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A Review on Safety of Herbal Medicines for Doping

Article information

J Korean Med. 2019;40(3):139-176
Publication date (electronic) : 2019 September 30
doi : https://doi.org/10.13048/jkm.19032
Ju-ran Kim1orcid_icon, Sung Joong Yun2,3orcid_icon, Yun Kyu Lee1orcid_icon, Hyun-Jong Lee1orcid_icon, Jae Soo Kim1,orcid_icon
1Department of Acupuncture & Moxibustion medicine, College of Korean medicine, Daegu Haany University
2Anti-dopping committee in Society of Sports Korean Medicine
3Kyunghee Jangsu Korean Medical clinic
Correspondence to: Jae Soo Kim, Department of Acupuncture & Moxibustion medicine, Daegu Oriental hospital of Daegu Haany University 136, Sincheondong-ro, Suseong-gu, Daegu, 706-828, Republic of Korea Tel: +82-53-770-2108, Fax: +82-53-770-2055, E-mail: jaice@daum.net
Received 2019 August 12; Revised 2019 August 28; Accepted 2019 August 29.

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: WADA; doping; safety; herbal medicines
Fig. 1

Structure of synephrine and isomer

The above is the structure of synephrine. The below three structures are the possible isomers of synephrine depending on the position of the phenolic hydroxyl group.

Herbal Medicines Prohibited In-competition

Herbal Medicines Prohibited at All Times

Pharmacokinetics of Ephedrine, Pseudoephedrine, Methylephedrine

Content of Ephedrine, Pseudoephedrine, Methylephedrine in Ephedrae Herba

Pharmacokinetics of Δ9-tetrahydrocannabinol (THC)

Pharmacokinetics of Strychnine

Content of Strychnine

Content of Ephedrine in Pinelliae Tuber, Rhizoma Pinelliae

Pharmacokinetics of Synephrine

Content of Synephrine

Steroid Content in Musk (μg/g)

Higenamine Content of Herbal Medicine according to the Method of Analysis

Content of Higenamine of Herbal Medicine according to the Extraction Method (μg/g)

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Article information Continued

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Fig. 1

Fig. 1

Structure of synephrine and isomer

The above is the structure of synephrine. The below three structures are the possible isomers of synephrine depending on the position of the phenolic hydroxyl group.

Table 1

Herbal Medicines Prohibited In-competition

Country Agency Prohibited herbal medicine
Korea Korea Anti Doping Agency(KADA)11) A. Herbal medicine containing prohibited substances

  • Ephedrae Herba

  • Cannabis Semen

  • Strychni Semen

  • Strychni Ignatii Semen
B. Herbal medicine that may contain a small amount of prohibited substances

  • Pinelliae Tuber

  • Rhizoma Pinelliae

  • Chelidonii Herba

  • Liriopis Tuber

  • Moschus

  • Rehmanniae Radix Recens

  • Cistanchis Herba

  • Ponciri Fructus Immaturus

  • Aurantii Fructus Immaturus

  • Testudinis Plastrum
C. Drugs manufactured from raw materials that may contain prohibited substances Hominis Placenta
China China Anti-Doping Agency(CHINADA)12) Not specified
China Food & Drug Administration(CFDA)13) Ephedrae Herba, Strychni Semen, Papaveris Fructus Deseminatus, Moschus (Artificial musk)
Japan Japan Anti-Doping Agency(JADA)14) Not specified
Japan Sport Association(JSPO)15) Ephedrae Herba, Strychni Semen
Tokyo Pharmaceutical Association16) Ephedrae Herba, Strychni Semen, Otariae Testis et Penis, Moschus

Table 2

Herbal Medicines Prohibited at All Times

Country Agency Prohibited herbal medicine
Korea Korea Anti Doping Agency(KADA)11) Not specified
China China Anti-Doping Agency(CHINADA)12)

  • Aconiti Lateralis Preparata Radix

  • Aconiti Tuber

  • Linderae Radix

  • Asia Radix

  • Nelumbinis semen

  • Nelumbinis Plumula (Do not prescribe 408 prescriptions containing this herbal medicine)
Japan Japan Anti-Doping Agency(JADA)14)

  • Nelumbinis semen

  • Tinospora crispa

  • Aconiti Lateralis Preparata Radix

  • Caryophylli Flos

  • Asia Radix

  • Nandina domestica

  • Evodiae Fructus (Do not prescribe 24 prescriptions containing this herbal medicine)

