Towards a decade of detecting new analogues of sildenafil, tadalafil and vardenafil in food supplements: A history, analytical aspects and health risks

Journal of Pharmaceutical and Biomedical Analysis

Volumn 69, Issue , 2012, Pages 196-208

  Venhuis, B J ^a   de Kaste, D ^a  

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

Author keywords

Adulterated food supplements; Analogues; Erectile dysfunction medicines; Patent literature; PDE 5 inhibitors

Indexed keywords

22 DIHYDRO ACETILDENAFIL; ACETILDENAFIL; AMINO TADALAFIL; CARBODENAFIL; CHLORO PRETADALAFIL; CHLORODENAFIL; DESMETHYLHONGDENAFIL; DIMETHYLACETILDENAFIL; DIOXO ACETILDENAFIL; DITHIO DESMETHYL CARBODENAFIL; GENDENAFIL; HOMOSILDENAFIL; HONGDENAFIL; HYDROXYCHLORODENAFIL; HYDROXYHOMOSILDENAFIL; MORPHOLINO ACETILDENAFIL; N DESMETHYLSILDENAFIL; NITRODENAFIL; NITROSO PRODENAFIL; NORACETILDENAFIL; NORNEOSILDENAFIL; OXOHONGDENAFIL; PIPERIDINO ACETILDENAFIL; PIPERIDINO HONGDENAFIL; SILDENAFIL; TADALAFIL; UNCLASSIFIED DRUG; UNINDEXED DRUG; VARDENAFIL; ZAPRINAST;

ANGINA PECTORIS; DIET SUPPLEMENTATION; DRUG DESIGN; DRUG DETERMINATION; DRUG INDUSTRY; DRUG MECHANISM; DRUG SCREENING; DRUG STRUCTURE; DRUG SURVEILLANCE PROGRAM; DRUG SYNTHESIS; ERECTILE DYSFUNCTION; HEALTH HAZARD; HUMAN; INFRARED SPECTROPHOTOMETRY; LIQUID CHROMATOGRAPHY; MASS SPECTROMETRY; PATENT; PRIORITY JOURNAL; RAMAN SPECTROMETRY; REVIEW; RISK ASSESSMENT; RISK BENEFIT ANALYSIS; TOXICOLOGY; TREATMENT INDICATION; VASCULAR DISEASE;

CARBOLINES; CHEMISTRY TECHNIQUES, ANALYTICAL; CYCLIC NUCLEOTIDE PHOSPHODIESTERASES, TYPE 5; DIETARY SUPPLEMENTS; DRUG CONTAMINATION; ERECTILE DYSFUNCTION; HUMANS; IMIDAZOLES; IONS; MALE; MODELS, CHEMICAL; PHOSPHODIESTERASE 5 INHIBITORS; PIPERAZINES; PURINES; SULFONES; TRIAZINES; VASODILATOR AGENTS;

EID: 84865076838     PISSN: 07317085     EISSN: 1873264X     Source Type: Journal    
DOI: 10.1016/j.jpba.2012.02.014     Document Type: Review

References (123)

1. Interpol, Pharmaceutical Crime, (accessed 16.12.11). http://www.interpol.int/Crime-areas/Pharmaceutical-crime/Operations/Operation-Pangea.
2. Schnetzler G., Banks I., Kirby M., Zou K.H., Symonds T. Characteristics, behaviors, and attitudes of men bypassing the healthcare system when obtaining phosphodiesterase type 5 inhibitors. J. Sex. Med. 2010, 7:1237-1246.
3. Sugita M., Miyakawa M. Economic analysis of use of counterfeit drugs: health impairment risk of counterfeit phosphodiesterase type 5 inhibitor taken as an example. Environ. Health Preventive Med. 2010, 15:244-251.
4. B.J. Venhuis, M.E. Zwaagstra, J.D.J.v.d. Berg, A.J.H.P.v. Riel, H.W.G. Wagenaar, K.v. Grootheest, D. Barends, D.d. Kaste, in: Illicit erectile dysfunction products in the Netherlands; a decade of trends and a 2007-2010 product update, RIVM rapport 370030003, National Institute for Public Health and the Environment, 2010, pp. 75.
5. Goldenberg M.M. Safety and efficacy of sildenafil citrate in the treatment of male erectile dysfunction. Clin. Therap. 1998, 20:1033-1048.
