The Journal of Korean Medicine (대한한의학회지)

The Society of Korean Medicine (대한한의학회)
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A Review on Safety of Herbal Medicines for Doping

한약의 도핑 안전성에 대한 고찰

  • Kim, Ju-ran (Department of Acupuncture & Moxibustion medicine, College of Korean medicine, Daegu Haany University) ;
  • Yun, Sung Joong (Anti-dopping committee in Society of Sports Korean Medicine) ;
  • Lee, Yun Kyu (Department of Acupuncture & Moxibustion medicine, College of Korean medicine, Daegu Haany University) ;
  • Lee, Hyun-Jong (Department of Acupuncture & Moxibustion medicine, College of Korean medicine, Daegu Haany University) ;
  • Kim, Jae Soo (Department of Acupuncture & Moxibustion medicine, College of Korean medicine, Daegu Haany University)
  • 김주란 (대구한의대학교 한의과대학 침구의학교실) ;
  • 윤성중 (대한스포츠한의학회 도핑방지위원회) ;
  • 이윤규 (대구한의대학교 한의과대학 침구의학교실) ;
  • 이현종 (대구한의대학교 한의과대학 침구의학교실) ;
  • 김재수 (대구한의대학교 한의과대학 침구의학교실)
  • Received : 2019.08.12
  • Accepted : 2019.08.29
  • Published : 2019.09.01
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Abstract

Objectives: This study aims to review the herbal medicines containing substances banned by World Anti-Doping Agency(WADA), and to consider criteria for the using of herbal medicines. Methods: Using foreign(Pubmed, Cochrane, Embase, Google Scholar, WANFANG, CiNii) and domestic databases (NDSL, OASIS, RISS), we analyzed the content and pharmacokinetics of the prohibited substances in herbal medicines. Results: Herbal medicines containing the prohibited substances proposed in Korea, China, and Japan are Ephedrae Herba, Cannabis Semen, Strychni Semen, Strychni Ignatii Semen, Pinelliae Tuber, Rhizoma Pinelliae, Chelidonii Herba, Papaveris Fructus Deseminatus, Liriopis Tuber, Rehmanniae Radix Recens, Cistanchis Herba, Ponciri Fructus Immaturus, Aurantii Fructus Immaturus, Moschus, Testudinis Plastrum, Otariae Testis et Penis, and Hominis Placenta. Of these, when using Ephedrae Herba, Cannabis Semen, Strychni Semen, Moschus, Strychni Ignatii Semen, and Otariae Testis et Penis, caution is needed in relation to the doping test. Other herbal medicines are considered safe for the doping test. In addition, by analyzing data related to higenamine added to the WADA's prohibited list of doping since 2017, we don't recommend using Nelumbinis Plumula. And in the case of the other herbal medicines containing higenamine, it is considered that care should be taken in doping test depending on the amount of usage. Conclusions: As a result of analyzing the herbal medicines which are in prohibited list about doping, we were able to know the criteria and precautions to use when prescribing the herbal medicines. Further research will be needed about common used herbal medicines and the amount of detection depending on extraction and boiling method.

Keywords

References

  1. Verroken M. Drug use and abuse in sport. Baillieres Best Pract Res Clin Endocrinal Metab. 2000;14:1-23. https://doi.org/10.1016/S1521-6942(00)90096-2
  2. Kim JH. Sports-moral and ethical aspects. Seoul:Rainbowbooks. 2015:97-9.
  3. Lee HS. Sports sociology. Seoul:Sungshin press. 2004:301.
  4. Kim JR. A counter-strategy of Korea for anti-doping policy in world sports [dissertation]. Seoul: Hansung University; 2002.
  5. Judkins C, Prock P. Supplements and inadvertent doping - how big is the risk to athletes. Med Sport Sci. 2012;59:143-52. https://doi.org/10.1159/000341970
  6. Kim JK, Chun YS, Kang SK, Cho HC. The use of herbal/traditional products supplementation and doping tests in elite athletes. Korean Journal of Sport Science. 2009;20(4):734-42. https://doi.org/10.24985/kjss.2009.20.4.734
  7. Yun SJ, Je JJ, Lee H, Kim YJ, Lee HS. Anti-dopping of herbal medicine in 2015. J Sports Korean Med. 2015;15(1):1-9.
  8. Kim JK, Kang SK, Jung HS, Chun YS, Trilk J, Jung SH. Dietary supplementation patterns of Korean olympic athletes participating in the Beijing 2008 summer olympic games. Int J Sport Nutr Exerc Metab. 2011 Apr;21(2):166-74.
  9. Yun SJ. Anti-doping of herbal medicine in 2018. The Korean Medicine Times. 2018 Jul 2;2171:23 (col. 1).
  10. World anti-doping agency(WADA) [Internet]. Montreal(Quebec): WADA 2018; c2018 [cited 2018 Oct 3]. Available from: https://www.wada-ama.org/.
  11. Korea anti doping agent [Internet]. Seoul: KOREA ANTI-DOPING AGENCY; c2014 [cited 2018 Oct 3]. Available from: https://www.kada-ad.or.kr/.