Table 3

Pharmacokinetics of Ephedrine, Pseudoephedrine, Methylephedrine

Year Author Doses and administration Clinical specimen E/PE/ ME PK parameter
1976 Pickup et al29) 22mg of E p.o. serum E Cmax: 79.4ng/mL, Tmax: 1.81h, T1/2: 6.75h
11mg of E p.o.(3 times/day, for 2 weeks) serum E Cmax: 87.4ng/mL, Tmax: 1.86h, T1/2: 6.69h
1997 White et al34) 4 capsules of a powdered ma-huang product* (375mg Ephedra sinica each) p.o.(twice/day) serum E Cmax: 81ng/mL., Tmax: 3.9h, mean T1/2: 5.20h
1998 Gurley et al30) 25mg of E p.o. serum E T1/2: 5.37h
2002 Haller et al28) 2 capsules of Metabolift Thermogenic Diet Formula† with water at 8 a.m.(10mg of ephedrine) p.o. serum E Cmax: 63.5ng/mL, Tmax: 2.4h, T1/2: 6.06±1.3h
PE Cmax: 24.1ng/mL, Tmax: 2.4h, T1/2: 6.26±1.6h
2004 He et al35) Mahuang tang‡ p.o. serum E Cmax: 248.50±32.97ng/mL, Tmax: 2.025±0.38h, T1/2: 4.230±1.01h
PE Cmax: 78.89±9.69ng/mL, Tmax: 2.019±0.297h, T1/2: 4.335±0.841h
2005 Chan et al31) 0.6 g of the Mahwang TCM preparation (the therapeutic single-dose amounts) p.o. urine E Cmax: 8.2±0.5μg/mL, Tmax: 7.0±4.8h, T1/2: 5.6±1.2h
PE Cmax: 4.1±0.4μg/mL, Tmax: 6.5±4.3h, T1/2: 4.9±0.9h
2006 Tseng et al32) 25mg of E, 30mg of PE, 20mg of ME p.o. urine E Cmax: 26.9±29.2μg/mL, Tmax: 2–6h
PE Cmax: 115.5±143.8μg/mL, Tmax: 2–6h
ME Cmax: 8.3±7.7μg/mL, Tmax: 4–12h

  • - E, PE in urine completely eliminated from the body at approximately 24–48 h and ME completely eliminated in approximately 48h.
2008 Chan et al36)

  1. single dose(2.5g) Kakkon-to§ extract granules p.o.

  2. multiple dose study; single dose (2.5g) Kakkon-to§ extract granules 3 times/day p.o.(for 3 days, to only one subject)

 urine E

  1. Cmax: 4.35±1.82μg/mL (eliminated by the 48h after administration)

  2. 39.03μg/mL

  • - Cmax: 5.33±1.47μg/mL, Tmax: 7.8±4.1h, T1/2: 5.2±1.2h
PE Cmax: 2.66±0.94 μg/mL, Tmax: 7.3±3.6h, T1/2: 4.2±0.9 h
2009 Chan et al37)

  1. single dose(2.5g) Sho-seiryu-to|| extract granules p.o.

  2. multiple dose study; single dose(2.5g) Sho-seiryu-to|| extract granules p.o.(3 times/day, for 3 days, to only 1 subject)

 urine E

  1. Cmax: 3.9±1.9μg/mL (eliminated by the 48h after administration)

  2. The first urine’s E concentration: 13.73μg/mL (at 3 days after administration)

  • - Cmax: 4.67±2.11μg/mL, Tmax: 4.75h, T1/2: 5.3±1.2h
PE Cmax: 2.40±1.26μg/mL, T1/2: 4.4±1.0h
2009 Strano-Rossi et al39) 60mg of PE p.o. urine PE

  • - 63.6μg/mL

  • - In 2 of 9 subjects, PE is more than 100μg/mL

  • - 160μg/mL

  • - In 4 of 7 subjects, PE is above 100μg/mL
60mg of PE p.o.(twice/day)
60mg of PE p.o.(twice/day, for 5 weeks) above 100μg/mL(maximum concentration is 275μg/mL.).
60mg of PE p.o.(3 times/day) above 100μg/mL.
12mg of sustained-release formulation of E p.o. E

  • - In 2 of 3 subjects, E is above 10μg/mL.
2010 Strano-Rossi et al40) 60mg of PE p.o. saliva PE

  • - 2h after administration, Cmax is 95ng/mL.

