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Review Article

Analytical methods for the detection and characterization of unapproved phosphodiesterase type 5 inhibitors (PDE-5i) used in adulteration of dietary supplements- a review

, , , &
Pages 1495-1530 | Received 08 Sep 2023, Accepted 31 Oct 2023, Published online: 27 Nov 2023

References

  • Abdel-Halim M, Sigler S, Racheed NAS, Hefnawy A, Fathalla RK, Hammam MA, Maher A, Maxuitenko Y, Keeton AB, Hartmann RW, et al. 2021. From celecoxib to a novel class of phosphodiesterase 5 inhibitors: trisubstituted pyrazolines as novel phosphodiesterase 5 inhibitors with extremely high potency and phosphodiesterase isozyme selectivity. J Med Chem. 64(8):4462–4477. doi: 10.1021/acs.jmedchem.0c01120.
  • Alp M, Coşkun M, Göker H. 2013. Isolation and identification of a new sildenafil analogue adulterated in energy drink: propoxyphenyl sildenafil. J Pharm Biomed Anal. 72:155–158. doi: 10.1016/j.jpba.2012.09.017.
  • Assemat G, Balayssac S, Gerdova A, Gilard V, Caillet C, Williamson D, Malet-Martino M. 2019. Benchtop low-field 1H nuclear magnetic resonance for detecting falsified medicines. Talanta. 196:163–173. doi: 10.1016/j.talanta.2018.12.005.
  • Assemat G, Balayssac S, Gilard V, Martins-Froment N, Fabing I, Rodriguez F, Génisson Y, Martino R, Malet-Martino M. 2020. Isolation and identification of ten new sildenafil derivatives in an alleged herbal supplement for sexual enhancement. J Pharm Biomed Anal. 191:113482. doi: 10.1016/j.jpba.2020.113482.
  • Bakota EL, Kelly AT, Walterscheid JP, Phatak DR. 2017. A case report of fatal desmethyl carbodenafil toxicity. J Anal Toxicol. 41(3):250–255. doi: 10.1093/jat/bkw128.
  • Balayssac S, Gilard V, Zedde C, Martino R, Malet-Martino M. 2012. Analysis of herbal dietary supplements for sexual performance enhancement: first characterization of propoxyphenyl-thiohydroxyhomosildenafil and identification of sildenafil, thiosildenafil, phentolamine and tetrahydropalmatine as adulterants. J Pharm Biomed Anal. 63:135–150. doi: 10.1016/j.jpba.2012.01.035.
  • Balayssac S, Danoun S, Gilard V, Martino R, Malet-Martino M. 2023. The POWER saga from 2007 to 2022: an example of a sexual enhancement dietary supplement tainted by different adulterants and still on the market. J Pharm Biomed Anal. 227:115283. doi: 10.1016/j.jpba.2023.115283.
  • Blok-Tip L, Zomer B, Bakker F, Hartog KD, Hamzink M, ten Hove J, Vredenbregt M, de Kaste D. 2004. Structure elucidation of sildenafil analogues in herbal products. Food Addit Contam. 21(8):737–748. doi: 10.1080/02652030412331272467.
  • Bujang NB, Chee CF, Heh CH, Rahman NA, Buckle MJC. 2017. Phosphodiesterase-5 inhibitors and their analogues as adulterants of herbal and food products: analysis of the Malaysian market 2014–16. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 34(7):1101–1109. doi: 10.1080/19440049.2017.1336674.
  • Choi DM, Park S, Yoon TH, Jeong HK, Pyo JS, Park J, Kim D, Kwon SW. 2008. 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. AOAC Int. 91(3):580–588. doi: 10.1093/jaoac/91.3.580.
  • Daugan A, Grondin P, Ruault C, de Gouville ALM, Coste H, Linget JM, Kirilovsky J, Hyafil F, Labaudinière R. 2003. 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. 46(21):4533–4542. doi: 10.1021/jm0300577.
  • Demizu Y, Wakana D, Kamakura D, Kurihara M, Okuda H, Goda Y. 2011. Identification of mutaprodenafil in a dietary supplement and its subsequent synthesis. Chem Pharm Bull. 59(10):1314–1316. doi: 10.1248/cpb.59.1314.
  • Doi T, Takahashi K, Yamazaki M, Asada A, Takeda A, Kiyota K, Tagami T, Sawabe Y, Yamano T. 2018. Characterization of a new illicit phosphodiesterase-type-5 inhibitor identified in the softgel shell of a dietary supplement. J Pharm Biomed Anal. 161:61–65. doi: 10.1016/j.jpba.2018.08.031.
  • Dong P-Z, Liu X-P, Zhang L, Shen G-H, Wang Z-L, Yang G-W, Li W, Xiang X-H. 2020. Isolation and characterisation of N-benzyl tadalafil as a novel adulterant in a coffee-based dietary supplement. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 37(12):2033–2039. doi: 10.1080/19440049.2020.1825829.