  12. China anti-doping agency [Internet]. Beijing: CHINADA; c2015-2016 [cited 2018 Oct 3]. Available from: http://www.chinada.cn/.
  13. CFDA [Internet]. Beijing: CFDA [cited 2018 Oct 3]. Available from: http://eng.sfda.gov.cn/WS03/CL0755/.
  14. Japan anti-doping agency(JADA) [Internet]. Tokyo: JAPAN Anti-Doping Agency; [cited 2018 Oct 3]. Available from: https://www.playtruejapan.org/.
  15. JSPO [Internet]. Tokyo: Japan Sport Association; [cited 2018 Oct 3]. Available from: https://www.japan-sports.or.jp/.
  16. Tokyo pharmaceutical association [Internet]. Tokyo: TOKYO PHARMACEUTICAL ASOCIATION; [cited 2018 Oct 3]. Available from: http://www.toyaku.or.jp/index.html.
  17. UEFA [Internet]. Switzerland: UEFA; c1998-2018. UEFA competitions cases: July-december 2016; 2017 Apr 19 [cited 2018 Nov 24]; [about 104 p.]. Available from: https://www.uefa.com/MultimediaFiles/Download/OfficialDocument/uefaorg/UEFACompDisCases/02/45/96/63/2459663_DOWNLOAD.pdf.
  18. Ministry of Food and Drug Safety [Internet]. Cheongju: Ministry of Food and Drug Safety; The Korean pharmacopoeia 11th edition; 2018 Oct 14 [cited 2018 Nov 24]; [about 2554 p.]. Available from: http://drug.mfds.go.kr/html/menuLinkBody.jsp?p_menuId=0514.
  19. Andraws R, Chawla P, Brown DL. Cardiovascular effects of ephedra alkaloids: A comprehensive review. Prog Cardiovasc Dis. 2005 Jan-Feb; 47(4):217-25. https://doi.org/10.1016/j.pcad.2004.07.006
  20. Herbal Pharmacology textbook compilation committee, editor. Herbal pharmacology. 4th ed. Seoul:Shinilbooks. 2015:202-7, 260-5, 348-64, 365-9, 733-5, 799-803, 877-80, 934-7.
  21. Kim HC. Herbal medicine pharmacology. Seoul:Jipmoon. 2001:63-6, 180..
  22. Rice J, Proctor K, Lopardo L, Evans S, Kasprzyk-Hordern B. Stereochemistry of ephedrine and its environmental significance: Exposure and effects directed approach. J Hazard Mater. 2018 Apr 15;348:39-46. https://doi.org/10.1016/j.jhazmat.2018.01.020
  23. Soni MG, Carabin IG, Griffiths JC, Burdock GA. Safety of ephedra: Lessons learned. Toxicol Lett. 2004 Apr 15;150(1):97-110. https://doi.org/10.1016/j.toxlet.2003.07.006
  24. Maglione M, Miotto K, Iguchi M, Jungvig L, Morton SC, Shekelle PG. Psychiatric effects of ephedra use: An analysis of food and drug administration reports of adverse events. Am J Psychiatry. 2005 Jan;162(1):189-91. https://doi.org/10.1176/appi.ajp.162.1.189
  25. Song YK, Lim HH. Clinical application of ma huang in the obesity treatment. Journal of Society of Korean Medicine for Obesity Research. 2007;7(1):1-7.
  26. Astrup A, Toubro S. Thermogenic, metabolic, and cardiovascular responses to ephedrine and caffeine in man. Int J Obes Relat Metab Disord. 1993 Feb;17 Suppl 1:S41-3.
  27. Wilkinson GR, Beckett AH. Absorption, metabolism, and excretion of the ephedrines in man. II. Pharmacokinetics. J Pharm Sci. 1968 Nov;57(11):1933-8. https://doi.org/10.1002/jps.2600571122
  28. Haller CA, Jacob P 3rd. Benowitz NL. Pharmacology of ephedra alkaloids and caffeine after single-dose dietary supplement use. Clin Pharmacol Ther. 2002 Jun;71(6):421-32. https://doi.org/10.1067/mcp.2002.124523
  29. Pickup ME, May CS, Ssendagire R, Paterson JW. The pharmacokinetics of ephedrine after oral dosage in asthmatics receiving acute and chronic treatment. Br J Clin Pharmacol. 1976 Feb;3(1):123-34. https://doi.org/10.1111/j.1365-2125.1976.tb00579.x
  30. Gurley BJ, Gardner SF, White LM, Wang PL. Ephedrine pharmacokinetics after the ingestion of nutritional supplements containing Ephedra sinica (ma huang). Ther Drug Monit. 1998 Aug;20(4):439-45. https://doi.org/10.1097/00007691-199808000-00015
  31. Chan KH, Pan RN, Hsu MC. Simultaneous quantification of six ephedrines in a Mahwang preparation and in urine by high‐performance liquid chromatography. Biomed Chromatogr. 2005 Jun;19(5):337-42. https://doi.org/10.1002/bmc.452