  • - 12h after administration, PE was detected at low concentration or not detected.
urine Tmax: 8–24h

  • - Some subjects was above 100μg/mL.

120mg of sustained-release formulation of PE p.o. saliva PE Cmax: 360ng/mL(at 2–4 h after administration
urine Cmax: 105μg/mL, Tmax: 8–24h
2012 Barroso et al41) 60mg of PE p.o.(4 times/day, for 2 days) (radomized, open-label, two-way crossover study) urine PE Cmax: 170.42μg/mL, Tmax: 36h, T1/2: 4.78h
120mg of PE p.o.(twice/day, for 2 days) (radomized, open-label, two-way crossover study) urine PE Cmax: 173.96μg/mL, Tmax: 44h, T1/2: 7.66h
120mg of PE p.o.(twice/day, for 2 days) (open-label, one-way study) urine PE Cmax: 99.52μg/mL, Tmax: 30h, T1/2: 7.43h
2012 Jo38) Multiple dose study; single dose (2.5g) Ojeok-san extract granules 3 times p.o. urine E Cmax: 3.71±1.5μg/mL, T1/2: 4.77±0.95h

  • - After last administration, Tmax is 3.25±1.79h

2016 Kojima et al33) 25mg of Ephedrine Nagai ® (ephedrine hydrochloride 25 mg/ tablet) and dl-methylephedrine urine E Cmax: 10.3–47.3μg/mL, Tmax: 12h
ME Cmax: 5.9–21.3μg/mL, Tmax: 12h
Powder Fuso ®** (dl-methylephedrine hydrochloride 100mg/g) p.o. serum E Cmax: 113.5–186.1ng/mL, Tmax: 2–8h
ME Cmax: 59.6–121.9ng/mL, Tmax: 2–3h
*

Solaray, Inc., Ogden, UT,

†

Weight loss aid manufactured by Twin Laboratories Inc, Ronkonkoma, NY

‡

First boil E. sinica Stapf 18g for 20 min, with 10 times water, and then boiled with remaining medicine (Cinnamomum cassia Presl 12g, Prunus armeniaca L. var. ansu Maxim. 12g, Glycyrrhiza uralensis Fisch 6g) for 30 min. After that, filter the boiled Mahuang tang.

§

Galgeun-tang,

||

Socheongryong-tang,

Purchased from Nichi-Iko Pharmaceutical Co., Ltd (Toyama, Japan)

**

Purchased from Fuso Pharmaceutical Industries, Ltd (Osaka, Japan)

PK: pharmacokinetics, p.o.: per oral, E: ephedrine, PE: pseudoephedrine, ME: methylephedrine, Cmax: the maximum (or peak) concentration that a drug achieves in a specified compartment, Tmax: the time that it takes a drug or other substance to reach the maximum concentration, T1/2: the time required for a quantity to reduce to half its initial value, h: hours

Table 4

Content of Ephedrine, Pseudoephedrine, Methylephedrine in Ephedrae Herba

Year Author Species Analysis method Extraction method E/PE/ ME Content
1994 Tyler46) - - 2g Ephedrae Herba boiled with 240 mL water, for 10min E 7.5-15mg/g
1997 White et al34) E.sinica UPLC 4 capsules of a powdered ma-huang product* (375mg Ephedra sinica each) twice a day p.o. E 19.4mg/g
PE 4.9mg/g
ME 1.2mg/g
2000 Lee et al42) - UPLC 20g of grinded or ungrinded ma-huang was extracted with 200mL water, for 0.5 or 2h. E

  • - When boiling ungrinded ma-huang for 0.5h (2h), the E content was 5.37mg/g (6.23mg/g).

  • - The concentration was higher when boiled for 2h than 0.5h

  • - The concentration was higher ungrinded ma-huang than grinded ma-huang.
2002 Haller et al28) - LC-MS/MS 2 capsules of Metabolift Thermogenic Diet Formula† with water at 8a.m.(equivalent to 10mg of ephedrine) p.o. E 17.3mg/g
PE 5.3mg/g
ME 0.5mg/g
2 capsules consisted of a total of 23.7mg ephedrine alkaloids
2005 Chan et al31) E.sinica Stapf HPLC 0.6g of the Mahwang TCM preparation(the therapeutic single-dose amounts) p.o. E 5660.20μg per 0.6g of the Mahwang TCM preparation
PE 2568.17μg per 0.6g of the Mahwang TCM preparation
ME 682.02μg per 0.6g of the Mahwang TCM preparation
2006 Song et al45) - UPLC 5g of ma-huang(A) or processed ma-huang‡ (B) were boiled with 300mL water for 15min, 30min, 1h, and 2h, respectively. E

  • - After 2h boiling, B’s E content was 21.4mg/g and A’s E content was 18.0mg/g.