  • Falconer TM, Schneider B, Baessmann C, Wendt K, Filipenko A. 2023. Combining trapped ion mobility spectrometry with liquid chromatography and tandem mass spectrometry for analysis of isomeric PDE-5 inhibitor analogs. J Pharm Biomed Anal. 225:115210. doi: 10.1016/j.jpba.2022.115210.
  • Ge X, Low MY, Zou P, Lin L, Oh SY, Bloodworth BC, Koh HL. 2008. Structural elucidation of a PDE-5 inhibitor detected as an adulterant in a health supplement. J Pharm Biomed Anal. 48(4):1070–1075. doi: 10.1016/j.jpba.2008.08.019.
  • Ge X, Li L, Koh HL, Low MY. 2011. Of a new sildenafil analogue in a health supplement. J Pharm Biomed Anal. 56(3):491–496. Identificationdoi: 10.1016/j.jpba.2011.06.004.
  • Gilard V, Balayssac S, Tinaugus A, Martins N, Martino R, Malet-Martino M. 2015. Detection, identification and quantification by 1H NMR of adulterants in 150 herbal dietary supplements marketed for improving sexual performance. J Pharm Biomed Anal. 102:476–493. doi: 10.1016/j.jpba.2014.10.011.
  • Göker H, Coskun M, Alp M. 2010. Isolation and identification of a new acetildenafil analogue used to adulterate a dietary supplement: dimethylacetildenafil. Turkish J. Chem. 34:157–163. doi: 10.3906/kim-1002-25.
  • Gratz SR, Gamble BM, Flurer RA. 2006. 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. 20(15):2317–2327. doi: 10.1002/rcm.2594.
  • Gratz SR, Zeller M, Mincey DW, Flurer CL. 2009. Structural characterization of sulfoaildenafil, an analog of sildenafil. J Pharm Biomed Anal. 50(2):228–231. doi: 10.1016/j.jpba.2009.04.003.
  • Gu Y, Hu Q, Sun J, Yu H, Pan H, Zhao X, Ji S. 2020. Isolation and identification of a new sildenafil analogue, hydroxycarbodenafil, found as an adulterant in a health supplement. J Pharm Biomed Anal. 185:113222. doi: 10.1016/j.jpba.2020.113222.
  • Häberli A, Girard P, Low MY, Ge X. 2010. Isolation and structure elucidation of an interaction product of aminotadalafil found in an illegal health food product. J Pharm Biomed Anal. 53(1):24–28. doi: 10.1016/j.jpba.2010.03.008.
  • Han KM, Lee JH, Park HJ, Hwang I, Heo OS, Kim WS. 2014. Isolation and identification of novel propoxyphenyl thiosildenafil found in natural health food product. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 31(1):1–6. doi: 10.1080/19440049.2013.855948.
  • Haning H, Niewöhner U, Schenke T, Es-Sayed M, Schmidt G, Lampe T, Bischoff E. 2002. Imidazo[5,1-f] [1,2,4]triazin-4(3H)-ones, a new class of potent PDE 5 inhibitors. Bioorg Med Chem Lett. 12(6):865–868. doi: 10.1016/S0960-894X(02)00030-6.
  • Hasegawa T, Saijo M, Ishii T, Nagata T, Haishima Y, Kawahara N, Goda Y. 2008. Structural elucidation of a tadalafil analogue found in a dietary supplement. Shokuhin Eiseigaku Zasshi. 49(4):311–315. doi: 10.3358/shokueishi.49.31.
  • Hasegawa T, Takahashi K, Saijo M, Ishii T, Nagata T, Kurihara M, Haishima Y, Goda Y, Kawahara N. 2009. Isolation and structural elucidation of cyclopentynafil and N-octylnortadalafil found in a dietary supplement. Chem Pharm Bull. 57(2):185–189. doi: 10.1248/cpb.57.185.
  • Hou P, Zou P, Low MY, Chan E, Koh HL. 2006. Structural identification of a new acetildenafil analogue from pre-mixed bulk powder intended as a dietary supplement. Food Addit Contam. 23(9):870–875. doi: 10.1080/02652030600803856.
  • HSA. 2008. Cautions against consuming Menergy M-essence capsules found to contain undeclared ingredients, Health Sciences Authority 2008. Singapore, press release, 12 December [accessed 2017 Mar 3]. http://www.hsa.gov.sg/publish/hsaportal/ en/news events/press releases/2008.html.
  • HSA. 2012. Alerts public to adverse reactions related to the consumption of adulterated health products, including a fatal case. Health Sciences Authority, Singapore. [accessed 2023 Apr 26]. Available: http://www.hsa.gov.sg/publish/hsaportal/en/news_events/press_releases/2012.html.
