Chemistry:Amineptine

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Short description: Widely withdrawn Tricyclic Antidepressant
Amineptine
Amineptine.svg
Clinical data
Trade namesSurvector, others
Other namesS-1694
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
MetabolismHepatic
Elimination half-lifeAmineptine: 0.8–1.0 hours[1][2]
Metabolite: 1.5–2.5 hours[1][2]
ExcretionRenal
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC22H28NO2
Molar mass338.471 g·mol−1
3D model (JSmol)
  (verify)

Amineptine, formerly sold under the brand name Survector among others, is an atypical antidepressant of the tricyclic antidepressant (TCA) family.[3][4] It acts as a selective and mixed dopamine reuptake inhibitor and releasing agent, and to a lesser extent as a norepinephrine reuptake inhibitor.[3][4]

Amineptine was developed by the French Society of Medical research in the 1960s.[5] Introduced in France in 1978 by the pharmaceutical company Servier,[6] amineptine soon gained a reputation for abuse due to its short-lived, but pleasant, stimulant effect experienced by some patients.

After its release into the European market, cases of hepatotoxicity emerged, some serious. This, along with the potential for abuse, led to the suspension of the French marketing authorization for Survector in 1999.[7]

Amineptine is illegal in both Germany and the United States


Medical uses

Amineptine was approved in France for severe clinical depression of endogenous origin in 1978.[8]

Contraindications

  • Chorea
  • Hypersensitivity: Known hypersensitivity to amineptine, in particular antecedents of hepatitis after dosage of the product.
  • MAO inhibitors

Precautions for use

Warnings and precautions before taking amineptine:[9]

Effects on the fetus

  • Lacking information in humans
  • Non-teratogenic in rodents

Side effects

Dermatological

Severe acne due to amineptine was first reported in 1988 by various authors—Grupper, Thioly-Bensoussan, Vexiau, Fiet, Puissant, Gourmel, Teillac, Levigne, to name a few—simultaneously[10][11][12][13][14] in the same issue of Annales de Dermatologie et de Vénéréologie and in the 12 March 1988 issue of The Lancet.[15] A year later, Dr Martin-Ortega and colleagues in Barcelona, Spain reported a case of "acneiform eruption" in a 54-year-old woman whose intake of amineptine was described as "excessive."[16] One year after that, Vexiau and colleagues reported six women, one of whom never admitted to using amineptine, getting severe acne concentrated in the face, back and thorax, the severity of which varied with the dosage.[17] Most of them were treated unsuccessfully with isotretinoin (Accutane) for about 18 months; two of the three that discontinued amineptine experienced a reduction in cutaneous symptoms, with the least affected patient going into remission.[17]

Psychiatric

Psychomotor excitation can very rarely occur with this drug.

  • Insomnia
  • Irritability
  • Nervousness
  • Suicidal ideation. Seen early in the treatment, by lifting of psychomotor inhibition.

Abuse and dependence

The risk of addiction is low, but exists nonetheless. Between 1978 and 1988, there were 186 cases of amineptine addiction reported to the French Regional Centres of Pharmacovigilance; an analysis of 155 of those cases found that they were predominantly female, and that two-thirds of cases had known risk factors for addiction.[18] However, a 1981 study of known opiate addicts and schizophrenia patients found no drug addiction in any of the subjects.[19] In a 1990 study of eight amineptine dependence cases, the gradual withdrawal of amineptine could be achieved without problems in six people; in two others, anxiety, psychomotor agitation, and/or bulimia appeared.[20]

Withdrawal

Pharmacodependence is very common with amineptine compared to other antidepressants.[21] A variety of psychological symptoms can occur during withdrawal from amineptine,[22] such as anxiety and agitation.[23]

Cardiovascular

Very rarely:

Hepatic

Amineptine can rarely cause hepatitis, of the cytolytic, cholestatic varieties.[24] Amineptine-induced hepatitis, which is sometimes preceded by a rash, is believed to be due to an immunoallergic reaction.[25] It resolves upon discontinuation of the offending drug.[24] The risk of getting this may or may not be genetically determined.[26]

Additionally, amineptine is known to rarely elevate transaminases, alkaline phosphatase, and bilirubin.[27]

