Analytical approaches for the detection of emerging therapeutics and non-approved drugs in human doping controls

Journal of Pharmaceutical and Biomedical Analysis

Volumn 101, Issue , 2014, Pages 66-83

  Thevis, Mario ^a   Schänzer, Wilhelm ^b  

^a GERMAN SPORT UNIVERSITY COLOGNE   (Germany)

^b European Monitoring Center for Emerging Doping Agents   (Germany)

Author keywords

Anti myostatin antibody; Doping; Emerging drugs; Mass spectrometry; Sport; Stamulumab

Indexed keywords

2,3,4,5 TETRAHYDRO 7 METHOXY 4 METHYL 1,4 BENZOTHIAZEPINE; 4 [3 (4 BENZYL 1 PIPERIDINYL)PROPIONYL] 2,3,4,5 TETRAHYDRO 7 METHOXY 1,4 BENZOTHIAZEPINE; 5 AMINO 4 IMIDAZOLECARBOXAMIDE RIBOSIDE; CAPROMORELIN; CILOMILAST; COBALT CHLORIDE; ENZYME ACTIVATOR; ERYTHROPOIETIN; GROWTH FACTOR; GROWTH HORMONE RELEASING FACTOR DERIVATIVE; GROWTH HORMONE SECRETAGOGUE; HUMAN GROWTH HORMONE[176-191][176 TYROSINE]; IBUTAMOREN; L 739943; MECHANO GROWTH FACTOR; N [2 [3 (1 PIPERAZINYLMETHYL)IMIDAZO[2,1 B]THIAZOL 6 YL]PHENYL] 2 QUINOXALINECARBOXAMIDE; NEW DRUG; PEGINESATIDE; PERFORMANCE ENHANCING SUBSTANCE; PHOSPHODIESTERASE IV INHIBITOR; RECOMBINANT ERYTHROPOIETIN; ROFLUMILAST; ROLIPRAM; SELECTIVE ANDROGEN RECEPTOR MODULATOR; SM 130686; SRT1460; SRT2104; STABILIZING AGENT; STAMULUMAB; TB 500; UNCLASSIFIED DRUG; DRUG;

ANALYTIC METHOD; ATHLETIC PERFORMANCE; BLOOD; CHROMATOGRAPHY; CONCENTRATION (PARAMETERS); DOPING; DRUG DETERMINATION; DRUG METABOLISM; HUMAN; MASS SPECTROMETRY; MOLECULAR WEIGHT; MUSCLE FUNCTION; MUSCLE STRENGTH; NONHUMAN; OXYGEN TRANSPORT; PHYSICAL CHEMISTRY; PRIORITY JOURNAL; REVIEW; RNA INTERFERENCE; SKELETAL MUSCLE; TREATMENT WITHDRAWAL; URINE; CHEMISTRY; DRUG APPROVAL; PREVENTION AND CONTROL; PROCEDURES; SUBSTANCE ABUSE; TANDEM MASS SPECTROMETRY;

DOPING IN SPORTS; DRUG APPROVAL; HUMANS; PERFORMANCE-ENHANCING SUBSTANCES; PHARMACEUTICAL PREPARATIONS; SUBSTANCE ABUSE DETECTION; TANDEM MASS SPECTROMETRY;

EID: 84928397070     PISSN: 07317085     EISSN: 1873264X     Source Type: Journal    
DOI: 10.1016/j.jpba.2014.05.020     Document Type: Article

References (166)

1. Thevis M., Thomas A., Kohler M., Beuck S., Schänzer W. Emerging drugs: mechanism of action, mass spectrometry and doping control analysis. J. Mass Spectrom. 2009, 44:442-460.
2. World Anti-Doping Agency The 2014 Prohibited List 2014, http://www.wada-ama.org/Documents/World_Anti-Doping_Program/WADP-Prohibited-list/2014/WADA-prohibited-list-2014-EN.pdf (11.11.13).
3. Thevis M., Thomas A., Schänzer W. Current role of LC-MS(/MS) in doping control. Anal. Bioanal. Chem. 2011, 401:405-420.
4. Thevis M., Volmer D.A. Recent instrumental progress in mass spectrometry: advancing resolution, accuracy, and speed of drug detection. Drug Test. Anal. 2012, 4:242-245.
5. Thevis M., Kuuranne T., Geyer H., Schänzer W. Annual banned-substance review: analytical approaches in human sports drug testing. Drug Test. Anal. 2013, 5:1-19.
6. Bellinger A.M., Reiken S., Carlson C., Mongillo M., Liu X., Rothman L., Matecki S., Lacampagne A., Marks A.R. Hypernitrosylated ryanodine receptor calcium release channels are leaky in dystrophic muscle. Nat. Med. 2009, 15:325-330.
7. Andersson D.C., Betzenhauser M.J., Reiken S., Meli A.C., Umanskaya A., Xie W., Shiomi T., Zalk R., Lacampagne A., Marks A.R. Ryanodine receptor oxidation causes intracellular calcium leak and muscle weakness in aging. Cell Metab. 2011, 14:196-207.
8. Gehlert S., Bungartz G., Willkomm L., Korkmaz Y., Pfannkuche K., Schiffer T., Bloch W., Suhr F. Intense resistance exercise induces early and transient increases in ryanodine receptor 1 phosphorylation in human skeletal muscle. PLoS ONE 2012, 7:e49326.