  • HSA ALERT. 2022. ‘Prime KOPI PEJUANG 3 IN 1’ found to contain a potent medicinal ingredient which led to adverse effects in consumers, published on May 26 2022. https://www.hsa.gov.sg/announcements/press-release/hsa-alert-prime-kopi-pejuang-3-in-1.
  • Huang YC, Lee HC, Lin YL, Li CY, Tsai CF, Cheng HF. 2016. Separation and identification of a novel tadalafil analogue adulterant in a dietary supplement. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 33(2):179–185. doi: 10.1080/19440049.2015.1125531.
  • Huang YC, Lee HC, Lin YL, Lin YT, Tsai CF, Cheng HF. 2016. Identification of a new sildenafil analogue adulterant, desethylcarbodenafil, in a herbal supplement. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 33(11):1637–1642. doi: 10.1080/19440049.2016.1236402.
  • Huang YC, Lee HC, Lin YL, Tsai CF, Cheng HF. 2016. Identification of a new tadalafil analogue, dipropylaminopretadalafil in a dietary supplement. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 33(6):953–958. doi: 10.1080/19440049.2016.1184530.
  • Huang YC, Lee HC, Lin YL, Tsai CF, Cheng HF. 2018. Identification of a new type tadalafil analogue in a supplement product. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 35(7):1233–1237. doi: 10.1080/19440049.2018.1459052.
  • Jankovics P, Lohner S, Darcsi A, Németh-Palotás J, Béni S. 2013. Detection and structure elucidation of hydroxythiovardenafil as an adulterant in a herbal dietary supplement. J Pharm Biomed Anal. 74:83–91. doi: 10.1016/j.jpba.2012.10.013.
  • Japanese Food and Drug Administration Ministry. 2004. Concerning the discovery of a so-called health food (unlicensed and non-permitted) containing a sildenafil-like substance (hydroxy-homosildenafil). [accessed 2023 Apr 26]. http://www.mhlw.go.jp/houdou/2004/02/h0213-3.html.
  • Jiru M, Stranska-Zachariasova M, Dzuman Z, Hurkova K, Tomaniova M, Stepan R, Cuhra P, Hajslova J. 2019. Analysis of phosphodiesterase type 5 inhibitors as possible adulterants of botanical-based dietary supplements: extensive survey of preparations available at the Czech market. J Pharm Biomed Anal. 164:713–724. doi: 10.1016/j.jpba.2018.11.007.
  • Johannson M, Frassan D, Rundlöf T, Huynh N-H, Arvidsson T. 2014. A general analytical platform and strategy in search for illegal drugs. J Pharm Biomed Anal. 100:214–229. doi: 10.1016/j.jpba.2014.07.026.
  • Jung J, Choi S, Cho SH, Ghim JL, Hwang A, Kim U, Kim BS, Koguchi A, Miyoshi A, Okabe H, et al. 2010. Tolerability and pharmacokinetics of avanafil, a phosphodiesterase type 5 inhibitor: a single- and multiple- dose, double-blind, randomized, placebo-controlled, dose-escalation study in healthy Korean male volunteers. Clin Ther. 32(6):1178–1187. doi: 10.1016/j.clinthera.2010.06.011.
  • Kee CL, Ge X, Koh HL, Low MY. 2012. Isolation and characterization of propoxyphenyl linked sildenafil and thiosildenafil analogues in health supplements. J Pharm Biomed Anal. 70:265–272. doi: 10.1016/j.jpba.2012.07.008.
  • Kee CL, Ge X, Koh HL, Low MY. 2013. Structural elucidation of a new sildenafil analogue using high resolution Orbitrap mass spectrometry. Rapid Commun Mass Spectrom. 27(12):1380–1384. doi: 10.1002/rcm.6590.
  • Kee CL, Koh HL, Bloodworth BC, Zeng Y, Kiang KK, Low MY, Ge X. 2014. Structural elucidation of propoxyphenyl isobutyl aildenafil, adulterant in a health supplement using high-resolution Orbitrap mass spectrometry. J Pharm Biomed Anal. 98:153–159. doi: 10.1016/j.jpba.2014.05.029.
  • Kee CL, Ge X, Low MY. 2015. Application of Orbitrap-mass spectrometry to differentiate isomeric sildenafil- and thiosildenafil-like analogues used for the adulteration of dietary supplements. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 32(10):1737–1748. doi: 10.1080/19440049.2015.1062923.
  • Kee CL, Low MY, Ge X. 2017. Isolation and characterization of a novel dithio-carbodenafil analogue from a health supplement. J Pharm Biomed Anal. 137:132–138. doi: 10.1016/j.jpba.2017.01.010.
  • Kee CL, Ge X, Gilard V, Malet-Martino M, Low MY. 2018. A review of synthetic phosphodiesterase type 5 inhibitors (PDE-5i) found as adulterants in dietary supplements. J Pharm Biomed Anal. 147:250–277. doi: 10.1016/j.jpba.2017.07.031.