  32. Tseng YL, Shieh MH, Kuo FH. Metabolites of ephedrines in human urine after administration of a single therapeutic dose. Forensic Sci Int. 2006 Mar 10;157(2-3):149-55. https://doi.org/10.1016/j.forsciint.2005.04.008
  33. Kojima A, Nishitani Y, Sato M, Kageyama S, Dohi M, Okano M. Comparison of urine analysis and dried blood spot analysis for the detection of ephedrine and methylephedrine in doping control. Drug Test Anal. 2016 Feb;8(2):189-98. https://doi.org/10.1002/dta.1803
  34. White LM, Gardner SF, Gurley BJ, Marx MA, Wang PL, Estes M. Pharmacokinetics and cardiovascular effects of ma‐huang (Ephedra sinica) in normotensive adults. J Clin Pharmacol. 1997 Feb;37(2):116-22. https://doi.org/10.1002/j.1552-4604.1997.tb04769.x
  35. He F, Luo J, Chen F, Yu L. Human pharmacokinetics of ephedrine and pseudoephedrine in Mahuang Tang by GC-MS. Traditional Chinese Drug Research and Clinical Pharmacology. 2004 Sep;15(5):336-8,347. https://doi.org/10.3321/j.issn:1003-9783.2004.05.012
  36. Chan KH, Pan RN, Hsu MC, Hsu KF. Urinary elimination of ephedrines following administration of the traditional Chinese medicine preparation Kakkon-to. J Anal Toxicol. 2008 Nov-Dec;32(9):763-7. https://doi.org/10.1093/jat/32.9.763
  37. Chan KH, Hsu MC, Chen FA, Hsu KF. Elimination of ephedrines in urine following administration of a Sho-seiryu-to preparation. J Anal Toxicol. 2009 Apr;33(3):162-6. https://doi.org/10.1093/jat/33.3.162
  38. Jo YK. The study on anti-doping stability of ojeok-san by measuring ephedrine concentration of urine after taking ojeok-san [dissertation]. Seoul: KyungHee University; 2012.
  39. Strano-Rossi S, Leone D, de la Torre X, Botre F. The relevance of the urinary concentration of ephedrines in anti-doping analysis: Determination of pseudoephedrine, cathine, and ephedrine after administration of over-the-counter medicaments. Ther Drug Monit. 2009 Aug;31(4):520-6. https://doi.org/10.1097/FTD.0b013e3181ac6006
  40. Strano-Rossi S, Leone D, de la Torre X, Botre F. Analysis of stimulants in oral fluid and urine by gas chromatography-mass spectrometry II: Pseudophedrine. J Anal Toxicol. 2010 May;34(4):210-5. https://doi.org/10.1093/jat/34.4.210
  41. Barroso O, Goudreault D, Carbo Banus ML, Ayotte C, Mazzoni I, Boghosian T, et al. Determination of urinary concentrations of pseudoephedrine and cathine after therapeutic administration of pseudoephedrine-containing medications to healthy subjects: Implications for doping control analysis of these stimulants banned in sport. Drug Test Anal. 2012 May;4(5):320-9. https://doi.org/10.1002/dta.291
  42. Lee MK, Cheng BW, Che CT, Hsieh DP. Cytotoxicity assessment of Ma-huang (Ephedra) under different conditions of preparation. Toxicol Sci. 2000 Aug;56(2): 424-30. https://doi.org/10.1093/toxsci/56.2.424
  43. Lee NR, Ha HK, Shin HK, Seo CS. Quantification, anti-inflammatory and antioxidant effects of mahwang-tang decoction according to the storage temperature and period. Kor J Pharmacogn. 2018;49(2):172-81.
  44. Seo CS, Shin HK. Quantitative determination of twelve bioactive components in mahwang-tang, a traditional herbal prescription, using an LC-MS/MS. Yakhak Hoeji. 2016;60(6):320-6. https://doi.org/10.17480/psk.2016.60.6.320
  45. Song MY, Kim HJ, Lee MJ. The safety guidelines for use of ma-huang in obesity treatment. Journal of Korean Oriental Association for Study of Obesity. 2006;6(2):17-27.
  46. Tyler VE. Herbs of choice: The therapeutic use of phytomedicinals. New York:Pharmaceutical procucts press. 1994:88-90.
  47. Tong JY, Chao J, Dai YT, Fan ZQ, Wang DD, Qin XM, et al. Establish quality evaluation system for standard ephedrae herba decoction. Zhongguo Zhong Yao Za Zhi. 2017 Mar;42(5):823-9.
  48. Aghdasi M, Bojnoordi MM, Mianabadi M, Nadaf M. Chemical components of the Ephedra major from Iran. Nat Prod Res. 2016;30(3):369-71. https://doi.org/10.1080/14786419.2015.1058794
  49. Herbalism textbook compilation committee, editor. Herbalism. 2nd ed. Seoul:Young Lim Press. 2011:231-3, 289-90, 313-4, 392-5, 645-7, 677-8, 726.
