Pharmaceutical doses of the banned stimulant oxilofrine found in dietary supplements sold in the USA

Drug Testing and Analysis

Volumn 9, Issue 1, 2017, Pages 135-142

  Cohen, Pieter A ^a,b   Avula, Bharathi ^c   Venhuis, Bastiaan ^d   Travis, John C ^e   Wang, Yan Hong ^c   Khan, Ikhlas A ^c  

^a HARVARD MEDICAL SCHOOL   (United States)

^b CAMBRIDGE HEALTH ALLIANCE   (United States)

^c UNIVERSITY OF MISSISSIPPI   (United States)

^d NATIONAL INSTITUTE FOR PUBLIC HEALTH AND THE ENVIRONMENT   (Netherlands)

^e NSF INTERNATIONAL   (United States)

Author keywords

dietary supplements; hydroxyephedrine; methylsynephrine; oxilofrine; UHPLC QToF MS

Indexed keywords

BLOOD PRESSURE; COPYRIGHTS; FOOD ADDITIVES; HEALTH RISKS; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; MASS SPECTROMETRY; NUTRITION; SPORTS; VITAMINS;

ADVERSE EVENTS; CARDIAC ARREST; HYDROXYEPHEDRINE; LIQUID CHROMATOGRAPHY/QUADRUPOLE-TIME OF FLIGHT MASS SPECTROMETRIES; METHYLSYNEPHRINE; OXILOFRINE; PRESCRIPTION DRUGS; SPORT SUPPLEMENTS; UHPLC-QTOF-MS; ULTRA-HIGH PERFORMANCE LIQUID CHROMATOGRAPHIES;

DIETARY SUPPLEMENTS;

ACETONITRILE; OXILOFRINE; WATER; CARDIOTONIC AGENT; EPHEDRINE; METHYLSYNEPHRINE; OXEDRINE; STREET DRUG;

ARTICLE; CONTROLLED STUDY; DIETARY SUPPLEMENT; FOOD ANALYSIS; FOOD COMPOSITION; PRIORITY JOURNAL; PROCESS DEVELOPMENT; QUANTITATIVE ANALYSIS; SEPARATION TECHNIQUE; TIME OF FLIGHT MASS SPECTROMETRY; ULTRA PERFORMANCE LIQUID CHROMATOGRAPHY; UNITED STATES; ANALOGS AND DERIVATIVES; ANALYSIS; ELECTROSPRAY MASS SPECTROMETRY; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; LIMIT OF DETECTION; PROCEDURES; VALIDATION STUDY;

CARDIOTONIC AGENTS; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; DIETARY SUPPLEMENTS; EPHEDRINE; LIMIT OF DETECTION; SPECTROMETRY, MASS, ELECTROSPRAY IONIZATION; STREET DRUGS; SYNEPHRINE;

EID: 84963818628     PISSN: 19427603     EISSN: 19427611     Source Type: Journal    
DOI: 10.1002/dta.1976     Document Type: Article

References (66)

