Phenibut

Last updated

Phenibut
Phenibut skeletal formula.svg
Phenibut ball-and-stick model.png
Clinical data
Trade names Anvifen, Fenibut, Noofen, others [1]
Other namesAminophenylbutyric acid; Fenibut; Fenigam; Phenigam; Phenybut; Phenygam; Phenylgamma; Phenigama; PHG; PhGABA; β-Phenyl-γ-aminobutyric acid; β-Phenyl-GABA [2]
Routes of
administration 		Common: By mouth [3]
Uncommon: Rectal [3]
Drug class GABA receptor agonist; Gabapentinoid
ATC code
Legal status
Legal status
  • AU: S9 (Prohibited substance)
  • US:Unapproved "New Drug" (as defined by 21 U.S. Code § 321(p)(1)). Use in dietary supplements, food, or medicine is unlawful; otherwise uncontrolled. [4]

Illegal in Alabama [5]

  • RU : Rx-only
Pharmacokinetic data
Bioavailability Well-absorbed [6]
≥63% (250 mg) [7]
Metabolism Liver (minimal) [6] [7]
Metabolites Inactive [6]
Onset of action Oral: 2–4 hours [3]
Rectal: 20–30 minutes [3]
Elimination half-life 5.3 hours (250 mg) [7]
Duration of action 15–24 hours (1–3 g) [3]
Excretion Urine: 63% (unchanged) [7]
Identifiers
  • 4-Amino-3-phenylbutanoic acid
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.012.800 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C10H13NO2
Molar mass 179.219 g·mol−1
3D model (JSmol)
Melting point 253 °C (487 °F)
  • O=C(O)CC(c1ccccc1)CN
  • InChI=1S/C10H13NO2/c11-7-9(6-10(12)13)8-4-2-1-3-5-8/h1-5,9H,6-7,11H2,(H,12,13) Yes check.svgY
  • Key:DAFOCGYVTAOKAJ-UHFFFAOYSA-N Yes check.svgY
   (verify)

Phenibut, sold under the brand names Anvifen, Fenibut, and Noofen among others, [1] is a central nervous system depressant with anxiolytic effects, and is used to treat anxiety, insomnia, and for a variety of other indications. [7] It is usually taken by mouth as a tablet, but may be given intravenously. [6] [7]

Contents

Side effects of phenibut can include sedation, sleepiness, nausea, irritability, agitation, dizziness, euphoria and sometimes headache, among others. [6] [8] Overdose of phenibut can produce marked central nervous system depression including unconsciousness. [6] [8] The medication is structurally related to the neurotransmitter γ-aminobutyric acid (GABA), and hence is a GABA analogue. [7] Phenibut is thought to act as a GABAB receptor agonist, similarly to baclofen and γ-hydroxybutyrate (GHB). [7] However, at low concentrations, phenibut mildly increases the concentration of dopamine in the brain, providing stimulatory effects in addition to the anxiolysis. [9]

Phenibut was developed in the Soviet Union and was introduced for medical use in the 1960s. [7] Today, it is marketed for medical use in Russia, Ukraine, Belarus, Kazakhstan, and Latvia. [7] The medication is not approved for clinical use in the United States and most of Europe, but it is sold on the Internet as a supplement and purported nootropic. [3] [10] Phenibut has been used recreationally and can produce euphoria as well as addiction, dependence, and withdrawal. [3] It is a controlled substance in Australia, and it has been suggested that its legal status should be reconsidered in Europe as well. [3]

Medical uses

Phenibut is used in Russia, Ukraine, Belarus and Latvia as a pharmaceutical drug to treat anxiety and to improve sleep (e.g., in the treatment of insomnia). [7] [6] It is also used for various other indications, including the treatment of asthenia, depression, alcoholism, alcohol withdrawal syndrome, post-traumatic stress disorder, stuttering, tics, vestibular disorders, Ménière's disease, dizziness, for the prevention of motion sickness, and for the prevention of anxiety before or after surgical procedures or painful diagnostic tests. [6] [7]

Available forms

Phenibut is available as a medication in the form of 250 mg or 500 mg tablets for oral administration and as a solution at a concentration of 10 mg/mL for infusion. [6] [8] [11] In the US, dietary supplements labeled as containing phenibut have been found to contain zero to greater than 1,100 mg of phenibut per serving. [10]

