergic transmission through appropriate developmental processes, specificity to neural cell types, and responsiveness to activity is crucial for the proper functioning of nearly all aspects of the central nervous system (CNS). Upon opening, the GABAA receptor on the postsynaptic cell is selectively permeable to chloride ions (Cl−) and, to a lesser extent, bicarbonate ions (HCO3−).

<span class="mw-page-title-main">Neurosteroid</span> Compounds that affect neuronal excitability through modulation of specific ionotropic receptors

Neurosteroids, also known as neuroactive steroids, are endogenous or exogenous steroids that rapidly alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors. The term neurosteroid was coined by the French physiologist Étienne-Émile Baulieu and refers to steroids synthesized in the brain. The term, neuroactive steroid refers to steroids that can be synthesized in the brain, or are synthesized by an endocrine gland, that then reach the brain through the bloodstream and have effects on brain function. The term neuroactive steroids was first coined in 1992 by Steven Paul and Robert Purdy. In addition to their actions on neuronal membrane receptors, some of these steroids may also exert effects on gene expression via nuclear steroid hormone receptors. Neurosteroids have a wide range of potential clinical applications from sedation to treatment of epilepsy and traumatic brain injury. Ganaxolone, a synthetic analog of the endogenous neurosteroid allopregnanolone, is under investigation for the treatment of epilepsy.

<span class="mw-page-title-main">Clorazepate</span> Benzodiazepine medication

Clorazepate, sold under the brand name Tranxene among others, is a benzodiazepine medication. It possesses anxiolytic, anticonvulsant, sedative, hypnotic, and skeletal muscle relaxant properties. Clorazepate is an unusually long-lasting benzodiazepine and serves as a prodrug for the equally long-lasting desmethyldiazepam, which is rapidly produced as an active metabolite. Desmethyldiazepam is responsible for most of the therapeutic effects of clorazepate.

<span class="mw-page-title-main">Alpidem</span> Anxiolytic medication

Alpidem, sold under the brand name Ananxyl, is a nonbenzodiazepine anxiolytic medication which was briefly used to treat anxiety disorders but is no longer marketed. It was previously marketed in France, but was discontinued due to liver toxicity. Alpidem is taken by mouth.

<span class="mw-page-title-main">Bretazenil</span> Chemical compound

Bretazenil (Ro16-6028) is an imidazopyrrolobenzodiazepine anxiolytic drug which is derived from the benzodiazepine family, and was invented in 1988. It is most closely related in structure to the GABA antagonist flumazenil, although its effects are somewhat different. It is classified as a high-potency benzodiazepine due to its high affinity binding to benzodiazepine binding sites where it acts as a partial agonist. Its profile as a partial agonist and preclinical trial data suggests that it may have a reduced adverse effect profile. In particular bretazenil has been proposed to cause a less strong development of tolerance and withdrawal syndrome. Bretazenil differs from traditional 1,4-benzodiazepines by being a partial agonist and because it binds to α1, α2, α3, α4, α5 and α6 subunit containing GABAA receptor benzodiazepine receptor complexes. 1,4-benzodiazepines bind only to α1, α2, α3 and α5GABAA benzodiazepine receptor complexes.

<span class="mw-page-title-main">Translocator protein</span> Human protein

Translocator protein (TSPO) is an 18 kDa protein mainly found on the outer mitochondrial membrane. It was first described as peripheral benzodiazepine receptor (PBR), a secondary binding site for diazepam, but subsequent research has found the receptor to be expressed throughout the body and brain. In humans, the translocator protein is encoded by the TSPO gene. It belongs to a family of tryptophan-rich sensory proteins. Regarding intramitochondrial cholesterol transport, TSPO has been proposed to interact with StAR to transport cholesterol into mitochondria, though evidence is mixed.

<span class="mw-page-title-main">Ocinaplon</span> Chemical compound

Ocinaplon is an anxiolytic drug in the pyrazolopyrimidine family of drugs. Other pyrazolopyrimidine drugs include zaleplon and indiplon.

<span class="mw-page-title-main">Imidazenil</span> Chemical compound

Imidazenil is an experimental anxiolytic drug which is derived from the benzodiazepine family, and is most closely related to other imidazobenzodiazepines such as midazolam, flumazenil, and bretazenil.

<span class="mw-page-title-main">SL651498</span> Chemical compound

SL651498 is an anxiolytic and anticonvulsant drug used in scientific research, with a chemical structure most closely related to β-carboline derivatives such as abecarnil and gedocarnil. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic.

<span class="mw-page-title-main">GABRA2</span> Protein in humans

Gamma-aminobutyric acid receptor subunit alpha-2 is a protein in humans that is encoded by the GABRA2 gene.

<span class="mw-page-title-main">ELB-139</span> Chemical compound

ELB-139 (LS-191,811) is an anxiolytic drug with a novel chemical structure, which is used in scientific research. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic.

<span class="mw-page-title-main">Emapunil</span> Chemical compound

Emapunil is an anxiolytic drug which acts as a selective agonist at the peripheral benzodiazepine receptor, also known as the mitochondrial 18 kDa translocator protein or TSPO. This protein has multiple functions, among which is regulation of steroidogenesis, particularly the production of neuroactive steroids such as allopregnanolone in the brain. In both animal and human trials, emapunil produced fast acting anxiolytic and anti-panic effects, without producing sedation or withdrawal symptoms following cessation of use. Emapunil is also used in its 11C radiolabelled form to map the distribution of TSPO receptors in the brain.

<span class="mw-page-title-main">DAA-1106</span> Chemical compound

DAA-1106 is a drug which acts as a potent and selective agonist at the peripheral benzodiazepine receptor, also known as the mitochondrial 18 kDa translocator protein or TSPO, but with no affinity at the GABAA receptor. It has anxiolytic effects in animal studies. DAA-1106 has a sub-nanomolar binding affinity (Ki) of 0.28 nM, and has been used extensively in its 3H or 11C radiolabelled form to map TSPO in the body and brain, which has proved especially helpful in monitoring the progress of neurodegenerative diseases such as Alzheimer's disease.

GABA<sub>A</sub> receptor positive allosteric modulator GABAA receptor positive modulators

In pharmacology, GABAA receptor positive allosteric modulators, also known as GABAkines or GABAA receptor potentiators, are positive allosteric modulator (PAM) molecules that increase the activity of the GABAA receptor protein in the vertebrate central nervous system.

A neurosteroidogenesis inhibitor is a drug that inhibits the production of endogenous neurosteroids. Neurosteroids include the excitatory neurosteroids pregnenolone sulfate, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEA-S), and the inhibitory neurosteroids allopregnanolone, tetrahydrodeoxycorticosterone (THDOC), and 3α-androstanediol, among others. By inhibiting the synthesis of endogenous neurosteroids, neurosteroidogenesis inhibitors have effects in the central nervous system.

<span class="mw-page-title-main">Darigabat</span> Chemical compound

Darigabat is a GABAergic medication which is under development for the treatment of photosensitive epilepsy, focal onset seizures, panic disorder, and other anxiety disorders. It was also under development for the treatment of generalized anxiety disorder and chronic lower back pain, but development for these indications was discontinued. It is taken via oral administration.

Deuterated etifoxine is a deuterated drug which is under development for the treatment of anxiety disorders and mood disorders.

References

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