9. Mei Y., Xu L., Kramer H.F., Tomberlin G.H., Townsend C., Meissner G. Stabilization of the skeletal muscle ryanodine receptor ion channel-FKBP12 complex by the 1,4-benzothiazepine derivative S107. PLoS ONE 2013, 8:e54208.
10. Thevis M., Beuck S., Thomas A., Kohler M., Schlörer N., Vajiala I., Schänzer W. Screening for the Calstabin-Ryanodine-receptor complex stabilizers JTV-519 and S-107 in doping control analysis. Drug Test. Anal. 2009, 1:32-42.
11. 2+-Channel Stabilizer S-107 and its implementation into routine doping control. Rapid Commun. Mass Spectrom. 2009, 23:2363-2370.
12. Thevis M., Beuck S., Thomas A., Kortner B., Kohler M., Rodchenkov G., Schänzer W. Doping control analysis of emerging drugs in human plasma - identification of GW501516, S-107, JTV-519, and S-40503 Rapid Commun. Mass Spectrom. 2009, 23:1139-1146.
13. Beuck S., Schänzer W., Thevis M. Investigation of the in vitro metabolism of the emerging drug candidate S107 for doping-preventive purposes. J. Mass Spectrom. 2011, 46:112-130.
14. The ChEMBL-og Open Data For Drug Discovery. Aladorian 2012, http://www.ama-assn.org/resources/doc/usan/aladorian.pdf (11.11.2013).
15. Bhasin S., Jasuja R. Selective androgen receptor modulators as function promoting therapies. Curr. Opin. Clin. Nutr. Metab. Care 2009, 12:232-240.
16. Dalton J.T., Taylor R.P., Mohler M.L., Steiner M.S. Selective androgen receptor modulators for the prevention and treatment of muscle wasting associated with cancer. Curr. Opin. Support. Palliat. Care 2013, 7:345-351.
17. Anker M.S., von Haehling S., Springer J., Banach M., Anker S.D. Highlights of mechanistic and therapeutic cachexia and sarcopenia research 2010 to 2012 and their relevance for cardiology. Arch. Med. Sci.: AMS 2013, 9:166-171.
18. Zhang X., Sui Z. Deciphering the selective androgen receptor modulators paradigm. Expert Opin. Drug Discov. 2013, 8:191-218.
19. Furuya K., Yamamoto N., Ohyabu Y., Makino A., Morikyu T., Ishige H., Kuzutani K., Endo Y. The novel non-steroidal selective androgen receptor modulator S-101479 has additive effects with bisphosphonate, selective estrogen receptor modulator, and parathyroid hormone on the bones of osteoporotic female rats. Biol. Pharm. Bull. 2012, 35:1096-1104.
20. Furuya K., Yamamoto N., Ohyabu Y., Morikyu T., Ishige H., Albers M., Endo Y. Mechanism of the tissue-specific action of the selective androgen receptor modulator S-101479. Biol. Pharm. Bull. 2013, 36:442-451.
21. Akita K., Harada K., Ichihara J., Takata N., Takahashi Y., Saito K. A novel selective androgen receptor modulator, NEP28, is efficacious in muscle and brain without serious side effects on prostate. Eur. J. Pharmacol. 2013, 720:107-114.
22. Thevis M., Geyer H., Kamber M., Schänzer W. Detection of the arylpropionamide-derived selective androgen receptor modulator (SARM) S-4 (Andarine) in a black-market product. Drug Test. Anal. 2009, 1:387-392.
23. Thevis M., Geyer H., Thomas A., Schänzer W. Trafficking of drug candidates relevant for sports drug testing: detection of non-approved therapeutics categorized as anabolic and gene doping agents in products distributed via the Internet. Drug Test. Anal. 2011, 3:331-336.
24. Grata E., Perrenoud L., Saugy M., Baume N. SARM-S4 and metabolites detection in sports drug testing: a case report. Forensic Sci. Int. 2011, 213:104-108.
25. Starcevic B., Ahrens B.D., Butch A.W. Detection of the selective androgen receptor modulator S-4 (Andarine) in a doping control sample. Drug Test. Anal. 2013, 5:377-379.
26. Thomas A., Guddat S., Kohler M., Krug O., Schänzer W., Petrou M., Thevis M. Comprehensive plasma-screening for known and unknown substances in doping controls. Rapid Commun. Mass Spectrom. 2010, 24:1124-1132.
27. Thomas A., Geyer H., Guddat S., Schänzer W., Thevis M. Dried blood spots (DBS) for doping control analysis. Drug Test. Anal. 2011, 3:806-813.
28. Thevis M., Gerace E., Thomas A., Beuck S., Geyer H., Schlörer N., Kearbey J.D., Dalton J.T., Schänzer W. Characterization of in vitro generated metabolites of the selective androgen receptor modulators S-22 and S-23 and in vivo comparison to post-administration canine urine specimens. Drug Test. Anal. 2010, 2:589-598.
29. Thevis M., Thomas A., Fusshöller G., Beuck S., Geyer H., Schänzer W. Mass spectrometric characterization of urinary metabolites of the selective androgen receptor modulator andarine (S-4) for routine doping control purposes. Rapid Commun. Mass Spectrom. 2010, 24:2245-2254.
30. Thevis M., Thomas A., Möller I., Geyer H., Dalton J.T., Schänzer W. Mass spectrometric characterization of urinary metabolites of the selective androgen receptor modulator S-22 to identify potential targets for routine doping controls. Rapid Commun. Mass Spectrom. 2011, 25:2187-2195.