Contraindications

Contraindications of phenibut include: [6] [8]

Phenibut should not be combined with alcohol. [8]

Side effects

Phenibut is generally well-tolerated. [7] [8] Possible side effects may include sedation, somnolence, nausea, irritability, agitation, anxiety, dizziness, headache, and allergic reactions such as skin rash and itching. [6] [8] At high doses, motor incoordination, loss of balance, and hangovers may occur. [3] Due to its central nervous system depressant effects, people taking phenibut should refrain from potentially dangerous activities such as operating heavy machinery. [6] [8] With prolonged use of phenibut, particularly at high doses, the liver and blood should be monitored, due to risk of fatty liver disease and eosinophilia. [6] [8]

Overdose

In overdose, phenibut can cause severe drowsiness, nausea, vomiting, eosinophilia, lowered blood pressure, renal impairment, and, above 7 grams, fatty liver degeneration. [6] [8] There are no specific antidotes for phenibut overdose. [8] Lethargy, somnolence, agitation, delirium, tonic–clonic seizures, reduced consciousness or unconsciousness, and unresponsiveness have been reported in recreational users who have overdosed. [3] Management of phenibut overdose includes activated charcoal, gastric lavage, induction of vomiting, and symptom-based treatment. [6] [8] There have been three associated deaths which found Phenibut in the users system but only one of these cases single-handedly included Phenibut. [12]

Dependency and withdrawal

Tolerance to phenibut easily develops with repeated use leading to dependency. [7] [ needs update ] Withdrawal symptoms may occur upon discontinuation, and, in recreational users taking high doses, have been reported to include severe rebound anxiety, insomnia, anger, irritability, agitation, visual and auditory hallucinations, and acute psychosis. [3] Baclofen has successfully been used for treatment of phenibut dependence. [13]

Interactions

Phenibut may mutually potentiate and extend the duration of the effects of other central nervous system depressants including anxiolytics, antipsychotics, sedatives, opioids, anticonvulsants, and alcohol. [6] [8]

Pharmacology

Pharmacodynamics

GABA and analogues
at biological targets [14]
Compound GABAB GABAA
GABA Tooltip γ-Aminobutyric acid0.080.12
GHB Tooltip γ-Hydroxybutyric acid>100>100
GABOB Tooltip γ-Amino-β-hydroxybutyric acid1.101.38
Phenibut9.6>100
4-F-phenibut 1.70>100
Baclofen 0.13>100
   (R)-Baclofen 0.13>100
   (S)-Baclofen 74.0>100
Values are IC50 (μM) in rat brain.

Phenibut acts as a full agonist of the GABAB receptor, similarly to baclofen. [15] [16] It has between 30- and 68-fold lower affinity for the GABAB receptor than baclofen, and, in accordance, is used at far higher doses in comparison. [15] (R)-Phenibut has more than 100-fold higher affinity for the GABAB receptor than does (S)-phenibut; hence, (R)-phenibut is the active enantiomer at the GABAB receptor. [17]


Phenibut and analogues
at biological targets [18]
Compound α2δ GABAB
PhenibutND177
  (R)-Phenibut2392
  (S)-Phenibut39>1,000
Baclofen 1566
Gabapentin 0.05>1,000
Values are Ki (μM) in rat brain.

Phenibut also binds to and blocks α2δ subunit-containing VDCCs, similarly to gabapentin and pregabalin, and hence is a gabapentinoid. [18] [19] Both (R)-phenibut and (S)-phenibut display this action with similar affinity (Ki = 23 and 39 μM, respectively). [18]

Pharmacokinetics

Little information thus far has been published on the clinical pharmacokinetics of phenibut. [7] The drug is reported to be well-absorbed. [6] It distributes widely throughout the body and across the blood–brain barrier. [6] Approximately 0.1% of an administered dose of phenibut reportedly penetrates into the brain, with this said to occur to a much greater extent in young people and the elderly. [6] Following a single 250 mg dose in healthy volunteers, its elimination half-life was approximately 5.3 hours and the drug was largely (63%) excreted in the urine unchanged. [7]