6. Poon W.T., Lam Y.H., Lee H.H., Ching C.K., Chan W.T., Chan S.S., Lai C.K., Tse M.L., Chan A.Y., Mak T.W. Outbreak of hypoglycaemia: sexual enhancement products containing oral hypoglycaemic agent. Hong Kong Med. J. 2009, 15:196-200.
7. Low M.Y., Zeng Y., Li L., Ge X.W., Lee R., Bloodworth B.C., Koh H.L. Safety and quality assessment of 175 illegal sexual enhancement products seized in red-light districts in Singapore. Drug Saf. 2009, 32:1141-1146.
8. Singh S., Prasad B., Savaliya A.A., Shah R.P., Gohil V.M., Kaur A. Strategies for characterizing sildenafil, vardenafil, tadalafil and their analogues in herbal dietary supplements, and detecting counterfeit products containing these drugs. Trends Anal. Chem. 2009, 28:13-28.
9. Holzgrabe U., Malet-Martino M. Analytical challenges in drug counterfeiting and falsification-the NMR approach. J. Pharm. Biomed. Anal. 2011, 55:679-687.
10. Lee H.M., Lee B.J. A novel approach to simultaneous screening and confirmation of regulated pharmaceutical compounds in dietary supplements by LC/MS/MS with an information-dependent acquisition method. Food Addit. Contam. Part A Chem. Anal. Control Expo. Risk Assess. 2011, 28:396-407.
11. Shin M.H., Hong M.K., Kim W.S., Lee Y.J., Jeoung Y.C. Identification of a new analogue of sildenafil added illegally to a functional food marketed for penile erectile dysfunction. Food Addit. Contam. 2003, 20:793-796.
12. Japanese Food and Drug Administration Ministry, Concerning the discovery of a so-called health food (unlicensed and non-permitted) containing a sildenafil-like substance (hydroxy-homosildenafil), 2004. http://www.mhlw.go.jp/houdou/2004/02/h0213-3.html.
13. Blok-Tip L., Zomer B., Bakker F., Hartog K.D., Hamzink M., Ten Hove J., Vredenbregt M., De Kaste D. Structure elucidation of sildenafil analogues in herbal products. Food Addit. Contam. 2004, 21:737-748.
14. Shin C., Hong M., Kim D., Lim Y. Structure determination of a sildenafil analogue contained in commercial herb drinks. Magn. Reson. Chem. 2004, 42:1060-1062.
15. Zou P., Hou P., Low M.-Y., Koh H.-L. Structural elucidation of a tadalafil analogue found as an adulterant of a herbal product. Food Addit. Contam. 2006, 23:446-451.
16. Zou P., Hou P., Oh S.S., Low M.Y., Koh H.L. Electrospray tandem mass spectrometric investigations of tadalafil and its analogue. Rapid Commun. Mass Spectrom. 2006, 20:3488-3490.
17. Gratz S.R., Flurer C.L., Wolnik K.A. Analysis of undeclared synthetic phosphodiesterase-5 inhibitors in dietary supplements and herbal matrices by LC-ESI-MS and LC-UV. J. Pharm. Biomed. Anal. 2004, 36:525-533.
18. Gratz S.R., Gamble B.M., Flurer R.A. Accurate mass measurement using Fourier transform ion cyclotron resonance mass spectrometry for structure elucidation of designer drug analogs of tadalafil, vardenafil and sildenafil in herbal and pharmaceutical matrices. Rapid Commun. Mass Spectrom. 2006, 20:2317-2327.
19. Hou P., Zou P., Low M.Y., Chan E., Koh H.L. Structural identification of a new acetildenafil analogue from pre-mixed bulk powder intended as a dietary supplement. Food Addit. Contam. 2006, 23:870-875.
20. Reepmeyer J.C., Woodruff J.T. Use of liquid chromatography-mass spectrometry and a hydrolytic technique for the detection and structure elucidation of a novel synthetic vardenafil designer drug added illegally to a natural herbal dietary supplement. J. Chromatogr. A 2006, 1125:67-75.
21. Lai K.C., Liu Y.C., Tseng M.C., Lin J.H. Isolation and identification of sildenafil analogue illegally added in dietary supplements. J. Food Drug Anal. 2006, 14:19-23.