31. Thevis M., Thomas A., Piper T., Krug O., Delahaut P., Schänzer W. Liquid chromatography-high resolution/high accuracy (tandem) mass spectrometry-based identification of in vivo generated metabolites of the selective androgen receptor modulator ACP-105 for doping control purposes. Eur. J. Mass. Spectrom. 2013, 20:73-83. 10.1255/ejms.1236.
32. Thevis M., Schänzer W. Synthetic anabolic agents: steroids and nonsteroidal selective androgen receptor modulators. Handb. Exp. Pharmacol. 2010, 195:99-126.
33. Thomas A., Geyer H., Schänzer W., Crone C., Kellmann M., Moehring T., Thevis M. Sensitive determination of prohibited drugs in dried blood spots (DBS) for doping controls by means of a benchtop quadrupole/Orbitrap mass spectrometer. Anal. Bioanal. Chem. 2012, 403:1279-1289.
34. Thevis M. Mass Spectrometry in Sports Drug Testing - Characterization of Prohibited Substances and Doping Control Analytical Assays 2010, Wiley, Hoboken.
35. Rydevik A., Thevis M., Krug O., Bondesson U., Hedeland M. The fungus Cunninghamella elegans can produce human and equine metabolites of selective androgen receptor modulators (SARMs). Xenobiotica 2013, 43:409-420.
36. Thevis M., Piper T., Beuck S., Geyer H., Schänzer W. Expanding sports drug testing assays: mass spectrometric characterization of the selective androgen receptor modulator drug candidates RAD140 and ACP-105. Rapid Commun. Mass Spectrom. 2013, 27:1173-1182.
37. Sobolevsky T., Dikunets M., Prasolov I., Rodchenkov G. In vitro and in vivo metabolism of RAD140, a novel nonsteroidal SARM. Presented at 31st Cologne Workshop on Dope Analysis 2013.
38. L. Zhi, US2012/0004220 A9, Ligand Pharmaceuticals Incorporated, 2012.
39. Sanders B.D., Jackson B., Marmorstein R. Structural basis for sirtuin function: what we know and what we don't. Biochim. Biophys. Acta 2010, 1804:1604-1616.
40. Elliott P.J., Jirousek M. Sirtuins: novel targets for metabolic disease. Curr. Opin. Investig. Drugs 2008, 9:371-378.
41. Lavu S., Boss O., Elliott P.J., Lambert P.D. Sirtuins-novel therapeutic targets to treat age-associated diseases. Nat. Rev. Drug Discov. 2008, 7:841-853.
42. Hubbard B.P., Gomes A.P., Dai H., Li J., Case A.W., Considine T., Riera T.V., Lee J.E., Lamming S.Y.E.D.W., Pentelute B.L., Schuman E.R., Stevens L.A., Ling A.J., Armour S.M., Michan S., Zhao H., Jiang Y., Sweitzer S.M., Blum C.A., Disch J.S., Ng P.Y., Howitz K.T., Rolo A.P., Hamuro Y., Moss J., Perni R.B., Ellis J.L., Vlasuk G.P., Sinclair D.A. Evidence for a common mechanism of SIRT1 regulation by allosteric activators. Science 2013, 339:1216-1219.
43. Gut P., Verdin E. Rejuvenating SIRT1 activators. Cell Metab. 2013, 17:635-637.
44. Revollo J.R., Li X. The ways and means that fine tune Sirt1 activity. Trends Biochem. Sci. 2013, 38:160-167.
45. Pan M., Yuan H., Brent M., Ding E.C., Marmorstein R. SIRT1 contains N- and C-terminal regions that potentiate deacetylase activity. J. Biol. Chem. 2012, 287:2468-2476.
46. Denu J.M. Fortifying the link between SIRT1, resveratrol, and mitochondrial function. Cell Metab. 2012, 15:566-567.
47. Höppner S., Schänzer W., Thevis M. Fragmentation studies of SIRT1-activating drugs and their detection in human plasma for doping control purposes. Rapid Commun. Mass Spectrom. 2013, 27:35-50.
48. Höppner S., Schänzer W., Thevis M. Mass spectrometric studies on the in vitro generated metabolites of SIRT1 activating drugs for doping control purposes. J. Mass Spectrom. 2013, 48:830-843.
49. Höppner S., Delahaut P., Schänzer W., Thevis M. Mass spectrometric studies on the in vivo metabolism and excretion of SIRT1 activating drugs in rat urine, dried blood spots, and plasma samples for doping control purposes. J. Pharm. Biomed. Anal. 2014, 88:649-659.
50. Park S.J., Ahmad F., Philp A., Baar K., Williams T., Luo H., Ke H., Rehmann H., Taussig R., Brown A.L., Kim M.K., Beaven M.A., Burgin A.B., Manganiello V., Chung J.H. Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell 2012, 148:421-433.
51. Russell A.P., Foletta V.C., Snow R.J., Wadley G.D. Skeletal muscle mitochondria: a major player in exercise, health and disease. Biochim. Biophys. Acta 2013, (in press). 10.1016/j.bbagen.2013.1011.1016.
52. Komen J.C., Thorburn D.R. Turn up the power - pharmacological activation of mitochondrial biogenesis in mouse models. Br. J. Pharmacol. 2013.
53. Golubitzky A., Dan P., Weissman S., Link G., Wikstrom J.D., Saada A. Screening for active small molecules in mitochondrial complex I deficient patient's fibroblasts, reveals AICAR as the most beneficial compound. PLoS ONE 2011, 6:e26883.