  • - In a closed state for 1 day, B’s E content was 23.0mg/g and A’s E content was 19.7mg/g.

  • - The E was more extracted in B than A.

  • - The longer the heating time was, and the more E content was measured.

  • - When left in a closed state for 1 day than after boiling immediately, the more E content was measured.
2008 Chan et al36) - HPLC single dose (2.5g) of Kakkon-to§ extract granules E 3437.50μg/g
PE 1549.23μg/g
ME 415.65μg/g
2009 Chan et al37) - HPLC single dose (2.5g) of Sho-seiryu-to|| extract granules E 2984.2μg/g
PE 1353.6μg/g
ME 361.9μg/g
2016 Aghdasi et al48) E.major HPLC - E

  • - E was not detected in the root of ma-huang.

  • - Dry weight E was 1.21-2.112mg/g in the stem of ma-huang.
2016 Seo et al44) E.sinica Stapf LC-MS/MS 5kg of ma-huang tang (1.75kg of ma-huang) was boiled in 50L of water for 2h. E 204.01mg/g
2017 Tong et al47) E.sinica UPLC 100g of ma-huang in 1.2L of water was boiled for 30min, then cooled for 30min. And remove the foam of the ma-huang, then added 1L of water and boiled for 20min. And remove the foam of the ma-huang one more. E 0.14-3.69mg/mL
PE 0.65-2.57mg/mL
2018 Lee et al43) E.sinica Stapf UPLC 2kg of ma-huang tang (0.7kg of ma-huang) was boiled in 20L of water for 2h. And it is stored at room temperature (23±1°C) and refrigerated (4°C). E

  • - Both at room temperature and refrigerated, both were measured that 2.23-2.68mg/g of E was contained.

  • - After 3 months of storage, there was no significant difference in E content.
*

Solaray, Inc., Ogden, UT,

†

a weight loss aid manufactured by Twin Laboratories Inc, Ronkonkoma, NY

‡

ma-huang in water was boiled, then remove the foam of the ma-huang,

§

Galgeun-tang,

||

Socheongryong-tang

-, not presented in the study

p.o.: per oral, E: ephedrine, PE: pseudoephedrine, ME: methylephedrine, h: hours, E.: Ephedra, UPLC: Ultra Performance Liquid Chromatography, HPLC: High Performance Liquid Chromatography, LC-MS/MS: Liquid Chromatography with tandem Mass Spectrometry

Table 5

Pharmacokinetics of Δ9-tetrahydrocannabinol (THC)

Year Author Doses and administration Clinical specimen PK parameter
1971 Lemberger et al66) THC administered intravenously to chronic marihuana smokers and non-smokers. serum T1/2 : 28h(chronic smokers), 58h(non-smokers)
1985 Ellis et al57) Cannabis abusers(retrospective study) - The average period of excretion was 27.1 days (20ng/mL or less).
2000 Bosy et al51) 2 capsules containing 48.6μg THC p.o. urine Cmax: 5.2ng/mL, Always detect less than 50ng/mL
Oil containing 172.5μg THC p.o. urine Cmax: 1.8ng/mL, Always detect less than 50ng/mL
Oil containing 315.0μg THC p.o. Cmax: 13.9ng/mL, Detected immediately upon ingestion but detected less than 15ng/mL.. Not detected within 24h after stopping ingestion.
Oil containing 540.0μg THC p.o. Cmax: 21.1ng/mL, Detected within 3-4 days after ingesting oil. Not detected within 24h after stopping ingestion.
Oil containing 546.0μg THC p.o. Cmax: 13.1ng/mL, Detected within 3-4 days after ingesting oil. Not detected within 24h after stopping ingestion.
Oil containing 1762.5μg THC p.o. Cmax: 48.7ng/mL, Detected within 1 day after ingesting oil. Not detected within 72h after stopping ingestion.
2007 Kauert et al61) THC as a low dose(18.2±2.8mg) serum Cmax: 47.8±35μg/L, T1/2: 1.5±0.1h, And fell below 1μg/L for 6h.
THC as a high dose(36.5±5.6mg) serum Cmax: 79.1±42.5μg/L, T1/2: 1.4±0.1h, And fell below 1g/L for 6h.
2008 Zuurman et al64) Rising doses of THC (2, 4, 6 and 8mg) using a Volcano® vaporizer serum T1/2: 7.68min
2008 Hunault et al62) 29.3mg of THC serum Cmax: 135.1μg/L, Tmax: 9.5min
49.1mg of THC Cmax: 202.9μg/L, Tmax: 14.1min
69.4mg of THC Cmax: 231.0μg/L, Tmax: 12.3min
2010 Toennes et al60) Cannabis abusers using an average of 33mg THC, for 10min saliva