22. Reepmeyer J.C., Woodruff J.T. Use of liquid chromatography-mass spectrometry and a chemical cleavage reaction for the structure elucidation of a new sildenafil analogue detected as an adulterant in an herbal dietary supplement. J. Pharm. Biomed. Anal. 2007, 44:887-893.
23. Pissarnitski D. Phosphodiesterase 5 (PDE 5) inhibitors for the treatment of male erectile disorder: attaining selectivity versus PDE6. Med. Res. Rev. 2006, 26:369-395.
24. Corbin J.D., Beasley A., Blount M.A., Francis S.H. Vardenafil: structural basis for higher potency over sildenafil in inhibiting cGMP-specific phosphodiesterase-5 (PDE5). Neurochem. Int. 2004, 45:859-863.
25. Daugan A., Grondin P., Ruault C., Le Monnier de Gouville A.C., Coste H., Kirilovsky J., Hyafil F., Labaudiniere R. The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 1: 5,6,11,11a-tetrahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indole-1,3(2H)-dione analogues. J. Med. Chem. 2003, 46:4525-4532.
26. Daugan A., Grondin P., Ruault C., Le Monnier de Gouville A.C., Coste H., Linget J.M., Kirilovsky J., Hyafil F., Labaudiniere R. The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 2: 2,3,6,7,12,12a-Hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione analogues. J. Med. Chem. 2003, 46:4533-4542.
27. Sandner P., Svenstrup N., Tinel H., Haning H., Bischoff E. Phosphodiesterase 5 inhibitors and erectile dysfunction. Exp. Opin. Therap. Patents 2008, 18:21-33.
28. Palmer M.J., Bell A.S., Fox D.N., Brown D.G. Design of second generation phosphodiesterase 5 inhibitors. Curr. Top. Med. Chem. 2007, 7:405-419.
29. A.S. Bell, D. Brown, N.K. Terrett, Pyralozopyrimidone antianginal agents, Pfizer Research and Development Company, EP0463756 A1, 1991.
30. A.S. Bell, N.K. Terrett, Pyrazolopyrimidone antianginal agents, Pfizer Research and Development Company, EP0526004 A1, 1992.
31. P. Ellis, N.K. Terrett, Pyralozopyrimidones for the treatment of impotence, Pfizer Research and Development company, WO94/28902, 1994.
32. M.W. Orme, J.S. Sawyer, A.C. Daugan, A. Bombrun, F. Gellibert, L.M. Schultze, R.E. Brown, R.L. Gosmini, Carboline derivatives as PDEV inhibitors, Lilly Icos LLC, WO2003/000691, 2002.
33. M.W. Orme, J.S. Sawyer, L.M. Schultze, Tetracyclic compounds as PDE-5 inhibitors, Lilly ICOS LLC, WO02/098428, 2002.
34. M.W. Orme, J.S. Sawyer, L.M. Schultze, A.C. Daugan, F. Gellibert, Pirazino [1',2':1,6] Pyrido [3,4b] Indole derivatives, Lilly Icos LLC, WO2002/00656 A2, 2001.
35. U. Niewöhner, M. Es-Sayed, H. Haning, T. Schenke, K.H. Schlemmer, J. Keldenich, E. Bischoff, E. Perzborn, K. Dembowski, P. Serno, M. Nowakowski, 2-Phenyl substituted imidazotriazinones as phosphodiesterase inhibitors, Bayer Aktiengesellschaft, US6362178B1, 2002.
36. U. Niewöhner, M. Es-Sayed, H. Haning, T. Schenke, G. Schmidt, K.H. Schlemmer, E. Bischoff, K. Dembowski, E. Perzborn, 7-Alkyl- and cycloalkyl-substituted imidazotriazinones, Bayer Aktiengesellschaft, WO99/67244, 1999.
37. A. Daugan, Tetracyclic derivatives: process preparation and use, ICOS-cooperation, US5859006, 1999.
38. Pfizer, The Viagra story. (accessed 13.12.11). http://resources.schoolscience.co.uk/pfizer/viagra/index.html.
39. H.W. Hamilton, 5-Substituted pyrazolo[4,3-d] pyrimidones, process for preparing the compounds and pharmaceutical compositions comprising the compounds, Warner-Lambert Company, EP0201188A2, 1986.
