A review of synthetic phosphodiesterase type 5 inhibitors (PDE-5i) found as adulterants in dietary supplements

Kee, Chee‐Leong; Ge, Xiaowei; Gilard, Véronique; Malet‐Martino, Myriam; Low, Min‐Yong

doi:10.1016/j.jpba.2017.07.031

Cited by 67 publications

(43 citation statements)

References 98 publications

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“…PDE5 inhibitors (PDE5Is) are used in the treatment of pulmonary hypertension or erectile dysfunction (ED) [27]. ED therapy with PDE5 inhibitors, e.g., sildenafil (Viagra, Pfizer Inc., first generation PDE5Is) or avanafil (Stendra, Metuchen Pharmaceuticals, LLC., second generation PDE5Is) is preferred as the first-line medication [28]. Moreover, the number of various PDE5Is in dietary supplements has increased from 1 in 2003 to 69 in 2016 [28].…”

Section: Introductionmentioning

confidence: 99%

“…ED therapy with PDE5 inhibitors, e.g., sildenafil (Viagra, Pfizer Inc., first generation PDE5Is) or avanafil (Stendra, Metuchen Pharmaceuticals, LLC., second generation PDE5Is) is preferred as the first-line medication [28]. Moreover, the number of various PDE5Is in dietary supplements has increased from 1 in 2003 to 69 in 2016 [28]. Recently, PDE5Is have been proposed as medicines for heart failure [29].…”

Section: Introductionmentioning

confidence: 99%

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Revisiting the halogen bonding between phosphodiesterase type 5 and its inhibitors

Jedwabny

Dyguda-Kazimierowicz

2019

J Mol Model

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Halogenated ligands are nowadays commonly designed in order to increase their potency against protein targets. Although novel computational methods of evaluating the affinity of such halogenated inhibitors have emerged, they still lack the sufficient accuracy, which is especially noticeable in the case of empirical scoring functions, being the method of choice in the drug design process. Here, we evaluated a series of halogenated inhibitors of phosphodiesterase type 5 with ab initio methods, revealing the physical nature of ligand binding and determining the components of interaction energy that are essential for proper inhibitor ranking. In particular, a nonempirical scoring model combining long-range contributions to the interaction energy provided a significant correlation with experimental binding potency, outperforming a number of commonly used empirical scoring functions. Considering the low computational cost associated with remarkable predictive abilities of the aforementioned model, it could be used for rapid assessment of the ligand affinity in the process of rational design of novel halogenated compounds.Electronic supplementary materialThe online version of this article (10.1007/s00894-018-3897-z) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Revisiting the halogen bonding between phosphodiesterase type 5 and its inhibitors

Jedwabny

Dyguda-Kazimierowicz

2019

J Mol Model

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“…Many consumers assume sex‐enhancement products are safe since they are composed of “natural” ingredients or mistakenly believe they are evaluated for safety before marketing. However, these products may be adulterated with phosphodiesterase‐5 (PDE5) inhibitors, which are drugs used to treat erectile dysfunction . Erectile dysfunction drugs inhibit the activity of PDE5 in the corpus cavernosum, which prevents the breakdown of cyclic guanosine monophosphate (cGMP); this ultimately leads to muscle relaxation, improved blood flow, and enhanced erectile function.…”

Section: Introductionmentioning

confidence: 99%

“…Erectile dysfunction drugs inhibit the activity of PDE5 in the corpus cavernosum, which prevents the breakdown of cyclic guanosine monophosphate (cGMP); this ultimately leads to muscle relaxation, improved blood flow, and enhanced erectile function. Among 7 PDE5 inhibitor drugs marketed globally, the most common drugs in adulterated sex‐enhancement products are sildenafil, tadalafil, and vardenafil . Additionally, over 80 analogs of these drugs have been detected in sex‐enhancement products, along with some PDE5 inhibitors with chemical structures that differ considerably from marketed drugs (eg, xanthoanthrafil) …”

Section: Introductionmentioning

confidence: 99%

Phosphodiesterase (PDE5) inhibition assay for rapid detection of erectile dysfunction drugs and analogs in sexual enhancement products