54. Narkar V.A., Downes M., Yu R.T., Embler E., Wang Y.X., Banayo E., Mihaylova M.M., Nelson M.C., Zou Y., Juguilon H., Kang H., Shaw R.J., Evans R.M. AMPK and PPARdelta agonists are exercise mimetics. Cell 2008, 134:405-415.
55. Benkimoun P. Police find unlicensed drugs after trawling bins. Br. Med. J. 2009, 339:b4201.
56. Velonation Colombian doctor Beltrán Nino arrested with AICAR and TB-500 doping products 2012, http://www.velonation.com/DesktopModules/DnnForge%20-%20NewsArticles/Print.aspx?tabid=55&tabmoduleid=197&articleId=11406&moduleId=374&PortalID=0 (05.05.2014).
57. Thomas A., Beuck S., Eickhoff J.C., Guddat S., Krug O., Kamber M., Schänzer W., Thevis M. Quantification of urinary AICAR concentrations as a matter of doping controls. Anal. Bioanal. Chem. 2010, 396:2899-2908.
58. Thomas A., Vogel M., Piper T., Krug O., Beuck S., Schänzer W., Thevis M. Quantification of AICAR-ribotide concentrations in red blood cells by means of LC-MS/MS. Anal. Bioanal. Chem. 2013, 405:9703-9709.
59. Piper T., Emery C., Saugy M. Recent developments in the use of isotope ratio mass spectrometry in sports drug testing. Anal. Bioanal. Chem. 2011, 401:433-447.
60. Piper T., Thomas A., Baume N., Sobolevsky T., Saugy M., Rodchenkov G., Schänzer W., Thevis M. Determination of (13) C/(12) C ratios of endogenous urinary 5-amino-imidazole-4-carboxamide 1beta-d-ribofuranoside (AICAR). Rapid Commun. Mass Spectrom. 2014, 28:1194-1202.
61. Salari P., Abdollahi M. Phosphodiesterase inhibitors in inflammatory bowel disease. Expert. Opin. Investig. Drugs 2012, 21:261-264.
62. Michalski J.M., Golden G., Ikari J., Rennard S.I. PDE4: a novel target in the treatment of chronic obstructive pulmonary disease. Clin. Pharmacol. Ther. 2012, 91:134-142.
63. Diamant Z., Spina D. PDE4-inhibitors: a novel, targeted therapy for obstructive airways disease. Pulm. Pharmacol. Ther. 2011, 24:353-360.
64. Blum C.A., Ellis J.L., Loh C., Ng P.Y., Perni R.B., Stein R.L. SIRT1 modulation as a novel approach to the treatment of diseases of aging. J. Med. Chem. 2011, 54:417-432.
65. Pages L., Gavalda A., Lehner M.D. PDE4 inhibitors: a review of current developments (2005-2009). Exp. Opin. Ther. Patents 2009, 19:1501-1519.
66. Hatzelmann A., Morcillo E.J., Lungarella G., Adnot S., Sanjar S., Beume R., Schudt C., Tenor H. The preclinical pharmacology of roflumilast-a selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease. Pulm. Pharmacol. Ther. 2010, 23:235-256.
67. Rabe K.F. Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease. Br. J. Pharmacol. 2011, 163:53-67.
68. Giembycz M.A. Cilomilast: a second generation phosphodiesterase 4 inhibitor for asthma and chronic obstructive pulmonary disease. Expert. Opin. Investig. Drugs 2001, 10:1361-1379.
69. Thevis M., Krug O., Schänzer W. Monitoring phosphodiesterase-4 inhibitors using liquid chromatography/(tandem) mass spectrometry in sports drug testing. Rapid Commun. Mass Spectrom. 2013, 27:993-1004.
70. Moulin A., Ryan J., Martinez J., Fehrentz J.A. Recent developments in ghrelin receptor ligands. ChemMedChem 2007, 2:1242-1259.
71. Thevis M., Schänzer W. Emerging Drugs - Potential for misuse in sport and doping control detection strategies. Mini-Rev. Med. Chem. 2007, 7:533-539.
72. Hersch E.C., Merriam G.R. Growth hormone (GH)-releasing hormone and GH secretagogues in normal aging: fountain of youth or pool of tantalus?. Clin. Interv. Aging 2008, 3:121-129.
73. Bowers C.Y., Momany F.A., Reynolds G.A., Hong A. On the in vitro and in vivo activity of a new synthetic hexapeptide that acts on the pituitary to specifically release growth hormone. Endocrinology 1984, 114:1537-1545.
74. Momany F.A., Bowers C.Y., Reynolds G.A., Chang D., Hong A., Newlander K. Design, synthesis, and biological activity of peptides which release growth hormone in vitro. Endocrinology 1981, 108:31-39.
75. Bowers C.Y. History to the discovery of ghrelin. Methods Enzymol. 2012, 514:3-32.
76. Chihara K., Shimatsu A., Hizuka N., Tanaka T., Seino Y., Katofor Y. A simple diagnostic test using GH-releasing peptide-2 in adult GH deficiency. Eur. J. Endocrinol. 2007, 157:19-27.
77. Thomas A., Kohler M., Mester J., Geyer H., Schänzer W., Petrou M., Thevis M. Identification of the growth-hormone-releasing peptide-2 (GHRP-2) in a nutritional supplement. Drug Test. Anal. 2010, 2:144-148.
78. Kohler M., Thomas A., Geyer H., Petrou M., Schänzer W., Thevis M. Confiscated black market products and nutritional supplements with non-approved ingredients analyzed in the Cologne Doping Control Laboratory 2009. Drug Test. Anal. 2010, 2:533-537.