40. A.S. Bell, D. Brown, N.K. Terrett, Intermediates useful in the synthesis of pyrazolopyrimidone antianginal agents, Pfizer Inc., US5719283, 1998.
41. Allerton C.M., Barber C.G., Beaumont K.C., Brown D.G., Cole S.M., Ellis D., Lane C.A., Maw G.N., Mount N.M., Rawson D.J., Robinson C.M., Street S.D., Summerhill N.W. A novel series of potent and selective PDE5 inhibitors with potential for high and dose-independent oral bioavailability. J. Med. Chem. 2006, 49:3581-3594.
42. M.C. Maytom, I.H. Osterloh, Method of treating impotence deu to spinal cord injury, Pfizer Limited, EP0951908A2, 1999.
43. D.H. Kim, J.H. Kim, K.I. Choi, Y. Kim, G. Nam, J.H. Seo, Novel Pyrzolopyrimidinethione derivatives. Preparation methods thereof and their use as therapeutics for erectile dysfunction, Korea Institute of Science and Technology, WO 02/102802 A1, 2002.
44. Cho E.Y., Chung S., Kim J.H., Kim D., Jin C. Effects of a new selective phosphodiesterase type 5 inhibitor, KJH-1002, on the relaxation of rabbit corpus cavernosum tissue. J. Appl. Pharmacol. 2003, 11:232-237.
45. Reepmeyer J.C., Woodruff J.T., d'Avignon D.A. Structure elucidation of a novel analogue of sildenafil detected as an adulterant in an herbal dietary supplement. J. Pharm. Biomed. Anal. 2007, 43:1615-1621.
46. Deng K.P., Luo Z.Y., Lei Y. Detection of a new type of phosphodiesterase-5 inhibitor, aildenafil, in health care products for promoting sexual function. Chin. Pharm. J. (China) 2011, 46:1441-1444.
47. B. Liu, 1,6-Dihydro-7H-pyrazolo[3,4-D]pyrimidin-7-one compound for the treatment of impotence, US10/736,732, 2005.
48. He Z.J., Zhang K., Jin J., Li N.C., Na Y.Q., Bai W.J., Wang X.F., Zhu J.C., Jiang H., Yuan R.P., Hong B.F., Song T., Yang Y., Dai D.X. Aildenafil citrate: a new potent and highly selective phosphodiesterase type 5 inhibitor for the treatment of erectile dysfunction. Zhonghua Nan Ke Xue 2006, 12:1080-1083.
49. Wang J., Jiang Y., Wang Y., Zhao X., Cui Y., Gu J. Liquid chromatography tandem mass spectrometry assay to determine the pharmacokinetics of aildenafil in human plasma. J. Pharm. Biomed. Anal. 2007, 44:231-235.
50. S. Li, J. Ren, Y. Zhao, Q. Lv, J. Guo, Pyrazolopyrimidinethione derivatives, salts and solvates thereof, preparation methods and use thereof, US 2007/0219220 A1, 2007.
51. Gryniewicz C.M., Reepmeyer J.C., Kauffman J.F., Buhse L.F. Detection of undeclared erectile dysfunction drugs and analogues in dietary supplements by ion mobility spectrometry. J. Pharm. Biomed. Anal. 2009, 49:601-606.
52. Reepmeyer J.C., d'Avignon D.A. Structure elucidation of thioketone analogues of sildenafil detected as adulterants in herbal aphrodisiacs. J. Pharm. Biomed. Anal. 2009, 49:145-150.
53. Ge X., Li L., Koh H.-L., Low M.-Y. Identification of a new sildenafil analogue in a health supplement. J. Pharm. Biomed. Anal. 2011, 56:491-496.
54. Wollein U., Eisenreich W., Schramek N. Identification of novel sildenafil-analogues in an adulterated herbal food supplement. J. Pharm. Biomed. Anal. 2011, 56:705-712.
55. Venhuis B.J., Zomer G., Hamzink M., Meiring H.D., Aubin Y., de Kaste D. The identification of a nitrosated prodrug of the PDE-5 inhibitor aildenafil in a dietary supplement: a Viagra with a pop. J. Pharm. Biomed. Anal. 2011, 54:735-741.
