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Analysis of Herbal Dietary Supplements for Sexual Performance Enhancement

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Analysis of Herbal Dietary Supplements for Sexual Performance Enhancement Journal of Pharmaceutical and Biomedical Analysis 63 (2012) 135–150 Contents lists available at SciVerse ScienceDirect Journal of Pharmaceutical and Biomedical Analysis jou rnal homepage: www.elsevier.com/locate/jpba Analysis of herbal dietary supplements for sexual performance enhancement: First characterization of propoxyphenyl-thiohydroxyhomosildenafil and identification of sildenafil, thiosildenafil, phentolamine and tetrahydropalmatine as adulterants ∗ Stéphane Balayssac, Véronique Gilard, Chantal Zedde, Robert Martino, Myriam Malet-Martino Groupe de RMN Biomédicale, Laboratoire SPCMIB (UMR CNRS 5068), Université Paul Sabatier, 118 route de Narbonne, 31062 Toulouse cedex, France a r t i c l e i n f o a b s t r a c t Article history: Nine herbal dietary supplements intended to be beverages for enhancing sexual performance were ana- Received 8 December 2011 lyzed before their possible launch on the market. Four of them contained a sildenafil analog reported for Received in revised form 24 January 2012 the first time as an adulterant. After isolation and characterization using NMR, MS, IR and UV, this analog Accepted 26 January 2012 was named propoxyphenyl-thiohydroxyhomosildenafil as the ethoxy chain on the phenyl ring of the Available online 4 February 2012 already known analog thiohydroxyhomosildenafil was replaced by a propoxy moiety. One formulation was tainted with thiosildenafil, another unapproved PDE-5 inhibitor. Sildenafil along with the natural Keywords: alkaloid tetrahydropalmatine that has no documented effect for enhancing erectile dysfunction were Dietary supplements Adulterants identified in two formulations. Another formulation was adulterated with phentolamine, a drug that is Propoxyphenyl-thiohydroxyhomosildenafil not approved for boosting male sexual performance when taken orally. The last formulation containing NMR osthole, a bioactive natural coumarine improving sexual dysfunction, is most probably truly natural. MS © 2012 Elsevier B.V. All rights reserved. 1. Introduction herbal drugs and dietary supplements [2,3]. Besides PDE-5 inhibitor analogs, the most common adulterants, many other pharmacologi- Dietary supplements are products between medicines and con- cally active substances have been used to taint dietary supplements ventional foods whose consumption is rising steeply. The control and herbal products consumed for enhancing sexual performance of their quality is therefore of paramount importance in order to [4]. ensure their safety and to protect consumers. There is a grow- In this study, nine dietary supplements intended to be intro- ing trend in the intentional adulteration of dietary supplements duced into the South European market were submitted for analysis. with drugs, which represents an alarming emerging risk to pub- Their exact composition was unknown but they were claimed to lic health. Some recent articles have highlighted this problem and contain only a mixture of various herbs and sugars. They were demonstrated the complexity to combat it (see for example [1]). presented in unlabeled plastic bags as brown powders (10 g per Adulterants are frequently detected in dietary supplements or bag) to be dissolved in water for beverages and to be taken once herbal medicines aimed at increasing sexual function. In addition a day. Four were adulterated with a new sildenafil analog called to the approved phosphodiesterase-5 (PDE-5) inhibitors, sildenafil propoxyphenyl-thiohydroxyhomosildenafil (PP-THHS), one with ® ® ® (Viagra ), tadalafil (Cialis ) and vardenafil (Levitra ) in Europe thiosildenafil (THIO), two with sildenafil (SILD) along with tetrahy- ® and USA, udenafil (Zydena ) in South Korea and Malaysia, mirode- dropalmatine (THP), one with phentolamine (PHE) and the last ® ® nafil (Mvix ) in South Korea, and lodenafil carbonate (Helleva ) in contained osthole (OST). The chemical structures of these com- Brazil, it has been reported that “natural” herbal products were also pounds were elucidated using NMR and MS. adulterated with unapproved analogs in which most often minor modifications were brought to the parent structure and for which no toxicological data are available. To our knowledge, 33 analogs have been described so far in the literature as illegal additives in 2. Experimental 2.1. Chemicals ∗ Authentic standards of SILD citrate, OST and PHE mesylate Corresponding author. Tel.: +33 5 61 55 68 90; fax: +33 5 61 55 76 25. E-mail address: [email protected] (M. Malet-Martino). (methanesulfonate) were purchased from Sigma–Aldrich (St. Louis, 0731-7085/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.jpba.2012.01.035 136 S. Balayssac et al. / Journal of Pharmaceutical and Biomedical