Some limited information has been described on the pharmacokinetics of phenibut in recreational users taking much higher doses (e.g., 1–3 grams) than typical clinical doses. [3] [20] In these individuals, the onset of action of phenibut has been reported to be 2 to 4 hours orally and 20 to 30 minutes rectally, the peak effects are described as occurring 4 to 6 hours following oral ingestion, and the total duration for the oral route has been reported to be 15 to 24 hours (or about 3 to 5 terminal half-lives). [3]

Chemistry

Phenibut is a synthetic aromatic amino acid. It is a chiral molecule and thus has two potential configurations, as (R)- and (S)-enantiomers. [16]

Structure and analogues

Chemical structures of phenibut and analogues. Phenibut and analogues.png
Chemical structures of phenibut and analogues.

Phenibut is a derivative of the inhibitory neurotransmitter GABA. [7] Hence, it is a GABA analogue. [7] Phenibut is specifically the analogue of GABA with a phenyl ring substituted in at the β-position. [7] As such, its chemical name is β-phenyl-γ-aminobutyric acid, which can be abbreviated as β-phenyl-GABA. [7] The presence of the phenyl ring allows phenibut to cross the blood–brain barrier significantly, unlike the case of GABA. [7] Phenibut also contains the trace amine β-phenethylamine in its structure. [7]

Phenibut is closely related to a variety of other GABA analogues including baclofen (β-(4-chlorophenyl)-GABA), 4-fluorophenibut (β-(4-fluorophenyl)-GABA), tolibut (β-(4-methylphenyl)-GABA), pregabalin ((S)-β-isobutyl-GABA), gabapentin (1-(aminomethyl)cyclohexane acetic acid), and GABOB (β-hydroxy-GABA). [7] [18] It has almost the same chemical structure as baclofen, differing from it only in having a hydrogen atom instead of a chlorine atom at the para position of the phenyl ring. [7] Phenibut is also close in structure to pregabalin, which has an isobutyl group at the β position instead of phenibut's phenyl ring. [18]

A glutamate-derivative analogue of phenibut is glufimet (dimethyl 3-phenylglutamate hydrochloride). [21]

Synthesis

A chemical synthesis of phenibut has been published. [11]

History

Phenibut was synthesized at the A. I. Herzen Leningrad Pedagogical Institute (USSR) by Professor Vsevolod Perekalin's team and tested at the Institute of Experimental Medicine, USSR Academy of Medical Sciences. [7] It was introduced into clinical use in Russia in the 1960s. [7]

Society and culture

Olainfarm's pharmaceutical phenibut sold in Russia. Phenibut from Russia.png
Olainfarm's pharmaceutical phenibut sold in Russia.

Other names

Alternate spellings include fenibut and phenybut. [2] It is also sometimes referred to as aminophenylbutyric acid. [1] The word phenibut is a contraction of the chemical name of the drug, β-phenyl-γ-aminobutyric acid. [7] In early publications, phenibut was referred to as fenigam and phenigama. [7] [22] The drug has not been assigned an INN Tooltip International Nonproprietary Name. [2] [6]

Brand names

Phenibut is marketed in Russia, Ukraine, Belarus and Latvia under the brand names Anvifen, Fenibut, Bifren and Noofen (Russian: Анвифен, Фенибут, Бифрен and Ноофен, respectively). [1]

Availability

Phenibut is approved in Russia, Ukraine, Belarus and Latvia for medical use. [3] It is not approved or available as a medication in other countries in the European Union, the United States, or Australia. [3] In countries where phenibut is not a licensed pharmaceutical drug, it is sold online without a prescription as a "nutritional supplement". [3] [10] It is often used as a form of self-medication for social anxiety. [3]

Recreational use

Phenibut is used recreationally due to its ability to produce euphoria, anxiolysis, and increased sociability, [3] as well as remaining undetected in routine urinalysis. Because of its delayed onset of effects, first-time users often mistakenly take an additional dose of phenibut in the belief that the initial dose did not work. [3] Recreational users usually take the drug orally; there are a few case reports of rectal administration and one report of insufflation, which was described as "very painful" and causing swollen nostrils. [3]