56. Demizu Y., Wakana D., Kamakura H., Kurihara M., Okuda H., Goda Y. Identification of mutaprodenafil in a dietary supplement and its subsequent synthesis. Chem. Pharm. Bull. (Tokyo) 2011, 59:1314-1316.
57. Porst H., Padma-Nathan H., Giuliano F., Anglin G., Varanese L., Rosen R. Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36hours after dosing: a randomized controlled trial. Urology 2003, 62:121-125. (discussion 125-126).
58. Hedelin H., Stroberg P. Treatment for erectile dysfunction based on patient-reported outcomes: to every man the PDE5 inhibitor that he finds superior. Drugs 2005, 65:2245-2251.
59. Beghyn T., Hounsou C., Deprez B.P. PDE5 inhibitors: an original access to novel potent arylated analogues of tadalafil. Bioorg. Med. Chem. Lett. 2007, 17:789-792.
60. van Deursen M.M., Lock E.R., Poortman-van der Meere A.J. Organic impurity profiling of 3,4-methylenedioxymethamphetamine (MDMA) tablets seized in The Netherlands. Sci. Justice 2006, 46:135-152.
61. Bohn M., Bohn G., Blaschke G. Synthesis markers in illegally manufactured 3,4-methylenedioxyamphetamine and 3,4-methylenedioxymethamphetamine. Int. J. Legal Med. 1993, 106:19-23.
62. Zou P., Hou P., Low M.Y., Koh H.L. Structural elucidation of a tadalafil analogue found as an adulterant of a herbal product. Food Addit. Contam. 2006, 23:446-451.
63. Kurita H., Mizuno K., Kuromi K., Suzuki N., Ueno C., Kamimura M., Fujiwara A., Owada K., Ogo N., Yamamoto M. Identification of aminotadalafil and its stereoisomers contained in health foods using chiral liquid chromatography-mass spectrometry. J. Health Sci. 2008, 54:310-314.
64. Toomey V.M., Litzau J.J., Flurer C.L. Isolation and structural characterization of two tadalafil analogs found in dietary supplements. J. Pharm. Biomed. Anal. 2011.
65. Hasegawa T., Takahashi K., Saijo M., Ishii T., Nagata T., Kurihara M., Haishima Y., Goda Y., Kawahara N. Isolation and structural elucidation of cyclopentynafil and N-octylnortadalafil found in a dietary supplement. Chem. Pharm. Bull. (Tokyo) 2009, 57:185-189.
66. Korean National Institute of Food and Drug Safety Evaluation, Instrumental Analysis Data of Illegal Compounds in Food, 2010. http://www.nifds.go.kr/.
67. Venhuis B.J., Zomer G., Vredenbregt M.J., de Kaste D. The identification of (-)-trans-tadalafil, tadalafil, and sildenafil in counterfeit Cialis and the optical purity of tadalafil stereoisomers. J. Pharm. Biomed. Anal. 2009, 51:723-727.
68. Venhuis B.J., Zomer G., de Kaste D. Structure elucidation of a novel synthetic thiono analogue of sildenafil detected in an alleged herbal aphrodisiac. J. Pharm. Biomed. Anal. 2008, 46:814-817.
69. Hudson S., Ramsey J., King L., Timbers S., Maynard S., Dargan P.I., Wood D.M. Use of high-resolution accurate mass spectrometry to detect reported and previously unreported cannabinomimetics in herbal high products. J. Anal. Toxicol. 2010, 34:252-260.
70. Lee H., Hyan Yoo H., Kang M.Y., Kim D.H. Low-energy collision-induced dissociation of sildenafil thiono analogues: gas-phase intramolecular nucleophilic substitution through ion-neutral complexes between a cationic substrate and a thione-containing neutral nucleophile. Rapid Commun. Mass Spectrom. 2005, 19:1767-1770.
71. Reepmeyer J.C. Direct intramolecular gas-phase transfer reactions during fragmentation of sildenafil and thiosildenafil analogs in electrospray ionization mass spectrometry. Rapid Commun. Mass Spectrom. 2009, 23:927-936.
72. Levsen K., Schiebel H.M., Behnke B., Dötzer R., Dreher W., Elend M., Thiele H. Structure elucidation of phase II metabolites by tandem mass spectrometry: an overview. J. Chromatogr. A 2005, 1067:55-72.
