Min-Yong Low

Isolation and identification of thiohomosildenafil and thiosildenafil in health supplements

Two unknown compounds are detected and isolated from health supplements for the enhancement of sexual function. The structures of the unknown compounds are elucidated using high-resolution MS, ESI-MS/MS, NMR, UV and IR. One compound is identified as an analogue of sildenafil in which the oxygen atom is substituted with a sulfur atom in the pyrazolopyrimidine moiety, and an ethyl group instead of a methyl group is attached to the piperazinyl nitrogen. Hence, this compound is named thiohomosildenafil. Another compound is also a sildenafil analogue in which the oxygen atom is substituted with a sulfur atom in the pyrazolopyrimidine moiety. This compound is named thiosildenafil. Both the two compounds are first detected in health supplements. The UV, IR and completely assigned NMR data of thiohomosildenafil and thiosildenafil are first reported.

Structural elucidation of a tadalafil analogue found as an adulterant of a herbal product

A tadalafil analogue and hydroxyhomosildenafil were isolated from a herbal product marketed for erectile dysfunction. The structure of the tadalafil analogue was elucidated using LC-UV, high resolution MS, ESI-MS/MS, IR, and NMR. The compound was determined to be (6R,12aR)-2-amino-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6] pyrido[3,4-b]indole-1,4-dione. This compound should be included as a target compound when screening for adulterants in herbal products. This is the first published paper on a tadalafil analogue and hydroxyhomosildenafil found as adulterants of a herbal product.

Structural identification of a new acetildenafil analogue from pre-mixed bulk powder intended as a dietary supplement

An analogue of acetildenafil was detected in an extract of pre-mixed bulk powder. To our knowledge, the powder was destined to be encapsulated and sold as a dietary supplement. The structure was identified by NMR, HR-ESI–MS, ESI–MS n and FTIR analyses. Owing to the inclusion of a hydroxyl group in acetildenafil, the detected compound was called ‘hydroxyacetildenafil’. With increasing use of dietary supplements marketed for penile erectile dysfunction, the detection of analogues of sexual performance enhancers is important and timely.

Adverse events associated with the use of complementary medicine and health supplements: an analysis of reports in the Singapore Pharmacovigilance database from 1998 to 2009.

Context. The use of complementary and alternative medicine (CAM), particularly herbal medicine and their derived products, have been increasing. However, sporadic reports of serious adverse effects associated with the use of these products have become a source of concern. Spontaneous adverse event reporting may be used to monitor the safety of these products. Objective. The objectives of this study is to analyze and describe the patterns of adverse events associated with the use of Chinese Proprietary Medicine, other complementary medicine and health supplements (termed CAM products) in the Singapore Pharmacovigilance database from 1998 to 2009 and to highlight areas of safety concerns. Methods. Adverse events associated with CAM products reviewed by the Vigilance Branch of the Health Sciences Authority for the period 1998–2009 were collated and analyzed. The following information was extracted and collated: patient demographics, type and indication of CAM products, system-organ class affected, seriousness of the adverse event, route of administration, hospitalization status, outcome of adverse event, concomitant use of conventional medicine, adulterant testing and profession of the reporter. Results. In the period 1998–2009, 627 cases of adverse events due to CAM products were reported. Most of these 627 cases (80.2%) were found to be serious and most of the patients used CAM products for sexual performance enhancement (291, 46.4%), to relieve pain such as joint and neck pain (36, 5.9%) and for slimming purposes (27, 4.3%). Of the 627 cases, endocrine disorders constituted 22.5% and central nervous system disorders constituted 20.6%. Liver was the main organ involved in the serious cases. Twenty-two fatalities were reported and hepatotoxicity was responsible for the deaths of 10 patients during the study period. Conclusions. In conclusion, 627 adverse event reports associated with CAM products had been successfully analyzed and described. They constituted ∼3.8% of the total number of adverse events reported from 1998 to 2009. Outbreaks of severe hypoglycemia in 2008 and 2009 were associated with the use of adulterated and illegal sexual performance enhancement products. Further work to confirm the hepatotoxicity of implicated CAM products is warranted. Reporting of suspected adverse events is strongly encouraged even if the causality is not confirmed because any signs of clustering will allow rapid regulatory actions to be taken. The analysis of spontaneously reported adverse events is important in monitoring the safety of CAM products and helps in the understanding of the benefits and risks associated with the use of such products.

