Screening results for non-declared synthetic phosphodiesterase-5 inhibitors being added to dietary supplements of plant origin
I.B. Perova, K.I. Eller, E.V. Tumol`skaya
Federal research centre of nutrition and biotechnology, 2/14 Ustinskiy Proezd, Moscow, 109240, Russian Federation
Non-declared addition of synthetic phosphodiesterase-5 inhibitors (PDE-5 inhibitors) to dietary supplements (DS) of plant origin in order to stimulate potency is a serios problem. Such counterfeiting strengthens therapeutic effects produced by a product; similar effects can’t occur only due to components of DS of plant origin. Synthetic PDE-5 inhibitors are both substances of official medications and their structural analogues. When synthetic PDE-5 inhibitors are consumed as components in DS in order to increase potency, it can be hazardous for consumers’ health due to unpredictable or even lethal side effects.
Our research goal was to reveal concentrations of non-declared synthetic PDE-5 inhibitors in DS consumed by males. Our research objects were 175 DS selected by Rospotrebnadzor in different Russian regions. Synthetic PDE-5 inhibitors were detected in samples by HPLC with diode array spectrophotometric detection and MS-detection as per guidelines developed by us and approved on by Rospotrebnadzor (MG 4.1.3331-16).
Our research revealed that 36% of DS that were consumed to increase potency contained non-declared synthetic PDE-5 inhibitors with Tadalafil and Sildenafil being the most widely spread ones 42.9% and 28.6% of all counterfeit cases). Their combination or analogues of PDE-5 inhibitors were detected significantly less frequently; complicated mixtures containing three or more components were also rather rare. Contents of Tadalafil, Sildenafil, or Vardenafil in DS varied from trace quantities to concentrations that corresponded to recommended daily doses for these medications or even higher than such doses. We identified derivatives of Sildenafil and Tadalafil among PDE-5 inhibitors; their quantities varied from 1.2 mg/capsule to 24.3 mg/capsule.
The developed procedure allowed detecting counterfeited DS with not only Tadalafil, Sildenafil, or Vardenafil being added to them, but also analogues of synthetic PDE-5 inhibitors.
- Moon D.G. Evolution of PDE5 inhibitors in Korea. Transl. Androl. Urol., 2015, vol. 4, no. 1, pp. AB041. DOI: 10.3978/j.issn.2223-4683.2015.s041
- Huang S.A., Lie J.D. Phosphodiesterase-5 (PDE-5) inhibitors in the management of erectile dysfunction. Pharmacy and Therapeutics, 2013, vol. 38, no. 7, pp. 414–419.
- Peak T.C., Yafi F.A., Sangkum P., Hellstrom W.J.G. Emerging drugs for the treatment of erectile dysfunction. Expert Opinion on Emerging Drugs, 2015, vol. 20, pp. 263–275.
- Shin M.H., Hong M.K., Kim W.S., Lee Y.J., Jeong Y.C. Identification of a new analogue of sildenafil added illegally to a functional food marketed for penile erectile dysfunction. Food Addit. Contam., 2003, vol. 20, no. 9, pp. 793–796.