79. Pinyot A., Nikolovski Z., Bosch J., Segura J., Gutierrez-Gallego R. On the use of cells or membranes for receptor binding: growth hormone secretagogues. Anal. Biochem. 2010, 399:174-181.
80. Pinyot A., Nikolovski Z., Bosch J., Such-Sanmartin G., Kageyama S., Segura J., Gutierrez-Gallego R. Growth hormone secretagogues: out of competition. Anal. Bioanal. Chem. 2012, 402:1101-1108.
81. Okano M., Nishitani Y., Sato M., Ikekita A., Kageyama S. Influence of intravenous administration of growth hormone releasing peptide-2 (GHRP-2) on detection of growth hormone doping: growth hormone isoform profiles in Japanese male subjects. Drug Test. Anal. 2010, 2:548-556.
82. Thomas A., Höppner S., Geyer H., Schänzer W., Petrou M., Kwiatkowska D., Pokrywka A., Thevis M. Determination of growth hormone releasing peptides (GHRP) and their major metabolites in human urine for doping controls by means of liquid chromatography mass spectrometry. Anal. Bioanal. Chem. 2011, 401:507-516.
83. Thomas A., Walpurgis K., Krug O., Schänzer W., Thevis M. Determination of prohibited, small peptides in urine for sports drug testing by means of nano-liquid chromatography/benchtop quadrupole orbitrap tandem-mass spectrometry. J. Chromatogr. A 2012, 1259:251-257.
84. Thomas A., Delahaut P., Krug O., Schänzer W., Thevis M. Metabolism of growth hormone releasing peptides. Anal. Chem. 2012, 84:10252-10259.
85. Cabrales A., Gil J., Fernandez E., Valenzuela C., Hernandez F., Garcia I., Hernandez A., Besada V., Reyes O., Padron G., Berlanga J., Guillen G., Gonzalez L.J. Pharmacokinetic study of Growth Hormone-Releasing Peptide 6 (GHRP-6) in nine male healthy volunteers. Eur. J. Pharm. Sci. 2013, 48:40-46.
86. Gil J., Cabrales A., Reyes O., Morera V., Betancourt L., Sanchez A., Garcia G., Moya G., Padron G., Besada V., Gonzalez L.J. Development and validation of a bioanalytical LC-MS method for the quantification of GHRP-6 in human plasma. J. Pharm. Biomed. Anal. 2012, 60:19-25.
87. Henninge J., Pepaj M., Hullstein I., Hemmersbach P. Identification of CJC-1295, a growth-hormone-releasing peptide, in an unknown pharmaceutical preparation. Drug Test. Anal. 2010, 2:647-650.
88. Kohler M., Thomas A., Walpurgis K., Terlouw K., Schänzer W., Thevis M. Detection of His-tagged Long-R(3)-IGF-I in a black market product. Growth Horm. IGF Res. 2010, 20:386-390.
89. Cai R., Schally A.V., Cui T., Szalontay L., Halmos G., Sha W., Kovacs M., Jaszberenyi M., He J., Rick F.G., Popovics P., Kanashiro-Takeuchi R., Hare J.M., Block N.L., Zarandi M. Synthesis of new potent agonistic analogs of growth hormone-releasing hormone (GHRH) and evaluation of their endocrine and cardiac activities. Peptides 2014, 52:104-112.
90. Jette L., Leger R., Thibaudeau K., Benquet C., Robitaille M., Pellerin I., Paradis V., van Wyk P., Pham K., Bridon D.P. Human growth hormone-releasing factor (hGRF)1-29-albumin bioconjugates activate the GRF receptor on the anterior pituitary in rats: identification of CJC-1295 as a long-lasting GRF analog. Endocrinology 2005, 146:3052-3058.
91. Thomas A., Schänzer W., Delahaut P., Thevis M. Immunoaffinity purification of peptide hormones prior to liquid chromatography-mass spectrometry in doping controls. Methods 2012, 56:230-235.
92. Matheny R.W., Nindl B.C., Adamo M.L. Minireview Mechano-growth factor: a putative product of IGF-I gene expression involved in tissue repair and regeneration. Endocrinology 2010, 151:865-875.
93. Goldspink G., Wessner B., Tschan H., Bachl N. Growth factors, muscle function, and doping. Endocrinol. Metab. Clin. North Am. 2010, 39:169-181. xi.
94. Fornaro M., Hinken A.C., Needle S., Hu E., Trendelenburg A.U., Mayer A., Rosenstiel A., Chang C., Meier V., Billin A.N., Becherer J.D., Brace A.D., Evans W.J., Glass D.J., Russell A.J. Mechano-growth factor peptide, the COOH terminus of unprocessed insulin-like growth factor 1, has no apparent effect on myoblasts or primary muscle stem cells, Am. J. Physiol. Endocrinol. Metab. 2014, 306:E150-E156.
95. Esposito S., Deventer K., Van Eenoo P. Characterization and identification of a C-terminal amidated mechano growth factor (MGF) analogue in black market products. Rapid Commun. Mass Spectrom. 2012, 26:686-692.
96. Lee S.J., McPherron A.C. Regulation of myostatin activity and muscle growth. Proc. Natl. Acad. Sci. U. S. A. 2001, 98:9306-9311.