As of 2021, phenibut is a controlled substance in Australia, [3] France, [23] Hungary, [24] Italy, [25] and Lithuania. [26] [27] In 2015, it was suggested that the legal status of phenibut in Europe should be reconsidered due to its recreational potential. [3] In February 2018, the Australian Therapeutic Goods Administration declared it a prohibited (schedule 9) substance, citing health concerns due to withdrawal and overdose. [28] [29]

As of 14 November 2018, Hungary added phenibut and 10 other items to its New Psychoactive Substances ban list. [30]

As of 26 August 2020, Italy added phenibut to its New Psychoactive Substances ban list. [25]

As of 18 September 2020, France added phenibut to the controlled psychoactive substances list, prohibiting production, sale, storage and use. [31]

In the United States, phenibut is not a Controlled Substance. However, Dietary supplements that contain phenibut are unlawful to introduce into interstate commerce, because phenibut is considered a "New Drug" and any food, supplement, cosmetic, or drug that contains phenibut is therefore misbranded. Alabama placed phenibut and tianeptine into Schedule I status on 2021, first by action of the Alabama Department of Public Health and then followed by the state legislature. [5]

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.

<i>gamma</i>-Hydroxybutyric acid Chemical compound

gamma-Hydroxybutyric acid is a naturally occurring neurotransmitter and a depressant drug. It is a precursor to GABA, glutamate, and glycine in certain brain areas. It acts on the GHB receptor and is a weak agonist at the GABAB receptor. GHB has been used in the medical setting as a general anesthetic and as treatment for cataplexy, narcolepsy, and alcoholism. The substance is also used illicitly for various reasons, including as a performance-enhancing drug, date rape drug, and as a recreational drug.

γ-Aminobutyric acid Main inhibitory neurotransmitter in the mammalian brain

γ-Aminobutyric acid, or GABA, is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system.

<span class="mw-page-title-main">Sedative</span> Drug that reduces excitement without inducing sleep

A sedative or tranquilliser is a substance that induces sedation by reducing irritability or excitement. They are CNS depressants and interact with brain activity causing its deceleration. Various kinds of sedatives can be distinguished, but the majority of them affect the neurotransmitter gamma-aminobutyric acid (GABA). In spite of the fact that each sedative acts in its own way, most produce relaxing effects by increasing GABA activity.

Colloquially known as "downers", depressants or central depressants are drugs that lower neurotransmission levels, or depress or reduce arousal or stimulation in various areas of the brain. Depressants do not change the mood or mental state of others. Stimulants, or "uppers", increase mental or physical function, hence the opposite drug class from depressants are stimulants, not antidepressants.

<span class="mw-page-title-main">GABA receptor</span> Receptors that respond to gamma-aminobutyric acid

The GABA receptors are a class of receptors that respond to the neurotransmitter gamma-aminobutyric acid (GABA), the chief inhibitory compound in the mature vertebrate central nervous system. There are two classes of GABA receptors: GABAA and GABAB. GABAA receptors are ligand-gated ion channels ; whereas GABAB receptors are G protein-coupled receptors, also called metabotropic receptors.

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

Muscimol is one of the principal psychoactive constituents of Amanita muscaria and related species of mushroom. Muscimol is a potent and selective orthosteric agonist for the GABAA receptor and displays sedative-hypnotic, depressant and hallucinogenic psychoactivity. This colorless or white solid is classified as an isoxazole.

<span class="mw-page-title-main">Baclofen</span> Medication for muscle movement disorders

Baclofen, sold under the brand name Lioresal among others, is a medication used to treat muscle spasticity such as from a spinal cord injury or multiple sclerosis. It may also be used for hiccups and muscle spasms near the end of life, and off-label to treat alcohol use disorder or opioid withdrawal symptoms. It is taken orally or by intrathecal pump. It is also sometimes used transdermally in combination with gabapentin and clonidine prepared at a compounding pharmacy.

GABAB receptors (GABABR) are G-protein coupled receptors for gamma-aminobutyric acid (GABA), therefore making them metabotropic receptors, that are linked via G-proteins to potassium channels. The changing potassium concentrations hyperpolarize the cell at the end of an action potential. The reversal potential of the GABAB-mediated IPSP is −100 mV, which is much more hyperpolarized than the GABAA IPSP. GABAB receptors are found in the central nervous system and the autonomic division of the peripheral nervous system.