Mixed hepatitis, which is very rare, generally occurs between the 15th and 30th day of treatment. Often preceded by sometimes intense abdominal pains, nausea, vomiting or a rash, the jaundice is variable. Hepatitis is either of mixed type or with cholestatic prevalence. The evolution was, in all the cases, favorable to the discontinuation of the drug. The mechanism is discussed (immunoallergic and/or toxic).[28]

In circa 1994 Spain, there was a case associating acute pancreatitis and mixed hepatitis, after three weeks of treatment.[29]

Lazaros and colleagues at the Western Attica General Hospital in Athens, Greece reported two cases of drug induced hepatitis 18 and 15 days of treatment.[30]

One case of cytolytic hepatitis occurred after ingestion of only one tablet.[31]

Gastrointestinal

  • Acute pancreatitis (very rare) A case associating acute pancreatitis and mixed hepatitis after three weeks of treatment.[29]

Immunological

In 1989, Sgro and colleagues at the Centre de Pharmacovigilance[32] in Dijon reported a case of anaphylactic shock in a woman who had been taking amineptine.[33]

Pharmacology

Pharmacodynamics

Site Ki (nM) Species Ref
SERT >100,000 (IC50) Rat [34]
5-HT1A >100,000 Rat [35]
5-HT2A 74,000 Rat [35]
α1 >100,000 Rat [35]
α2 >100,000 Rat [35]
β >100,000 Rat [35]
D1 >100,000 Canine [34]
D2 >100,000 Rat/canine [34][35]
H1 >100,000
13,000		 Rat
Guinea pig		 [35]
[36]
mACh >100,000 Rat [35]
Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.

Amineptine inhibits the reuptake of dopamine and, to a much lesser extent, of norepinephrine.[37][34][38] In addition, it has been found to induce the release of dopamine.[37][34][38] However, amineptine is much less efficacious as a dopamine releasing agent relative to D-amphetamine, and the drug appears to act predominantly as a dopamine reuptake inhibitor.[37][34][38] In contrast to the case for dopamine, amineptine does not induce the release of norepinephrine, and hence acts purely as a norepinephrine reuptake inhibitor.[37][34][38] Unlike other TCAs, amineptine interacts very weakly or not at all with the serotonin, adrenergic, dopamine, histamine, and muscarinic acetylcholine receptors.[35][36][38] The major metabolites of amineptine have similar activity to that of the parent compound, albeit with lower potency.[38]

No human data appear to be available for binding or inhibition of the monoamine transporters by amineptine.[39]

Pharmacokinetics

Peak plasma levels of amineptine following a single 100 mg oral dose have been found to range between 277 and 2,215 ng/mL (818–6,544 nM), with a mean of 772 ng/mL (2,281 nM), whereas maximal plasma concentrations of its major metabolite ranged between 144 and 1,068 ng/mL (465–3,452 nM), with a mean of 471 ng/mL (1,522 nM).[1] After a single 200 mg oral dose of amineptine, mean peak plasma levels of amineptine were around 750 to 940 ng/mL (2,216–2,777 nM), while those of its major metabolite were about 750 to 970 ng/mL (2,216–3,135 nM).[2] The time to peak concentrations is about 1 hour for amineptine and 1.5 hours for its major metabolite.[1][2] The elimination half-life of amineptine is about 0.80 to 1.0 hours and that of its major metabolite is about 1.5 to 2.5 hours.[1][2] Due to their very short elimination half-lives, amineptine and its major metabolite do not accumulate significantly with repeated administration.[1]

Society and culture

Brand names

Amineptine has been sold under a variety of brand names including Survector, Maneon, Directim, Neolior, Provector, and Viaspera.