Detection of Sildenafil Analogues in Herbal Products for Erectile Dysfunction

Sildenafil, the active ingredient in Viagra (Pfizer), is a prescription medicine used for erectile dysfunction. Compounds with chemical structures similar to that of sildenafil were isolated and purified during the analysis of some herbal products marketed for treatment of erectile dysfunction. Structural elucidation using liquid chromatography–diode array detection, infrared spectroscopy, liquid chromatography–tandem mass spectrometry, and nuclear magnetic resonance spectroscopy confirmed that the compounds were homosildenafil, hydroxyhomosildenafil, and acetildenafil. The implications of adulteration by compounds structurally related to prescription drugs are discussed. Unlike established drugs, the efficacy and safety of such analogues are largely unknown. This poses a great challenge for safety and health administrators to detect these modified structures and to regulate them. Consumers who use such adulterated products are at risk of developing serious adverse reactions, potentially leading to death. Greater collaboration and exchange of information between various health authorities, health professionals, academics, researchers, and industry, as well as public education, are key steps in the efforts to stem the growing trend of adulteration of herbal products by analogues of prescription drugs.

Identification of benzamidenafil, a new class of phosphodiesterase-5 inhibitor, as an adulterant in a dietary supplement

A sample labeled to be a natural herbal supplement for the enhancement of sexual function, was sent to Health Sciences Authority (HSA) of Singapore for testing. An unknown compound was detected and isolated from the product. The structure of the unknown compound was identified using LC-UV, high-resolution MS, ESI-MS/MS, IR, and NMR. The compound was characterized as a phosphodiesterase-5 (PDE-5) inhibitor, benzamidenafil. This is the first report of benzamidenafil, representing a new class of PDE-5 inhibitors, as an adulterant of a dietary supplement.

Isolation and structure elucidation of an interaction product of aminotadalafil found in an illegal health food product

An interaction product of aminotadalafil was isolated from an illegal health food product. The structure of the interaction product was elucidated by means of IR, NMR, and mass spectroscopy. The hitherto unknown compound was characterized as condensation product of aminotadalafil and hydroxymethylfuraldehyde and is probably the result of a drug-excipient incompatibility.

Isolation and characterization of propoxyphenyl linked sildenafil and thiosildenafil analogues in health supplements

Two new phosphodiesterase-5 inhibitors (PDE-5) which consist of one sildenafil analogue and one thiosildenafil analogue have been found in heath supplements. The structural properties of these analogues have been elucidated by NMR, high resolution MS, MS(2), UV and IR spectroscopy. The sildenafil analogue is very similar to aildenafil and the thiosildenafil analogue is similar to thioaildenafil, except the ethoxy group bonded to phenyl ring is replaced by a propoxy group. Hence, the sildenafil analogue is named as propoxyphenyl aildenafil or propoxyphenyl methisosildenafil and the thiosildenafil analogue as propoxyphenyl thioaildenafil or propoxyphenyl thiomethisosildenafil.

Structural elucidation of a PDE-5 inhibitor detected as an adulterant in a health supplement

A PDE-5 inhibitor was detected and isolated from a health supplement claimed to be a preparation of fresh oyster extracts and be able to promote and support healthy sexual function and endurance, etc. The structure of this PDE-5 inhibitor was elucidated using LC-UV, LC-TOF-MS, MS-MS, IR spectroscopy, and 2D NMR. It was characterized as 8-(2-(4-(hydroxymethyl)piperidin-1-yl)benzylamino)-3-ethyl-1H-imidazo[4,5-g]quinazoline-2(3H)-thione, a compound reported to be a PDE-5 inhibitor.

Isolation and identification of hydroxythiohomosildenafil in herbal dietary supplements sold as sexual performance enhancement products

An unknown compound is detected and isolated from two herbal dietary supplements bought on the internet. The structure of the unknown compound is elucidated using ESI–MS/MS, NMR, UV and IR. The compound, named hydroxythiohomosildenafil, is identified as an analogue of sildenafil in which the oxygen atom is substituted with a sulfur atom in the pyrazolopyrimidine moiety, and a hydroxyethyl group instead of a methyl group is attached to the piperazinyl nitrogen. It is the first report of this compound being detected in herbal dietary supplements. The UV, IR and completely assigned NMR data of hydroxythiohomosildenafil is recorded.