Santillo

Mapa

2018

Drug Testing and Analysis

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Products marketed as dietary supplements for sexual enhancement are frequently adulterated with phosphodiesterase-5 (PDE5) inhibitors, which are erectile dysfunction drugs or their analogs that can cause adverse health effects. Due to widespread adulteration, a rapid screening assay was developed to detect PDE5 inhibitors in adulterated products. The assay employs fluorescence detection and is based on measuring inhibition of PDE5 activity, the pharmacological mechanism shared among the adulterants. Initially, the assay reaction scheme was established and characterized, followed by analysis of 9 representative PDE5 inhibitors (IC , 0.4-4.0 ng mL ), demonstrating sensitive detection in matrix-free solutions. Next, dietary supplements serving as matrix blanks (n = 25) were analyzed to determine matrix interference and establish a threshold value; there were no false positives. Finally, matrix blanks were spiked with 9 individual PDE5 inhibitors, along with several mixtures. All 9 adulterants were successfully detected (≤ 5 % false negative rate; n = 20) at a concentration of 1.00 mg g , which is over 5 times lower than concentrations commonly encountered in adulterated products. A major distinction of the PDE5 inhibition assay is the ability to detect adulterants without prior knowledge of their chemical structures, demonstrating a broad-based detection capability that can address a continuously evolving threat of new adulterants. The PDE5 inhibition assay can analyze over 40 samples simultaneously within 15 minutes and involves a single incubation step and simple data analysis, all of which are advantageous for combating the widespread adulteration of sex-enhancement products.

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“…Начиная с 2003 г. появляются работы, в которых методами высокоэффективной жидкостной хроматографии (ВЭЖХ) с диодно-матричным детектором (ДМД) и масс-спектрометрическими детекторами высокого и низкого разрешения, а также ИК-спектроскопии и спектроскорпии ЯМР были открыты и идентифицированы различные аналоги силденафила, тадалафила и варденафила . Таким образом, к 2018 г. в БАД для увеличения потенции было обнаружено порядка 80 синтети-ческих иФДЭ-5, среди которых преобладают аналоги силденафила [33].…”

unclassified

Screening Results for Non-Declared Synthetic Phosphodiesterase-5 Inhibitors Being Added to Dietary Supplements of Plant Origin

Perova¹,

Eller²,

Tumol`skaya³

2019

Health Risk Analysis

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Добавление недекларированных синтетических ингибиторов фосфодиэстеразы 5-го типа (иФДЭ-5) в биологически активные добавки (БАД) к пище растительного происхождения для увеличения потенции является серьезной проблемой. Такой вид фальсификации повышает терапевтический эффект продукта, который, как правило, не достигается только компонентами БАД к пище растительного происхождения. Синтетические иФДЭ-5 представлены как субстанциями официальных лекарственных препаратов (ЛП), так и их структурными аналогами. Потребление синтетических иФДЭ-5 в составе БАД к пище для увеличения потенции представляет опасность для здоровья потребителей из-за риска возникновения непредсказуемых или даже летальных побочных эффектов. Выявлено содержание недекларированных синтетических иФДЭ-5 в БАД к пище для мужчин. Объектами исследования являлись 175 БАД к пище, отобранных Роспотребнадзором в различных регионах РФ. Определение синтетических иФДЭ-5 в образах проводилось методом высокоэффективной жидкостной хроматографии с диодно-матричным спектрофотометрическим и масс-спектрометрическим детектированием по разработанной нами и утвержденной Роспотребнадзором методике (МУК 4.1.3331-16). Исследования показали, что 36 % БАД к пище для увеличения потенции содержат незаявленные синтетические иФДЭ-5, среди которых преобладают тадалафил и силденафил (42,9 и 28,6 % всех случаев фальсификации). Существенно реже встречались комбинации тадалафила с силденафилом, варденафилом или аналогами иФДЭ-5, а также сложные смеси из трех компонентов и более. Содержание тадалафила, варденафила и силденафила в БАД к пище составило от следовых количеств до концентраций, соответствующих рекомендуемым суточным дозам для этих ЛП и даже превышающих эти дозы. Среди аналогов иФДЭ-5 идентифицированы производные силденафила и тадалафила, количество которых варьировалось от 1,2 до 24,3 мг/капс. Разработанная методика позволила обнаружить случаи фальсификации БАД к пище не только тадалафилом, варденафилом и силденафилом, но и аналогами синтетических иФДЭ-5.

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A review of synthetic phosphodiesterase type 5 inhibitors (PDE-5i) found as adulterants in dietary supplements

Cited by 67 publications

References 98 publications

Revisiting the halogen bonding between phosphodiesterase type 5 and its inhibitors

Revisiting the halogen bonding between phosphodiesterase type 5 and its inhibitors

Phosphodiesterase (PDE5) inhibition assay for rapid detection of erectile dysfunction drugs and analogs in sexual enhancement products

Screening Results for Non-Declared Synthetic Phosphodiesterase-5 Inhibitors Being Added to Dietary Supplements of Plant Origin

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