  • Kee CL, Chin LC, Cheah NP, Ge X, Low MY. 2019. Elucidation of the absolute configuration of a tadalafil analogue found as adulterant in a health supplement by mass spectrometry, chiroptical methods and NMR spectroscopy. J Pharm Biomed Anal. 173:47–55. doi: 10.1016/j.jpba.2019.05.010.
  • Kee CL, Ge X, Tran CS, Bui QD, Cheah NP, Low MY. 2020. Isolation and characterization of N-hydroxyethyl dithio-desethyl carbodenafil from a health supplement. J Pharm Biomed Anal. 189:113431. doi: 10.1016/j.jpba.2020.113431.
  • Kee CL, Low MY, Ge X. 2022. Isolation and characterization of N-phenyl propoxyphenyl carbodenafil from an illegal coffee powder product. J Pharm Biomed Anal. 209:114481. doi: 10.1016/j.jpba.2021.114481.
  • Keizers PHJ, Bakker F, Ferreira J, Wacker PFK, van Kollenburg D, van der Aa E, van Beers A. 2020. Benchtop NMR spectroscopy in the analysis of substandard and falsified medicines as well as illegal drugs. J Pharm Biomed Anal. 178:112939. doi: 10.1016/j.jpba.2019.112939.
  • Kern SE, Nickum EA, Flurer RA, Toomey VM, Litzau JJ. 2015a. Isolation and structural characterization of a new tadalafil analog (2-hydroxyethylnortadalafil) found in a dietary supplement. J Pharm Biomed Anal. 103:99–103. doi: 10.1016/j.jpba.2014.10.021.
  • Kern SE, Nickum EA, Flurer RA, Toomey VM, Litzau JJ. 2015b. Isolation and structural characterization of a new tadalafil analog (chloropropanoylpretadalafil) found in a dietary supplement. J Pharm Biomed Anal. 103:99–103. doi: 10.1016/j.jpba.2014.10.021.
  • Kim BG, Jung SY, Kwon K, Park BJ. 2015. Utilization, safety, and related factors of illegal phosphodiesterase type 5 inhibitors in South Korean men. Korean J Clin Pharm. 25:50–55.
  • Kim JY, Hwang IG, Oh JH, Kang IH, Kwon SW, Kim D. 2013. Efficient synthesis of dichlorodenafil, an unapproved sildenafil analogue appearing in non-prescription supplements. Chem Pharm Bull. 61(5):572–575. doi: 10.1248/cpb.c12-00907.
  • Kim NS, Lee JH, Han KM, Kim HJ, Cho S, Han SY, Kim WS. 2013. Isolation and structural characterisation of a propoxyphenyl-linked thiohomosildenafil analogue found in a herbal product. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 30(10):1693–1700. doi: 10.1080/19440049.2013.823571.
  • Korean National Institute of Food and Drug Safety Evaluation. 2010. Instrumental analysis data of illegal compounds in food [accessed 2017 Mar 3]. http://www.nifds.go.kr.
  • Kumasaka K, Kawahara N, Doi K, Kojima T, Goda Y. 2008. Determination of (R)- xanthoanthrafil, a phosphodiesterase-5 inhibitor, in a dietary supplement promoted for sexual enhancement. Chem Pharm Bull. 56(2):227–230. doi: 10.1248/cpb.56.227.
  • Kurita H, Mizuno K, Kuromi K, Suzuki N, Ueno C, Kamimura M, Fujiwara A, Owada K, Ogo N, Yamamoto M. 2008. Identification of aminotadalafil and its stereoisomers contained in health foods using chiral liquid chromatography–mass spectrometry. J Health Sci. 54(3):310–314. doi: 10.1248/jhs.54.310.
  • Lam YH, Poon WT, Lai CK, Chan AYW, Mak TWL. 2008. Of a novel vardenafil analogue in herbal product. J Pharm Biomed Anal. 46(4):804–807. Identificationdoi: 10.1016/j.jpba.2007.12.004.
  • Lee ES, Kim JW, Lee JH, Han KM, Cho S, Hwang IS, Han SY, Chae K, Kim J. 2013. Identification of a new tadalafil analogue found in a dietary supplement. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 30(4):621–626. doi: 10.1080/19440049.2013.766766.
  • Lee H, Lee BJ. 2011. 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. 28(4):396–407. doi: 10.1080/19440049.2011.551947.
  • Lee HM, Kim CS, Jang YM, Kwon SW, Lee BJ. 2011. 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. 54(3):491–496. doi: 10.1016/j.jpba.2010.09.022.
  • Lee JH, Kim HY, Noh E, Kim JY, Cho SH, Do JA, Yoon CY, Cho S, Kim WS. 2015. Identification and screening of a tadalafil analogue found in adulterated herbal products. J Pharm Biomed Anal. 103:80–84. doi: 10.1016/j.jpba.2014.03.023.
