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Oxilofrine

Not to be confused with Oxyfedrine.

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.[4][5][6] It is taken by mouth.[1]

Oxilofrine
Clinical data
Trade namesCarnigen, Cophylac, Suprifen, others
Other namesOxilophrine; Hydroxyephedrine; (±)-Hydroxyephedrine; 4-Hydroxyephedrine; p-Hydroxyephedrine; Oxyephedrine; Methylsynephrine; 4-HMP; 4,β-Dihydroxy-N-methyl-α-methylphenethylamine; 4,β-Dihydroxy-N-methylamphetamine
Routes of
administration		Oral[1]
ATC code
  • None
Legal status
Legal status
Identifiers
  • (1S*,2R*)-(±)-4-(1-Hydroxy-2-methylamino-propyl)phenol
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.006.067 Edit this at Wikidata
Chemical and physical data
FormulaC10H15NO2
Molar mass181.235 g·mol−1
  • InChI=1S/C10H15NO2/c1-7(11-2)10(13)8-3-5-9(12)6-4-8/h3-7,10-13H,1-2H3 checkY
  • Key:OXFGTKPPFSCSMA-UHFFFAOYSA-N checkY
  (verify)

Oxilofrine acts as a norepinephrine releasing agent and hence is an indirectly acting sympathomimetic.[7][6][8] It is a substituted amphetamine and is closely related to ephedrine (with oxilofrine also being known as 4-hydroxyephedrine).[4][8]

Oxilofrine was first developed in the 1930s.[9] It is mostly no longer marketed today.[10]

Pharmacology

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Oxilofrine is described as an ephedrine-like indirectly acting sympathomimetic and antihypotensive agent.[4][7][6] It acts as a norepinephrine releasing agent and indirectly activates the α- and β-adrenergic receptors.[6][8] The drug has positive inotropic effects (increases myocardial contractility).[6]

Chemistry

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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.[4][10] It is the racemic 4-hydroxylated analogue of ephedrine ((1R,2S)-β-hydroxy-N-methylamphetamine).[4] It is also related to pholedrine (4-hydroxy-N-methylamphetamine).[4]

The predicted log P of oxilofrine ranges from -0.13 to 0.6.[11][1][12] 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.[13][14][15]

History

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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).[9]

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.[16]

Several other sympathomimetics and vasodilators were developed as chemical derivatives of oxilofrine, such as the β2-adrenergic receptor agonists buphenine and isoxsuprine.[17][18]

Society and culture

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Names

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Oxilofrine is the generic name of the drug and its INNTooltip International Nonproprietary Name.[4][7][10] It is also known by synonyms including methylsynephrine, oxyphedrine, and hydroxyephedrine.[4][10] Brand names of oxilofrine include Carnigen, Cophylac (with normethadone), Suprifen, and Ticarda (also with normethadone), among others.[4][10][9]

Availability

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Oxilofrine has been marketed in Austria, Canada, and Germany.[4][10]

Use in exercise and sports

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Oxilofrine is currently a World Anti-Doping Agency (WADA) prohibited substance when used in competition.[19] It has been found as an adulterant in some dietary supplements.[9][20] Even after receiving warning letters from the FDA,[21] some sports and weight loss supplement companies continue to use oxilofrine as an undeclared ingredient in their products despite it being prohibited.[22]

List of doping cases

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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.[23] 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.[24]
  • 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.[25]
  • On July 14, 2013, Jamaican runners Asafa Powell and Sherone Simpson tested positive for oxilofrine prior to the 2013 World Athletics Championships.[26] Powell, however, maintained that he did not take any banned supplements knowingly or willfully.[27] 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.[28] However, after appealing to the Court of Arbitration for Sport (CAS), both athletes' suspensions were lifted on 14 July 2014.[29]
  • 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.[30]
  • 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.[31]

Other drugs

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Oxilofrine is a known metabolite of para-methoxymethamphetamine (PMMA).[6]