Analysis 63 (2012) 135–150 MO, USA). THIO was previously purified from a formulation adul- gradient of 20 to 50% acetonitrile from 0 to 20 min with 0.1% trifluo- terated with this analog [2]. roacetic acid in both aqueous and organic phases. The flow rate was −1 15 mL min . The eluted fractions were collected and analyzed with 2.2. NMR analysis a Waters Acquity UPLC-DAD system controlled by Waters Empower 2 software. The analysis conditions were: Acquity UPLC BEH C18 2.2.1. Preparation of samples for NMR analysis column (50 mm × 2.1 mm i.d.; 1.7 ␮m particle size); mobile phase: Around 500 mg of each powder was mixed with 2 mL of (A) demineralized water and (B) acetonitrile (HPLC grade) both −1 CD3CN:D2O (80:20 v/v) under vortex agitation during 10 min and containing 0.1% (v/v) trifluoroacetic acid; flow rate: 0.3 mL min ; then sonication for 10 min. The suspension was then centrifuged detection wavelength: 270 nm. The gradient condition was as fol- (10 min, 4000 rpm) and 550 ␮L of the supernatant was analyzed. lows: 0–1 min, isocratic elution with a 90:10 A:B mixture; 1–6 min, One of the referee of this article underlined that tadalafil which is linear increase to 10:90 A:B ratio; isocratic elution during 1 min; re- active at low doses (2 mg/day) could have not been extracted in the equilibration for 1 min with a 90:10 A:B mixture before the start of solvent system used owing to its poor solubility in most organic the next run. The unknown compound eluted at 4.5 min. solvents and water. To demonstrate that the method was valid for For the purification of THP and OST, 500 mg of each formula- detecting low-dosed tadalafil, 500 mg of powder 9 was spiked with tion 6 and 9 was dissolved in 20 mL of water and the solutions left ◦ 2 or 5 mg of pure tadalafil and treated as described above. In both overnight at 4 C. The precipitates were filtered, washed three times 1 cases, the H NMR signals of tadalafil were easily detected in the with water and evaporated to complete dryness. CD3CN:D2O extracts, thus showing that the method of extraction is appropriate even for low quantities of this PDE-5 inhibitor. 2.4. MS, MS/MS and high resolution MS analyses For the quantitative analysis, around 40 mg of each powder was mixed with 10 mL of methanol under magnetic stirring dur- The methanolic extracts of powders and the purified com- ing 15 min, then sonicated for 10 min. After centrifugation (5 min, pounds dissolved in methanol were directly infused in an Applied 4000 rpm), an aliquot of 1 mL was evaporated to dryness and the Biosystems API 365 triple-quadrupole mass spectrometer (Applied residue dissolved in 1 mL of methanol-d4. The experiments were Biosystems Inc., Foster City, CA, USA), equipped with a TIS inter- 1 done in triplicate. The quantification was performed on the H face and controlled by the Analyst software (version 1.4). The mass NMR signals of the aromatic protons H15 and H18 (doublets) for spectrometer was operated in positive ionization mode. Nitrogen SILD, THIO and PP-THHS, H1 and H4 (singlets) for THP, H9/H13 and served both as auxiliary and collision gas and oxygen served as H10/H12 (respectively XX and AA parts of an AA XX system) for nebulizer gas. The operating conditions for TIS interface were as PHEN and H4 and H5 (doublets) for OST (see Fig. 1 for numbering). follows: (1) in MS mode: scan range m/z 100–1000, step size 0.1. The solid residue from the first extraction was re-extracted with Q1 TIS MS spectra were recorded in profile mode, IS 4700 V, DP the same protocol. The mixture obtained was centrifuged (5 min, 65 V, FP 330 V for the new analog and IS 5000 V, DP 25 V, FP 200 V 4000 rpm) and the supernatant evaporated to dryness. The residue for PHE and OST; and (2) in MS–MS mode: precursor ions at m/z 1 was dissolved in 1 mL of methanol-d4 for H NMR analysis. The 535 for the unknown analog, 282 for PHE and 245 for OST; scan proton signals used for quantification could not be detected. range m/z 30–600 for the unknown analog and 50–300 for PHE and OST, step size 0.1; MS–MS spectra were recorded in profile mode, 2.2.2. NMR recording conditions IS 5000 V, DP 65 V, FP 330 V, CE 50 V, CAD 3 for the new analog, and The NMR experiments were performed on a Bruker Avance IS 5000 V, DP 25 V, FP 200 V, CE 25 V, CAD 3 for PHE and OST. 500 spectrometer (Bruker BioSpin AG, Fällanden, Switzerland) The accurate masses of the new analog, PHE and OST were 1 13 equipped with a 5 mm dual H– C TCI cryoprobe. Sodium 2,2,3,3- determined on a Waters GCT Premier time-of-flight (TOF) mass tetradeutero-3-trimethylsilylpropionate (TSP; Sigma–Aldrich) was spectrometer equipped with a Desorption Chemical Ionization used as an internal reference for chemical shift (ı) measurement (DCI) probe employing methane as the reagent gas and controlled and quantification. A solution of TSP (10 ␮L) was added before the by the MassLynx 4.1 software.
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