  • Lee JH, Kim HY, Mandava S, Hwang J, Park HJ, Cho S, Baek SY, Lee J. 2015. Identification of a new tadalafil analogue in an adulterated dietary supplement: trans-Bisprehomotadalafil. J Pharm Biomed Anal. 115:352–358. doi: 10.1016/j.jpba.2015.07.023.
  • Lee JH, Mandava S, Baek SY, Lee YM. 2016. Identification and structural elucidation of three new tadalafil analogues found in a dietary supplement. J Pharm Biomed Anal. 123:1–9. doi: 10.1016/j.jpba.2015.10.039.
  • Lee JH, Park HN, Ganganna G, Jeong JH, Park SK, Lee J, Baek SY. 2016. Isolation and structural elucidation of a new tadalafil analogue in health supplements: bisprenortadalafil. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 33(6):945–952. doi: 10.1080/19440049.2016.1179134.
  • Lee HC, Lin YL, Huang YC, Tsai CF, Wang DY. 2018. Identification of a new tadalafil analogue, N-3-hydroxypropylnortadalafil, in a supplement product. J Pharm Biomed Anal. 158:257–261. doi: 10.1016/j.jpba.2018.05.049.
  • Lee JH, Park HN, Jung A, Mandava S, Park S, Lee J, Kang H. 2018. Isolation and characterisation of a novel sildenafil analogue adulterant, desmethylpiperazinyl propoxysildenafil, in a dietary supplement. Sci Justice. 58(6):447–454. doi: 10.1016/j.scijus.2018.07.003.
  • Lee JH, Min AY, Park OK, Han JH, Yang YJ, Kim H, Baek SY. 2021. Detection of 94 compounds related to sexual enhancement including sildenafil, tadalafil, vardenafil and their analogues in various formulations of dietary supplements and food samples using HPLC and LC-MS/MS. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 38(5):769–781. doi: 10.1080/19440049.2021.1881623.
  • Lee JH, Park OR, Yang YJ, Han JH, Jung EJ, Kim NS, Baek SY. 2022. Detection of 94 PDE-5is and their analogs including N-desmethylthiosildenafil in various formulations of dietary supplements and food samples using HPLC and LC-Q-TOF/MS. J Chromatogr Sci. 60(10):953–962. doi: 10.1093/chromsci/bmac015.
  • Lee W, Kim H, Lee ME, Kim BH, Park S, Lee JH, Lee YM, Oh HB, Hong J. 2020. Reliable screening and classification of phosphodiesterase type 5 inhibitors in dietary supplements using gas chromatography/mass spectrometry combined with specific common ions. J Chromatogr A. 1623:461210. doi: 10.1016/j.chroma.2020.461210.
  • Li C, Wang X, Wu S, Zhao J, Fang J, Li H, Zhu Y, Zhang K, Peng J, Mao J, et al. 2023. Separation and structural elucidation of a novel vardenafil analogue as an adulterant in a natural health care dietary supplement. Heliyon. 9(4):e15418. doi: 10.1016/j.heliyon.2023.e15418.
  • Li L, Low MY, Aliwarga F, Teo J, Ge X, Zeng Y, Bloodworth BC, Koh HL. 2009. 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. 26(2):145–151. doi: 10.1080/02652030802368757.
  • Li L, Low MY, Ge X, Bloodworth BC, Koh HL. 2013. Isolation and structural elucidation of a new sildenafil analogue from a functional coffee. Anal Bioanal Chem. 405(13):4443–4450. doi: 10.1007/s00216-012-6236-8.
  • Lin MC, Liu YC, Lin YL, Lin JH. 2020. Isolation and identification of a novel sildenafil analogue adulterated in dietary supplements. J. Food Drug Anal. 16(4):15–20. doi: 10.38212/2224-6614.2340.
  • Lin YT, Huang YC, Lee HC, Liao CH, Lin YL, Tsai CF, Cheng HF. 2017. Isolation and identification of a novel sildenafil analogue adulterant in herbal products. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 34(3):330–334. doi: 10.1080/19440049.2016.1272137.
  • Liu J, Sun J, Wei H, Yu H, Dai X, Hu Q. 2023. Isolation and characterization of a novel tadalafil analogue adulterant, N-cyclohexyl nortadalafil, in a dietary supplement. J Pharm Biomed Anal. 227:115144. doi: 10.1016/j.jpba.2022.115144.
  • Man CN, Nor NM, Lajis R, Harn GL. 2009. Identification of sildenafil, tadalafil and vardenafil by gas chromatography–mass spectrometry on short capillary column. J Chromatogr A. 1216(47):8426–8430. doi: 10.1016/j.chroma.2009.10.016.
  • Mandava S, Ganganna B, Hwang J, Jang Y, Hwang J, Samala M, Kim KB, Park H, Lee JH, Baek SY, Lee J. 2017. Synthesis and structure revision of dimeric tadalafil analogue adulterants in dietary supplements. Chem Pharm Bull. 65(5):498–503. doi: 10.1248/cpb.c17-00034.
