Amineptine 2987576 224322189 2008-07-08T09:53:49Z DOI bot 6652755 Citation maintenance. Formatted: title, doi. Initiated by [[User:Closedmouth|Closedmouth]]. You can [[WP:DOI|use this bot]] yourself! Please [[User:DOI_bot/bugs|report any bugs]]. {{Drugbox| |IUPAC_name = ''7-[(10,11-dihydro-5H-dibenzo[a,d]-<br>cyclohepten-5-yl)amino]heptanoic acid'' | image=Amineptine.gif | caption=Amineptine chemical structure | width=210px | CAS_number=57574-09-1 | ATC_prefix=N06 | ATC_suffix=AA19 | ATC_supplemental= | PubChem=34869 | DrugBank=? | C=22 | H=28 | N=1 | O=2 | molecular_weight = 337.455 g/mol | bioavailability= ? | metabolism = [[Hepatic]] | elimination_half-life=48 [[minute|mins]] (original drug)<br>2.5 [[hour]]s (metabolites)<ref name=halflife>{{cite journal | author= Lachatre G Riche C, Dumont D, Defrance R, Mocaer E, Nicot G | title=Single-dose pharmacokinetics of amineptine and of its main metabolite in healthy young adults | journal=Fundamental & Clinical Pharmacology | volume=3 | issue=1 | year=1989 | pages=19&ndash;26 }}</ref> | excretion = [[Renal]] | pregnancy_category = ? | legal_status = United Nations: Schedule II<br>Canada: Schedule III<br>USA: Unscheduled<br>UK: Unscheduled | routes_of_administration= Oral }} '''Amineptine''' (trade name '''Survector''' [Spain, Philippines], also previously known as '''Maneon''' in some countries where it has been withdrawn) is an atypical [[tricyclic antidepressant]] that selectively [[Dopamine reuptake inhibitor|inhibits the reuptake of dopamine]]<ref name="pmid10371658">{{cite journal |author=Vaugeois JM, Corera AT, Deslandes A, Costentin J |title=Although chemically related to amineptine, the antidepressant tianeptine is not a dopamine uptake inhibitor |journal=Pharmacol. Biochem. Behav. |volume=63 |issue=2 |pages=285&ndash;90 |year=1999 |pmid=10371658 |doi=}}</ref> and to a lesser extent [[norepinephrine]], thus exerting a powerful and fast-acting [[antidepressant]] effect.{{Fact|date=October 2007}} Introduced in [[France]] in [[1978]] by the [[pharmaceutical]] giant [[Servier]]<ref name=amineptine_manufacture>{{cite book | last = Sittig | first = Marshall | title = Pharmaceutical Manufacturing Encyclopedia | origyear = 1979 | origmonth = June | url = http://www.amineptine.com/synthesis/manufacture.html | accessdate = 2005-10-29 | edition = 2nd edition | date = 1988-04-01 | publisher = William Andrew Publishing/Noyes Publications | location = Park Ridge, New Jersey, United States American | id = ISBN 0-8155-1144-2}}</ref> 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 7 days after commencing treatment.) This led to the [[Food and Drug Administration]] suspending the marketing authorisation for Survector in 1999 and France withdrew it from the market, however several [[developing countries]] continued to produce it up until [[2005]]. Currently amineptine is off-patent and very difficult to obtain. Rare cases of [[hepatotoxicity]], some serious, have been reported, but these were thought to be due to a [[genetics|genetic]] predisposition. ==Therapeutic indications== ===Approved=== Amineptine was approved in France for severe [[clinical depression]] of endogenous origin in 1978.<ref name=French_approval>{{cite web | author=Doctissimo | year=2005 | url=http://www.doctissimo.fr/medicament-SURVECTOR.htm | title=SURVECTOR - Amineptine| language = French | accessdate=27 October | accessyear=2005}}</ref> ===Unapproved/Off-Label/Investigational=== [[Parkinson's Disease]], amotivational syndromes, ADHD (Attention Deficit/Hyperactivity Disorder) ==Mechanism of action== *Inhibitor of the reuptake of [[norepinephrine]] and [[dopamine]]. *Little [[anticholinergic]] or [[antihistaminic]] effects. ==Side effects== ===Dermatological=== Severe [[Acne vulgaris|acne]] due to amineptine was first reported in 1988 by various authors&mdash;Grupper, Thioly-Bensoussan, Vexiau, Fiet, Puissant, Gourmel, Teillac, Levigne, to name a few&mdash;simultaneously<ref name=adv_acne_1988_1>{{cite journal | author=Grupper C | title=[New iatrogenic acne: acne caused by amineptin (Survector)] | journal=Annales de Dermatologie et de Venereologie | volume=115 | issue=11 | year=1988 | pages=1174&ndash;6 | pmid=2977079}} [Article in French] [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=2977079&dopt=ExternalLink&ExternalLink=libs List of Library Holdings Worldwide]</ref><ref name=adv_acne_1988_2>{{cite journal | author=Thioly-Bensoussan D, Charpentier A, Triller R, Thioly F, Blanchet P, Tricoire N, Noury JY, Grupper C | title=[Iatrogenic acne caused by amineptin (Survector). Apropos of 8 cases] | journal=Annales de Dermatologie et de Venereologie | volume=115 | issue=11 | year=1988 | pages=1177&ndash;80 | pmid=2977080}} [Article in French] [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=2977080&dopt=ExternalLink&ExternalLink=libs List of Library Holdings Worldwide]</ref><ref name=adv_acne_1988_3>{{cite journal | author=Vexiau P, Gourmel B, Husson C, Castot A, Rybojad M, Julien R, Fiet J, Puissant A, Cathelineau G | title=[Severe lesions of acne type induced by chronic amineptin poisoning: apropos of 6 cases] | journal=Annales de Dermatologie et de Venereologie | volume=115 | issue=11 | year=1988 | pages=1180&ndash;2| pmid=2977081}} [Article in French] [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=2977081&dopt=ExternalLink&ExternalLink=libs List of Library Holdings Worldwide]</ref><ref name=adv_acne_1988_4>{{cite journal | author=Teillac D, Weber MJ, Lowenstein W, de Prost Y | title=[Acne caused by Survector] | journal=Annales de Dermatologie et de Venereologie | volume=115 | issue=11 | year=1988 | pages=1183&ndash;4 | pmid=2977082}} [Article in French] [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=2977082&dopt=ExternalLink&ExternalLink=libs List of Library Holdings Worldwide]</ref><ref name=adv_acne_1988_5>{{cite journal | author=Levigne V, Faisant M, Mourier C, Garcier F, Millon-Paitel M, Barthelemy H, Claudy A | title=[Monstrous acne in the adult. Inducer role of Survector?] | journal=journal=Annales de Dermatologie et de Venereologie | volume=115 | issue=11 | year=1988 | pages=1184&ndash;5 | pmid=2977083}} [Article in French] [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=2977083&dopt=ExternalLink&ExternalLink=libs List of Library Holdings Worldwide]</ref> in the same issue of ''Annales de Dermatologie et de Venereologie'' and in the 12 March 1988 of ''The Lancet.''<ref name=Vexiau_et_al_1988_Lancet>{{cite journal | author=Vexiau P, Gourmel B, Julien R, Husson C, Fiet J, Puissant A, Dreux C, Cathelineau G | title=Severe acne-like lesions caused by amineptine overdose | journal=Lancet | volume=1 | issue=8585 | year=1988 | pages=585 | pmid=2894512 | doi=10.1016/S0140-6736(88)91373-6}} [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=2894512&dopt=ExternalLink&ExternalLink=libs List of Library Holdings Worldwide]</ref> 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."<ref name=Martin-Ortega_et_al_1989>{{cite journal | author=Martin-Ortega E, Zamora E, Herrero C, Palou J | title=[Acneiform eruption induced by amineptin (Survector)] | journal=Medicina Cutanea Ibero-Latino-Americana | volume=17 | issue=6 | year=1989 | pages=414&ndash;6 | pmid=2534534}} [Article in Spanish] [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=2534534&dopt=ExternalLink&ExternalLink=libs List of Library Holdings Worldwide]</ref> 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.<ref name=Vexiau_et_al_1990>{{cite journal | author=Vexiau P, Gourmel B, Castot A, Husson C, Rybojad M, Julien R, Fiet J, Hardy N, Puissant A, Cathelineau G | title=Severe acne due to chronic amineptine overdose | journal= Archives of Dermatological Research | volume=282 | issue=2 | year=1990 | pages=103&ndash;7 | pmid=2141246 | doi=10.1007/BF00493467}} [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=2141246&dopt=ExternalLink&ExternalLink=libs List of Library Holdings Worldwide]</ref> 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.<ref name=Vexiau_et_al_1990 /> This can be seen as a general side effect of central dopamine enhancement, due to the inhibitory effect of dopamine on prolactine, 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.