Efficacy of etifoxine compared to lorazepam monotherapy in the treatment of patients with adjustment disorders with anxiety: a double‐blind controlled study in general practice

Nguyễn, Ngọc Tuấn; Fakra, É.; Pradel, Vincent; Jouve, Élisabeth; Alquier, Christine; Guern, M-E. Le; Micallef, Joëlle; Blin, Olivier

doi:10.1002/hup.757

Cited by 121 publications

(71 citation statements)

References 38 publications

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“…Etifoxine fulfills the criteria of a drug that is clinically useful for the treatment of altered peripheral axons: i) easy diffusion into nerve tissues; ii) selective modulation of inflammatory responses to injury; iii) able to increase the expression of neurotrophic factors; iv) suitable for long-term use (52,53) and (v) convenient administration. Considering the important benefits of etifoxine, etifoxine treatment may represent a promising strategy for the treatment of peripheral nerve injury.…”

Section: Discussionmentioning

confidence: 99%

Etifoxine promotes glial-derived neurotrophic factor-induced neurite outgrowth in PC12 cells

Zhou

et al. 2013

Molecular Medicine Reports

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Abstract. Nerve regeneration and functional recovery are major issues following nerve tissue damage. Etifoxine is currently under investigation as a therapeutic strategy for promoting neuroprotection, accelerating axonal regeneration and modulating inflammation. In the present study, a well-defined PC12 cell model was used to explore the underlying mechanism of etifoxine-stimulated neurite outgrowth. Etifoxine was found to promote glial-derived growth factor (GDNF)-induced neurite outgrowth in PC12 cells. Average axon length increased from 50.29±9.73 to 22.46±5.62 µm with the use of etifoxine. However, blockage of GDNF downstream signaling was found to lead to the loss of this phenomenon. The average axon length of the etifoxine group reduces to a normal level after the blockage of the GDNF family receptor α1 (GFRα1) and receptor tyrosine kinase (RETS) receptors (27.46 ± 3.59 vs. 22.46 ± 5.62 µm and 25.31±3.68 µm vs. 22.46±5.62 µm, respectively, p>0.05). In addition, etifoxine markedly increased GDNF mRNA and protein expression (1.55-and 1.36-fold, respectively). However, blockage was not found to downregulate GDNF expression. The results of the current study demonstrated that etifoxine stimulated neurite outgrowth via GDNF, indicating that GDNF represents a key molecule in etifoxine-stimulated neurite outgrowth in PC12 cells. IntroductionTraumatic injury to peripheral nerves results in considerable loss of sensory and motor function, decreasing quality of life in patients (1). Peripheral nerve injuries substantially impact quality of life through loss of function and increased risk of secondary disabilities from falls, fractures and other injuries. Several research groups have attempted to improve the regeneration of traumatized nerves by developing favorable microsurgical techniques. However, clinicians soon noted that despite advancement in these techniques, complete recovery is rarely achieved (2,3). Therefore, complete recovery remains an important clinical challenge for the improvement of functional recovery following peripheral nerve injury. In a discussion of future trends in the management of brachial plexus injuries, Birch hypothesized that the administration of nerve growth factor may represent a useful treatment strategy (4).Neurotrophic factors are important in a number of biological processes, including survival, proliferation, differentiation and apoptosis of neurons in the nervous system (5-7). However, direct use of trophic factors in clinical practice is extremely challenging as they are difficult to administer and have severe side effects (8). However, molecules that easily diffuse into nerve tissues, including ligands of the progesterone and thyroid hormone receptors, and immunophilins, have beneficial effects on peripheral nerves in various experimental lesion and disease models (9-12). We hypothesize that clinically established drugs may be suitable to elevate trophic factor levels to improve the outcome of peripheral nerve injuries.Previous studies have demonstrated that the drug, etifoxi...

