348. 3 : 348-357 2012 Ann. Rept. Food Drug Res. 3 : 348-357 2012 100 1002,864 52818.4% 27.4% (225/822)14.8% (303/2,042) 180.1% (423/528)216.7% (88/528) 3 N-desmethylsibutramineSibutramineCaffeine SildenafilTadalafilVardenafilSibutramine22 100 ㈠ 100 2,864 ㈡ A c e t a m i n o p h e n A c e t i l a c i d ( S i l d e n a f i l a n a l o g u e 3 5 6 ) A c e t i l d e n a f i l ( S i l d e n a f i l analogue466)acetyl vardenafil ( Va r d e n a f i l a n a l o g u e 4 6 6 ) Aminotadalafil (Tadalafil analogue 390)BenzylpiperazineBisacodyl BumetanideCaffeineChloramphenicol ChlorpheniramineChloropretadalafil ( Ta d a l a f i l a n a l o g u e 4 2 6 ) ClobenzorexDehydroepiandrosterone DiclofenacDimethylsildenafil (Sildenafil a n a l o g u e 4 8 8 ) E p h e d r i n e FenofibrateFlunitrazepamFluoxetine FurosemideGemfibrozilGendenafil
100 349 ( S i l d e n a f i l a n a l o g u e 3 5 4 ) Homosildenafil (Sildenafil analogue 4 8 8 ) H y d r o c h l o r o t h i a z i d e Hydroxyacetildenafil (Sildenafil analogue 4 8 2 ) H y d r o x y h o m o s i l d e n a f i l ( S i l d e n a f i l a n a l o g u e 5 0 4 ) Hydroxythiohomosildenafil (Sildenafil analogue520)imidazosagatriazinone ( S i l d e n a f i l a n a l o g u e 3 1 2 ) L o v a s t a t i n M e l a t o n i n M e t f o r m i n MethyltestosteroneMetoclopramide N-butyltadalafil (Tadalafil analogue 4 3 1 ) N - d e s m e t h y l s i b u t r a m i n e (Sibutramine analogue265) N-did esmethylsibutramine (Sibutramine analogue251)nicotinamide Nor-acetildenafil (Sildenafil analogue 452)Nortadalafil (Tadalafil analogue 375)OrlistatPhenolphthalein PhenylephrinePiperidenafil (Vardenafil a n a l o g u e 4 5 9 ) P i r o x i c a m PropranololRimonabantSennosides SibutramineSildenafilSynephrine Ta d a l a f i l Te s t o s t e r o n e p r o p i o n a t e TheophyllineThiamineThioaildenafil (Sildenafil analogue504)thioctic a c i d T h i o h o m o s i l d e n a f i l ( S i l d e n a f i l analogue504)thiosildenafil (Sildenafil analogue490)vardenafil a n a l o g u e ( 3 1 2 ) Yo h i m b i n e Zolpidem4-methylethcathinone7-ketodehydroepiandrosteroneSIGMA TLC PharmaChemCacheSyn 95% ㈢ (1-3) 1. Dragendorff s Spray Reagent 2. 50%Spray Reagent 3. 4. Tetrazolium Blue Spray Reagent 5. p-dimethylaminobenzaldehyde Spray Reagent 6. Ninhydrin Spray Reagent 7. Anisaldehyde-Sulfuric Acid Spray Reagent 8. 2,4-Dinitrophenylhydrazine Spray Reagent 9. p-dimethylaminocinnamaldehyde Spray Reagent 10. 5% Ferric Chloride Spray Reagent 11. Iodoplatinate Spray Reagent 12. Iodoplatinate Spray Reagent, acidified 13. 1% Mercurous Nitrate Spray Reagent 14. Potassium Permanganate Spray Reagent 15. Potassium Permanganate Spray Reagent, acidified 16. 1% Vanillin-Sulfuric Acid Spray Reagent ㈣ 1. Merck TLC plates, silica gel 60 F25420 20 cm 2. Varian CARY 300 Bio spectrophotometer 3. (GC/MS)HP 6890 GC system with HP5973 mass selective detector Thermo DSQ with Thermo TRACE GC ULTRA 4. (HPLC)Agilent 1100 series with photodiode array detector Hitachi L-2000 series with photodiode array detector 5. (LC/MS/MS) Waters 2695 Alliance LC & 2998 photodiode array detector with Quattro Premier XE 95% 5 ml 5 (721 v/v)(811v/v)