73. Bordas-Nagy J., Despeyroux D., Jennings K. Comparison of helium and argon as collision gases in the high energy collision-induced decomposition of MH+ ions of peptides. J. Am. Soc. Mass Spec. 1992, 3:502-514.
74. Lai K.C., Liu Y.C., Liao Y.C., Lin Y.L., Tsai L.Y., Lin J.H., Lo C.F. Isolation and identification of three thio-sildenafil analogues in dietary supplements. J. Food Drug Anal. 2010, 18:269-278.
75. Vaysse J., Gilard V., Balayssac S., Zedde C., Martino R., Malet-Martino M. Identification of a novel sildenafil analogue in an adulterated herbal supplement. J. Pharm. Biomed. Anal. 2012, 59:58-66.
76. Personal communication with the author.
77. Porst H., Hell-Momeni K., Buttner H. Chronic PDE-5 inhibition in patients with erectile dysfunction: new treatment approach using once daily Tadalafil. Urologe A 2009, 48. 1318, pp. 1319-1320.
78. Washington S.L., Shindel A.W. A once-daily dose of tadalafil for erectile dysfunction: compliance and efficacy. Drug Design Dev. Therapy 2010, 4:159-171.
79. Balayssac S., Trefi S., Gilard V., Malet-Martino M., Martino R., Delsuc M.A. 2D and 3D DOSY 1H NMR, a useful tool for analysis of complex mixtures: application to herbal drugs or dietary supplements for erectile dysfunction. J. Pharm. Biomed. Anal. 2009, 50:602-612.
80. Champagne A.B., Emmel K.V. Rapid screening test for adulteration in raw materials of dietary supplements. Vib. Spec. 2011, 55:216-223.
81. Sacre P.Y., Deconinck E., De Beer T., Courselle P., Vancauwenberghe R., Chiap P., Crommen J., De Beer J.O. Comparison and combination of spectroscopic techniques for the detection of counterfeit medicines. J. Pharm. Biomed. Anal. 2010, 53:445-453.
82. FDA, Published as FDA alert number 07/2005, 2005. http://www.fda.gov/.
83. Venhuis B.J., Blok-Tip L., de Kaste D. Designer drugs in herbal aphrodisiacs. Forensic Sci. Int. 2008, 172-173. 177.
84. EMA, The initial scientific discussion for the approval of VIAGRA, pg 7, 2010.
85. Boyce E.G., Umland E.M. Sildenafil citrate: a therapeutic update. Clin. Therapeutics 2001, 23:2-23.
86. European Medicines Agency, EPAR summary for Viagra. http://www.ema.europa.eu/.
87. B.J. Venhuis, D.M. Barends, M.E. Zwaagstra, D. de Kaste, in: Recent developments in counterfeits and imitations of Viagra, Cialis and Levitra, A 2005-2006 update, RIVM Report 370030001/2007, National Institute for Public Health and the Environment, The Netherlands, 2007, pp. 35.
88. Häberli A., Girard P., Low M.Y., Ge X. Isolation and structure elucidation of an interaction product of aminotadalafil found in an illegal health food product. J. Pharm. Biomed. Anal. 2010, 53:24-28.
89. Elder D.P., Snodin D., Teasdale A. Control and analysis of hydrazine, hydrazides and hydrazones-genotoxic impurities in active pharmaceutical ingredients (APIs) and drug products. J. Pharm. Biomed. Anal. 2011, 54:900-910.
90. Koller W.C., Rueda M.G. Mechanism of action of dopaminergic agents in Parkinson's disease. Neurology 1998, 50:S11-S14. (discussion S44-18).
91. Barr D.B., Barr J.R., Weerasekera G., Wamsley J., Kalb S.R., Sjodin A., Schier J.G., Rentz E.D., Lewis L., Rubin C., Needham L.L., Jones R.L., Sampson E.J. Identification and quantification of diethylene glycol in pharmaceuticals implicated in poisoning epidemics: an historical laboratory perspective. J. Anal. Toxicol. 2007, 31:295-303.