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Section: Discussionmentioning

confidence: 99%

Etifoxine promotes glial-derived neurotrophic factor-induced neurite outgrowth in PC12 cells

Zhou

et al. 2013

Molecular Medicine Reports

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“…Likewise, the anticonvulsant loreclezole has ␤ 2/3 -subunit selectivity, diazepam-like efficacy, and anxiolytic/ anticonvulsant activity in animal models with reduced sedative effects (Smith et al, 2004;Groves et al, 2006) and is a nonsedating antiepileptic in human clinical trials (Fisher and Blum, 1995). Etifoxine, with ␤ 2/3 -subunit selectivity, also has diazepam-like efficacy at GABA A Rs (Smith et al, 2004) and is used clinically as a nonsedating anxiolytic (Nguyen et al, 2006). We firmly believe that these clinical observations along with our own data provide a cogent argument that designing compounds (see Supplemental Data for SAR on ␤-subunit isoform selectivity) with reduced activity at ␤ 1 -subunit-containing GABA A Rs will ultimately result in anxioselective drugs.…”

Section: Discussionmentioning

confidence: 99%

Limiting Activity at β₁-Subunit-Containing GABA_A Receptor Subtypes Reduces Ataxia

Gee¹,

Tran²,

Hogenkamp³

et al. 2009

J Pharmacol Exp Ther

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GABA A receptor (R) positive allosteric modulators that selectively modulate GABA A Rs containing ␤ 2 -and/or ␤ 3 -over ␤ 1 -subunits have been reported across diverse chemotypes. Examples include loreclezole, mefenamic acid, tracazolate, and etifoxine. In general,"␤ 2/3 -selective" GABA A R positive allosteric modulators are nonbenzodiazepines (nonBZs), do not show ␣-subunit isoform selectivity, yet have anxiolytic efficacy with reduced ataxic/sedative effects in animal models and humans. Here, we report on an enantiomeric pair of nonBZ GABA A R positive allosteric modulators that demonstrate differential ␤-subunit isoform selectivity. We have tested this enantiomeric pair along with a series of other ␤ 2/3 -subunit selective, ␣-subunit isoform-selective, BZ and nonBZ GABA A positive allosteric modulators using electrophysiological, pharmacokinetic, and behavioral assays to test the hypothesis that ataxia may be correlated with the extent of modulation at ␤ 1 -subunit-containing GABA A Rs. Our findings provide an alternative strategy for designing anxioselective allosteric modulators of the GABA A R with BZ-like anxiolytic efficacy by reducing or eliminating activity at ␤ 1 -subunit-containing GABA A Rs.Positive allosteric modulators of the GABA A receptor (R) such as the benzodiazepines (BZs) continue to be used to treat anxiety, despite the well-known side effect of sedation. Diverse drug discovery efforts over two decades have focused on generating "anxioselective" (i.e., reducing anxiety without sedation) GABA A R positive allosteric modulators. Medicinal chemistry efforts have focused primarily on modifications of the BZ template with limited success in reducing sedative liability (Whiting, 2006).One strategy to generate anxioselective positive allosteric modulators involves creation of positive allosteric modulators that selectively modulate individual GABA A R subtypes involved in anxiety, while avoiding those mediating sedation. Several laboratories have focused on ␣-subunit isoform-selective BZ site agonists that evoke positive modulation of ␣ 2 -and ␣ 3 -but not ␣ 1 -subunit-containing GABA A Rs. This "␣ 2/3 -selective" approach is based on pharmacological and genetic data suggesting that ␣ 2 -and ␣ 3 -subunit-containing GABA A Rs mediate the anxiolytic actions of BZs, whereas those with ␣ 1 -subunits, especially the ␣ 1 ␤ 2 ␥ 2 subtype, are thought to mediate their sedative effects (Rudolph et al., 1999;McKernan et al., 2000). Consistent with this general theory, L-838,417 is a ␣ 2,3 -subunit-selective partial agonist BZ receptor ligand reported to be anxioselective in animal models (McKernan et al., 2000). However, recent clinical studies designed to determine whether ␣ 2,3 -subunit selectivity imparts reduced sedative liability has resulted in equivocal results where BZ-like side effects were observed (de Haas et al., 2008(de Haas et al., , 2009. Moreover, the ␣ 3 -subunit-selective BZ site partial agonist adipiplon has potent sedative activity and was in clinical development as a sedative...