  50. Nahas GG. Marijuana in science and medicine. New York:Raven Press. 1984:25.
  51. Bosy TZ, Cole KA. Consumption and quantitation of delta9-tetrahydrocannabinol in commercially available hemp seed oil products. J Anal Toxicol. 2000 Oct;24(7):562-6. https://doi.org/10.1093/jat/24.7.562
  52. Cooper ZD, Haney M. Actions of delta-9-tetrahydrocannabinol in cannabis: Relation to use, abuse, dependence. Int Rev Psychiatry. 2009 Apr;21(2):104-12. https://doi.org/10.1080/09540260902782752
  53. Katzung BG, Masters SB, Tevor AJ. Basic and clinical pharmacology. 12th ed. Seoul:Panmun. 2014:42, 587.
  54. Ware MA, Jensen D, Barrette A, Vernec A, Derman W. Cannabis and the health and performance of the elite athlete. Clin J Sport Med. 2018 Sep;28(5):480-4. https://doi.org/10.1097/JSM.0000000000000650
  55. Hilderbrand RL. Hemp & cannabidiol: What is a medicine? Mo Med. 2018 Jul-Aug;115(4):306-9.
  56. Lowe RH, Abraham TT, Darwin WD, Herning R, Cadet JL, Huestis MA. Extended urinary ${\Delta}9$-tetrahydrocannabinol excretion in chronic cannabis users precludes use as a biomarker of new drug exposure. Drug Alcohol Depend. 2009 Nov 1;105(1-2):24-32. https://doi.org/10.1016/j.drugalcdep.2009.05.027
  57. Ellis GM Jr, Mann MA, Judson BA, Schramm NT, Tashchian A. Excretion patterns of cannabinoid metabolites after last use in a group of chronic users. Clin Pharmacol Ther. 1985 Nov;38(5):572-8. https://doi.org/10.1038/clpt.1985.226
  58. Campos DR, Yonamine M, de Moraes Moreau RL. Marijuana as doping in sports. Sports Med. 2003;33(6):395-9. https://doi.org/10.2165/00007256-200333060-00001
  59. Brenneisen R, Meyer P, Chtioui H, Saugy M, Kamber M. Plasma and urine profiles of ${\Delta}9$-tetrahydrocannabinol and its metabolites 11-hydroxy-${\Delta}9$-tetrahydrocannabinol and 11-nor-9-carboxy-${\Delta}9$-tetrahydrocannabinol after cannabis smoking by male volunteers to estimate recent consumption by athletes. Anal Bioanal Chem. 2010 Apr;396(7):2493-502. https://doi.org/10.1007/s00216-009-3431-3
  60. Toennes SW, Ramaekers JG, Theunissen EL, Moeller MR, Kauert GF. Pharmacokinetic properties of ${\Delta}9$-tetrahydrocannabinol in oral fluid of occasional and chronic users. J Anal Toxicol. 2010 May;34(4):216-21. https://doi.org/10.1093/jat/34.4.216
  61. Kauert GF, Ramaekers JG, Schneider E, Moeller MR, Toennes SW. Pharmacokinetic properties of ${\Delta}9$-tetrahydrocannabinol in serum and oral fluid. J Anal Toxicol. 2007 Jun;31(5):288-93. https://doi.org/10.1093/jat/31.5.288
  62. Hunault CC, Mensinga TT, de Vries I, Kelholt-Dijkman HH, Hoek J, Kruidenier M, et al. Delta-9-tetrahydrocannabinol (THC) serum concentrations and pharmacological effects in males after smoking a combination of tobacco and cannabis containing up to 69 mg THC. Psychopharmacology (Berl). 2008 Dec;201(2):171-81. https://doi.org/10.1007/s00213-008-1260-2
  63. Hunault CC, van Eijkeren JC, Mensinga TT, de Vries I, Leenders ME, Meulenbelt J. Disposition of smoked cannabis with high ${\Delta}9$-tetrahydrocannabinol content: A kinetic model. Toxicol Appl Pharmacol. 2010 Aug 1;246(3):148-53. https://doi.org/10.1016/j.taap.2010.04.019
  64. Zuurman L, Roy C, Schoemaker RC, Hazekamp A, den Hartigh J, Bender JC, et al. Effect of intrapulmonary tetrahydrocannabinol administration in humans. J Psychopharmacol. 2008 Sep;22(7):707-16. https://doi.org/10.1177/0269881108089581
  65. Pacifici R, Pichini S, Pellegrini M, Tittarelli R, Pantano F, Mannocchi G, et al. Determination of cannabinoids in oral fluid and urine of "light cannabis" consumers: A pilot study. Clin Chem Lab Med. 2018 Dec 19;57(2):238-43. https://doi.org/10.1515/cclm-2018-0566
  66. Lemberger L, Tamarkin NR, Axelrod J, Kopin IJ. Delta-9-tetrahydrocannabinol: Metabolism and disposition in long-term marihuana smokers. Science. 1971 Jul 2;173(3991):72-4. https://doi.org/10.1126/science.173.3991.72
  67. General information on herbal medicine [Internet]. Cheongju: National Institute of Food and Drug Safety Evaluation; c2009. Strychni Ignatii Semen; [cited 2018 Nov 18]; [about 1 p.]. Available from: http://nifds.go.kr/herb/m_442/view.do;jsessionid=u45mKSqBUljNUaMuzwQvB29NZjHdkwRgwxelQTMPSAjn5unI0MvSyh0AE3A8jt7c.nifds_was2_servlet_engine1?code=KHP-N136&page=22.