350 (91v/v)(11v/ v)(41v/v) 254366 nm95% R f 1 0 0 7-keto-dehydroepiandrosteroneCaffeine DehydroepiandrosteroneSynephrine ( 100 )()100 93100 822 2,042 2,864 225 303 528 (%) 27.4 14.8 18.4 件數 3000 2500 2000 1500 1000 500 0 548 305 243 799 458 815 544 341 271 794 574 220 772 492 1256 1066 ( 280 913 486 427 2322 2864 2042 93 94 95 96 97 98 99 100 年度 服務案件 抽查案件 合計 93 100 檢出率 (%) 45.0 40.0 35.0 30.0 25.0 20.0 15.0 10.0 35.8 28.8 41.3 37.8 39.7 38.9 32.4 30.6 26.9 35.9 33.9 33.1 41.8 40.7 40.0 93 94 95 96 97 98 99 100 年度 29.6 30.9 30.2 28.5 21.9 16.3 服務案件抽查案件合計 93 100 822 27.4 18.4 14.8 100 2 14 3 479 498 688 110 13 13 101 925 1,441 2,864 0 0 1 78 79 95 24 6 6 27 158 291 528 (%) 0 0 33.3 16.3 15.9 13.8 21.8 46.2 46.2 26.7 17.1 20.2 18.4
100 351 )4 () 15.9% (16.333.3%) 17.1%( 46.2%)(26.7%)(21.8%) 1,44150.3% 20.2% 64651 528 1.2393100 (4-9) 100 種類數 80 70 60 50 40 30 20 64 651 528 1.23 30 49 50 60 44 45 48 64 各年度檢出西藥種類數 93 94 95 96 97 98 99 100 年度 93 100 平均個數 2 1 0 93 100 100 1.11 1.25 1.43 1.36 1.42 1.38 1 63 N-desmethylsibutramine 2 62 Sibutramine 3 50 Caffeine 4 49 Aminotadalafil 4 49 Tadalafil 5 41 Phenolphthalein 5 41 Sildenafil 6 39 Thioaildenafil 7 38 Sennosides 8 26 Nortadalafil 9 14 Acetil acid 9 14 Dimethylsildenafil 10 13 N-didesmethylsibutramine 11 11 Nor-acetildenafil 12 10 Acetildenafil 12 10 Melatonin 13 9 Hydroxyhomosildenafil 13 9 Hydroxythiohomosildenafil 13 9 Yohimbine 14 7 Bisacodyl 14 7 Fluoxetine 15 6 Piperidenafil 16 5 Gendenafil 16 5 Synephrine 17 4 Gemfibrozil 17 4 Thiosildenafil 18 3 Furosemide 18 3 Imidazosagatriazinone 1.33 1.23 每件檢出檢體平均含西藥成分個數 93 94 95 96 97 98 99 100 年度
352 100 () 18 3 Lovastatin 19 2 7-ketodehydroepiandrosterone 19 2 Acetyl vardenafil 19 2 Chlorpheniramine 19 2 Clobenzorex 19 2 Fenofibrate 19 2 Hydrochlorothiazide 19 2 Hydroxyacetildenafil 19 2 Metformin 19 2 Methyltestosterone 19 2 Metoclopramide 19 2 Propranolol 19 2 Vardenafil analogue ( 312) 20 1 4-methylethcathinone 20 1 Acetaminophen 20 1 Benzylpiperazine 20 1 Bumetanide 20 1 Chloramphenicol 20 1 Chloropretadalafil 20 1 Dehydroepiandrosterone 20 1 Diclofenac 20 1 Ephedrine 20 1 Flunitrazepam 20 1 Homosildenafil 20 1 N-butyltadalafil 20 1 Nicotinamide 20 1 Orlistat 20 1 Phenylephrine 20 1 Piroxicam 20 1 Rimonabant 20 1 Testosterone propionate 20 1 Theophylline 20 1 Thiamine 20 1 Thioctic acid 20 1 Thiohomosildenafil 20 1 Zolpidem (10,11) N-desmethylsibutramineSibutramineCaffeine AminotadalafilTadalafil 64 23Aminotadalafil Tadalafil49Sildenafil 41Thioaildenafil39 4 6 8 ( )10 N-desmethylsibutramine63Sibutramine 62Phenolphthalein41 126 Sennosides(Sennoside AB )12 mg 93100 (1-3) (528) 49.1% (259/528)46.4% (245/528) 100.0% (1/1)30.2% (245/812)19.5% (259/1,328) 2,864 3 46.4% (1,328/2,864)28.4% (812/2,864)11.6% (332/2,864) 74.7% (2,140/2,864)
