Amineptine

Amineptine

Amineptine chemical structure
Systematic (IUPAC) name
7-[(10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-yl)amino]heptanoic acid
Clinical data
  • ?
  • AU: Unscheduled
  • United Nations: Schedule II
    Canada: Schedule III
    USA: Unscheduled
    UK: Schedule 2[1]
    Germany: Anlage II (not prescribable)
Oral
Pharmacokinetic data
Bioavailability ?
Metabolism Hepatic
Half-life 48 mins (original drug)
2.5 hours (metabolites)[2]
Excretion Renal
Identifiers
57574-09-1 Yes
N06AA19
PubChem CID 34870
DrugBank DB04836 Yes
ChemSpider 32091 Yes
UNII 27T1I13L6G Yes
KEGG D07335 Yes
ChEBI CHEBI:32499 Yes
ChEMBL CHEMBL418995 Yes
Chemical data
Formula C22H28NO2
338.4653 g/mol
 Yes (what is this?)  (verify)

Amineptine was developed by the French Society of Medical research in the 1960s.[3] Under the trade-names (Survector, Maneon, Directim, Neolior, Provector, Viaspera) is used as an atypical tricyclic antidepressant (TCA) that selectively inhibits the reuptake of dopamine[4] and to a lesser extent norepinephrine, in turn producing an antidepressant effect.[5]

Introduced in France in 1978 by the pharmaceutical company Servier[6] and marketed under the trade name Survector, amineptine soon gained a reputation for abuse due to its short-lived, but pleasant, stimulant effect experienced by some patients. (This is to be distinguished from its antidepressant effect, which appears in approximately seven days after commencing treatment.)

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 was never approved by the U.S. Food and Drug Administration (FDA) for marketing in the United States, meaning that it is not legal to market or sell amineptine for any medical uses in the US.

Therapeutic indications

Approved

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

Unapproved/off-label/investigational

Parkinson's Disease, amotivational syndromes, ADHD (Attention Deficit Hyperactivity Disorder)

Mechanism of action

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[9][10][11][12][13] in the same issue of Annales de dermatologie et de vénéréologie and in 12 March 1988 of The Lancet.[14] 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."[15] 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.[16] 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.[16]

This can be seen as a general side effect of central dopamine enhancement, due to the inhibitory effect of dopamine on prolactin, with the subsequent increase in testosterone output, leading in turn to the same potential for acne as is typical of pubescents.

Psychiatric

Psychomotor excitation can very rarely occur with this drug.

Cardiovascular

Very rarely:

Hepatic

Amineptine can rarely cause hepatitis, of the cytolytic, cholestatic varieties.[17] Amineptine-induced hepatitis, which is sometimes preceded by a rash, is believed to be due to an allergic reaction.[18] It resolves upon discontinuation of the offending drug.[17] The risk of getting this may or may not be genetically determined.[19]

Additionally, amineptine is known to rarely elevate transaminases, alkaline phosphatase, and bilirubin.[20]

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).[21]

In circa 1994 Spain, there was a case associating acute pancreatitis and mixed hepatitis, after three weeks of treatment.[22]

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.[23]

One case of cytolytic hepatitis occurred after ingestion of only one tablet.[24]

Gastrointestinal

Immunological

In 1989, Sgro and colleagues at the Centre de Pharmacovigilance[25] in Dijon reported a case of anaphylactic shock in a woman who had been taking amineptine.[26]

Withdrawal

Pharmacodependence is very common with amineptine compared to other antidepressants.[27] A variety of psychological symptoms can occur during withdrawal from amineptine,[28] such as anxiety and agitation.[29]

Effects on the fetus

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.[30] However, a 1981 study of known opiate addicts and schizophrenia patients found no drug addiction in any of the subjects.[31] 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.[32]

Precautions for use

Warnings and precautions before taking amineptine:[33]