  • Martino R, Menendez C, Balayssac S, Martins-Froment N, Lherbet C, Couderc F, Gilard V, Malet-Martino M. 2017. A revisited structure for nitrosoprodenafil from NMR, mass spectrometry. J Pharm Biomed Anal. 135:31–49. doi: 10.1016/j.jpba.2016.12.011.
  • Mokhtar SU, Chin ST, Kee CL, Low MY, Drummer OH, Marriott PJ. 2016. Rapid determination of sildenafil and its analogues in dietary supplements using gas chromatography–triple quadrupole mass spectrometry. J Pharm Biomed Anal. 121:188–196. doi: 10.1016/j.jpba.2016.01.034.
  • Moser D, Hussain S, Yaqoob M, Rainer M, Jakschitz T, Bonn GK. 2022. Fast and semiquantitative screening for sildenafil in herbal over-the-counter formulations with atmospheric pressure solid analysis probe (ASAP) to prevent medicinal adulteration. J Pharm Biomed Anal. 214:114720. doi: 10.1016/j.jpba.2022.114720.
  • Pagès G, Gerdova A, Williamson D, Gilard V, Martino R, Malet-Martino M. 2014. Evaluation of a benchtop cryogen-free low-field 1H NMR spectrometer for the analysis of sexual enhancement and weight loss dietary supplements adulterated with pharmaceutical substances. Anal Chem. 86(23):11897–11904. doi: 10.1021/ac503699u.
  • Park HN, Lee JH, Park SK, Lee J, Baek SY. 2017. Identification of a new tadalafil analogue in commercial dietary supplements: isopropylnortadalafil. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 34(2):162–169. doi: 10.1080/19440049.2016.1263878.
  • Patel DN, Li L, Kee CL, Ge X, Low MY, Koh HL. 2014. Screening of synthetic PDE-5 inhibitors and their analogues as adulterants: analytical techniques and challenges. J Pharm Biomed Anal. 87:176–190. doi: 10.1016/j.jpba.2013.04.037.
  • Poon WT, Lam YH, Lai CK, Chan AYW, Mak TWL. 2007. Analogues of erectile dysfunction drugs: an under recognised threat. Hong Kong Med J. 13:359–363.
  • Qi R, Wang X, Huang M, Dai W, Liang J. 2023. Rapid screening of illegal additives in functional food using desorption electrospray ionization mass spectrometry imaging. J Pharm Biomed Anal. 229:115351. doi: 10.1016/j.jpba.2023.115351.
  • Reddy GL, Dar MI, Hudwekar AD, Mahajan P, Nargotra A, Baba AM, Nandi U, Wazir P, Singh G, Vishwakarma RA, et al. 2019. Design, synthesis and biological evaluation of pyrazolopyrimidinone based potent and selective PDE5 inhibitors for treatment of erectile dysfunction. Bioorg Chem. 89:103022. doi: 10.1016/j.bioorg.2019.103022.
  • Reepmeyer JC, Woodruff JT. 2006. 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. 1125(1):67–75. doi: 10.1016/j.chroma.2006.05.018.
  • Reepmeyer JC, Woodruff JT. 2007a. 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. 44(4):887–893. doi: 10.1016/j.jpba.2007.04.011.
  • Reepmeyer JC, Woodruff JT, d‘Avignon DA. 2007. Structure elucidation of a novel analogue of sildenafil detected as an adulterant in an herbal dietary supplement. J Pharm Biomed Anal. 43(5):1615–1621. doi: 10.1016/j.jpba.2006.11.037.
  • Reepmeyer JC, d‘Avignon DA. 2009. Structure elucidation of thioketone analogues of sildenafil detected as adulterants in herbal aphrodisiacs. J Pharm Biomed Anal. 49(1):145–150. doi: 10.1016/j.jpba.2008.10.007.
  • Reepmeyer JC. 2009. Direct intramolecular gas-phase transfer reactions during fragmentation of sildenafil and thiosildenafil analogs in electrospray ionization mass spectrometry. Rapid Commun Mass Spectrom. 23(6):927–936. doi: 10.1002/rcm.3948.
  • Sakamoto M, Moriyasu T, Minowa K, Kishimoto K, Kadoi H, Hamano T, Fukaya H. 2012. Structure elucidation of a novel analog of sildenafil detected as an adulterant in a dietary supplement using LC-UV and LC/MS. J AOAC Int. 95(4):1048–1052. doi: 10.5740/jaoacint.11-235.
  • Sakamoto M, Suzuki J, Saito Y, Shimizu S, Kobayashi K, Nagashima M, Moriyasu T, Fukaya H, Saito K. 2018. Structural characterization of dimethyldithiodenafil and dimethylthiocarbodenafil, analogs of sildenafil. J Pharm Biomed Anal. 148:136–141. doi: 10.1016/j.jpba.2017.09.025.