  68. Gu ZP, Zhang SM, Wang CL, Lian WY, Xiao PG, Chen JM. Determation of strychnine and brucine in strychnos by HPLC. Yao Xue Xue Bao. 1997 Oct;32(10):791-4.
  69. Duverneuil C, de la Grandmaison GL, de Mazancourt P, Alvarez JC. Liquid chromatography/photodiode array detection for determination of strychnine in blood: A fatal case report. Forensic Sci Int. 2004 Apr 20;141(1):17-21. https://doi.org/10.1016/j.forsciint.2003.12.010
  70. Emergency Response Safety and Health Database [Internet]. Atlanta: The National Institute for Occupational Safety and Health (NIOSH). [date unknown] - . STRYCHNINE : Biotoxin; [reviewed 2011 May 12; cited 2018 Nov 29]; [about 12 screens]. Available from: https://www.cdc.gov/niosh/ershdb/emergencyresponsecard_29750018.html.
  71. Gossel TA, Bricker JD, editors. Principles of clinical toxicology. 3rd ed. New York:Raven Press. 1994:351.
  72. Goodman LS, Gilman AG. Goodman and gilman's the pharmacological basis of therapeutics. New York:Macmillan Publishing & Co., Inc.. 1985:582-4.
  73. Ellenhorn MJ, Schonwald S, Ordog G, Wasserberger J. Ellenhorn's medical toxicology: Diagnosis and treatment of human poisoning. 2nd ed. Baltimore, MD:Williams and Wilkins. 1997:1660.
  74. Palatnick W, Meatherall R, Sitar D, Tenenbein M. Toxicokinetics of acute strychnine poisoning. J Toxicol Clin Toxicol. 1997;35(6):617-20. https://doi.org/10.3109/15563659709001242
  75. Edmunds M, Sheehan TM, Van't Hoff W. Strychnine poisoning: Clinical and toxicological observations on a non-fatal case. J Toxicol Clin Toxicol. 1986;24(3):245-55. https://doi.org/10.3109/15563658608990462
  76. Wood DM, Webster E, Martinez D, Dargan PI, Jones AL. Case report: Survival after deliberate strychnine self-poisoning, with toxicokinetic data. Crit Care. 2002 Oct;6(5):456-9. https://doi.org/10.1186/cc1549
  77. Gupta RC, Patocka J. Handbook of toxicology of chemical warfare agents. London:Academic Press. 2009:199.
  78. Van Eenoo P, Deventer K, Roels K, Delbeke FT. Quantitative LC–MS determination of strychnine in urine after ingestion of a strychnos nux-vomica preparation and its consequences in doping control. Forensic Sci Int. 2006 Dec 20;164(2-3):159-63. https://doi.org/10.1016/j.forsciint.2005.12.029
  79. Li J, Jiang Y. Rapid and sensitive determination of strychnine and brucine in human urine by capillary electrophoresis with field‐amplified sample stacking. Biomed Chromatogr. 2010 Feb;24(2):186-94. https://doi.org/10.1002/bmc.1270
  80. Kong HY, Zhou W, Guo PH, Sang ZC, Wu GN, Chen YJ, et al. Safety of individual medication of Ma Qian Zi (semen strychni) based upon assessment of therapeutic effects of Guo's therapy against moderate fluorosis of bone. J Tradit Chin Med. 2011 Dec;31(4):297-302. https://doi.org/10.1016/S0254-6272(12)60007-7
  81. Xu T, Zhang Y, Yu J. HPLC determination of strychnine in nux vomica powder. Heilongjiang Medicine Journal. 2012;25(1):11-2. https://doi.org/10.3969/j.issn.1006-2882.2012.01.006
  82. Tang HB, Zhang LJ, Li XL, Sun CF, Ma PJ. The experimental study of diferent solvent extracting total alkaloid from semen strychni. Guiding Journal of Traditional Chinese Medicine and Pharmacy. 2009;15(11):52-3.
  83. Hu TG. Impact of traditional chinese medicine processing on physicochemical properties and efficacy of herbs. E-J Transl Med. 2015;2(4):115-6.
  84. Xu WF, Zhang BG, Li M, Liu GH. Determination of ephedrine in rhizoma pinelliae, rhizoma typhonii flagelliformis and their processed products by HPLC. LISHIZHEN MEDICINE AND MATERIA MEDICA RESEARCH. 2007;18(4):884-5. https://doi.org/10.3969/j.issn.1008-0805.2007.04.061
  85. Qi HH, Wu JL, Xiang LY, Duan GL. Determination of ephedrine hydrochloride and pseudoephedrine hydrochloride in rhizoma pinelliae granules by HPLC. Science and Technology Innovation Herald. 2008 Aug 12;16:2 (col. 1).