- 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, vol. 21, no. 8, pp. 737–748. DOI: 10.1080/02652030412331272467
- Zou P., Oh S.S., Hou P., Low M.Y., Koh H.L. Simultaneous determination of synthetic phosphodiesterase-5 inhibitors found in a dietary supplement and pre-mixed bulk powders for dietary supplements using high-performance liquid chromatography with diode array detection and liquid chromatography-electrospray ionization tandem mass spectrometry. J. Chromatogr. A, 2006, vol. 1104, no. 1–2, pp. 113–122. DOI: 10.1016/j.chroma.2005.11.103
- Park H.J., Jeong H.K., Chang M.I., Im M.H., Jeong J.Y., Choi D.M., Park K., Hong M.K. [et al.]. Structure deter-mination of new analogues of vardenafil and sildenafil in dietary supplements. Food Addit. Contam., 2007, vol. 24, no. 2, pp. 122–129. DOI: 10.1080/02652030600983625
- 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, vol. 46, no. 4, pp. 804–807. DOI: 10.1016/j.jpba.2007.12.004
- Zou P., Hou P., Oh S.S.Y., Ge X., Bloodworth B.C., Low M.Y., Koh H.L. Identification of benzamidenafil, a new class of phosphodiesterase-5 inhibitor, as an adulterant in a dietary supplement. J. Pharm. Biomed. Anal., 2008, vol. 47, no. 2, pp. 255–259. DOI: 10.1016/j.jpba.2008.01.004
- 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, vol. 49, no. 1, pp. 145–150. DOI: 10.1016/j.jpba.2008.10.007
- Balayassac S., Trefi S., Gilard V., Malet-Martino M., Martino R., Delsuk 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. Biomed. Anal., 2009, vol. 50, no. 4, pp. 602–612. DOI: 10.1016/j.jpba.2008.10.034
- Lee H.M., Kim C.S., Yang 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, vol. 54, no. 3, pp. 491–496. DOI: 10.1016/j.jpba.2010.09.022
- Venhuis B.J., Zomer G., Hamzink M., Meiring H.D., Aubin Y., De Kaste D. The identification of a nitrosatedprodrug of the PDE-5 inhibitor aildenafil in a dietary supplement: A Viagra with a pop. J. Pharm. Biomed. Anal., 2011, vol. 54, no. 4, pp. 735–741. DOI: 10.1016/j.jpba.2010.11.020
- 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, vol. 28, no. 4, pp. 396–407. DOI:10.1080/19440049.2011.551947
- Sacré P.Y., Deconinck E., Chiap P., Crommen J., Mansion F., Rozet E., Courselle P., De Beer J.O. Development and validation of a ultra-high-performance liquid chromatography-UV method for detection and quantification of erectile dysfunction drugs and some of their analogues found in counterfeit medicines. J. Chromarogr. A, 2011, vol. 1218, no. 37, pp. 6439–6447. DOI: 10.1016/j.chroma.2011.07.029
- Balayssac S., Gilard V., Zedde C., Martino R., Malet-Martino M. 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., 2012, vol. 63, pp. 135–150. DOI: 10.1016/j.jpba.2012.01.035
- Vaysse J., Gilard V., Balayssac S., Zedde C., Martino R., Malet-Martino M. Identification of a novel sildenafil ana-logue in an adulterated herbal supplement. J. Pharm. Biomed. Anal., 2012, vol. 59, pp. 58–66. DOI:10.1016/j.jpba.2011.10.001
- Sakamoto M., Moriyasu T., Minowa K., Kishimoto K., Kadoi H., Hamano T., Fukaya H. Structure elucidation of a novel analog of sildenafil detected as an adulterant in a dietary supplement using LC-UV and LC/MS. Journal of AOAC In-ternational, 2012, vol.95, no. 4, pp. 1048–1052.
- Liao Y.-C., Lai K.-C., Lee C., Liu Y.-C., Lin Y.-L., Shin D.Y.-C. Isolation and identification of new sildenafil analodues from dietary supplements. Journal of Food and Drug Analysis, 2013, vol. 21, no. 1, pp. 40–49. DOI:10.6227/jfda.2013210105
- Campbell N., Clark J.P., Stecher V.J., Thomas J.W., Callanan A.C., Donnelly B.F., Goldstein I., Kaminetsky J.C. Adulteration of purported herbal and natural sexual performance enhancement dietary supplements with synthetic phos-phodiesterase type 5 inhibitors. J. Sex. Med., 2013, vol. 10, no.7, pp. 1842–1849. DOI:10.1111/jsm.12172
