Oxilofrine Explained

Oxilofrine, sold under the brand names Carnigen and Suprifen among others, is a sympathomimetic medication which has been used as an antihypotensive agent and cough suppressant.^[1] It is taken by mouth.

Oxilofrine acts as a norepinephrine releasing agent and hence is an indirectly acting sympathomimetic. It is a substituted amphetamine and is closely related to ephedrine (with oxilofrine also being known as 4-hydroxyephedrine).

Oxilofrine was first developed in the 1930s. It is mostly no longer marketed today.

Pharmacology

Oxilofrine is described as an ephedrine-like indirectly acting sympathomimetic and antihypotensive agent.^{[2] [3]} It acts as a norepinephrine releasing agent and indirectly activates the α- and β-adrenergic receptors.^{[4] [5]} The drug has positive inotropic effects (increases myocardial contractility).

Chemistry

Oxilofrine, also known as 4,β-dihydroxy-N-methyl-α-methylphenethylamine or as 4,β-dihydroxy-N-methylamphetamine, is a substituted phenethylamine and amphetamine derivative. It is the racemic 4-hydroxylated analogue of ephedrine ((1R,2S)-β-hydroxy-N-methylamphetamine). It is also related to pholedrine (4-hydroxy-N-methylamphetamine).

The predicted log P of oxilofrine ranges from -0.13 to 0.6.^{[6] [7] [8]} It is more hydrophilic than ephedrine, which has an experimental log P of 1.13 and a predicted log P of 0.9 to 1.32.^{[9] [10] [11]}

History

Oxilofrine was originally developed in the 1930s as a cardiac stimulant. Trade names included Suprifen (Bayer) and, combined with an adenosine-containing standardized organ extract, Carnigen (Hoechst AG).

In combination with normethadone, it was marketed as a cough suppressant under the trade name Ticarda. As of 2021, this formulation was still manufactured in Canada by Valeant and sold as Cophylac.^[12]

Several other sympathomimetics and vasodilators were developed as chemical derivatives of oxilofrine, such as the β₂-adrenergic receptor agonists buphenine and isoxsuprine.^{[13] [14]}

Society and culture

Names

Oxilofrine is the generic name of the drug and its . It is also known by synonyms including methylsynephrine, oxyphedrine, and hydroxyephedrine. Brand names of oxilofrine include Carnigen, Cophylac (with normethadone), Suprifen, and Ticarda (also with normethadone), among others.

Availability

Oxilofrine has been marketed in Austria, Canada, and Germany.^[15]

Use in exercise and sports

Oxilofrine is currently a World Anti-Doping Agency (WADA) prohibited substance when used in competition.^[16] It has been found as an adulterant in some dietary supplements.^{[17] [18]} Even after receiving warning letters from the FDA,^[19] some sports and weight loss supplement companies continue to use oxilofrine as an undeclared ingredient in their products despite it being prohibited.^[20]

List of doping cases

Several doping cases involving oxilofrine have been publicized, including:

• In 2009, Brazilian/American cyclist Flávia Oliveira was suspended for 2 years after taking a supplement known as "HyperDrive 3.0+" which contained methylsynephrine, a chemical equivalent of oxilofrine, among other substances.^[21] Her sentence was eventually reduced to 18 months after an appeal as there was enough evidence that she had unknowingly consumed said substance as the old label did not list methylsynephrine.^[22]
• On 18 September 2010, Vietnamese weightlifter Hoàng Anh Tuấn, silver medalist in 2008 Summer Olympics was handed a four year ban, later reduced to two years, for testing positive with the substance. It was found out that the substance came from unlabeled drinks he consumed during his training in China.^[23]
• On July 14, 2013, Jamaican runners Asafa Powell and Sherone Simpson tested positive for oxilofrine prior to the 2013 World Athletics Championships.^[24] Powell, however, maintained that he did not take any banned supplements knowingly or willfully.^[25] Powell voluntarily withdrew as a result of the test. On 10 April 2014, both athletes received an 18-month suspension from competing, which was set to expire in December that year.^[26] However, after appealing to the Court of Arbitration for Sport (CAS), both athletes' suspensions were lifted on 14 July 2014.^[27]
• On July 16, 2015, Red Sox pitching prospect Michael Kopech was suspended without pay for 50 games after testing positive for oxilofrine, which is a banned substance under the Minor League Drug Prevention and Treatment Program. Kopech denied knowingly taking the substance.^[28]
• In October 2018, the WBO stripped boxer Billy Joe Saunders of its middleweight world title after he tested positive for oxilofrine, as a result of a drug test administered by the Voluntary Anti-Doping Association (VADA). In his defense, Saunders held that while the substance was proscribed by VADA it was not banned "out of competition" by UK Anti-Doping, or the British Boxing Board of Control, but this appeal was rejected.^[29]

Other drugs

Oxilofrine is a known metabolite of para-methoxymethamphetamine (PMMA).