100 353 93100 93 94 95 96 97 98 99 100 Acetil acid 10 12 14 Acetildenafil 60 33 18 12 1 3 10 Acetyl vardenafil 2 Aminotadalafil 1 13 12 11 5 55 49 Carbodenafil 1 Chloropretadalafil 1 Dimethylsildenafil 22 14 Gendenafil 4 11 15 6 11 2 5 Homosildenafil 2 2 11 6 1 1 1 Hydroxyacetildenafil 4 1 8 2 Hydroxyhomosildenafil 2 12 25 6 18 15 15 9 Hydroxythiohomosildenafil 6 35 9 Imidazosagatriazinone 3 N-butyltadalafil 1 Nor-acetildenafil 6 11 Nortadalafil 26 Piperidenafil 2 12 13 7 11 16 6 Sildenafil 30 92 57 57 47 86 48 41 Tadalafil 19 36 23 10 24 15 24 49 Thioaildenafil 17 68 39 Thiohomosildenafil 4 2 1 Thiosildenafil 13 9 4 Vardenafil 2 3 11 2 8 Vardenafil analogue (312) 3 2 5 5 1 2 Vardenafil analogue (437) 2 Yohimbine 6 9 5 10 5 1 1 9 100 93100 93 94 95 96 97 98 99 100 Clobenzorex 3 4 1 2 1 5 2 N-Desmethylsibutramine 13 9 44 45 45 63 N-Didesmethylsibutramine 7 13 13 Orlistat 1 Phenolphthalein 3 3 32 21 73 41 Rimonabant 4 3 1 Sennosides 15 23 12 21 28 9 23 38 Sibutramine 4 9 22 23 88 29 93 62 100
354 100 / (%) / (%) / (%) 1 259/ 528 (49.1) 259/ 1,328 (19.5) 1,328/ 2,864 (46.4) 2 245/ 528 (46.4) 245/ 812 (30.2) 812/ 2,864 (28.4) 3 12/ 528 (2.3) 12/ 64 (18.8) 64/ 2,864 (2.2) 4 4/ 528 (0.8) 4/ 332(1.2) 332/ 2,864 (11.6) 5 2/ 528 (0.4) 2/ 32 (6.3) 32/ 2,864 (1.1) 5 2/ 528 (0.4) 2/ 26 (7.7) 26/ 2,864 (0.9) 7 1/ 528 (0.2) 1/ 56 (1.8) 56/ 2,864 (2.0) 7 1/ 528 (0.2) 1/ 1 (100.0) 1/ 2,864 (0.0) 7 1/ 528 (0.2) 1/ 10 (10.0) 10/ 2,864 (0.3) 7 1/ 528 (0.2) 1/ 32 (3.1) 32/ 2,864 (1.1) 15171 100 1 2 3 4 423 88 16 1 /(%) 80.1 16.7 3.0 0.2 1 80.1%2 16.7% 4 1 SildenafilHydroxyacetildenafilHydroxyhomosildenfilHydroxythiohomosildenfil4 100 1 2 3 4 206 48 5 197 36 11 1 11 1 3 1 1 1 1 1 1 1 1 1 ( ) 21.1% (367/1,743)15.6% (82/524)9.8% (36/368) 40.0% (4/10) 28.9% (35/121)
100 355 100 1,743 524 368 121 82 10 16 367 82 36 35 2 4 2 (%) 21.1 15.6 9.8 28.9 2.4 40.0 12.5 1002,864 9954298 3.1 13 98 4861002,042 29.6%14.8%2,864 52818.4% 30% 88 SildenafilTadalafilVardenafil Sildenafil14 (12,13,18) Acetil acid (356) Acetildenafil (466)Carbodenafil ( 452)Dimethylsildenafil (488) Gendenafil (354)Homosildenafil (488)Hydroxyacetildenafil ( 482)Hydroxyhomosildenafil (504) Hydroxythiohomosildenafil (520) Imidazosagatriazinone (312)Noracetildenafil (452)Thioaildenafil (504)Thiohomosildenafil ( 504)Thiosildenafil (490) Tadalafil4 (17) Aminotadalafil (390)Chloropretadalafil ( 426)N-butyltadalaf il (431) Nortadalaf il (375)Vardenafil 4 (14,15) Acetyl vardenafil ( 466)Piperidenafil (459)Vardenafil analogue (312)Vardenafil analogue (437) 2291 Homosildenafil93Acetildenafil Hydroxyhomosildenafil 294 GendenafilAminotadalafil Piperidenafil395 Vardenafil(312)96 Hydroxyacetildenafil97 Vardenafil(437) 98Acetil acidcarbodenafil HydroxythiohomosildenafilThioaildenafil ThiohomosildenafilThiosildenafil6 99DimethylsildenafilNoracetildenafil 2Acetyl vardenafil ChloropretadalafilImidazosagatriazinone N-butyltadalafilNortadalafil100 S i l d e n a f i l Ta d a l a f i l VardenafilSildenafil TadalafilVardenafil SAR
