[Not Available]. / Naar schatting ten minste 150.000 gebruikers van illegale erectiemiddelen in Nederland.

Online shopping is on the rise and this extends to purchasing of medicines. Patients can deliberately or unwittingly purchase medicines from one of the many illegal suppliers. On this illegal market, erectile dysfunction medicines play a prominent role. We estimate that at least 70% of sildenafil used in the Netherlands is purchased from illegal suppliers. Price cuts on the legal market with the introduction of generics have not made a difference. It is important to gain an insight into the scale of illegal use of medicines and the potential harmful effects we may encounter.

Pharmacologically effective red yeast rice preparations marketed as dietary supplements illustrated by a case report.

This paper reports a typical statin-related adverse reaction from a red yeast rice (RYR) supplement and the analytical findings from the supplement. It also examines the regulatory framework governing botanical supplements in Europe. Two key events that shaped the current regulatory framework are reviewed. First, the Hecht-Pharma judgement by the European Court of Justice (ECJ) that inverted the precautionary principle in the Medicines Act to a reactionary principle. Following the Hecht-Pharma judgement, pharmacological active dietary supplements can be sold until sufficient signals of harm show that they are an unregistered medicine, placing a huge burden on regulatory authorities. Secondly, the European Food Safety Authority (EFSA) in 2011 approved the first health claim for pharmacologically active RYR dietary supplements. If the current regulatory status for pharmacologically active RYR dietary supplements does not permit adequate warning and active monitoring of adverse drug reactions, then the current regulatory framework may not be adequate to ensure consumer safety.Copyright © 2016 John Wiley & Sons, Ltd.

Dose-to-dose variations with single packages of counterfeit medicines and adulterated dietary supplements as a potential source of false negatives and inaccurate health risk assessments.

In this report, we show three examples of how the variability in dose units in single packages of counterfeit medicines and adulterated dietary supplements may contribute to a false negative screening result and inaccurate health risk assessments. We describe a counterfeit Viagra 100mg blister pack and a box of an instant coffee both containing dose units with and without an active pharmaceutical ingredient (API). We also describe a purportedly herbal slimming product with capsules that mutually differed in API and impurities. The adulterated dietary supplements contained sibutramine, benzyl-sibutramine, N-desmethyl-sibutramine (DMS), N,N-didesmethyl-sibutramine (DDMS) and several other related impurities. Counterfeit medicines and adulterated dietary supplements are a health risk because their quality is unreliable. Health risks are even greater when such unreliability extends to fundamental differences between dose units in one package. Because dose-to-dose variability for these products is unpredictable, the confidence interval of a sample size is unknown. Consequently, the analyses of a selection of dose units may not be representative for the package. In the worst case, counterfeit or unauthorised medicines are not recognised as such or a health risk is not identified. In order to reduce erroneous results particular care should be taken when analysing a composite of dose units, when finding no API in a dietary supplement and when finding conformity in a suspect counterfeit medicine.

Sildenafil and analogous phosphodiesterase type 5 (PDE-5) inhibitors in herbal food supplements sampled on the Dutch market.

Herbal food supplements, claiming to enhance sexual potency, may contain deliberately added active pharmacological ingredients (APIs) that can be used for the treatment of erectile dysfunction (ED). The aim of this study was to determine whether herbal food supplements on the Dutch market indeed contain APIs that inhibit phosphodiesterase type 5 (PDE-5) inhibitors, such as sildenafil and analogous PDE-5 inhibitors. Herbal food supplements intended to enhance sexual potency (n = 71), and two soft drinks, were sampled from 2003 up to and including 2012. In 23 herbal supplements, nine different PDE-5 inhibitors were identified; in a few cases (n = 3), more than one inhibitor was indentified. The presence of these APIs was however not stated on the label. The concentrations of PDE-5 inhibitors per dose unit were analysed. Furthermore, the potential pharmacologically active properties of the detected PDE-5 inhibitors were estimated by using data from the scientific and patent literature regarding (1) in vitro PDE-5 activity, (2) reported effective doses of registered drugs with PDE-5 inhibitor activity and (3) similarity to other structural analogues. It was concluded that 18 of the 23 herbal food supplements, when used as recommended, would have significant pharmacological effects due to added APIs. Adequate use of existing regulation and control measures seems necessary to protect consumers against the adverse effects of these products.