  • - occasional marijuana user; Cmax: 49.1±24.9μg/mL, Tmax: 0.1h, T1/2: 1.6±0.2h

  • - heavy marijuana user; Cmax: 120.9±78.1μg/mL, Tmax: 0.1h, T1/2: 3.0±1.5h
2010 Hunault et al63) Cannabis cigarettes containing 29.3mg of THC serum Cmax: 99.5ng/mL, Tmax: 14min, T1/2: 150min
Cannabis cigarettes containing 49.1mg of THC Cmax: 125.0ng/mL, Tmax: 14min, T1/2: 150min
Cannabis cigarettes containing 69.4mg of THC Cmax: 175ng/mL, Tmax: 14min, T1/2: 150min
2010 Brenneisen et al59) 70mg of THC serum Cmax: 20.9±16.7ng/mL, Tmax: 5min
urine Cmax : 0.7±0.3ng/mL within 2h after administration

  • - Not detected within 4-12h after administration.
2018 Pacifici et al65) 1g of marijuana(containing of 0.16% THC) saliva

  • - The concentration was in the range of 2.5-21.5 ng/mL for the first 30 min after smoking and gradually decreased.
urine

  • - The concentration of THC-COOH(major metabolites of THC in urine)was 1.8ng/mL.

THC: Δ9-tetrahydrocannabinol, PK: pharmacokinetics, Cmax: the maximum (or peak) concentration that a drug achieves in a specified compartment, Tmax: the time that it takes a drug or other substance to reach the maximum concentration, T1/2: the time required for a quantity to reduce to half its initial value, h: hours

Table 6

Pharmacokinetics of Strychnine

Year Author Doses and administration Clinical specimen PK parameter
1986 Edmunds et al75) - serum T1/2: 10h, Detection of 1.6mg/L strychnine after 4h of inhalation
1997 Palatnick et al74) Ingested half of a 250mL container of 2% strychnine sulfate(2.5g) serum Cmax: 2.1mg/L, Tmax: 3h, T1/2: 15.9h
- Lethal dose was 100-120mg.
2002 Wood et al76) - serum T1/2: 12h
- The initial concentration at 1.5h after ingestion was 4.73mg/L, falling to 0.38mg/L at 74h post ingestion.
2006 Van Eenoo et al78) Over the counter(OTC) drug 10 pills(380μg of strychnine) p.o. urine Cmax: 22.6-176ng/mL
- Strychnine was detected during 24-48h after administration. And 2.2 8.6% of all ingested strychnine was excreted unchanged in urine during the first 12h after administration.
2010 Li et al79) Treated with 2 Gujinwan capsules (160μg of strychnine) urine 58.2ng/mL at 6h, 28.5ng/mL at 12h, 14.1ng/mL at 18h
2011 Kong et al80) Guo’s Ma Qian Decoction(0.4-1.2 g/day of Ma Qian Zi) p.o.(twice/day, for 8 weeks) serum - Strychnine was detected below 10ng in all subjects. And, during administration and even after the 8-week administration period, there was no accumulated strychnine in the blood.