References

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  1. ^ a b c "Oxilofrine: Uses, Interactions, Mechanism of Action". DrugBank Online. 31 December 1957. Retrieved 1 September 2024.
  2. ^ "Methylsynephrine in Dietary Supplements". FDA. February 22, 2023. Retrieved June 9, 2023.
  3. ^ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  4. ^ a b c d e f g h i j Schweizerischer Apotheker-Verein (2000). Index Nominum 2000: International Drug Directory. Medpharm Scientific Publishers. p. 772. ISBN 978-3-88763-075-1. Retrieved 2024-09-01.
  5. ^ Fourcroy JL (2008). Pharmacology, doping and sports: a scientific guide for athletes, coaches, physicians, scientists and administrators. Taylor & Francis. ISBN 978-0-415-42845-3.
  6. ^ a b c d e f Docherty JR (June 2008). "Pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA)". Br J Pharmacol. 154 (3): 606–622. doi:10.1038/bjp.2008.124. PMC 2439527. PMID 18500382.
  7. ^ a b c Morton IK, Hall JM (2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Netherlands. p. 211. ISBN 978-94-011-4439-1. Retrieved 2024-09-01.
  8. ^ a b c Derendorf H (1995). Drug Actions: Basic Principles and Theraputic Aspects. CRC-Press. p. 227. ISBN 978-0-8493-7774-7. Retrieved 1 September 2024.
  9. ^ a b c d Cohen PA, Avula B, Venhuis B, Travis JC, Wang YH, Khan IA (January 2017). "Pharmaceutical doses of the banned stimulant oxilofrine found in dietary supplements sold in the USA". Drug Testing and Analysis. 9 (1): 135–142. doi:10.1002/dta.1976. PMID 27062112.
  10. ^ a b c d e f "Oxilofrine". drugs.com. 2013-07-17. Archived from the original on 2016-04-13. Retrieved 2024-09-01.
  11. ^ "Suprifen". PubChem. Retrieved 1 September 2024.
  12. ^ "oxilofrine". ChemSpider. 1 September 2024. Retrieved 1 September 2024.
  13. ^ "Ephedrine". PubChem. Retrieved 30 August 2024.
  14. ^ "Ephedrine: Uses, Interactions, Mechanism of Action". DrugBank Online. 29 April 2016. Retrieved 14 July 2024.
  15. ^ "L-(−)-Ephedrine". ChemSpider. 30 August 2024. Retrieved 30 August 2024.
  16. ^ "Prescribing Information Including Patient Medication Information – Cophylac® Drops" (PDF). Valeant Canada. 2010-01-17. Retrieved 2022-01-06.
  17. ^ Külz F, Schneider M (1950). "Über neue gefäßerweiternde Sympathomimetika" [On new vasodilating sympathomimetics]. Klin Wochenschr (in German). 28 (31–32): 535–537. doi:10.1007/BF01481535. PMID 14775050.
  18. ^ Freedman L (1955). "Arlidin: a new vasodilative sympathomimetic drug". Angiology. 6 (1): 52–58. doi:10.1177/000331975500600106. PMID 14350296. S2CID 46317963.
  19. ^ "Substances Prohibited In-Competition". WADA. Archived from the original on 2013-07-02. Retrieved 2013-07-15.
  20. ^ Zovko Končić M (April 2018). "Getting More Than You Paid For: Unauthorized "Natural" Substances in Herbal Food Supplements on EU Market". Planta Medica. 84 (6–07): 394–406. doi:10.1055/s-0044-100042. PMID 29341031.
  21. ^ "Products & Ingredients - Methylsynephrine in Dietary Supplements". Center for Food Safety and Applied Nutrition. U.S. Food and Drug Administration. 22 October 2020.
  22. ^ Cohen PA, Wen A, Gerona R (December 2018). "Prohibited Stimulants in Dietary Supplements After Enforcement Action by the US Food and Drug Administration". JAMA Internal Medicine. 178 (12): 1721–1723. doi:10.1001/jamainternmed.2018.4846. PMC 6583602. PMID 30422217.
  23. ^ Pelkey C (2010-04-13). "Oliveira suspended for two years". Velonews. Archived from the original on 2015-10-06.
  24. ^ Pelkey C (2011-02-24). "Court of Arbitration for Sport reduces Flavia Oliveira suspension". Velonews. Archived from the original on 2015-12-23.
  25. ^ "Dính doping, lực sỹ Hoàng Anh Tuấn bị cấm thi đấu 2 năm". dantri.com.vn. 22 January 2011.
  26. ^ "Jamaicans Powell, Simpson test positive - SuperSport - Athletics". SuperSport. Reuters. Retrieved 2013-07-15.
  27. ^ "Jamaican Sprinter Asafa Powell slapped 18-month ban for doping". IANS. news.biharprabha.com. Archived from the original on 14 April 2014. Retrieved 10 April 2014.
  28. ^ "Asafa Powell banned for 18 months for doping". BBC Sport. 10 April 2014. Archived from the original on 9 May 2014.
  29. ^ "Jamaican sprinters Asafa Powell and Sherone Simpson have doping bans cut". The Guardian. 14 July 2014. Retrieved 14 July 2014.
  30. ^ Wild D (16 July 2015). "Red Sox No. 10 prospect Kopech suspended". MiLB.com. Archived from the original on 9 March 2016. Retrieved 8 March 2016.
  31. ^ Worsell E (12 October 2018). "The ins and outs of Billy Joe Saunders, oxilofrine and VADA". Boxing News.
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