<ref name=psychomotor_excitation>{{cite web | url=http://www.biam2.org/www/Gsu238.html | title=AMINEPTINE CHLORHYDRATE | work=BIAM | language=French | accessdate=27 October | accessyear=2005 }}</ref> *[[Nervousness]] (very rare) *Irritability (very rare) *[[Insomnia]] (very rare) *[[Suicidal]] ideation (very rare) Seen in beginning of treatment. By lifting of psychomotor inhibition. Increase monitoring at the beginning of treatment. ===Cardiovascular=== *[[Vasomotor episode]] (very rare) *[[Arterial]] [[hypotension]] (very rare) *[[Palpitation]]s (very rare) ===Hepatic=== Amineptine can very rarely cause [[hepatitis]], of the [[cytolysis|cytolytic]], [[Hepatitis#Cholestatic|cholestatic]] varieties.<ref name=types_of_hepatitis>{{cite journal | author=Bories P, Pomier-Layrargues G, Chotard JP, Citron D, Capron-Chivrac D, Capron JP, Michel H. | title=[Amineptine-induced cholestatic hepatitis. 5 cases (author's transl)] | journal= La Nouvelle Presse Medicale | volume=9 | issue=48 | year=1980 | pages=3689&ndash;92 | pmid=7454584}} [Article in French] [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=7454584&dopt=ExternalLink&ExternalLink=libs List of Library Holdings Worldwide]</ref> Amineptine-induced hepatitis, which is sometimes preceded by a rash, is believed to be due to an allergic reaction.<ref name=rash>{{cite journal | author=Pessayre D, Larrey D. | title=Acute and chronic drug-induced hepatitis | journal=Bailliere's Clinical Gastroenterology | volume=2 | issue=2 | year=1988 | pages=385&ndash;422 | pmid=3044468 | doi=10.1016/0950-3528(88)90009-7}} [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=3044468&dopt=ExternalLink&ExternalLink=libs List of Library Holdings Worldwide]</ref> It resolves upon discontinuation of the offending drug.<ref name=types_of_hepatitis /> The risk of getting this may or may not be genetically determined.<ref name=genetic>{{cite journal | author=Larrey D, Pageaux GP | title=Genetic predisposition to drug-induced hepatotoxicity | journal=Journal of Hepatology | volume=26 | issue=Suppl 2 | year=1997 | pages=12&ndash;21 | pmid =9204405 | url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=9204405&dopt=ExternalLink | doi=10.1016/S0168-8278(97)80492-8}} [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=9204405&dopt=ExternalLink&ExternalLink=libs List of Library Holdings Worldwide]</ref> Additionally, amineptine is known to rarely elevate [[transaminase]]s, [[alkaline phosphatase]], and [[bilirubin]].<ref name=transaminase_etc>{{cite journal | author=[No authors listed] | title=[Drug-induced liver disorders. Questions for Professor Daniel Dhumeaux] | journal=Gastroenterologie Clinique et Biologique | volume=23 | issue=8-9 | year=1999 | pages=917&ndash;20 | pmid=10533145 | url = http://www.masson.fr/masson/MDOI-GCB-08-1999-23-8-9-0399-8320-101019-ART15}} [Article in French] [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=10533145&dopt=ExternalLink&ExternalLink=libs List of Library Holdings Worldwide]</ref> 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). **Concours Med 1982; 104:5733-5734. In circa 1994 Spain, there was a case associating acute pancreatitis and mixed hepatitis, after three weeks of treatment.<ref name=pancreatitis_and_hepatitis>{{cite journal | first = J. J. | last = Sebastian Domingo | coauthors = M. A. Simon Marco and R. Uribarrena Echebarria | year = 1994 | month = March | title = Hepatic and pancreatic injury associated with amineptine therapy | journal = Journal of Clinical Gastroenterology | volume = 18 | issue = 2 | pages = 168&ndash;9 | pmid=8189020 | doi = 10.1097/00004836-199403000-00023}}</ref> 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.<ref name=Lazaros_et_al_1996>{{cite journal | first = GA | last = Lazaros | coauthors = Stavrinos C, Papatheodoridis GV, Delladetsima JK, Toliopoulos A, Tassopoulos NC | year = 1996 | month = July-August | title = Amineptine induced liver injury. Report of two cases and brief review of the literature | journal = Hepato-gastroenterology | volume = 43 | issue = 10 | pages = 1015&ndash;9 | pmid = 8884331}}</ref> One case of cytolytic hepatitis occurred after ingestion of only one tablet.