Contraindications

See also

References

  1. ↑ "New Schedule 2 controlled drugs – amineptine and tapentadol". NeLM. Retrieved 13 February 2012.
  2. ↑ Lachatre G, Piva C, Riche C et al. (1989). "Single-dose pharmacokinetics of amineptine and of its main metabolite in healthy young adults". Fundamental & Clinical Pharmacology 3 (1): 19–26. doi:10.1111/j.1472-8206.1989.tb00026.x. PMID 2714729.
  3. ↑ DE Patent 2011806 - NEW TRICYCLIC DERIVATIVES AND PROCESS FOR THEIR MANUFACTURE
  4. ↑ Vaugeois JM, Corera AT, Deslandes A, Costentin J (June 1999). "Although chemically related to amineptine, the antidepressant tianeptine is not a dopamine uptake inhibitor". Pharmacology, Biochemistry, and Behavior 63 (2): 285–90. doi:10.1016/S0091-3057(98)00242-1. PMID 10371658.
  5. ↑ Dunlop, B.; Nemeroff, C. (2007). "The role of dopamine in the pathophysiology of depression". Archives of General Psychiatry 64 (3): 327–337. doi:10.1001/archpsyc.64.3.327. PMID 17339521.
  6. ↑ Sittig, Marshall (1 April 1988) [1979]. Pharmaceutical Manufacturing Encyclopedia (2nd ed.). Park Ridge, New Jersey, United States American: William Andrew Publishing/Noyes Publications. ISBN 0-8155-1144-2. Archived from the original on 23 October 2005. Retrieved 29 October 2005.
  7. ↑ "Docket No. 02N-0101". U.S. Food and Drug Administration. 2002-04-09. Retrieved 2014-01-30.
  8. ↑ Doctissimo (2005). "SURVECTOR - Amineptine" (in French). Retrieved 27 October 2005.
  9. ↑ Grupper C (1988). "[New iatrogenic acne: acne caused by amineptin (Survector)]". Annales de dermatologie et de vénéréologie (in French) 115 (11): 1174–6. PMID 2977079.
  10. ↑ Thioly-Bensoussan D, Charpentier A, Triller R et al. (1988). "[Iatrogenic acne caused by amineptin (Survector). Apropos of 8 cases]". Annales de dermatologie et de vénéréologie (in French) 115 (11): 1177–80. PMID 2977080.
  11. ↑ Vexiau P, Gourmel B, Husson C et al. (1988). "[Severe lesions of acne type induced by chronic amineptin poisoning: apropos of 6 cases]". Annales de dermatologie et de vénéréologie (in French) 115 (11): 1180–2. PMID 2977081.
  12. ↑ Teillac D, Weber MJ, Lowenstein W, de Prost Y (1988). "[Acne caused by Survector]". Annales de dermatologie et de vénéréologie (in French) 115 (11): 1183–4. PMID 2977082.
  13. ↑ Lévigne V, Faisant M, Mourier C et al. (1988). "[Monstrous acne in the adult. Inducer role of Survector?]". Annales de dermatologie et de vénéréologie (in French) 115 (11): 1184–5. PMID 2977083.
  14. ↑ Vexiau P, Gourmel B, Julien R et al. (March 1988). "Severe acne-like lesions caused by amineptine overdose". Lancet 1 (8585): 585. doi:10.1016/S0140-6736(88)91373-6. PMID 2894512.
  15. ↑ Martín-Ortega E, Zamora E, Herrero C, Palou J (1989). "[Acneiform eruption induced by amineptin (Survector)]". Medicina Cutánea Ibero-latino-americana (in Spanish) 17 (6): 414–6. PMID 2534534.
  16. ↑ 16.0 16.1 Vexiau P, Gourmel B, Castot A et al. (1990). "Severe acne due to chronic amineptine overdose". Archives of Dermatological Research 282 (2): 103–7. doi:10.1007/BF00493467. PMID 2141246.
  17. ↑ 17.0 17.1 Bories P, Pomier-Layrargues G, Chotard JP et al. (December 1980). "[Amineptine-induced cholestatic hepatitis. 5 cases (author's transl)]". La Nouvelle Presse Médicale (in French) 9 (48): 3689–92. PMID 7454584.