Legal status

It had been proposed that Amineptine become a Schedule I controlled substance in the United States in July 2021.[40] This announcement was followed by the placement of Amineptine into Schedule I. [41]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 "Single-dose pharmacokinetics of amineptine and of its main metabolite in healthy young adults". Fundam Clin Pharmacol 3 (1): 19–26. 1989. doi:10.1111/j.1472-8206.1989.tb00026.x. PMID 2714729. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 "Pharmacokinetics of amineptine in man". Eur J Drug Metab Pharmacokinet 6 (2): 123–6. 1981. doi:10.1007/bf03189478. PMID 7274306. 
  3. ↑ 3.0 3.1 "Although chemically related to amineptine, the antidepressant tianeptine is not a dopamine uptake inhibitor". Pharmacology Biochemistry and Behavior 63 (2): 285–90. June 1999. doi:10.1016/S0091-3057(98)00242-1. PMID 10371658. 
  4. ↑ 4.0 4.1 "The role of dopamine in the pathophysiology of depression". Arch. Gen. Psychiatry 64 (3): 327–37. 2007. doi:10.1001/archpsyc.64.3.327. PMID 17339521. 
  5. ↑ DE Patent 2011806 – NEW TRICYCLIC DERIVATIVES AND PROCESS FOR THEIR MANUFACTURE
  6. ↑ Sittig, Marshall (1 April 1988). Pharmaceutical Manufacturing Encyclopedia (2nd ed.). Park Ridge, New Jersey, United States American: William Andrew Publishing/Noyes Publications. ISBN 978-0-8155-1144-1. http://www.amineptine.com/synthesis/manufacture.html. Retrieved 29 October 2005. [page needed]
  7. ↑ "Docket No. 02N-0101". U.S. Food and Drug Administration. 2002-04-09. https://www.fda.gov/ohrms/dockets/98fr/040902a.htm. 
  8. ↑ Doctissimo (2005). "SURVECTOR – Amineptine" (in fr). http://www.doctissimo.fr/medicament-SURVECTOR.htm. 
  9. ↑ Amineptine Medication – Uses, Side Effects and Precautions of Amineptine. Health-care-information.org. Retrieved on 28 September 2013
  10. ↑ Grupper C (1988). "[New iatrogenic acne: acne caused by amineptin (Survector)]" (in fr). Annales de Dermatologie et de Vénéréologie 115 (11): 1174–6. PMID 2977079. 
  11. ↑ "[Iatrogenic acne caused by amineptin (Survector). Apropos of 8 cases]" (in fr). Annales de Dermatologie et de Vénéréologie 115 (11): 1177–80. 1988. PMID 2977080. 
  12. ↑ "[Severe lesions of acne type induced by chronic amineptin poisoning: apropos of 6 cases]" (in fr). Annales de Dermatologie et de Vénéréologie 115 (11): 1180–2. 1988. PMID 2977081. 
  13. ↑ "[Acne caused by Survector]" (in fr). Annales de Dermatologie et de Vénéréologie 115 (11): 1183–4. 1988. PMID 2977082. 
  14. ↑ "[Monstrous acne in the adult. Inducer role of Survector?]" (in fr). Annales de Dermatologie et de Vénéréologie 115 (11): 1184–5. 1988. PMID 2977083. 
  15. ↑ "Severe acne-like lesions caused by amineptine overdose". Lancet 1 (8585): 585. March 1988. doi:10.1016/S0140-6736(88)91373-6. PMID 2894512. 
  16. ↑ "[Acneiform eruption induced by amineptin (Survector)]" (in es). Medicina Cutánea Ibero-latino-americana 17 (6): 414–6. 1989. PMID 2534534. 
  17. ↑ 17.0 17.1 "Severe acne due to chronic amineptine overdose". Archives of Dermatological Research 282 (2): 103–7. 1990. doi:10.1007/BF00493467. PMID 2141246. 
  18. ↑ "[Amineptin abuse. Analysis of 155 cases. An evaluation of the official cooperative survey of the Regional Centers of Pharmacovigilance]" (in fr). Thérapie 45 (5): 399–405. 1990. PMID 2260032. 
  19. ↑ "[Amineptine and amotival syndrome (author's transl)]" (in fr). L'Encéphale 7 (1): 59–64. 1981. PMID 7227285. 
  20. ↑ "[Amineptin dependence. Detection of patients at risk. Report of 8 cases]" (in fr). L'Encéphale 16 (5): 405–9. 1990. PMID 2265603. 