<span class="mw-page-title-main">Pregabalin</span> Anticonvulsant medication

Pregabalin, sold under the brand name Lyrica among others, is an anticonvulsant, analgesic, and anxiolytic amino acid medication used to treat epilepsy, neuropathic pain, fibromyalgia, restless leg syndrome, opioid withdrawal, and generalized anxiety disorder (GAD). Pregabalin also has antiallodynic properties. Its use in epilepsy is as an add-on therapy for partial seizures. It is a gabapentinoid medication and acts by inhibiting certain calcium channels. When used before surgery, it reduces pain but results in greater sedation and visual disturbances. It is taken by mouth.

<span class="mw-page-title-main">Progabide</span> Pharmaceutical drug

Progabide is an analogue and prodrug of γ-aminobutyric acid (GABA) used in the treatment of epilepsy. Via conversion into GABA, progabide behaves as an agonist of the GABAA, GABAB, and GABAA-ρ receptors.

<span class="mw-page-title-main">Adinazolam</span> Triazolobenzodiazepine drug

Adinazolam is a tranquilizer of the triazolobenzodiazepine (TBZD) class, which are benzodiazepines (BZDs) fused with a triazole ring. It possesses anxiolytic, anticonvulsant, sedative, and antidepressant properties. Adinazolam was developed by Jackson B. Hester, who was seeking to enhance the antidepressant properties of alprazolam, which he also developed. Adinazolam was never FDA approved and never made available to the public market; however, it has been sold as a designer drug.

<span class="mw-page-title-main">GABA receptor agonist</span> Category of drug

A GABA receptor agonist is a drug that is an agonist for one or more of the GABA receptors, producing typically sedative effects, and may also cause other effects such as anxiolytic, anticonvulsant, and muscle relaxant effects. There are three receptors of the gamma-aminobutyric acid. The two receptors GABA-α and GABA-ρ are ion channels that are permeable to chloride ions which reduces neuronal excitability. The GABA-β receptor belongs to the class of G-Protein coupled receptors that inhibit adenylyl cyclase, therefore leading to decreased cyclic adenosine monophosphate (cAMP). GABA-α and GABA-ρ receptors produce sedative and hypnotic effects and have anti-convulsion properties. GABA-β receptors also produce sedative effects. Furthermore, they lead to changes in gene transcription.

<i>gamma</i>-Amino-<i>beta</i>-hydroxybutyric acid Anticonvulsant drug

γ-Amino-β-hydroxybutyric acid (GABOB), also known as β-hydroxy-γ-aminobutyric acid (β-hydroxy-GABA), and sold under the brand name Gamibetal among others, is an anticonvulsant which is used for the treatment of epilepsy in Europe, Japan, and Mexico. It is a GABA analogue, or an analogue of the neurotransmitter γ-aminobutyric acid (GABA), and has been found to be an endogenous metabolite of GABA.

<span class="mw-page-title-main">CGP-7930</span> Chemical compound

CGP-7930 was the first positive allosteric modulator of GABAB receptors described in literature. CGP7930 is also a GABAA receptor positive allosteric modulator and a blocker of Potassium channels.

<span class="mw-page-title-main">GS-39783</span> Chemical compound

GS-39783 is a compound used in scientific research which acts as a positive allosteric modulator at the GABAB receptor. It has been shown to produce anxiolytic effects in animal studies, and reduces self-administration of alcohol, cocaine and nicotine.

<span class="mw-page-title-main">Gabapentinoid</span> Calcium channel blockers

Gabapentinoids, also known as α2δ ligands, are a class of drugs that are derivatives of the inhibitory neurotransmitter gamma-Aminobutyric acid (GABA) which block α2δ subunit-containing voltage-dependent calcium channels (VDCCs). This site has been referred to as the gabapentin receptor, as it is the target of the drugs gabapentin and pregabalin.

<span class="mw-page-title-main">GABA analogue</span> Class of drugs

A GABA analogue is a compound which is an analogue or derivative of the neurotransmitter gamma-Aminobutyric acid (GABA).