  • Sakamoto T, Koga Y, Hikota M, Matsuki K, Murakami M, Kikkawa K, Fujishige K, Kotera J, Omori K, Morimoto H, et al. 2014. The discovery of avanafil for the treatment of erectile dysfunction: a novel pyrimidine-5-carboxamide derivative as a potent and highly selective phosphodiesterase 5 inhibitor. Bioorg Med Chem Lett. 24(23):5460–5465. doi: 10.1016/j.bmcl.2014.10.008.
  • Schramek N, Wollein U, Eisenreich W. 2014. Identification of new synthetic PDE-5 inhibitors analogues found as minor components in a dietary supplement. J Pharm Biomed Anal. 96:45–53. doi: 10.1016/j.jpba.2014.03.023.
  • Schramek N, Wollein U, Eisenreich W. 2015. Pyrazolopyrimidines in ‘all-natural’ products for erectile dysfunction treatment: the unreliable quality of dietary supplements. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 32(2):127–140. doi: 10.1080/19440049.2014.992980.
  • Shaaban MA, Elshaier YAMM, Hammad AH, Farag NA, Haredy HH, A, El-Ghany AA, Mohamed KO. 2020. Design and synthesis of pyrazolo[3,4-d]pyrimidinone derivatives: discovery of selective phosphodiesterase-5 inhibitors. Bioorg Med Chem Lett. 30(16):127337. doi: 10.1016/j.bmcl.2020.127337.
  • Shin MH, Hong MK, Kim WS, Lee YJ, Jeoung YC. 2003. Of a new analogue of sildenafil added illegally to a functional food marketed for penile erectile dysfunction. Food Addit Contam. 20(9):793–796. Identification doi: 10.1080/0265203031000121455.
  • Singh S, Prasad B, Savaliya AA, Shah RP, Gohil WM, Kaur A. 2009. Strategies for characterizing sildenafil, vardenafil, tadalafil and their analogues in herbal dietary supplements, and detecting counterfeit products containing these drugs. Trends Anal Chem. 28(1):13–28. doi: 10.1016/j.trac.2008.09.004.
  • Sun J, Yu H, Zhang J, Ran Y, Zhao Y, Ji S, Hu Q. 2023. Isolation and identification of a novel vardenafil analogue, propoxy-vardenafil, found as an adulterant in a health supplement. Heliyon. 9(6):e17253. doi: 10.1016/j.heliyon.2023.e17253.
  • Tachi M, Kobayashi S, Tomita K, Tanahashi T, Imanishi SY. 2022. Hierarchical clustering of liquid chromatography-tandem mass spectrometry data for screening of phosphodiesterase type 5 inhibitors and their analogues in adulterated dietary supplements. J Chromatogr A. 1678:463366. doi: 10.1016/j.chroma.2022.463366.
  • Tachikawa H, Nishiyama R, Ichikawa-Kaji Y, Uemura N, Takaku Y, Kishimoto K, Ono Y, Tayama K, Suzuki T, Suzuki J, et al. 2020. Structure elucidation of a PDE5 inhibitor detected as an illegal adulteration in a libido-boosting dietary supplement. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 37(12):2023–2032. doi: 10.1080/19440049.2020.1826582.
  • Terrett NK, Bell AS, Brown D, Ellis P. 1996. Sildenafil (VIAGRA™), a potent and selective inhibitor of type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction. Bioorg Med Chem Lett. 6(15):1819–1824. doi: 10.1016/0960-894X(96)00323-X.
  • Toomey VM, Litzau JJ, Flurer CL. 2012. Isolation and structural characterization of two tadalafil analogs found in dietary supplements. J Pharm Biomed Anal. 59:50–57. doi: 10.1016/j.jpba.2011.09.038.
  • Toque HA, Teixeira CE, Lorenzetti R, Okuyama CE, Antunes E, De Nucci G. 2008. Pharmacological characterization of a novel phosphodiesterase type 5 (PDE-5) inhibitor lodenafil carbonate on human and rabbit corpus cavernosum. Eur J Pharmacol. 591(1–3):189–195. doi: 10.1016/j.ejphar.2008.06.055.
  • Uchiyama N, Saisho K, Kikura-Hanajiri R, Haishima Y, Goda Y. 2008. Determination of a new type of phosphodiesterase-5 inhibitor, thioquinapiperifil, in a dietary supplement promoted for sexual enhancement. Chem Pharm Bull. 56(9):1331–1334. doi: 10.1248/cpb.56.1331.
  • USP General Chapter. 2023. <2251> Screening For Undeclared Drugs and Drug Analogues. doi: 10.31003/USPNF_M8206_01_01.