  86. Li ZH, Nie J, Ni KY, Du GH. Comparison of raizoma pinelliae from different producing areas. JOURNAL OF ANALYTICAL SCIENCE. 2005;21(4):393-5. https://doi.org/10.3969/j.issn.1006-6144.2005.04.012
  87. Zhu JJ, Guo ZY, Zhou Y, Yang J, Wang JZ, Zou K. Determination of alkaloids and the ephedrine in wild and tissue culture pinellia ternata(thunb) breit. Paper presented at: Seminar on the development and protection of Chinese herbal medicine and natural product resources; 2009 Sep 13; China Association for Pharmaceuticals and Medical Devices Technology Exchange(CPDE), Guilin, China.
  88. Wu H, Tan X, Cai B, Ye D. Effect of ginger-processing on l-ephedrine contents in rhizoma pinelliae. Zhongguo Zhong Yao Za Zhi. 1996 Mar;21(3):157,158,190.
  89. Jeong JG. A herbological study on the plants of papaveraceae in Korea. Kor J Herbol. 2016;31(5):63-9. https://doi.org/10.6116/kjh.2016.31.5.63.
  90. Choe S, Kim S, Lee C, Yang W, Park Y, Choi H, et al. Species identification of Papaver by metabolite profiling. Forensic Sci Int. 2011 Sep 10;211(1-3):51-60. https://doi.org/10.1016/j.forsciint.2011.04.015
  91. Sarkozi A, Janicsak G, Kursinszki L, Kery A. Alkaloid composition of Chelidonium majus L. studied by different chromatographic techniques. Chromatographia. 2006;63(13):S81-6. https://doi.org/10.1365/s10337-006-0728-7
  92. State Administration of Traditional Chinese Medicine, editor. Chinese herbal medicine. Vol. 3. Beijing:Shanghai Science and Technology Press. 1999:616-9.
  93. Xinwenfeng Publishing Editorial Department, editor. New chinese medicine dictionary. Taipei: Xinwenfeng Publishing Co., Ltd.. 1981:605-6.
  94. Fu Z, Fan X, Wang X, Gao X. Cistanches herba: An overview of its chemistry, pharmacology, and pharmacokinetics property. J Ethnopharmacol. 2018 Jun 12;219:233-47. https://doi.org/10.1016/j.jep.2017.10.015
  95. Koehler K, Thevis M, Schaenzer W. Metaanalysis: Effects of glycerol administration on plasma volume, haemoglobin, and haematocrit. Drug Test Anal. 2013 Nov-Dec;5(11-12):896-9. https://doi.org/10.1002/dta.1580
  96. Haaz S, Fontaine KR, Cutter G, Limdi N, Perumean‐Chaney S, Allison DB. Citrus aurantium and synephrine alkaloids in the treatment of overweight and obesity: An update. Obes Rev. 2006 Feb;7(1):79-88. https://doi.org/10.1111/j.1467-789X.2006.00195.x
  97. Stohs SJ, Preuss HG, Shara M. A review of the receptor-binding properties of p-synephrine as related to its pharmacological effects. Oxid Med Cell Longev. 2011;2011:482973.
  98. Gutierrez-Hellin J, Salinero JJ, Abian-Vicen J, Areces F, Lara B, Gallo C, et al. Acute consumption of p-synephrine does not enhance performance in sprint athletes. Appl Physiol Nutr Metab. 2016 Jan;41(1):63-9. https://doi.org/10.1139/apnm-2015-0299
  99. Kaats GR, Miller H, Preuss HG, Stohs SJ. A 60 day double-blind, placebo-controlled safety study involving Citrus aurantium (bitter orange) extract. Food Chem Toxicol. 2013 May;55:358-62. https://doi.org/10.1016/j.fct.2013.01.013
  100. Stohs SJ, Preuss HG, Shara M. A review of the human clinical studies involving Citrus aurantium (bitter orange) extract and its primary protoalkaloid p-synephrine. Int J Med Sci. 2012;9(7):527-38. https://doi.org/10.7150/ijms.4446
  101. Medana C, Calza P, Giancotti V, Dal Bello F, Aragno M, Baiocchi C. Study of the photocatalytic transformation of synephrine: A biogenic amine relevant in anti-doping analysis. Anal Bioanal Chem. 2013 Jan;405(2-3):1105-13. https://doi.org/10.1007/s00216-012-6593-3
  102. Shara M, Stohs SJ, Smadi MM. Safety evaluation of p‐synephrine following 15 days of oral administration to healthy subjects: A clinical study. Phytother Res. 2018 Jan;32(1):125-31. https://doi.org/10.1002/ptr.5956
  103. Ke X, Liu J, Chen C. HPLC fa ce ding cang zuo pen bi ye ji zuo shi yao cai zhong xin fu lin de han liang. Traditional Chinese Drug Research and Clinical Pharmacology. 2003;14(1):45-6. https://doi.org/10.3321/j.issn:1003-9783.2003.01.018
  104. Luo Z, Jing H. Content determination of synephrine in citrus auarntium L. by reversed phase ion-pair HPLC. China Pharmacy. 2006;17(19):1502-3.
  105. Lu XF, Wang RJ, Peng G P, Deng YT. Determination of the content of synephrine in fructus aurantii immaturus by packed-column supercritical fluid chromatography. Liaoning Journal of Traditional Chinese Medicine. 2006;33(2):222-3. https://doi.org/10.3969/j.issn.1000-1719.2006.02.062
  106. Zhao Y, Xie PS, Lu PH, Wang XH, Yang H. Determination of synephrine in Fructus aurantii immatus, Fructus aurantii, Pericarpium citri reticulatae viride and Pericarpium citri reticulatae. World Science and Technology/Modernization of Traditional Chinese Medicine and Materia Medica. 2006;8(4):64,67,106.