92. Bogdanich W., Hooker J. From China to Panama, A Trail of Poisoned Medicine 2007, New York Times.
93. Guerrini M., Beccati D., Shriver Z., Naggi A., Viswanathan K., Bisio A., Capila I., Lansing J.C., Guglieri S., Fraser B., Al-Hakim A., Gunay N.S., Zhang Z., Robinson L., Buhse L., Nasr M., Woodcock J., Langer R., Venkataraman G., Linhardt R.J., Casu B., Torri G., Sasisekharan R. Oversulfated chondroitin sulfate is a contaminant in heparin associated with adverse clinical events. Nat. Biotechnol. 2008.
94. Chyau J. Casting a global safety net-a framework for food safety in the age of globalization. Food Drug Law. J. 2009, 64:313-334.
95. Venhuis B.J., Tan J., Vredenbregt M.J., Ge X., Low M.Y., de Kaste D. Capsule shells adulterated with tadalafil. Forensic Sci. Int. 2012, 214:e20-e22.
96. Medsafe, Health product alert INV10019. , 2010. http://www.medsafe.govt.nz/.
97. Seftel A., Goldfischer E., Kim E.D., Dula E., Zeigler H., Burns P. Onset of efficacy of tadalafil once daily in men with erectile dysfunction: a randomized, double-blind, placebo controlled trial. J. Urol. 2011, 185:243-248.
98. Poon W.T., Lam Y.H., Lai C.K., Chan A.Y., Mak T.W. Analogues of erectile dysfunction drugs: an under-recognised threat. Hong Kong Med. J. 2007, 13:359-363.
99. Muller D., Weinmann W., Hermanns-Clausen M. Chinese slimming capsules containing sibutramine sold over the Internet: a case series. Dtsch. Arztebl. Int. 2009, 106:218-222.
100. Huang Z., Xiao S., Luo D., Chen B., Yao S. Simultaneous determination of sibutramine and N-Di-desmethylsibutramine in dietary supplements for weight control by HPLC-ESI-MS. J. Chromatogr. Sci. 2008, 46:707-711.
101. Chen S.P., Tang M.H., Ng S.W., Poon W.T., Chan A.Y., Mak T.W. Psychosis associated with usage of herbal slimming products adulterated with sibutramine: a case series. Clin. Toxicol. (Phila.) 2010, 48:832-838.
102. Roh S.H., Kang Y.P., Park S., Huh Y., Lee J., Park J.H., Kim D., Kwon S.W. Determination of tadalafil and N-desmethylsibutramine in health and dietary supplements using ultra-performance liquid chromatography (UPLC) coupled with quadrupole-time-of-flight mass spectrometry (Q-TOF MS). Food Addit. Contam. Part A Chem. Anal. Control Expo. Risk Assess. 2011, 28:1475-1482.
103. Chand N., Eyre P. The pharmacology of anaphylaxis in the chicken intestine. Br. J. Pharmacol. 1976, 57:399-408.
104. Bowman A., Drummond A.H. Cyclic GMP mediates neurogenic relaxation in the bovine retractor penis muscle. Br. J. Pharmacol. 1984, 81:665-674.
105. A.S. Bell, D. Brown, N.K. Terrett, Pyralozopyrimidone antianginal agents, Pfizer Research and Development Company, EP0463756 A1, 1992.
106. S. Yuk, Combating illegal foods and drugs containing unauthorized substances, 4th Seminar of European Customs Chemists, Helsinki, Finland, 2010.
107. Zhou P., Sze Yin Oh S., Kiang K.H., Low M.Y., Koh H.L. Letter: Liquid chromatography ion trap/time-of-flight mass spectrometric study on the fragmentation of an acetildenafil analogue. Eur. J. Mass Spectrom. 2007, 13:233-238.
108. Flores Toque H.A., Priviero F.B., Teixeira C.E., Perissutti E., Fiorino F., Severino B., Frecentese F., Lorenzetti R., Baracat J.S., Santagada V., Caliendo G., Antunes E., De Nucci G. Synthesis and pharmacological evaluations of sildenafil analogues for treatment of erectile dysfunction. J. Med. Chem. 2008, 51:2807-2815.
109. Oh S.S., Zou P., Low M.Y., Koh H.L. Detection of sildenafil analogues in herbal products for erectile dysfunction. J. Toxicol. Environ. Health A 2006, 69:1951-1958.
110. Göker H., CoşKun M., Alp M. Isolation and identification of a new acetildenafil analogue used to adulterate a dietary supplement: dimethylacetildenafil. Turkish J. Chem. 2010, 34:157-163.