  • Vaysse J, Gilard V, Balayssac S, Zedde C, Martino R, Malet-Martino M. 2012. Of a novel sildenafil analogue in an adulterated herbal supplement. J Pharm Biomed Anal. 59:58–66. Identificationdoi: 10.1016/j.jpba.2011.10.001.
  • Venhuis BJ, Zomer G, de Kaste D. 2008. Structure elucidation of a novel synthetic thiono analogue of sildenafil detected in an alleged herbal aphrodisiac. J Pharm Biomed Anal. 46(4):814–817. doi: 10.1016/j.jpba.2007.12.007.
  • Venhuis BJ, Zomer G, Vredenbregt MJ, de Kaste D. 2010. The identification of (−)-trans-tadalafil, tadalafil, and sildenafil in counterfeit Cialis and the optical purity of tadalafil stereoisomers. J Pharm Biomed Anal. 51(3):723–727. doi: 10.1016/j.jpba.2009.08.010.
  • Venhuis BJ, Zomer G, Hamzink M, Meiring HD, Aubin Y, de Kaste D. 2011. 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. 54(4):735–741. doi: 10.1016/j.jpba.2010.11.020.
  • Venhuis BJ, de Kaste D. 2012. Towards a decade of detecting new analogues of sildenafil, tadalafil and vardenafil in food supplements: a history, analytical aspects and health risks. J Pharm Biomed Anal. 69:196–208. doi: 10.1016/j.jpba.2012.02.014.
  • Venhuis BJ, Tan J, Vredenbregt MJ, Ge X, Low MY, de Kaste D. 2012. Capsule shells adulterated with tadalafil. Forensic Sci Int. 214(1–3):e20-e-22–e22. doi: 10.1016/j.forsciint.2011.07.013.
  • Wang XB, Zheng J, Li JJ, Yu HY, Li QY, Xu LH, Liu MJ, Xian RQ, Sun YE, Liu BJ. 2018. Simultaneous analysis of 23 illegal adulterated aphrodisiac chemical ingredients in health foods and Chinese traditional patent medicines by ultrahigh performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. J Food Drug Anal. 26(3):1138–1153. doi: 10.1016/j.jfda.2018.02.003.
  • Wollein U, Eisenreich W, Schramek N. 2011. Identification of novel sildenafil analogues in an adulterated herbal food supplement. J Pharm Biomed Anal. 56(4):705–712. doi: 10.1016/j.jpba.2011.07.012.
  • Xu Y, Kee CL, Ge X, Low MY, Koh HL. 2016. Isolation and characterization of a tadalafil analogue, N-cyclopentyl nortadalafil in health supplement. J Pharm Biomed Anal. 118:235–241. doi: 10.1016/j.jpba.2015.08.005.
  • Yuk S. 2010. Combating illegal foods and drugs containing unauthorized substances. In: 4th Seminar of European customs chemists. Helsinki, Finland.
  • Yun J, Shin KJ, Choi J, Kwon K, Jo C-H. 2018. Identification and structural elucidation of a new sildenafil analogue, dithiopropylcarbodenafil, from a premixed powder intended as a dietary supplement. J Chromatogr B Analyt Technol Biomed Life Sci. 1072:273–281. doi: 10.1016/j.jchromb.2017.11.029.
  • Zhang G, Yu Y, Wu X, Li J. 2014. Separation and structural elucidation of a new tadalafil analogue diethylaminopretadalafil included as an adulterant in a dietary supplement. J Pharm Biomed Anal. 94:210–214. doi: 10.1016/j.jpba.2014.01.043.
  • Zou P, Hou P, Low MY, Koh HL. 2006a. Structural elucidation of a tadalafil analogue found as an adulterant of a herbal product. Food Addit Contam. 23(5):446–451. doi: 10.1080/02652030500479690.
  • Zou P, Hou P, Oh SS, Low MY, Koh HL. 2006b. Electrospray tandem mass spectrometric investigations of tadalafil and its analogue. Rapid Commun Mass Spectrom. 20(22):3488–3490. doi: 10.1002/rcm.2752.
  • Zou P, Hou P, Oh SS-Y, Chong YM, Bloodworth BC, Low M-Y, Koh H-L. 2008. Isolation and identification of thiohomosildenafil and thiosildenafil in health supplements. J Pharm Biomed Anal. 47(2):279–284. doi: 10.1016/j.jpba.2008.01.016.
  • Zou P, Hou P, Oh SY, Ge X, Bloodworth BC, Low MY, Koh HL. 2008. Identification of benzamidenafil, a new class of phosphodiesterase-5 inhibitor, as an adulterant in a dietary supplement. J Pharm Biomed Anal. 47(2):255–259. doi: 10.1016/j.jpba.2008.01.004.
  • Zurawin JL, Stewart CA, Anaissie JE, Yafi FA, Hellstrom WJG. 2016. Avanafil for the treatment of erectile dysfunction. Expert Rev Clin Pharmacol. 9(9):1163–1170. doi: 10.1080/175124331212655.

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