  18. ↑ Pessayre D, Larrey D (April 1988). "Acute and chronic drug-induced hepatitis". Baillière's Clinical Gastroenterology 2 (2): 385–422. doi:10.1016/0950-3528(88)90009-7. PMID 3044468.
  19. ↑ Larrey D, Pageaux GP (1997). "Genetic predisposition to drug-induced hepatotoxicity". Journal of Hepatology 26 (Suppl 2): 12–21. doi:10.1016/S0168-8278(97)80492-8. PMID 9204405.
  20. ↑ "Questions au Professeur Daniel Dhumeaux" [Drug-induced liver disorders. Questions for Professor Daniel Dhumeaux]. Gastroentérologie Clinique et Biologique (in French) 23 (8–9): 917–20. 1999. PMID 10533145.
  21. ↑ Concours Med 1982; 104:5733-5734
  22. ↑ 22.0 22.1 Sebastián Domingo JJ, Simón Marco MA, Uribarrena Echebarría R (March 1994). "Hepatic and pancreatic injury associated with amineptine therapy". Journal of Clinical Gastroenterology 18 (2): 168–9. doi:10.1097/00004836-199403000-00023. PMID 8189020.
  23. ↑ Lazaros GA, Stavrinos C, Papatheodoridis GV, Delladetsima JK, Toliopoulos A, Tassopoulos NC (1996). "Amineptine induced liver injury. Report of two cases and brief review of the literature". Hepato-gastroenterology 43 (10): 1015–9. PMID 8884331.
  24. ↑ Jonville AP, Dutertre JP, Autret E (1992). "[Immediate acute hepatic cytolysis after the administration of a single amineptin tablet]". Gastroentérologie Clinique et Biologique (in French) 16 (4): 368. PMID 1397859.
  25. ↑ centres-pharmacovigilance.net
  26. ↑ Sgro C, Lacroix S, Waldner A, Lacroix M, Ferrut O, Bureau A (1989). "[Anaphylactic shock caused by amineptine. Report of a case]". La Revue De Médecine Interne (in French) 10 (5): 461–2. doi:10.1016/s0248-8663(89)80054-2. PMID 2488491.
  27. ↑ Blayac, JP.; Hillaire-Buys, D.; Peyrière, H. "[Pharmacovigilance of new antidepressants: evaluation of neuro-psychobehavioral disorders].". Therapie 52 (2): 117–22. PMID 9231505.
  28. ↑ Castot, A.; Benzaken, C.; Wagniart, F.; Efthymiou, ML. "[Amineptin abuse. Analysis of 155 cases. An evaluation of the official cooperative survey of the Regional Centers of Pharmacovigilance].". Therapie 45 (5): 399–405. PMID 2260032.
  29. ↑ Bertschy, G.; Luxembourger, I.; Bizouard, P.; Vandel, S.; Allers, G.; Volmat, R. "[Amineptin dependence. Detection of patients at risk. Report of 8 cases].". Encephale 16 (5): 405–9. PMID 2265603.
  30. ↑ Castot A, Benzaken C, Wagniart F, Efthymiou ML (1990). "[Amineptin abuse. Analysis of 155 cases. An evaluation of the official cooperative survey of the Regional Centers of Pharmacovigilance]". Thérapie (in French) 45 (5): 399–405. PMID 2260032.
  31. ↑ Deniker P, Lôo H, Zarifian E et al. (1981). "[Amineptine and amotival syndrome (author's transl)]". L'Encéphale (in French) 7 (1): 59–64. PMID 7227285.
  32. ↑ Bertschy G, Luxembourger I, Bizouard P, Vandel S, Allers G, Volmat R (1990). "[Amineptin dependence. Detection of patients at risk. Report of 8 cases]". L'Encéphale (in French) 16 (5): 405–9. PMID 2265603.
  33. ↑ Amineptine Medication - Uses, Side Effects and Precautions of Amineptine. Health-care-information.org. Retrieved on September 28, 2013