Notes and References

1. Book: Fourcroy JL . Pharmacology, doping and sports: a scientific guide for athletes, coaches, physicians, scientists and administrators . Taylor & Francis . 2008 . 978-0-415-42845-3.
2. Book: Schweizerischer Apotheker-Verein . Index Nominum 2000: International Drug Directory . Medpharm Scientific Publishers . 2000 . 978-3-88763-075-1 . 2024-09-01 . 772.
3. Book: Morton IK, Hall JM . Concise Dictionary of Pharmacological Agents: Properties and Synonyms . Springer Netherlands . 2012 . 978-94-011-4439-1 . 2024-09-01 . 211.
4. Docherty JR . Pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA) . Br J Pharmacol . 154 . 3 . 606–622 . June 2008 . 18500382 . 2439527 . 10.1038/bjp.2008.124 .
5. Book: Derendorf H . Drug Actions: Basic Principles and Theraputic Aspects . CRC-Press . 1995 . 978-0-8493-7774-7 . 1 September 2024 . 227.
6. Web site: Suprifen . PubChem . 1 September 2024.
7. Web site: Oxilofrine: Uses, Interactions, Mechanism of Action . DrugBank Online . 31 December 1957 . 1 September 2024.
8. Web site: oxilofrine . ChemSpider . 1 September 2024 . 1 September 2024.
9. Web site: Ephedrine . PubChem . 30 August 2024.
10. Web site: Ephedrine: Uses, Interactions, Mechanism of Action . DrugBank Online . 29 April 2016 . 14 July 2024.
11. Web site: L-(−)-Ephedrine . ChemSpider . 30 August 2024 . 30 August 2024.
12. Web site: Prescribing Information Including Patient Medication Information – Cophylac® Drops . Valeant Canada . 2010-01-17 . 2022-01-06.
13. Külz F, Schneider M. Über neue gefäßerweiternde Sympathomimetika . German . On new vasodilating sympathomimetics . Klin Wochenschr . 1950 . 28 . 31–32 . 535–537. 10.1007/BF01481535 . 14775050 .
14. Freedman L. Arlidin: a new vasodilative sympathomimetic drug . Angiology . 1955 . 6 . 1 . 52–58 . 14350296 . 10.1177/000331975500600106. 46317963 .
15. Web site: Oxilofrine . drugs.com . 2013-07-17 . https://web.archive.org/web/20160413113615/http://www.drugs.com/international/oxilofrine.html . 2016-04-13 . dead . 2024-09-01.
16. Web site: Substances Prohibited In-Competition . 2013-07-15 . dead . https://web.archive.org/web/20130702155110/http://list.wada-ama.org/prohibited-in-competition/prohibited-substances/ . 2013-07-02 . WADA .
17. Cohen PA, Avula B, Venhuis B, Travis JC, Wang YH, Khan IA . Pharmaceutical doses of the banned stimulant oxilofrine found in dietary supplements sold in the USA . Drug Testing and Analysis . 9 . 1 . 135–142 . January 2017 . 27062112 . 10.1002/dta.1976 . free .
18. Zovko Končić M . Getting More Than You Paid For: Unauthorized "Natural" Substances in Herbal Food Supplements on EU Market . Planta Medica . 84 . 6–07 . 394–406 . April 2018 . 29341031 . 10.1055/s-0044-100042 . free .
19. Web site: Center for Food Safety and Applied Nutrition . Products & Ingredients - Methylsynephrine in Dietary Supplements . 22 October 2020 . U.S. Food and Drug Administration . en.
20. Cohen PA, Wen A, Gerona R . Prohibited Stimulants in Dietary Supplements After Enforcement Action by the US Food and Drug Administration . JAMA Internal Medicine . 178 . 12 . 1721–1723 . December 2018 . 30422217 . 6583602 . 10.1001/jamainternmed.2018.4846 .
21. News: Oliveira suspended for two years. 2010-04-13. Pelkey C . Velonews. live. https://web.archive.org/web/20151006002117/http://velonews.competitor.com/2010/04/news/oliveira-suspended-for-two-years_111571. 2015-10-06.
22. News: Court of Arbitration for Sport reduces Flavia Oliveira suspension. 2011-02-24. Pelkey C . Velonews. live. https://web.archive.org/web/20151223154831/http://velonews.competitor.com/2010/12/news/court-of-arbitration-for-sport-reduces-flavia-olivera-suspension_152082. 2015-12-23.
23. Web site: Dính doping, lực sỹ Hoàng Anh Tuấn bị cấm thi đấu 2 năm . dantri.com.vn . 22 January 2011 .
24. Web site: Reuters . Jamaicans Powell, Simpson test positive - SuperSport - Athletics . SuperSport . 2013-07-15.
25. Web site: Jamaican Sprinter Asafa Powell slapped 18-month ban for doping. IANS. news.biharprabha.com. 10 April 2014. live. https://web.archive.org/web/20140414194427/http://news.biharprabha.com/2014/04/jamaican-sprinter-asafa-powell-slapped-18-month-ban-for-doping/. 14 April 2014.
26. News: Asafa Powell banned for 18 months for doping. 10 April 2014. BBC Sport. https://web.archive.org/web/20140509060737/http://www.bbc.co.uk/sport/0/athletics/26974788. 9 May 2014.
27. News: Jamaican sprinters Asafa Powell and Sherone Simpson have doping bans cut . . 14 July 2014 . 14 July 2014 .
28. Web site: Wild D . Red Sox No. 10 prospect Kopech suspended . . 16 July 2015 . 8 March 2016 . live . https://web.archive.org/web/20160309114419/http://www.milb.com/news/article.jsp?ymd=20150716&content_id=136960248&fext=.jsp&vkey=news_milb&sid=milb . 9 March 2016 .
29. Web site: Worsell E . The ins and outs of Billy Joe Saunders, oxilofrine and VADA . Boxing News . 12 October 2018 .