Adrafinil

Adrafinil
Clinical data
Trade names Olmifon
AHFS/Drugs.com International Drug Names
Routes of
administration		 Oral
ATC code N06BX17 (WHO)
Legal status
Legal status
  • US: Unscheduled
Pharmacokinetic data
Bioavailability 80%
Metabolism 75% (Liver)
Metabolites Modafinil
Biological half-life 1 hour (T1/2 is 12–15 hours for modafinil)[1]
Excretion Kidney
Identifiers
Synonyms CRL-40028
CAS Number 63547-13-7 N
PubChem (CID) 3033226
DrugBank DB08925 N
ChemSpider 2297976 YesY
UNII BI81Z4542G YesY
KEGG D07348 YesY
ChEMBL CHEMBL93077 YesY
Chemical and physical data
Formula C15H15NO3S
Molar mass 289.351 g/mol
3D model (Jmol) Interactive image
 NYesY (what is this?)  (verify)

Adrafinil (INN) (brand name Olmifon)[2] is a discontinued wakefulness-promoting agent (or eugeroic) that was formerly used in France to promote vigilance (alertness), attention, wakefulness, mood, and other parameters, particularly in the elderly.[3][4] It was also used off-label by individuals who wished to avoid fatigue, such as night workers or others who needed to stay awake and alert for long periods of time. Additionally, "adrafinil is known to a larger nonscientific audience, where it is considered to be a nootropic agent."[3]

Adrafinil is a prodrug; it is primarily metabolized in vivo to modafinil, resulting in very similar pharmacological effects.[3] Unlike modafinil, however, it takes time for the metabolite to accumulate to active levels in the bloodstream. Effects usually are apparent within 45–60 minutes when taken orally on an empty stomach.

Adrafinil was marketed in France under the trade name Olmifon[2] until September 2011 when it was voluntarily discontinued.[4]

Pharmacology

Pharmacodynamics

Because α1-adrenergic receptor antagonists were found to block effects of adrafinil and modafinil in animals, "most investigators assume[d] that adrafinil and modafinil both serve as α1-adrenergic receptor agonists."[3] However, adrafinil and modafinil have not been found to bind to the α1-adrenergic receptor and they lack peripheral sympathomimetic side effects associated with activation of this receptor;[5] hence, the evidence in support of this hypothesis is weak, and other mechanisms are probable.[3] Modafinil was subsequently screened at a variety of targets in 2009 and was found to act as a weak, atypical blocker of the dopamine transporter (and hence as a dopamine reuptake inhibitor), and this action may explain some or all of its pharmacological effects.[6][7][8] Relative to adrafinil, modafinil possesses greater specificity in its action, lacking or having a reduced incidence of many of the common side effects of the former (including stomach pain, skin irritation, anxiety, and elevated liver enzymes with prolonged use).[9][10][11]

There is a case report of two patients that adrafinil may increase interest in sex.[3]

A case report of adrafinil-induced orofacial dyskinesia exists.[12][13] Reports of this side effect also exist for modafinil.[12]

Pharmacokinetics

In addition to modafinil, adrafinil also produces modafinil acid (CRL-40467) and modafinil sulfone (CRL-41056) as metabolites, which form from metabolic modification of modafinil.

History

Adrafinil was discovered in 1974 by two chemists working for the French pharmaceutical company Laboratoires Lafon who were screening compounds in search of analgesics.[14] Pharmacological studies of adrafinil instead revealed psychostimulant-like effects such as hyperactivity and wakefulness in animals.[14] The substance was first tested in humans, specifically for the treatment of narcolepsy, in 1977–1978.[14] Introduced by Lafon (now Cephalon), it reached the market in France in 1984,[4] and for the treatment of narcolepsy in 1985.[14][15]

In 1976, two years after the discovery of adrafinil, modafinil, its active metabolite, was discovered.[14] Modafinil appeared to be more potent than adrafinil in animal studies, and was selected for further clinical development, with both adrafinil and modafinil eventually reaching the market.[14] Modafinil was first approved in France in 1994, and then in the United States in 1998.[15] Lafon was acquired by Cephalon in 2001.[16] As of September 2011, Cephalon has discontinued Olmifon, its adrafinil product, while modafinil continues to be marketed.[4]

Society and culture

Regulation

Athletic doping

Adrafinil and its active metabolite modafinil were added to the list of substances prohibited for athletic competition according to World Anti-Doping Agency in 2004.[17]

New Zealand

In 2005 a Medical Classification Committee in New Zealand recommended to MEDSAFE NZ that adrafinil be classified as a prescription medicine due to risks of it being used as a party drug. At that time adrafinil was not scheduled in New Zealand.[18]