-, not presented in the study

PK: pharmacokinetics, Cmax: the maximum (or peak) concentration that a drug achieves in a specified compartment, Tmax: the time that it takes a drug or other substance to reach the maximum concentration, T1/2: the time required for a quantity to reduce to half its initial value, h: hours

Table 7

Content of Strychnine

Year Author Species Analysis method Extraction method Content(mg/g)
2009 Tang et al82) - - Extraction with chloroform 18.27
Extraction with ethanol 17.57
Extraction with acidic water 16.04
Extraction with water 14.19
2011 Kong et al80) semen strychni HPLC Guo’s Ma Qian Decoction (0.4-1.2g/day of Ma Qian Zi) 9.55 (in 0.4g), 9.95 (in 0.6g), 9.78 (in 0.8g), 10.03 (in 1.0g), 9.31 (in 1.2g)
2012 Xu et al81) - HPLC Analyze Strychnos nux-vomica powders 6 times 12.1065
2015 Hu83) - - Raw Ma Qian Zi 18.24
Ma Qian Zi heated with sand* 16.25
Ma Qian Zi processed with Glycyrrhizae oil† 9.27
Ma Qian Zi with 5% acetic acid‡ 4.67
Deep frying Ma Qian Zi§ 10.25
Ma Qian Zi with vinegar|| 10.57

-, not presented in the study

*

砂烫, First, warm the sand with fire, then fill in the Ma Qian Zi. and fry until brown or dark brown, filter the sand and cool.

†

甘草制, After diluting the Glycyrrhizae oil 10 times, add the Ma Qian Zi and boil. After 4h boiling, remove the Glycyrrhizae oil, and dry at 60°C.

‡.

醋泡, Dipping the Ma Qian Zi in water for 2 days, running for 0.5 days, dividing into 1.5 mL. And dipping in 5% acetic acid for 5 days, washing with water, and drying at 60°C after 3 days.

§

油炸, Put the Ma Qian Zi into the boiling pots of oil, and when it is yellow, take it out and cool it down.

||

醋炙, Mix Ma Qian Zi and vinegar evenly, and when the vinegar disappears, cool down.

HPLC: High Performance Liquid Chromatography, p.o.: per oral

Table 8

Content of Ephedrine in Pinelliae Tuber, Rhizoma Pinelliae

Year Author Herbal medicine Content(mg/g)
2005 Li et al86) Anhuisheng-bozhou*’s Pinelliae Tuber, Rhizoma Pinelliae 0.007
Hubeisheng-daye†’s Pinelliae Tuber, Rhizoma Pinelliae 0.001
Hubeisheng-enshi‡’s Pinelliae Tuber, Rhizoma Pinelliae 0.001
Guiyang§’s Pinelliae Tuber, Rhizoma Pinelliae 0.003
Hubeisheng-Huangshi||’s Pinelliae Tuber, Rhizoma Pinelliae 0.004
Guizhou’s Pinelliae Tuber, Rhizoma Pinelliae 0.001
2007 Xu et al84) Analyze Rhizoma Pinelliae, Rhizoma Typhonii Flagelliformis and their processed products 5 times 0.0017
2008 Qi et al85) Analyze Pinelliae Tuber granules 6 times 0.0287
2009 Zhu et al87) Wild Pinelliae Tuber and Rhizoma Pinelliae 0.0055
Cultivated Pinelliae Tuber, Rhizoma Pinelliae 0.0039
*

安徽亳州,

†

湖北大冶,

‡

湖北恩施,

§

贵阳

||

湖北黄石,

贵州

Table 9

Pharmacokinetics of Synephrine

Year Author Doses and administration Clinical specimen PK parameter
2013 Medana et al101) 15mg of synephrine p.o. urine Cmax: 14.3μg/L (at 3h after administration)
2018 Shara et al102) A single oral dose of 49mg p-synephrine in bitter orange extract(for 15 days) serum - 1 week after administration: 2.54±1.54ng/mL
- 2 weeks after administration: 2.69±1.52ng/mL

PK: pharmacokinetics, p.o.: per oral, Cmax: the maximum (or peak) concentration that a drug achieves in a specified compartment, h: hours

Table 10

Content of Synephrine

Year Author Herbal medicine Content
2003 Ke et al103) Analyze Citrus Auarntium L. 3 times 1.1146mg/g, 1.129mg/g, 1.9553mg/g
2006 Luo et al104) Analyze Citrus Auarntium L. 5 times 8.3mg/g
2006 Lu et al105) Analyze Citrus Auarntium L. 6 times 8.4mg/g
2006 Zhao et al106) Analyze Aurantii Fructus Immaturus 4.5mg/g
Analyze Aurantii Fructus 1.3mg/g
2007 Nelson et al107) Analyze Citrus aurantium fruit 8.85mg/g (dry weight of synephrine)
Analyze Citrus aurantium extract 71.5mg/g (dry weight of synephrine)
2014 Shawky108) Analyze Citrus aurantium fruit(bitter orange) 2.53mg/g
2018 Tanaka et al109) In citrus fruits(mikan, orange, bitter orange, and ponkan samples) <(R)-synephrine>
exocarp(0.264±0.0087mg/g), mesocarp(0.174±0.0096mg/g), endocarp(0.094±0.0096mg/g), sarcocarp(0.021±0.0103mg/g)
<(S)-synephrine>
exocarp < 0.0025mg/g, the other parts < 0.0008mg/g