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“…Moreover, the drug is already efficiently used in long-duration (up to 3 months) treatment of adjustment disorders with anxiety, and it is devoid of many of the side effects linked to benzodiazepine anxiolytics (35)(36)(37). This is important, given that axonal regeneration after injury and in peripheral neuropathies is a slow process, and only molecules that can be administered over sufficient periods would be expected to have therapeutic benefits.…”

Section: Discussionmentioning

confidence: 99%

Etifoxine improves peripheral nerve regeneration and functional recovery

Girard

Liu

Cadepond

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

133

112

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Peripheral nerves show spontaneous regenerative responses, but recovery after injury or peripheral neuropathies (toxic, diabetic, or chronic inflammatory demyelinating polyneuropathy syndromes) is slow and often incomplete, and at present no efficient treatment is available. Using well-defined peripheral nerve lesion paradigms, we assessed the therapeutic usefulness of etifoxine, recently identified as a ligand of the translocator protein (18 kDa) (TSPO), to promote axonal regeneration, modulate inflammatory responses, and improve functional recovery. We found by histologic analysis that etifoxine therapy promoted the regeneration of axons in and downstream of the lesion after freeze injury and increased axonal growth into a silicone guide tube by a factor of 2 after nerve transection. Etifoxine also stimulated neurite outgrowth in PC12 cells, and the effect was even stronger than for specific TSPO ligands. Etifoxine treatment caused a marked reduction in the number of macrophages after cryolesion within the nerve stumps, which was rapid in the proximal and delayed in the distal nerve stumps. Functional tests revealed accelerated and improved recovery of locomotion, motor coordination, and sensory functions in response to etifoxine. This work demonstrates that etifoxine, a clinically approved drug already used for the treatment of anxiety disorders, is remarkably efficient in promoting acceleration of peripheral nerve regeneration and functional recovery. Its possible mechanism of action is discussed, with reference to the neurosteroid concept. This molecule, which easily enters nerve tissues and regulates multiple functions in a concerted manner, offers promise for the treatment of peripheral nerve injuries and axonal neuropathies.inflammation ͉ macrophage ͉ axonal growth ͉ Translocator Protein (18 kDa)

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Efficacy of etifoxine compared to lorazepam monotherapy in the treatment of patients with adjustment disorders with anxiety: a double‐blind controlled study in general practice

Cited by 121 publications

References 38 publications

Etifoxine promotes glial-derived neurotrophic factor-induced neurite outgrowth in PC12 cells

Etifoxine promotes glial-derived neurotrophic factor-induced neurite outgrowth in PC12 cells

Limiting Activity at β₁-Subunit-Containing GABA_A Receptor Subtypes Reduces Ataxia

Etifoxine improves peripheral nerve regeneration and functional recovery

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Efficacy of etifoxine compared to lorazepam monotherapy in the treatment of patients with adjustment disorders with anxiety: a double‐blind controlled study in general practice

Cited by 121 publications

References 38 publications

Etifoxine promotes glial-derived neurotrophic factor-induced neurite outgrowth in PC12 cells

Etifoxine promotes glial-derived neurotrophic factor-induced neurite outgrowth in PC12 cells

Limiting Activity at β1-Subunit-Containing GABAA Receptor Subtypes Reduces Ataxia

Etifoxine improves peripheral nerve regeneration and functional recovery

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Product

Resources

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Limiting Activity at β₁-Subunit-Containing GABA_A Receptor Subtypes Reduces Ataxia