1. G. Liljestrand, P. Linde. Die Wirkung von Oxy-ephedrinen auf Gaswechsel und Kreislauf beim Menschen. Arch. Inter. Pharmacodyn. Ther. 1933, 45, 318.
2. J. Oremus. Action comparée de la p-oxy-éphédrine et de l'éphédrine sur le débit cardiaque et la ventilation pulmonaire chez l'homme et chez le chien. Arch. Inter. Pharmacodyn. Ther. 1938, 59, 30.
3. nd Elsevier, London, UK 1992, pp. 210.
4. Carnigen® (Mono)/ -forte (Mono) Albert-Roussel. In: Bundesverband der Pharmazeutischen Industrie e.V. (Ed), Rote Liste 1984, Editio Cantor Aulendorf, Württ 1984.
5. The Court of Arbitration for Sport. Flavia Oliveira v. United States Anti-Doping Agency (USADA), CAS 2010/A/2107, 6 December 2010. Available at: http://www.doping.nl/filter?p17=440 [1 March 2016].
6. The Court of Arbitration for Sport. WADA v. Polish Rugby Union and Tomasz Świadek. 6/S/2012 26 June 2013. Available at: http://www.doping.nl/filter?p17=440 [1 March 2016].
7. The Jamaica Anti-Doping Disciplinary Panel. Disciplinary hearing before the Jamaica anti-doping disciplinary panel between Jamaica anti-doping commission and Asafa Powell. JADP2013/5, 1 May 2014. Available at: http://www.doping.nl/filter?p17=440 [1 March 2016].
8. National Anti-Doping Panel. UK Anti-Doping and Bruce Croall. Final decision of the anti-doping tribunal. SR/0000120110, 24 April 2014. Available at: http://www.doping.nl/filter?p17=440 [1 March 2016].
9. WADA. 2016 List of Prohibited Substances and Methods. Available at: http://list.wada-ama.org/list/s6-stimulants/#oxilofrine%20(methylsynephrine) [8 March 2016].
10. C. Görgens, S. Guddat, A.-K. Orlovius, G. Sigmund, A. Thomas, M. Thevis, W. Schänzer. "Dilute-and-inject" multi-target screening assay for highly polar doping agents using hydrophilic interaction liquid chromatography high resolution/high accuracy mass spectrometry for sports drug testing. Anal. Bioanal. Chem. 2015, 407, 5365.
11. G. Kauert, I. Herrle, B. Schoppek. Detection of oxilofrine in plasma and urine by high-performance liquid chromatography with electrochemical detection and comparison with gas chromatography-mass spectrometry. J. Chromatogr. B: Biomed. App. 1988, 428, 291.
12. N. Kong, R. Yi, S. Zhao, J. Sandhu, G. Lam, D. Loganathan, B. Morrissey. Development and validation of a hydrophilic interaction liquid chromatography with tandem mass spectrometry method for the simultaneous detection and quantification of etilefrine and oxilofrine in equine blood plasma and urine. J. Sep. Sci. 2014, 37, 3015.
13. J. C. Domínguez-Romero, J. F. García-Reyes, F. J. Lara-Ortega, A. Molina-Díaz. Screening and confirmation capabilities of liquid chromatography-time-of-flight mass spectrometry for the determination of 200 multiclass sport drugs in urine. Talanta. 2015, 134, 74.
14. B. Venhuis, P. Keizers, A. van Riel, D. de Kaste. A cocktail of synthetic stimulants found in a dietary supplement associated with serious adverse events. Drug Test. Anal. 2014, 6, 578.
15. P. A. Cohen. Assessing supplement safety — the FDA's controversial proposal. N. Engl. J. Med. 2012, 366, 389.
16. NIH Office of Dietary Supplements. Dietary Supplement Label Database (DSLD). 2015. Available at: http://ods.od.nih.gov/Research/Dietary_Supplement_Label_Database.aspx [15 August 2015].
17. Oxilofrine Hydrochloride. in Martindale: The Complete Drug Reference. London: The Royal Pharmaceutical Society of Great Britain, (Ed: S Sweetman). Electronic version, Truven Health Analytics: Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com [12 February 2016].
18. R. S. Pawar, E. Grundel, A. R. Fardin-Kia, J. I. Rader. Determination of selected biogenic amines in Acacia rigidula plant materials and dietary supplements using LC–MS/MS methods. J. Pharm. Biomed. Anal. 2014, 88, 457.
19. P. A. Cohen, C. Bloszies, C. Yee, R. Gerona. An amphetamine isomer whose efficacy and safety in humans has never been studied, β-methylphenylethylamine (BMPEA), is found in multiple dietary supplements. Drug Test. Anal. 2015. DOI:10.1002/dta.1793.