L.: Linne

Table 11

Steroid Content in Musk (μg/g)

Steroid 1* 2* 3*
An‡ 303 152 321
Etio‡ 3164 419 1673
5α-diol‡ 273 24 16
5β-diol‡ 269 26 399
DHEA‡ 88 41 46
EpiA‡ 180 61 188
T‡ 28 32 97
ET‡ 36 29 76
4-AD‡ 273 80 2968
DHT‡ <10 <10 <10
5α-3β,17α-diol‡ 838 97 1504
5α-3β,17β-diol‡ 14 <0.5 25
5α-dione‡ 119 73 580
E <24 - <24
Ediol - - -
Preg <24 <24 <24
Prog <21 - <21
Etriol - - -
17OHPreg - - -
Chol 1609 780 2571
*

musk sample number. 1, 2 is Moschus sp. and 3 is Moschus berezovskii.

†

Steroids prohibited according to the WADA Prohibited List 201810).

-, not detected.

An: androsterone, Etio: etiocholanolone, 5α-diol: 5α-androstane-3 α,17β-diol, 5β-diol: 5β-androstane-3α,17β-diol, DHEA: dehydroepiandrosterone, EpiA: epiandrosterone, T: testosterone, ET: epitestosterone, 4-AD: 4-androstene- 3,17-dione, DHT: 5α-dihydrotestosterone, 5α-3 β,17α-diol: 5α-androstane-3β,17α-diol, 5α-3β,17β-diol: 5α -androstane-3β,17β-diol, 5α-dione: 5α-androstane-3,17-dione, E: estrone, Ediol: estradiol, Preg: pregnenolone, Prog: progesterone, Etriol: estriol, 17OHPreg: 17-OH-pregnenolone, Chol: cholesterol

Table 12

Higenamine Content of Herbal Medicine according to the Method of Analysis

Year Author Herbal medicine Analysis method Content(μg/g)
2011 Tian134) Nelumbinis Plumula HPLC 920
Asiasarum heterotropoides F. Maekawa var. mandshuricum F. Maekawa 84
Aconiti Lateralis Preparata Radix 22
2012 Tian et al135) Nelumbinis Plumula HPLC 940
2018 Yang et al136) Phellodendri Cortex LC-MS/MS 8.216
Zanthoxylum bungeanum Maximowicz 5.010
Asia Radix 8.66
Kochiae Fructus 4.66
Caryophylli Flos, Phlomis umbrosa Turcz., Corydalis Tuber, Carthami Flos, Draconis Sanguis, Paeonia lactiflora Pall., Nelumbo nucifera, Aucklandiae Radix, Cinnamomi Cortex, Cnidium officinale Makino, Angelicae Pubescentis Radix, Angelicae Gigantis Radix, Osterici Radix, Rhei Rhizoma, Vladimiriae Radix, Myrrha, Sargendoxae Caulis, Angelicae Dahuricae Radix -

-, not extracted

HPLC: High Performance Liquid Chromatography, LC-MS/MS: Liquid Chromatography with tandem Mass Spectrometry

Table 13

Content of Higenamine of Herbal Medicine according to the Extraction Method (μg/g)

Herbal medicine Extraction method
In pressure Non-pressure
Water extraction (Water 100%) Alcohol extraction (Water: Alcohol=7:3) Water extraction (Water 100%) Alcohol extraction (Water: Alcohol=7:3)
Processed Aconiti Lateralis Preparata Radix 0.211 0.294 0.108 0.278
Asia Radix 5.168 3.841 3.114 6.415
Processed Evodiae Fructus 2.835 2.668 1.692 2.724
Linderae Radix 3.488 5.318 2.407 3.918
Nelumbinis Semen 1.074 1.407 1.117 1.09
Processed Aconiti Tuber 0.163 0.225 0.112 0.1305
Processed Aconiti Ciliare Tuber 7.002 9.322 5.476 5.38