  107. Nelson BC, Putzbach K, Sharpless KE, Sander LC. Mass spectrometric determination of the predominant adrenergic protoalkaloids in bitter orange (Citrus aurantium). J Agric Food Chem. 2007 Nov 28;55(24):9769-75. https://doi.org/10.1021/jf072030s
  108. Shawky E. Determination of synephrine and octopamine in bitter orange peel by HPTLC with densitometry. J Chromatogr Sci. 2014 Sep;52(8):899-904. https://doi.org/10.1093/chromsci/bmt113
  109. Tanaka S, Sekiguchi M, Yamamoto A, Aizawa S, Sato K, Taga A, et al. Separation of synephrine enantiomers in citrus fruits by a reversed phase HPLC after chiral precolumn derivatization. Anal Sci [Internet]. 2018 Dec 14 [cited 2018 Dec 15]:[about 27 p.]. Available from: https://doi.org/10.2116/analsci.18P441 doi:10.2116/analsci.18P441. PubMed PMID:30555107.
  110. Wang J, He Y, Liu X, Yang Z, Yang W. Steroid profile and IRMS analysis of musk administration for doping control. Drug Test Anal. 2017 Nov;9(11-12):1779-87. https://doi.org/10.1002/dta.2293
  111. Thevis M, Schanzer W, Geyer H, Thieme D, Grosse J, Rautenberg C, et al. Traditional Chinese medicine and sports drug testing: Identification of natural steroid administration in doping control urine samples resulting from musk (pod) extracts. Br J Sports Med. 2013 Jan;47(2):109-14. https://doi.org/10.1136/bjsports-2012-090988
  112. He Y, Wang J, Liu X, Xu Y, He Z. Influences of musk administration on the doping test. Steroids. 2013 Nov;78(11):1047-52. https://doi.org/10.1016/j.steroids.2013.06.010
  113. Zhang HL. Extracts from plastrum testudinis (PTD) promote proliferation of rat mesenchymal stem cell(MSCs) through BMP/ID pathway [dissertation]. Guangzhou: Guangzhou university of chinese medicine; 2009.
  114. State Administration of Traditional Chinese Medicine, editor. Chinese herbal medicine. Vol. 9. Beijing:Shanghai Science and Technology Press. 1999:536-40, 593-5.
  115. Granados J, Gillum TL, Christmas KM, Kuennen MR. Prohormone supplement 3b-hydroxy-5a-androst-1-en-17-one enhances resistance training gains but impairs user health. J Appl Physiol (1985). 2014 Mar 1;116(5):560-9. https://doi.org/10.1152/japplphysiol.00616.2013
  116. SLAUNWHITE WR Jr, SANDBERG AA. Metabolism of 4-C14-testosterone in human subjects III. Fate of androsterone and etiocholanolone. J Clin Endocrinol Metab. 1958 Oct;18(10):1056-66. https://doi.org/10.1210/jcem-18-10-1056
  117. Institute of pharmacopuncturology, editor. Pharmacopuncturology. Seoul:Elsevier Korea L.L.C.. 2008:200-7.
  118. Lee SK, Lee JD, Koh HK. The study on the Hominis Placenta aqua-acupuncture solution. The Journal of Korea Acupuncture & Moxibustion Society. 2000;17(1):67-74.
  119. NECA [Internet]. Seoul: NECA; c2017. Evaluation of medical technology regarding clinical effectiveness and safety of human placenta injection; 2010 Jul 19 [cited 2018 Nov 24]; [about 203 p.]. Available from: https://www.neca.re.kr/lay1/program/S1T11C145/report/view.do?seq=22.
  120. Melsmon [Internet]. Tokyo: Millennia Concepts (Official Website); c2015 [cited 2018 Nov 29]. Available from: http://melsmon.com/.
  121. Tsukiyama M, Ueki T, Yasuda Y, Kikuchi H, Akaishi T, Okumura H, et al. Β2-adrenoceptor-mediated tracheal relaxation induced by higenamine from Nandina domestica Thunberg. Planta Med. 2009 Oct;75(13):1393-9. https://doi.org/10.1055/s-0029-1185743
  122. Kashiwada Y, Aoshima A, Ikeshiro Y, Chen YP, Furukawa H, Itoigawa M, et al. Anti-HIV benzylisoquinoline alkaloids and flavonoids from the leaves of Nelumbo nucifera, and structure-activity correlations with related alkaloids. Bioorg Med Chem. 2005 Jan 17;13(2):443-8. https://doi.org/10.1016/j.bmc.2004.10.020
  123. Chang YC, Chang FR, Khalil AT, Hsieh PW, Wu YC. Cytotoxic benzophenanthridine and benzylisoquinoline alkaloids from Argemone mexicana. Z Naturforsch C. 2003 Jul-Aug;58(7-8):521-6.