97. McPherron A.C., Lawler A.M., Lee S.J. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature 1997, 387:83-90.
98. Wagner K.R., McPherron A.C., Winik N., Lee S.J. Loss of myostatin attenuates severity of muscular dystrophy in mdx mice. Ann. Neurol. 2002, 52:832-836.
99. Girgenrath S., Song K., Whittemore L.A. Loss of myostatin expression alters fiber-type distribution and expression of myosin heavy chain isoforms in slow- and fast-type skeletal muscle. Muscle Nerve 2005, 31:34-40.
100. Nadeau A., Karpati G. Are big muscles necessarily good muscles?. Ann. Neurol. 2008, 63:543-545.
101. Smith R.C., Lin B.K. Myostatin inhibitors as therapies for muscle wasting associated with cancer and other disorders. Curr. Opin. Support Palliat. Care 2013, 7:352-360.
102. Lee S.J., Reed L.A., Davies M.V., Girgenrath S., Goad M.E., Tomkinson K.N., Wright J.F., Barker C., Ehrmantraut G., Holmstrom J., Trowell B., Gertz B., Jiang M.S., Sebald S.M., Matzuk M., Li E., Liang L.F., Quattlebaum E., Stotish R.L., Wolfman N.M. Regulation of muscle growth by multiple ligands signaling through activin type II receptors. Proc. Natl. Acad. Sci. U. S. A. 2005, 102:18117-18122.
103. Arounleut P., Bialek P., Liang L.F., Upadhyay S., Fulzele S., Johnson M., Elsalanty M., Isales C.M., Hamrick M.W. A myostatin inhibitor (propeptide-Fc) increases muscle mass and muscle fiber size in aged mice but does not increase bone density or bone strength. Exp. Gerontol. 2013, 48:898-904.
104. Fedoruk M.N., Rupert J.L. Myostatin inhibition: a potential performance enhancement strategy?. Scand. J. Med. Sci. Sports 2008, 18:123-131.
105. Bogdanovich S., Krag T.O., Barton E.R., Morris L.D., Whittemore L.A., Ahima R.S., Khurana T.S. Functional improvement of dystrophic muscle by myostatin blockade. Nature 2002, 420:418-421.
106. Whittemore L.A., Song K., Li X., Aghajanian J., Davies M., Girgenrath S., Hill J.J., Jalenak M., Kelley P., Knight A., Maylor R., O'Hara D., Pearson A., Quazi A., Ryerson S., Tan X.Y., Tomkinson K.N., Veldman G.M., Widom A., Wright J.F., Wudyka S., Zhao L., Wolfman N.M. Inhibition of myostatin in adult mice increases skeletal muscle mass and strength. Biochem. Biophys. Res. Commun. 2003, 300:965-971.
107. Krivickas L.S., Walsh R., Amato A.A. Single muscle fiber contractile properties in adults with muscular dystrophy treated with MYO-029. Muscle Nerve 2009, 39:3-9.
108. Wagner K.R., Fleckenstein J.L., Amato A.A., Barohn R.J., Bushby K., Escolar D.M., Flanigan K.M., Pestronk A., Tawil R., Wolfe G.I., Eagle M., Florence J.M., King W.M., Pandya S., Straub V., Juneau P., Meyers K., Csimma C., Araujo T., Allen R., Parsons S.A., Wozney J.M., Lavallie E.R., Mendell J.R. A phase I/IItrial of MYO-029 in adult subjects with muscular dystrophy. Ann. Neurol. 2008, 63:561-571.
109. Gerlinger K., Petermann T., Sauter A. Gendoping Wissenschaftliche Grundlagen - Einfallstore - Kontrollen 2008, edition sigma, Berlin, Germany.
110. Peng W. Trends in biotech literature 2011. Nat. Biotechnol. 2012, 30:910.
111. Kawakami E., Kawai N., Kinouchi N., Mori H., Ohsawa Y., Ishimaru N., Sunada Y., Noji S., Tanaka E. Local applications of myostatin-siRNA with atelocollagen increase skeletal muscle mass and recovery of muscle function. PLoS ONE 2013, 8:e64719.
112. Liu C.M., Yang Z., Liu C.W., Wang R., Tien P., Dale R., Sun L.Q. Myostatin antisense RNA-mediated muscle growth in normal and cancer cachexia mice. Gene Ther. 2008, 15:155-160.
113. Tsuchida K. Targeting myostatin for therapies against muscle-wasting disorders. Curr. Opin. Drug Discov. Dev. 2008, 11:487-494.
114. Kurreck J. RNA interference: from basic research to therapeutic applications. Angew. Chem. Int. Ed. Engl. 2009, 48:1378-1398.
115. Kohler M., Schänzer W., Thevis M. RNA interference for performance enhancement and detection in doping control. Drug Test. Anal. 2011, 3:661-667.
116. Kohler M., Thomas A., Walpurgis K., Schänzer W., Thevis M. Detection of siRNA from plasma samples by mass spectrometry for doping control purposes. Anal. Bioanal. Chem. 2010, 398:1305-1312.
117. Thomas A., Walpurgis K., Delahaut P., Kohler M., Schanzer W., Thevis M. Detection of small interfering RNA (siRNA) by mass spectrometry procedures in doping controls. Drug Test. Anal. 2013, 5:853-860.
118. Lasne F., Martin L., Martin J.A., de Ceaurriz J. Isoelectric profiles of human erythropoietin are different in serum and urine. Int. J. Biol. Macromol. 2007, 41:354-357.
119. Lasne F., Martin L., Martin J.A., de Ceaurriz J. Detection of continuous erythropoietin receptor activator in blood and urine in anti-doping control. Haematologica 2009, 94:888-890.