  21. ↑ "[Pharmacovigilance of new antidepressants: evaluation of neuro-psychobehavioral disorders]". Thérapie 52 (2): 117–22. 1997. PMID 9231505. 
  22. ↑ "[Amineptin abuse. Analysis of 155 cases. An evaluation of the official cooperative survey of the Regional Centers of Pharmacovigilance]". Thérapie 45 (5): 399–405. 1990. PMID 2260032. 
  23. ↑ "[Amineptin dependence. Detection of patients at risk. Report of 8 cases]". L'Encéphale 16 (5): 405–9. 1990. PMID 2265603. 
  24. ↑ 24.0 24.1 "[Amineptine-induced cholestatic hepatitis. 5 cases (author's transl)]" (in fr). La Nouvelle Presse Médicale 9 (48): 3689–92. December 1980. PMID 7454584. 
  25. ↑ "Acute and chronic drug-induced hepatitis". Baillière's Clinical Gastroenterology 2 (2): 385–422. April 1988. doi:10.1016/0950-3528(88)90009-7. PMID 3044468. 
  26. ↑ "Genetic predisposition to drug-induced hepatotoxicity". Journal of Hepatology 26 (Suppl 2): 12–21. 1997. doi:10.1016/S0168-8278(97)80492-8. PMID 9204405. 
  27. ↑ "Questions au Professeur Daniel Dhumeaux" (in fr). Gastroentérologie Clinique et Biologique 23 (8–9): 917–20. 1999. PMID 10533145. http://www.masson.fr/masson/MDOI-GCB-08-1999-23-8-9-0399-8320-101019-ART15. 
  28. ↑ Concours Med 1982; 104:5733-5734[verification needed]
  29. ↑ 29.0 29.1 "Hepatic and pancreatic injury associated with amineptine therapy". Journal of Clinical Gastroenterology 18 (2): 168–9. March 1994. doi:10.1097/00004836-199403000-00023. PMID 8189020. 
  30. ↑ "Amineptine induced liver injury. Report of two cases and brief review of the literature". Hepato-gastroenterology 43 (10): 1015–9. 1996. PMID 8884331. 
  31. ↑ "[Immediate acute hepatic cytolysis after the administration of a single amineptin tablet]" (in fr). Gastroentérologie Clinique et Biologique 16 (4): 368. 1992. PMID 1397859. 
  32. ↑ centres-pharmacovigilance.net
  33. ↑ "[Anaphylactic shock caused by amineptine. Report of a case]" (in fr). La Revue de Médecine Interne 10 (5): 461–2. 1989. doi:10.1016/s0248-8663(89)80054-2. PMID 2488491. 
  34. ↑ 34.0 34.1 34.2 34.3 34.4 34.5 34.6 Cite error: Invalid <ref> tag; no text was provided for refs named pmid2698268
  35. ↑ 35.0 35.1 35.2 35.3 35.4 35.5 35.6 35.7 35.8 "Acute effects of atypical antidepressants on various receptors in the rat brain". Acta Pharmacol Toxicol (Copenh) 54 (5): 379–84. 1984. doi:10.1111/j.1600-0773.1984.tb01945.x. PMID 6464782. 
  36. ↑ 36.0 36.1 "Effects of antidepressant drugs on histamine-H1 receptors in the brain". Life Sci. 34 (6): 597–605. 1984. doi:10.1016/0024-3205(84)90494-6. PMID 6141518. 
  37. ↑ 37.0 37.1 37.2 37.3 Cite error: Invalid <ref> tag; no text was provided for refs named pmid3708219
  38. ↑ 38.0 38.1 38.2 38.3 38.4 38.5 "Pharmacology of amineptine, an antidepressant agent acting on the dopaminergic system: a review". Int Clin Psychopharmacol 12 (Suppl 3): S15–9. 1997. doi:10.1097/00004850-199707003-00003. PMID 9347388. 
  39. ↑ "Recent advances in the understanding of the interaction of antidepressant drugs with serotonin and norepinephrine transporters". Chem. Commun. (25): 3677–92. 2009. doi:10.1039/b903035m. PMID 19557250. 
  40. ↑ "2021 - Placement of Amineptine in Schedule I". https://www.deadiversion.usdoj.gov/fed_regs/rules/2021/fr0722_2.htm. 
  41. ↑ "Federal Register". National Archives & Drug Enforcement Administration. November 17, 2022. https://www.federalregister.gov/documents/2022/11/17/2022-25003/schedules-of-controlled-substances-placement-of-amineptine-in-schedule-i. 



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