  124. Kimura I, Chui LH, Fujitani K, Kikuchi T, Kimura M. Inotropic effects of ($\pm$)-higenamine and its chemically related components, ( )-Rcoclaurine and ( )-S-reticuline, contained in the traditional sino-japanese medicines "Bushi" and "Shin-i" in isolated guinea pig papillary muscle. Jpn J Pharmacol. 1989 May;50(1):75-8. https://doi.org/10.1254/jjp.50.75
  125. Bai G, Yang Y, Shi Q, Liu Z, Zhang Q, Zhu YY. Identification of higenamine in Radix Aconiti Lateralis Preparata as a beta2-adrenergic receptor agonist. Acta Pharmacol Sin. 2008 Oct;29(10):1187-94. https://doi.org/10.1111/j.1745-7254.2008.00859.x
  126. Kang YJ, Lee YS, Lee GW, Lee DH, Ryu JC, Yun-Choi HS, et al. Inhibition of activation of nuclear factor kappaB is responsible for inhibition of inducible nitric oxide synthase expression by higenamine, an active component of aconite root. J Pharmacol Exp Ther. 1999 Oct;291(1):314-20.
  127. Praman S, Mulvany MJ, Williams DE, Andersen RJ, Jansakul C. Hypotensive and cardio-chronotropic constituents of Tinospora crispa and mechanisms of action on the cardiovascular system in anesthetized rats. J Ethnopharmacol. 2012 Mar 6;140(1):166-78. https://doi.org/10.1016/j.jep.2012.01.006
  128. Minami H, Dubouzet E, Iwasa K, Sato F. Functional analysis of norcoclaurine synthase in Coptis japonica. J Biol Chem. 2007 Mar 2;282(9):6274-82. https://doi.org/10.1074/jbc.M608933200
  129. Zhang N, Lian Z, Peng X, Li Z, Zhu H. Applications of higenamine in pharmacology and medicine. J Ethnopharmacol. 2017 Jan 20;196:242-52. https://doi.org/10.1016/j.jep.2016.12.033
  130. Lee SR, Schriefer JM, Gunnels TA, Harvey IC, Bloomer RJ. Acute oral intake of a higenamine-based dietary supplement increases circulating free fatty acids and energy expenditure in human subjects. Lipids Health Dis. 2013 Oct 21;12:148. https://doi.org/10.1186/1476-511X-12-148
  131. Feng S, Jiang J, Hu P, Zhang JY, Liu T, Zhao Q, et al. A phase I study on pharmacokinetics and pharmacodynamics of higenamine in healthy chinese subjects. Acta Pharmacol Sin. 2012 Nov;33(11):1353-8. https://doi.org/10.1038/aps.2012.114
  132. Okano M, Sato M, Kageyama S. Determination of higenamine and coclaurine levels in human urine after the administration of a throat lozenge containing Nandina domestica fruit. Drug Test Anal. 2017 Nov;9(11-12):1788-93. https://doi.org/10.1002/dta.2258
  133. Du YR, Li F, Xu RY, Zhang Y, Ouyang M, Jing HL. Tolerability of higenamine hydrochloride in healthy volunteers. Chin J Clin Pharmacol. 2007;23(4):125-60.
  134. Tian HF. Determination of higenamine by reversed phase high performance liquid chromatography with precolumn derivatization [dissertation]. Yanji city: Yanbian university; 2011.
  135. Tian HF, Yi T, Jing DR. Determination of higenamine in Nelumbo nucifera by HPLC with precolumn derivatization. Journal of Yanbian University(Natural Sciene). 2012;38(2):150-3. https://doi.org/10.3969/j.issn.1004-4353.2012.02.015
  136. Yang M, He S, Zhang D, Sun B, Wang Y. Study on determination of higenamine in chinese medicinal materials by LC-MS/MS. China measurement & test. 2018;44(3):61-5.
  137. Kim SY, Geum DH, Lee MJ. A study on doping test of Bojungchisheup-tang. Korean J Ori Med. 1997;3(1):289-319.
  138. Yoo HJ. Verification of efficacy as an ergogenic aid and safety in doping of Sibjeondaebo-tang [dissertation]. Seoul: Kyunghee university; 2014.
  139. Lee JH. SK lim seok jin detection of doping...36 games 'suspension'. The Kyunghyang Shinmun. 2017 Oct 28;Sect. A:24 (col. 6).
  140. Kim HJ, Kwak BM, Ahn JH, Park JS. Simultaneous determination of synephrine and N-methyltyramine in orange fruit and juice from korean market by UPLC-FLD. Korean J Food Sci Technol. 2014;46(3):276-82. https://doi.org/10.9721/KJFST.2014.46.3.276
  141. Balasubramanian J, Maraicar KSH, Ananth DB, Vijayakumar N, Dhanalakishmi R. DHEA: The remedy for andropause. Indian J Med Healthcare. 2012 May;1(2):25-31.
  142. Son YI. Verification and verification, seeking 100% safety : The placenta, which has been processed for 11 weeks at the greencross placenta injection plant in chungbuk eumseong, has been turned into a medicine. Weekly Donga. 2009 Oct 27;(708):36-9.