356 100Sibutramine62 SibutramineN-Desmethylsibutramine (265) (16) N-Didesmethylsibutramine (251)6313 99Sibutramine Clobenzorex OrlistatRimonabantSennosides Rimonabant Clobenzorex Clobenzorex 69 90 4Clobenzorex 9394100 Phenolphthalein41 93 1. 1991 () 2. 1995 () () 3. 1996 ()() 4. 2011 2: 350-359 5. 2010 1: 200-211 6. 2009 27: 131-142 7. 2008 26: 86-97 8. 2007 25: 90-97 9. 2006 24: 166-179 10. 2007 11. 2011 12. Lai, K. C., Liu, Y. C., Tseng, M. C. and Lin, J. H.
100 357 2006. Isolation and identification of a sildenafil analogue illegally added in dietary supplements. J. Food Drug Anal. 14: 19-23. 13. Lin, M. C., Liu, Y. C. and Lin, J. H. 2006. Identification of a sildenafil analogue adulterated in two herbal food supplements. J. Food Drug Anal. 14: 260-264. 14. Lai, K. C., Liu, Y. C., Tseng, M. C., Lin, Y. L. and Lin, J. H. 2007. Isolation and identification of a vardenafil analogue in a functional food marketed for penile erectile dysfunction. J. Food Drug Anal. 15: 133-138. 15. Lai, K. C., Liu, Y. C., Tseng, M. C., Lin, Y. L. and Lin, J. H. 2007. Isolation and identification of a vardenafil analogue in a dietary supplement. J. Food Drug Anal. 15: 220-227. 16. Lai, K. C., Liu, Y. C., Tseng, M. C., Lin, Y. L. and Lin, J. H. 2007. Isolation and identification of a sibutramine analogue in a healthy food for weight loss. J. Food Drug Anal. 15: 20-24. 17. Lin, M. C., Liu, Y. C., Lin, Y. N. and Lin, J. H. 2009. Identification of a tadalafil analogue adulterated in a dietary supplement. J. Food Drug Anal. 17: 451-458. 18. Lai, K. C., Liu, Y. C., Liao, Y. C., Lin, Y. L., Tsai, L. Y., Lin, J. H. and Lo, C. F. 2010. Isolation and identification of three thio-sildenafil analogues in dietary supplements. J. Food Drug Anal. 18: 269-278. Survey on Pharmaceutical Adulterants in Dietary Supplements in the Fiscal Year 2011 YOE-RAY KU, LI-YAO TSAI, MEI-CHIH LIN, YA-HUI HSU, KUO-CHIN LAI, KANG-TSU LU, HUI-CHUN LEE, YI-CHU LIU, DANIEL YANG-CHIH SHIH AND CHI-FANG LO Division of Research and Analysis, FDA ABSTRACT In this report, the survey results were presented for the pharmaceutical adulterants in 2,864 samples of marketed dietary supplements, which were collected and analyzed during the year 2011. The results indicated that 27.4% (225/822) of the samples from the consumer service centers of the local health bureaus and other government institutions were adulterated with pharmaceutical compounds. Other samples, which were randomly collected from markets by the local health officers, had an adulteration rate of 14.8% (303/2,042). Among the 528 samples containing adulterants, 80.1% contained 1 adulterant and 16.7% 2 adulterants. In terms of usage, most of adulterants were used for anorexic or male erectile dysfunction. As the frequency of occurance was concerned, N-desmethylsibutramine, sibutramine and caffeine ranked the top. In addition to commercial sildenafil, tadalafil, vardenafil and sibutramine, 22 analogues of these drugs were found. Key words: adulterants in dietary supplements, erectile dysfunction, anorexic