title: The identification of a nitrosated prodrug of the PDE-5 inhibitor aildenafil in a dietary supplement: a Viagra with a pop.
abstract: A new unapproved analogue of sildenafil was detected in capsules of a herbal dietary supplement promoted as a libido enhancing product. Using LC-DAD-MS, MS-MS, HRMS, IR and NMR the analogue was shown to be a derivative of the PDE-5 inhibitor aildenafil with a nitrosamine moiety. A hydrolysis experiment showed that the new analogue was a prodrug of aildenafil and was therefore named nitroso-prodenafil. A capsule contained 108 mg of nitroso-prodenafil which is equivalent to 84 mg of aildenafil and 5.1 mg of nitrogen monoxide (NO). Although it is unknown how much NO can be usefully generated there is 3-fold more NO present than in a 10 mg isorbide nitrate tablet. Both PDE-5 inhibitors and nitrosamines cause vasodilatation by increasing levels of NO. To their coincidental use is warned against because it may cause a fatal drop in blood pressure. In addition, nitrosamines are known carcinogens. This is the first time a PDE-5 inhibitor and a potential NO donor were identified in one molecule. The findings indicate the dangerous level of advancement in medicinal chemistry by producers of unapproved drugs.
authors.affiliation: National Institute for Public Health and the Environment, Center for Quality of Chemical-Pharmaceutical Products, Anthonie van Leeuwenhoeklaan 9, Bilthoven, The Netherlands. Bastiaan.Venhuis@rivm.nl
authors.forename: B J
authors.initials: BJ
authors.lastname: Venhuis
authors.forename: G
authors.initials: G
authors.lastname: Zomer
authors.forename: M
authors.initials: M
authors.lastname: Hamzink
authors.forename: H D
authors.initials: HD
authors.lastname: Meiring
authors.forename: Y
authors.initials: Y
authors.lastname: Aubin
authors.forename: D
authors.initials: D
authors.lastname: de Kaste
mesh_terms: D015198:Designer Drugs / Q000032:analysis / Q000737:chemistry / Q000302:isolation & purification; D019587:Dietary Supplements / Q000032:analysis*; D007172:Erectile Dysfunction / Q000178:diet therapy; D006801:Humans; D006868:Hydrolysis; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D015394:Molecular Structure; D020030:Nitric Oxide Donors / Q000032:analysis* / Q000737:chemistry; D009602:Nitrosamines / Q000032:analysis* / Q000737:chemistry; D015538:Nitrosation; D058986:Phosphodiesterase 5 Inhibitors / Q000032:analysis* / Q000737:chemistry / Q000302:isolation & purification; D010879:Piperazines / Q000032:analysis* / Q000737:chemistry / Q000302:isolation & purification; D011355:Prodrugs / Q000032:analysis* / Q000737:chemistry / Q000302:isolation & purification; D021241:Spectrometry, Mass, Electrospray Ionization; D017550:Spectroscopy, Fourier Transform Infrared; D013450:Sulfones / Q000032:analysis* / Q000737:chemistry / Q000302:isolation & purification; D053719:Tandem Mass Spectrometry
chemical_list: D015198:Designer Drugs; D020030:Nitric Oxide Donors; D009602:Nitrosamines; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011355:Prodrugs; D013450:Sulfones; C520604:aildenafil; C557484:2-((5-(5-(3,5-dimethylpiperazine-1-sulfonyl)-2-ethoxyphenyl)-1-methyl-3-propyl-1H-pyrazolo(4,3-d)pyrimidin-7-yl)oxy)-N-methyl-N-nitroso-1,3-thiazol-5-amine