120. Reichel C. Sports drug testing for erythropoiesis-stimulating agents and autologous blood transfusion. Drug Test. Anal. 2012, 4:803-804.
121. Reichel C., Thevis M. Gel electrophoretic methods for the analysis of biosimilar pharmaceuticals using the example of recombinant erythropoietin. Bioanalysis 2013, 5:587-602.
122. Semenza G.L., Wang G.L. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol. Cell. Biol. 1992, 12:5447-5454.
123. Jelkmann W. Biosimilar recombinant human erythropoietins (epoetins) and future erythropoiesis-stimulating treatments. Expert Opin. Biol. Ther. 2012, 12:581-592.
124. Abraham I., MacDonald K. Clinical safety of biosimilar recombinant human erythropoietins. Expert Opin. Drug Saf. 2012, 11:819-840.
125. Beuck S., Schänzer W., Thevis M. Hypoxia-inducible factor stabilizers and other small-molecule erythropoiesis-stimulating agents in current and preventive doping analysis. Drug Test. Anal. 2012, 4:830-845.
126. Yan L., Colandrea V.J., Hale J.J. Prolyl hydroxylase domain-containing protein inhibitors as stabilizers of hypoxia-inducible factor: small molecule-based therapeutics for anemia. Exp. Opin. Ther. Patents 2010, 20:1219-1245.
127. Thevis M., Kohler M., Schlörer N., Schänzer W. Gas phase reaction of substituted isoquinolines to carboxylic acids in ion trap and triple quadrupole mass spectrometers after electrospray ionization and collision-induced dissociation. J. Am. Soc. Mass Spectrom. 2008, 19:151-158.
128. Thevis M., Schänzer W. Illicit organogenesis - methods and substances of doping and manipulation. Organogenesis 2008, 4:264-271.
129. Beuck S., Schwabe T., Grimme S., Schlörer N., Kamber M., Schänzer W., Thevis M. Unusual mass spectrometric dissociation pathway of protonated isoquinoline-3-carboxamides due to multiple reversible water adduct formation in the gas phase. J. Am. Soc. Mass Spectrom. 2009, 20:2034-2048.
130. Beuck S., Bornatsch W., Lagojda A., Schänzer W., Thevis M. Development of liquid chromatography-tandem mass spectrometry-based analytical assays for the determination of HIF stabilizers in preventive doping research. Drug Test. Anal. 2011, 3:756-770.
131. Thevis M., Thomas A., Kohler M., Beuck S., Möller I., Schäfer M., Rodchenkov G., Yin S., Loo J.A., Geyer H., Schänzer W. Mass spectrometry-based characterization of new drugs and methods of performance manipulation in doping control analysis. Eur. J. Mass Spectrom. 2010, 16:301-312.
132. Jelkmann W. The disparate roles of cobalt in erythropoiesis, and doping relevance. Open J. Hematol. 2012, 3:6.
133. Cotes P.M., Bangham D.R. The international reference preparation of erythropoietin. Bull. World Health Organ. 1966, 35:751-760.
134. Ebert B., Jelkmann W. Intolerability of cobalt salt as erythropoietic agent. Drug Test. Anal. 2014, 6:185-189.
135. P. Bartley, Racing probe into cobalt chloride use started more than a year ago, says integrity officer, The Sydney Morning Herald, Sydney, February 4, 2014.
136. Minakata K., Suzuki M., Suzuki O. Application of electrospray ionization tandem mass spectrometry for the rapid and sensitive determination of cobalt in urine. Anal. Chim. Acta 2008, 614:161-164.
137. Iarmarcovai G., Sari-Minodier I., Chaspoul F., Botta C., De Meo M., Orsiere T., Berge-Lefranc J.L., Gallice P., Botta A. Risk assessment of welders using analysis of eight metals by ICP-MS in blood and urine and DNA damage evaluation by the comet and micronucleus assays; influence of XRCC1 and XRCC3 polymorphisms. Mutagenesis 2005, 20:425-432.
138. Sarmiento-Gonzalez A., Marchante-Gayon J.M., Tejerina-Lobo J.M., Paz-Jimenez J., Sanz-Medel A. High-resolution ICP-MS determination of Ti, V, Cr, Co, Ni, and Mo in human blood and urine of patients implanted with a hip or knee prosthesis. Anal. Bioanal. Chem. 2008, 391:2583-2589.
139. Mazoochian F., Schmidutz F., Kiefl J., Fottner A., Michalke B., Schierl R., Thomas P., Jansson V. Levels of Cr, Co, Ni and Mo in erythrocytes, serum and urine after hip resurfacing arthroplasty. Acta Chir. Belg. 2013, 113:123-128.
140. Tvermoes B.E., Finley B.L., Unice K.M., Otani J.M., Paustenbach D.J., Galbraith D.A. Cobalt whole blood concentrations in healthy adult male volunteers following two-weeks of ingesting a cobalt supplement. Food Chem. Toxicol. 2013, 53:432-439.
141. Finley B.L., Monnot A.D., Paustenbach D.J., Gaffney S.H. Derivation of a chronic oral reference dose for cobalt. Regul. Toxicol. Pharmacol. 2012, 64:491-503.
142. Unice K.M., Monnot A.D., Gaffney S.H., Tvermoes B.E., Thuett K.A., Paustenbach D.J., Finley B.L. Inorganic cobalt supplementation: prediction of cobalt levels in whole blood and urine using a biokinetic model. Food Chem. Toxicol. 2012, 50:2456-2461.