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

Tolibut, also known as 3-(p-tolyl)-4-aminobutyric acid (or β-(4-methylphenyl)-GABA), is drug that was developed in Russia. It is an analogue of γ-aminobutyric acid (GABA) and is the 4-methyl analogue of phenibut, and is also an analogue of baclofen where the 4-chloro substitution has been replaced with a 4-methyl substitution. Tolibut has been described as possessing analgesic, tranquilizing, and neuroprotective properties. It is not fully clear as to whether the drug was ever approved or used medically in Russia.

<span class="mw-page-title-main">4-Fluorophenibut</span> GABAB receptor agonist and phenibut analogue

4-Fluorophenibut (developmental code name CGP-11130; also known as β-(4-fluorophenyl)-γ-aminobutyric acid or β-(4-fluorophenyl)-GABA) is a GABAB receptor agonist which was never marketed. It is selective for the GABAB receptor over the GABAA receptor (IC50 = 1.70 μM and > 100 μM, respectively). The drug is a GABA analogue and is closely related to baclofen (β-(4-chlorophenyl)-GABA), tolibut (β-(4-methylphenyl)-GABA), and phenibut (β-phenyl-GABA). It is less potent as a GABAB receptor agonist than baclofen but more potent than phenibut.

References

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  4. ↑ Nutrition, Center for Food Safety and Applied (6 March 2023). "Phenibut in Dietary Supplements". FDA.
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  19. ↑ Vavers E, Zvejniece L, Svalbe B, Volska K, Makarova E, Liepinsh E, et al. (November 2016). "The neuroprotective effects of R-phenibut after focal cerebral ischemia". Pharmacological Research. 113 (Pt B): 796–801. doi:10.1016/j.phrs.2015.11.013. PMID   26621244.
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  21. ↑ Perfilova VN, Popova TA, Prokofiev II, Mokrousov IS, Ostrovskii OV, Tyurenkov IN (June 2017). "Effect of Phenibut and Glufimet, a Novel Glutamic Acid Derivative, on Respiration of Heart and Brain Mitochondria from Animals Exposed to Stress against the Background of Inducible NO-Synthase Blockade". Bulletin of Experimental Biology and Medicine. 163 (2): 226–229. doi:10.1007/s10517-017-3772-4. PMID   28726197. S2CID   4907409.
  22. ↑ Khaunina RA, Lapin IP (1976). "Fenibut, a new tranquilizer". Pharmaceutical Chemistry Journal. 10 (12): 1703–1705. doi:10.1007/BF00760021. ISSN   0091-150X. S2CID   29071385.
  23. ↑ Par La liste des substances psychotropes
  24. ↑ "39/2018. (XI. 8.) EMMI rendelet Az új pszichoaktív anyaggá minősített anyagokról vagy vegyületcsoportokról szóló 55/2014. (XII. 30.) EMMI rendelet módosításáról" (PDF).
  25. 1 2 "Gazzetta Ufficiale 11/08/20". Lorenzo Arbolino. 11 August 2020. Retrieved 27 August 2020.
  26. ↑ "RINKOS RIBOJIMO PRIEMONĖS FENIBUTUI!". ntakd.lrv.lt (in Lithuanian). Archived from the original on 6 October 2021. Retrieved 27 January 2020.
  27. ↑ "V-1431 Dėl Lietuvos Respublikos sveikatos apsaugos ministro 2000 m. sausio 6 d. įsakymo Nr. 5 "Dėl Narko..." e-seimas.lrs.lt (in Lithuanian). Retrieved 27 January 2020.
  28. ↑ "3.3 Phenibut". Administration Therapeutic Goods Administration. Australian Government Department of Health. 31 October 2017. Retrieved 6 November 2017.
  29. ↑ "Mass school overdose investigation focuses on banned Russian drug". ABC News. Australian Broadcasting Corporation. 22 February 2018. Retrieved 22 February 2018.
  30. ↑ "EMMI Decree substances or groups of compounds classified as new psychoactive substances". Wolters Kluwer. 1 January 2015. Archived from the original on 8 August 2020. Retrieved 5 August 2020.
  31. ↑ Le phénibut interdit en France | Le Généraliste
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