111. Park H.J., Jeong H.K., Chang M.I., Im M.H., Jeong J.Y., Choi D.M., Park K., Hong M.K., Youm J., Han S.B., Kim D.J., Park J.H., Kwon S.W. Structure determination of new analogues of vardenafil and sildenafil in dietary supplements. Food Addit. Contam. 2007, 24:122-129.
112. Choi D.M., Park S., Yoon T.H., Jeong H.K., Pyo J.S., Park J., Kim D., Kwon S.W. Determination of analogs of sildenafil and vardenafil in foods by column liquid chromatography with a photodiode array detector, mass spectrometry, and nuclear magnetic resonance spectrometry. J.A.O.A.C. Int. 2008, 91:580-588.
113. Toque H.A., Teixeira C.E., Lorenzetti R., Okuyama C.E., Antunes E., De Nucci G. Pharmacological characterization of a novel phosphodiesterase type 5 (PDE5) inhibitor lodenafil carbonate on human and rabbit corpus cavernosum. Eur. J. Pharmacol. 2008.
114. Flores-Toque H.A., Priviero F.B., Teixeira C.E., Perissutti E., Fiorino F., Severino B., Frecentese F., Lorenzetti R., Baracat J.S., Santagada V., Caliendo G., Antunes E., De-Nucci G. Synthesis and pharmacological evaluations of sildenafil analogues for treatment of erectile dysfunction. J. Med. Chem. 2008, 51:2807-2810.
115. Bae S.K., Kang M.J., Yeo C.W., Kim M.J., Shon J.H., Liu K.H., Shin J.G. Simultaneous determination of udenafil and its active metabolite, DA-8164, in human plasma and urine using ultra-performance liquid chromatography-tandem mass spectrometry: application to a pharmacokinetic study. Biomed. Chromatogr. 2008, 22:939-946.
116. Kim B.H., Lim H.S., Chung J.Y., Kim J.R., Lim K.S., Sohn D.R., Cho J.Y., Yu K.S., Shin S.G., Paick J.S., Jang I.J. Safety, tolerability and pharmacokinetics of udenafil, a novel PDE-5 inhibitor, in healthy young Korean subjects. Br. J. Clin. Pharmacol. 2008, 65:848-854.
117. Paick J.S., Kim S.W., Yang D.Y., Kim J.J., Lee S.W., Ahn T.Y., Choi H.K., Suh J.K., Kim S.C. The efficacy and safety of udenafil, a new selective phosphodiesterase type 5 inhibitor, in patients with erectile dysfunction. J. Sex. Med. 2008, 5:946-953.
118. Salem E.A., Kendirci M., Hellstrom W.J. Udenafil, a long-acting PDE5 inhibitor for erectile dysfunction. Curr. Opin. Investig. Drugs 2006, 7:661-669.
119. Li L., Low M.Y., Aliwarga F., Teo J., Ge X.W., Zeng Y., Bloodworth B.C., Koh H.L. Isolation and identification of hydroxythiohomosildenafil in herbal dietary supplements sold as sexual performance enhancement products. Food Addit. Contam. Part A Chem. Anal. Control Expo. Risk Assess. 2009, 26:145-151.
120. Dorsey P., Keel C., Klavens M., Hellstrom W.J.G. Phosphodiesterase type 5 (PDE5) inhibitors for the treatment of erectile dysfunction. Exp. Opin. Pharmacoth. 2010, 11:1109-1122.
121. Hasegawa T., Saijo M., Ishii T., Nagata T., Haishima Y., Kawahara N., Goda Y. Structural elucidation of a tadalafil analogue found in a dietary supplement. Shokuhin Eiseigaku Zasshi 2008, 49:311-315.
122. Lam Y.H., Poon W.T., Lai C.K., Chan A.Y., Mak T.W. Identification of a novel vardenafil analogue in herbal product. J. Pharm. Biomed. Anal. 2008, 46:804-807.
123. Lee H.M., Kim C.S., Jang Y.M., Kwon S.W., Lee B.J. Separation and structural elucidation of a novel analogue of vardenafil included as an adulterant in a dietary supplement by liquid chromatography-electrospray ionization mass spectrometry, infrared spectroscopy and nuclear magnetic resonance spectroscopy. J. Pharm. Biomed. Anal. 2011, 54:491-496.