20. S.M. Andreu. Contribución al studio de las modificaciones electrocardiográficas producidas por la acetilcolina y la adrenalina. Variaciones en su acción por otros fármacos. Arch. Med. Exper. 1944, 2, 577.
21. C. Dupont, J. Wepierre, Y. Cohen, G. Valette. Étude comparée des effets cardiovasculaires de l'éphédrine, la p.hydroxyéphédrine et la p.hydroxyamphetamine chez le chien. J. Pharmacol. (Paris). 1972, 3, 85.
22. H. Gladewitz, H. Marguth, H. Schaefer. Analyse sympathicomimetischer Kreislaufwirkungen am Beispiel des Suprifens. Z. Ges. Exp. Med. 1951, 117, 445.
23. O. Schaumann. Über Oxy-Ephedrine. Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 1931, 160, 127.
24. T. Gotsev. Die Bedeutung der Blutgefäβe und des Herzens für die Regulierung des Blutdruckes. Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 1941, 194, 571.
25. R. Domenjoz, A. Fleisch. Venenwirkung kreislaufaktiver Pharmaca. Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 1939, 192, 645.
26. W. Riechert, H. Schmieder. Vergleichende pharmakologische Untersuchungen der Adrenalin-Ephedrinkörper. Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 1941, 198, 121.
27. J. R. Rapin, C. Jacquot. Wirkungen von Oxilofrin auf die Aktivität des sympathischen Nervensystems. Arzneim.-Forsch. 1980, 30, 1077.
28. B. v. Issekutz, P. Genersich. Über den Synergismus der bronchialkrampflösenden Arzneimittel. Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 1943, 202, 201.
29. M. Zell-Kanter, M. A. Quigley, J. B. Leikin. Reduction in ephedra poisonings after FDA ban. N. Engl. J. Med. 2015, 372, 2172.
30. Food and Drug Administration, HHS. Final rule declaring dietary supplements containing ephedrine alkaloids adulterated because they present an unreasonable risk. Final rule. Fed. Regist. 2004, 69, 6787.
31. N. Rasmussen, P. H. J. Keizers. History full circle: ‘Novel’ sympathomimetics in supplements. Drug Test. Anal. 2015. DOI:10.1002/dta.1852.
32. P. A. Cohen. DMAA as a dietary supplement ingredient. Arch. Intern. Med. 2012, 172, 1038.
33. P. A. Cohen, J. C. Travis, B. J. Venhuis. A methamphetamine analog (N,α-diethyl-phenylethylamine) identified in a mainstream dietary supplement. Drug Test. Anal. 2014, 6, 805.
34. P. A. Cohen, J. C. Travis, B. J. Venhuis. A synthetic stimulant never tested in humans, 1,3-dimethylbutylamine (DMBA), is identified in multiple dietary supplements. Drug Test. Anal. 2015, 7, 83.
35. D. Kwiatkowska, M. Wójtowicz, A. Jarek, C. Goebel, K. Chajewska, E. Turek-Lepa, A. Pokrywka, R. Kazlauskas. N, N-dimethyl-2-phenylpropan-1-amine–new designer agent found in athlete urine and nutritional supplement. Drug Test. Anal. 2015, 7, 331.
36. M. Verho, V. Malerczyk, G. Kauert, H. Lorenz. Dose linearity and relative bioavailability testing of oxilofrine, a sympathicomimetic drug, in healthy volunteers. Int. J. Clin. Pharm. Res. 1988, 8, 211.
37. P. Dominiak, F. Kees, D. Welzel, H. Grobecker. Cardiovascular parameters and catecholamines in volunteers during passive orthostasis. Arzneim.-Forsch. 1992, 42, 637.
38. K. Pohl, W. Kriech. Therapie orthostatischer Kreislaufregulationsstörungen: Plazebo-kontrollierte Doppelblindstudie mit Oxilofrin. Herz Kreislauf. 1991, 109, 685.
39. G. Kauert, C. Angermann, H. Lex, C. Spes. Clinical pharmacokinetics after a single oral dose of oxilofrine. Int. J. Clin. Pharm. Res. 1988, 8, 307.
40. 2O anesthesia in man. Kitasato Med. 1979, 9, 267.
41. K. Matthes, F. Gross. Untersuchungen über das Wirkungsbild gefäβaktiver Pharmaka beim Menschen. II. Mitteilung: sympathicomimetica. Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 1944, 203, 206.
42. F. Meyer, W. Spiegelhoff. Der Einfluβ peripher angreifender Kreislaufmittel auf Herzleistung, arteriellen Windkessel und Strömungswiderstand: Untersuchungen am gesunden Menschen. Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 1938, 190, 256.