Towards a decade of detecting new analogues of sildenafil, tadalafil and vardenafil in food supplements: a history, analytical aspects and health risks.

The scale at which erectile dysfunction (ED) medicines are obtained outside of the official health system rivals and possibly exceeds legitimate sales. According to literature a high-risk segment of this market is occupied by adulterated food supplements. The principle adulterants identified were structural analogues of the registered ED drugs sildenafil, tadalafil, and vardenafil. Currently, at least 46 different analogues have been reported and still more are expected. The intellectual origin of analogues was found in patent literature which described the drug discovery process. Patent literature offers a flexible approach to synthesize hundreds of analogues. Most of the analogues currently known had long been disclosed in patent literature. Screening for (new) analogues is best carried out by using advanced LC-MS/MS techniques that focus on marker fragment ions. Analogues are experimental drugs in essence because most have no known efficacy or safety profile. Their use in seemingly harmless food supplements is expected to cause serious adverse effects. However, few reports have emerged in literature on actual harm. Considering the exposure to analogues and their adverse effects being unknown a gross underreporting of complaints is expected.

On the formation of bromhexine impurity E and its chromatographic behaviour.

An unknown bromhexine hydrochloride (BRH) degradation product in BRH oral solutions (finished products) was potentially related to the purity of this API. Several degradation experiments were conducted and its identity and formation were investigated using LC-DAD and LC-DAD-MS/MS. Using the LC method described in the Ph.Eur monograph BRH the degradation product was observed at RRTBRH 0.1 and the specified impurities A-D were ruled out as candidates. Impurity E was initially not considered as a candidate as EDQM reported an expected RRTBRH of 1.8. Still, the LC-DAD-MS/MS results were consistent with the M+ ion for impurity E and its expected fragment ions. Therefore, standard addition was carried out using the Ph. Eur. method which confirmed that the degradation product at RRT 0.1 was impurity E. Upon changing the column type to a column described in the knowledge database, impurity E eluted at an RRT of 1.5. Nevertheless, both columns met all of the criteria in the monograph. The formation of impurity E was even observed in BRH solutions without added reagents. As the conversion from BRH to impurity E requires a source of carbon, we suggest that one BRH molecule degrades through a radical mechanism to a reactive species which subsequently is quenched by another BRH molecule producing impurity E. We suggest the transparency list for BRH to be more explicit on the formation of impurity E, its RRT and the permissible LC columns.

The identification of rimonabant polymorphs, sibutramine and analogues of both in counterfeit Acomplia bought on the internet.

Acomplia was ordered over the internet resulting in the delivery of counterfeit Acomplia and imitation products. The tablets were analyzed for the presence of rimonabant. Using LC-DAD-MSn the presence of effective quantities of rimonabant was confirmed in samples A-D. Samples A and D also contained traces of the rimonabant analogue NIDA-41020. Furthermore, NIR spectroscopy on the tablets indicated the presence of an unapproved rimonabant polymorph in samples C and D which was confirmed by Raman spectroscopy and X-ray diffraction (XRD). In sample E a low dose of sibutramine was found as well traces of N-desmethylsibutramine and bis-N-desmethylsibutramine. Rimonabant was withdrawn from the market because of serious adverse events and lack of efficacy. The availability of poor quality products with rimonabant, impurities and unapproved polymorphs is worrying. Suspect weight-loss medicines should be screened for the presence of novel analogues.

The identification of a nitrosated prodrug of the PDE-5 inhibitor aildenafil in a dietary supplement: a Viagra with a pop.

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.