Research

In a clinical trial with clomipramine and placebo as active comparators, adrafinil showed efficacy in the treatment of depression.[3] In contrast to clomipramine however, adrafinil was well-tolerated, and showed greater improvement in psychomotor retardation in comparison.[3] As such, "further investigations of the antidepressive effects of adrafinil are warranted."[3]

See also

References

  1. ↑ Robertson P, Hellriegel ET (2003). "Clinical pharmacokinetic profile of modafinil". Clin Pharmacokinet. 42 (2): 123–37. doi:10.2165/00003088-200342020-00002. PMID 12537513.
  2. 1 2 Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 20–. ISBN 978-3-88763-075-1.
  3. 1 2 3 4 5 6 7 8 9 Milgram, Norton (1999). "Adrafinil: A Novel Vigilance Promoting Agent". CNS Drug Reviews. 5 (3): 193–212. doi:10.1111/j.1527-3458.1999.tb00100.x. Retrieved 2 October 2014.
  4. 1 2 3 4 AFSSAPS (2011). "Point d'information sur les dossiers discutés en commission d'AMM Séance du jeudi 1er décembre 2011 - Communiqué".
  5. ↑ Simon P, Chermat R, Puech AJ (1983). "Pharmacological evidence of the stimulation of central alpha-adrenergic receptors". Prog. Neuropsychopharmacol. Biol. Psychiatry. 7 (2-3): 183–6. doi:10.1016/0278-5846(83)90105-7. PMID 6310690.
  6. ↑ Zolkowska D, Jain R, Rothman RB, Partilla JS, Roth BL, Setola V, Prisinzano TE, Baumann MH (May 2009). "Evidence for the involvement of dopamine transporters in behavioral stimulant effects of modafinil". The Journal of Pharmacology and Experimental Therapeutics. 329 (2): 738–46. doi:10.1124/jpet.108.146142. PMC 2672878Freely accessible. PMID 19197004.
  7. ↑ Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, Partilla JS, Rothman RB, Katz JL (Feb 2015). "Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter". Drug and Alcohol Dependence. 147: 1–19. doi:10.1016/j.drugalcdep.2014.12.005. PMC 4297708Freely accessible. PMID 25548026.
  8. ↑ Quisenberry AJ, Baker LE (Dec 2015). "Dopaminergic mediation of the discriminative stimulus functions of modafinil in rats". Psychopharmacology. 232 (24): 4411–9. doi:10.1007/s00213-015-4065-0. PMID 26374456.
  9. ↑ Ballas, Christos A; Deborah Kim; Claudia F Baldassano; Nicholas Hoeh (July 2002). "Modafinil: past, present and future". Expert Review of Neurotherapeutics. 2 (4): 449–57. doi:10.1586/14737175.2.4.449. PMID 19810941.
  10. ↑ Alan F. Schatzberg; Charles B. Nemeroff (2009). The American Psychiatric Publishing Textbook of Psychopharmacology. American Psychiatric Pub. pp. 850–. ISBN 978-1-58562-309-9.
  11. ↑ Ballas, Christos A; Kim, Deborah; Baldassano, Claudia F; Hoeh, Nicholas (2002). "Modafinil: past, present and future". Expert Review of Neurotherapeutics. 2 (4): 449–457. doi:10.1586/14737175.2.4.449. ISSN 1473-7175. PMID 19810941.
  12. 1 2 Jeffrey K Aronson (31 December 2012). Side Effects of Drugs Annual: A worldwide yearly survey of new data in adverse drug reactions. Newnes. pp. 6–. ISBN 978-0-444-59503-4.
  13. ↑ Thobois S, Xie J, Mollion H, Benatru I, Broussolle E (2004). "Adrafinil-induced orofacial dyskinesia". Mov. Disord. 19 (8): 965–6. doi:10.1002/mds.20154. PMID 15300665.
  14. 1 2 3 4 5 6 Antonio Guglietta (28 November 2014). Drug Treatment of Sleep Disorders. Springer. pp. 212–. ISBN 978-3-319-11514-6.
  15. 1 2 Jie Jack Li; Douglas S. Johnson (27 March 2013). Modern Drug Synthesis. John Wiley & Sons. pp. 2–. ISBN 978-1-118-70124-9.
  16. ↑ url=http://www.bloomberg.com/research/stocks/private/snapshot.asp?privcapId=1366624
  17. ↑ World Anti-Doping Agency - 2007 Prohibited List
  18. ↑ MCC Minutes Out of Session Meeting. Medsafe.govt.nz (2013-05-23). Retrieved on 2013-12-18.

External links

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