43. A. Sturm, F. Stückmann. Die stufentonosphygmographische Analyse der Kreislaufwirkung des Suprifens. Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 1937, 186, 287.
44. H. Fasching. Vergleichende Versuche über Kreislaufmittel am Menschen. Z. Ges. Exp. Med. 1937, 100, 378.
45. H. W. Bansi, M. Kalinke. Einwirkung der Analeptika auf den Kreislauf. II Mitteilung: Veränderung der Blutumlaufszeit sowie der arteriellen und venösen Blutgase nach Verabfolgung verschiedener Analeptika. Z. Ges. Exp. Med. 1938, 103, 301.
46. H. G. Dennemark. Hypertension und Adrenalinumkehrwirkung. Ther. Gegen. 1951, 90, 257.
47. A. Czech. Praktische notizen: Aspasan als Inhalat und in Tablettenform. Ärzt. Wochen. 1947, 1/2, 572.
48. G. Rudofsky, F.-E. Brock. Wirkungen von intravenöser Carnigen®-Gabe auf die Venenkapazität der unteren Extremitäten bei Gesunden. Herz Kreislauf. 1979, 11, 394.
49. E. Walczok, I. Marx-Heep, H. J. Adams. Sympthomimetische Therapie bei hypotonen Jugendlichen. Ärzt. Prax. 1980, 32, 319.
50. J. Iravani, I. Marx-Heep, H. J. Adams. Verhalten orthostatischer Reaktionsphasen im Liege-Steh-Test unter sympathikomimetischer Behandlung Therapiewoche. 1978, 28, 6055.
51. F. Zind, H.-J. Adams. Ergebnisse einer symathomimetischen Therapie bei Patienten mit ausgeprägter Hypotonie. Therapiewoche. 1980, 30, 6035.
52. U. Oesingmann, H.-J. Adams, I. Marx-Heep. Zur Frage der differenzierten Therapie hypoton-orthostatischer Kreislaufregulationsstörungen. Therapiewoche. 1981, 31, 2046.
53. E. Thäle, I. Marx-Heep, H.-J. Adams. Sympathikomimetische Therapie der orthostatischen Insuffizienz. Z. Allgemeinmed. 1980, 56, 1102.
54. H. Mayer, I. Marx-Heep, H.-J. Adams. Ergebnisse einer Feldstudie mit Carnigen®-Dragees bei orthostatisch-hypotonen Kreislauf-Regulationsstörungen. Fortschr. Med. 1976, 94, 215.
55. C. Angermann. Effekt einer intravenösen Gabe der Kombination von Oxilofrin mit einem Nukleosid-haltigen Organextrakt auf kardiovaskuläre Funktionsgröβen bei Herzgesunden. Herz Kreislauf. 1984, 5, 254.
56. V. Grigolato, G. C. Maggi, S. Ragaini. Studio clinico di un preparato di associazione con adenosine ed una sostanza simpaticomimetica (“Carnigen”) nelle affezioni coronariche. Gazz. Med. It. 1960, 119, 368.
57. J. Schmidt-Voigt. Therapeutische Erfahrungen mit Carnigen bei orthostatischen Kreislaufstörungen. Medizin. 1954, 15, 513.
58. Anon. Neue Arzneimittel, Spezialtäten und Vorschriften. Pharm. Zentralhalle Dtschl. 1942, 83, 128.
59. F. Eiden, G. Khammash. Über die Analyse flüssiger Hustenarzneimittel. Pharm. Zeit. 1972, 117, 1503.
60. A. I. Geller, N. Shehab, N. J. Weidle, M. C. Lovegrove, B. J. Wolpert, B. B. Timbo, R. P. Mozersky, D. S. Budnitz. Emergency department visits for adverse events related to dietary supplements. N. Eng. J. Med. 2015, 373, 1531.
61. P. A. Cohen. Hazards of hindsight — monitoring the safety of nutritional supplements. N. Engl. J. Med. 2014, 370, 1277.
62. A. Eichner, T. Tygart. Adulterated dietary supplements threaten the health and sporting career of up-and-coming young athletes. Drug Test. Anal. 2016. DOI:10.1002/dta.1899.
63. M. W. Evans, H. Ndetan, M. Perko, R. Williams, C. Walker. Dietary supplement use by children and adolescents in the United States to enhance sport performance: results of the National Health Interview Survey. J. Primary Prevent. 2012, 33, 3.
64. S. Attipoe, P. A. Cohen, A. Eichner, P. A. Deuster. Variability of stimulant levels in nine sports supplements over a nine-month period. Int. J. Sport Nutr. Exerc. Metab. 2016epub ahead of print.
65. P. A. Cohen, S. Attipoe, J. Travis, M. Stevens, P. Deuster. Caffeine content of dietary supplements consumed on military bases. JAMA Intern. Med. 2013, 173, 592.
66. Carnigen® Albert-Roussel. In: Bundesverband der Pharmazeutischen Industrie e.V. (Ed). Rote Liste 1983. Editio Cantor Aulendorf: Württ, 1983.