<ref name=Jonville_Dutertre_Autret_1992>{{cite journal | first = AP | last = Jonville | coauthors = Dutertre JP, Autret E | year = 1992 | title = [Immediate acute hepatic cytolysis after the administration of a single amineptin tablet] | journal = Gastroenterologie clinique et biologique | volume = 16 | issue = 4 | pages = 368 | pmid = 1397859}}</ref> ===Gastrointestinal=== *Acute pancreatitis (very rare) A case associating acute [[pancreatitis]] and mixed hepatitis after three weeks of treatment.<ref name=pancreatitis_and_hepatitis /> ===Immunological=== In 1989, Sgro and colleagues at the [[Centre de Pharmacovigilance]] in [[Dijon]] reported a case of [[anaphylactic shock]] in a woman who had been taking amineptine.<ref name=anaphylaxis>{{cite journal | author=Sgro C, Lacroix S, Waldner A, Lacroix M, Ferrut O, Bureau A. | title=[Anaphylactic shock caused by amineptine. Report of a case] | journal=La Revue de Medecine Interne | volume=10 | issue=5 | month=Sep-Oct | year=1989 | pages=461&ndash;2 | pmid=2488491 | doi=10.1016/S0248-8663(89)80054-2}} [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=2488491&dopt=ExternalLink&ExternalLink=libs List of Library Holdings Worldwide]</ref> ==Effects on the unborn child== *Non-[[teratogenic]] in animals *Lacking information in humans ==Abuse and Dependence== The risk of [[addiction]] is low, but it is there 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.<ref name=Castot_et_al_1990>{{cite journal | author=Castot A, Benzaken C, Wagniart F, Efthymiou ML | title=[Amineptin abuse. Analysis of 155 cases. An evaluation of the official cooperative survey of the Regional Centers of Pharmacovigilance] | journal=Therapie | volume=45 | issue=5 | year=1990 | pages=399&ndash;405 | pmid=2260032}} [Article in French] [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=2260032&dopt=ExternalLink&ExternalLink=libs List of Library Holdings Worldwide]</ref> However, a 1981 study of known [[opiate]] addicts and [[schizophrenia]] patients found no drug addiction in any of the subjects.<ref name=not_necessarily_addictive>{{cite journal | author=Deniker P, Loo H, Zarifian E, Peron P, Benyacoub A, Roux JM, Kamoun A | title=[Amineptine and amotival syndrome (author's transl)] | journal=L'Encephale | volume=7 | issue=1 | year=1981 | pages=59&ndash;64 | pmid=7227285}} [Article in French] [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=7227285&dopt=ExternalLink&ExternalLink=libs List of Library Holdings Worldwide]</ref> 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.<ref name=withdrawal_symptoms>{{cite journal | author=Bertschy G, Luxembourger I, Bizouard P, Vandel S, Allers G, Volmat R | title=[Amineptin dependence. Detection of patients at risk. Report of 8 cases] | journal=L'Encephale | volume=16 | issue=5 | year=1990 | pages=405&ndash;9 | pmid=2265603}} [Article in French] [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=2265603&dopt=ExternalLink&ExternalLink=libs List of Library Holdings Worldwide]</ref> ==Precautions for use== *[[General anaesthesia]]: Discontinue the drug 24 to 48 hours before anaesthesia. *[[Pregnancy]] (first trimester) *[[Breast feeding]] *Official sports/[[Olympic Games]]: Prohibited substance. **7 March Official Journal 2000. ==Contraindications== *[[Chorea (disease)|Chorea]] *[[MAO inhibitor]]s *Children less than 1 year of age *[[Hypersensitivity]]: Known hypersensitivity to amineptine, in particular antecedents of hepatitis after dosage of the product. ==References== {{Reflist|2}} == See also == * [[tianeptine]] * [[dopamine]] * [[antidepressant]] * [[hepatitis]] == External links == *[http://www.amineptine.com Amineptine.com] {{Antidepressants}} [[Category:Dopamine reuptake inhibitors]] [[Category:Withdrawn drugs]] [[de:Amineptin]] [[pl:Amineptyna]] [[pt:Amineptina]] [[ru:Аминептин]] [[sv:Amineptin]]