- Silva L.M., Filho E.G., Thomasi S.S., Silva B.F., Ferreira A.G., Venancio T. Use of diffusion-ordered NMR spec-troscopy and HPLC-UV-SPE-NMR to identify undeclared synthetic drugs in medicines illegally sold as phytotherapies. Magn. Reson. Chem., 2013, vol. 51, no. 9, pp. 541–548. DOI:10.1002/mrc.3984
- Lee E.S., Lee J.H., Kim J.W., Hwang I.S., Cho S., Han S.Y., Kim J. Simultaneous determination of 38 phos-phodiesterase-5 inhibitors in illicit erectile dysfunction products by liquid chromatography-electrospray ionization-tandem mass spectrometry. J. Pharm. Biomed. Anal., 2013, vol. 83, pp. 171–178. DOI: 10.1016/j.jpba.2013.05.009
- Reeuwijk N.M., Venhuis B.J., De Kaste D., Hoogenboom L.A.P., Rietjens I.M.C.M., Martena M.J. Sildenafil and analogous phosphodiesterase type 5 (PDE 5) inhibitors in herbal food supplements sampled on the Dutch market. Food Additives and Contaminants: Part A, 2013, vol. 30, no. 12, pp. 2027–2034. DOI:10.1080/19440049.2013.848294
- Mustazza C., Borioni A., Rodomonte A.L., Bartolomei M., Antoniella E., Di Martino P., Valvo L., Sestili I. [et al.]. Characterization of sildenafil analogs by MS/MS and NMR: a guidance for detection and structure elucidation of phosphodiesterase-5 inhibitors. Journal of Pharmaceutical and Biomedical Analysis, 2014, vol. 96, pp. 170–186. DOI: 10.1016/j.jpba.2014.03.038
- Patel D.N., Li L., Ge X.W., Low M.-Y., Koh H.-L. Screening of synthetic PDE-5 inhibitors and their analogues as adulterants: analytical techniques and challenges. J. Pharm. Biomed. Anal., 2014, vol. 87, pp. 176–190. DOI:10.1016/j.jpba.2013.04.037
- Shi F., Guo C., Gong L., Li J., Dong P., Zhang J. Application of a high resolution benchtopquadrupole-Orbitrap mass spectrometry for the rapid screening, confirmation and quantification of illegal adulterated phosphodiesterase-5 inhibitors in herbal medicines and dietary supplements. Journal of Chromatography A, 2014, vol. 1344, pp. 91–98. DOI: 10.1016/j.chroma.2013.12.030
- Ulloa J., Sambrotta L., Redko F., Mazza O.N., Garrido G., Becher E.F., Muschietti L. Detection of a tadalafil analogue as an adulterant in a dietary supplement for erectile dysfunction. The Journal of Sexual Medicine, 2015, vol. 12, no. 1, pp. 152–157. DOI:10.1111/jsm.12759
- Rocha T., Amaral J.S., Oliveira P.B.P.P. Adulteration of dietary supplements by the illegal addition of synthetic drugs: A review. Compr. Rev. Food Sci. F, 2016, vol. 15, pp. 43–62.
- Redko F., Flor S., Lucangioli S., Ulloa J., Ricco R., Fernandez C., Sambrotta L., Muschietti L. Identification and quantification of an adulterant in a dietary supplement marketed for sexual enhancement. Journal of Advanced Pharmaceutical Science and Technology, 2018, vol. 1, no. 4, pp. 25–33. DOI: 10.14302/issn.2328-0182.japst-18-2344
- Tucker J., Fisher T., Upjohn L., Mazzera D., Kumar M. Unapproved pharmaceutical ingredients included in dietary supplements associated with US Food and Drug Administration warnings. JAMA Network Open, 2018, vol. 1, no. 6, pp. e183337. DOI: 10.1001/jamanetworkopen.2018.3337
- Wang X.-B., Zheng J., Li J.-J., Yu H.-Y., Li Q.-Y., Xu L.-H., Liu M.-J., Xian R.-Q. [et al.]. 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. Journal of Food and Drug Analysis, 2018, vol. 26, no. 3, pp. 1138–1153. DOI: 10.1016/j.jfda.2018.02.003
- Vanhee C., Tuenter E., Kamugisha A., Canfyn M., Moens G., Courselle P., Pieters L., Deconinck E., V.Exarchou. Identification and quantification methodology for the analysis of suspected illegal dietary supplements: reference standard or no reference standard, that’s the question. J. Forensic. Toxicol. Pharmacol., 2018, vol. 7, no. 1, pp. 7. DOI:10.4172/2325-9841.1000156
- Kee C.L., Ge X., Gilard V., Malet-Martino M., Low M.Y. A review of synthetic phosphodiesterase type 5 inhibitors (PDE-5i) found as adulterants in dietary supplements. J. Pharm. Biomed. Anal., 2018, vol. 147, pp. 250–277. DOI:10.1016/j.jpba.2017.07.031