143. Macdougall I.C. Recent advances in erythropoietic agents in renal anemia. Semin. Nephrol. 2006, 26:313-318.
144. Macdougall I.C., Rossert J., Casadevall N., Stead R.B., Duliege A.M., Froissart M., Eckardt K.U. A peptide-based erythropoietin-receptor agonist for pure red-cell aplasia. N. Engl. J. Med. 2009, 361:1848-1855.
145. Jelkmann W. Erythropoietin after a century of research: younger than ever. Eur. J. Haematol. 2007, 78:183-205.
146. Reichel C., Gmeiner G. Erythropoietin and analogs. Handb. Exp. Pharmacol. 2010, 251-294.
147. Dumont J.A., Bitonti A.J., Clark D., Evans S., Pickford M., Newman S.P. Delivery of an erythropoietin-Fc fusion protein by inhalation in humans through an immunoglobulin transport pathway. J. Aerosol Med. 2005, 18:294-303.
148. Reichel C., Thevis M. Detection of EPO-Fc fusion protein in human blood: screening and confirmation protocols for sports drug testing. Drug Test. Anal. 2012, 4:818-829.
149. Wrighton N.C., Farrell F.X., Chang R., Kashyap A.K., Barbone F.P., Mulcahy L.S., Johnson D.L., Barrett R.W., Jolliffe L.K., Dower W.J. Small peptides as potent mimetics of the protein hormone erythropoietin. Science 1996, 273:458-464.
150. Möller I., Thomas A., Delahaut P., Geyer H., Schänzer W., Thevis M. Mass spectrometric detection of peginesatide in human urine in doping control analysis. J. Pharm. Biomed. Anal. 2012, 70:512-517.
151. Möller I., Thomas A., Geyer H., Schänzer W., Thevis M. Synthesis, characterisation, and mass spectrometric detection of a pegylated EPO-mimetic peptide for sports drug testing purposes. Rapid Commun. Mass Spectrom. 2011, 25:2115-2123.
152. Möller I., Thomas A., Geyer H., Schänzer W., Thevis M. Development and validation of a mass spectrometric detection method of peginesatide in dried blood spots for sports drug testing. Anal. Bioanal. Chem. 2012, 403:2715-2724.
153. Leuenberger N., Saugy J., Mortensen R.B., Schatz P.J., Giraud S., Saugy M. Methods for detection and confirmation of Hematide/peginesatide in anti-doping samples. Forensic Sci. Int. 2011, 213:15-19.
154. Thevis M. Gefährliche Substanzen, deren Missbrauch und Nachweis. Gyne 2012, 33:30-32.
155. Esposito S., Deventer K., Goeman J., Van der Eycken J., Van Eenoo P. Synthesis and characterization of the N-terminal acetylated 17-23 fragment of thymosin beta 4 identified in TB-500, a product suspected to possess doping potential. Drug Test. Anal. 2012, 4:733-738.
156. Sosne G., Qiu P., Goldstein A.L., Wheater M. Biological activities of thymosin beta4 defined by active sites in short peptide sequences. FASEB J. 2010, 24:2144-2151.
157. Sosne G., Qiu P., Kurpakus-Wheater M., Matthew H. Thymosin beta4 and corneal wound healing: visions of the future. Ann. N. Y. Acad. Sci. 2010, 1194:190-198.
158. Ho E.N., Kwok W.H., Lau M.Y., Wong A.S., Wan T.S., Lam K.K., Schiff P.J., Stewart B.D. Doping control analysis of TB-500, a synthetic version of an active region of thymosin beta(4), in equine urine and plasma by liquid chromatography-mass spectrometry. J. Chromatogr. A 2012, 1265:57-69.
159. Halpern A., Mancini M.C. Treatment of obesity: an update on anti-obesity medications. Obes. Rev. 2003, 4:25-42.
160. Ng F.M., Sun J., Sharma L., Libinaka R., Jiang W.J., Gianello R. Metabolic studies of a synthetic lipolytic domain (AOD9604) of human growth hormone. Horm. Res. 2000, 53:274-278.
161. Heffernan M., Summers R.J., Thorburn A., Ogru E., Gianello R., Jiang W.J., Ng F.M. The effects of human GH and its lipolytic fragment (AOD9604) on lipid metabolism following chronic treatment in obese mice and beta(3)-AR knock-out mice. Endocrinology 2001, 142:5182-5189.
162. World Anti-Doping Agency WADA statement on substance AOD-9604 2013, http://playtrue.wada-ama.org/news/wada-statement-on-substance-aod-9604/ (18.02.14).
163. Orlovius A.K., Thomas A., Schänzer W., Thevis M. AOD-9604 does not influence the WADA hGH isoform immunoassay. Drug Test. Anal. 2013, 5:850-852.
164. Walsh C. Drug in Essendon case, AOD-9604, was banned. The Australian July 18 2013.
165. Marhefka C.A., Gao W., Chung K., Kim J., He Y., Yin D., Bohl C., Dalton J.T., Miller D.D. Design, synthesis, and biological characterization of metabolically stable selective androgen receptor modulators. J. Med. Chem. 2004, 47:993-998.
166. Gerace E., Salomone A., Fasano F., Costa R., Boschi D., Di Stilo A., Vincenti M. Validation of a GC/MS method for the detection of two quinolinone-derived selective androgen receptor modulators in doping control analysis. Anal. Bioanal. Chem. 2011, 400:137-144.