The identification of (-)-trans-tadalafil, tadalafil, and sildenafil in counterfeit Cialis and the optical purity of tadalafil stereoisomers.

Four blisters with suspect Cialis (tadalafil) 20mg tablets were screened for authenticity using near infrared spectroscopy (NIRS) and for the presence of phosphodiesterase 5 (PDE-5) inhibitors using LC-DAD-MS. All samples were identified as counterfeit Cialis and contained sildenafil or a combination of tadalafil and sildenafil. Although the tablets contained efficacious amounts of PDE-5 inhibitors, neither the active ingredient nor the dosage corresponded to the description on the blister. This is the first reported case of a diastereomeric mixture of tadalafil and trans-tadalafil (3:1) being identified in a counterfeit medicine. The LC-DAD-CD revealed that both diastereomers had a high optical purity. The optical rotation of the diastereomeric mixture was measured indicating the presence of (-)-trans-tadalafil, which is the only other stereoisomer with some PDE-5 inhibitory activity. As no safety profiles are known for the stereoisomers of tadalafil, there is a potential health risk. In addition, the optical purity of tadalafil needs to be taken into account when calculating the dosage in illegal medicines.

Structure elucidation of a novel synthetic thiono analogue of sildenafil detected in an alleged herbal aphrodisiac.

A new analogue of sildenafil was detected in a herbal aphrodisiac. The structure of the compound was established using LC-MS, UV and IR spectroscopy, MS-MS, and NMR. The compound, named thio-homosildenafil is a synthetic N-ethylpiperazine analogue of sildenafil in which also the CO moiety has been converted into a CS group. This is the first time a sildenafil analogue modified at the chromophore was identified as an adulterant of a herbal aphrodisiac. Preliminary pharmacological analysis confirmed the erectogenic potency of thio-homosildenafil.

New (sulfonyloxy)piperazinyldibenzazepines as potential atypical antipsychotics: chemistry and pharmacological evaluation.

A series of 2- or 8-trifluoromethylsulfonyloxy (TfO) and 2- or 8-methylsulfonyloxy (MsO) 11-piperazinyldibenzodiazepines, -oxazepines, and -thiazepines were synthesized and evaluated in pharmacological models for their potential clozapine-like properties. In receptor binding assays, the 2-TfO analogues (18a, GMC2-83; 24, GMC3-06; and previously reported GMC1-169, 9a) of the dibenzazepines have profiles comparable to that of clozapine, acting on a variety of CNS receptors except they lack M1 receptor affinity. Introduction of 2-TfO to clozapine leads to compound 9e (GMC61-39) which has a similar binding profile as that of clozapine including having M1 receptor affinity. Interestingly, the MsO analogues, as well as the 8-TfO analogues, have no or weak dopaminergic and serotonergic affinities, but all 8-sulfonyloxy analogues do have M1 affinities. In behavioral studies performed to indicate the potential antipsychotic efficacy and the propensity to induce EPS, 2-TfO analogues blocked effectively the apomorphine-induced climbing in mice in a dose-dependent manner with ED50 values (mg/kg) of 2.1 sc for 9a, 1.3 po for 18a, 2.6 sc for 24, and 8.2 sc for 9e. On the other hand, they showed a clear dose separation with regard to their ED50 values (mg/kg) for indicating catalepsy in rats (>44 sc for 9a, 28 po for 18a, 30 sc for 24, and >50 sc for 9e, respectively), thus implicating a more favorable therapeutic ratio (K/A, ED50 climbing/ED50 catalepsy) in comparison with typical neuroleptics such as haloperidol and isoclozapine. Furthermore, compound 18a was also demonstrated to be an orally potent DA antagonist with an ED50 value of 0.7 mg/kg po in the ex vivo L-DOPA accumulation model. The present study contributes to the SAR of 11-piperazinyldibenzazepines, and the 2-TfO analogues of 11-piperazinyldibenzazepines are promising candidates as clozapine-like atypical antipsychotics with low propensity to induce EPS.