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1.
Molecules ; 28(10)2023 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-37241857

RESUMEN

This study proposed a high-performance thin-layer chromatography (HPTLC) screening method to detect phosphodiesterase 5 (PDE-5) inhibitors as possible adulterant agents in various dietary supplements. Chromatographic analysis was performed on silica gel 60F254 plates using a mixture of ethyl acetate:toluene:methanol:ammonia in a volume ratio of 50:30:20:0.5 as a mobile phase. The system provided compact spots and symmetrical peaks of sildenafil and tadalafil with retardation factor values of 0.55 and 0.90, respectively. The analysis of products purchased from the internet or specialized stores demonstrated the presence of sildenafil, tadalafil, or both compounds in 73.3% of products, highlighting inadequacies and inconsistencies in the labeling, as all dietary supplements were declared to be natural. The results were confirmed using ultra-high-performance liquid chromatography coupled with a positive electrospray ionization high-resolution tandem mass spectrometry (UHPLC-HRMS-MS) method. Furthermore, in some samples, vardenafil and various analogs of PDE-5 inhibitors were detected using a non-target HRMS-MS approach. The results of the quantitative analysis revealed similar findings between the two methods, with adulterant quantities found to be similar to or higher than those in approved medicinal products. This study demonstrated that the HPTLC method is a suitable and economical method for screening PDE-5 inhibitors as adulterants in dietary supplements intended for sexual activity enhancement.


Asunto(s)
Suplementos Dietéticos , Inhibidores de Fosfodiesterasa 5 , Inhibidores de Fosfodiesterasa 5/química , Citrato de Sildenafil , Tadalafilo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5 , Cromatografía Líquida de Alta Presión , Suplementos Dietéticos/análisis
2.
Molecules ; 27(19)2022 Oct 09.
Artículo en Inglés | MEDLINE | ID: mdl-36235271

RESUMEN

This paper reports an important investigation and quantification of adulteration of sexual enhancement supplements with prescription medicines available in United Arab Emirates (UAE): tadalafil, sildenafil and vardenafil. A total of 158 sexual enhancement supplements were collected and analyzed in the current study. The samples were screened using REVERSE-phase liquid chromatography tandem high-resolution mass spectrometry/mass spectrometry (RP-HPLC-MS/MS). Of all sexual enhancements, 12.7% (95% CI: 7.4-18) contained undeclared sildenafil, 3.8% (95% CI: 0.78-6.81) contained undeclared tadalafil and 1.9% (95% CI: 0.25-4.05) contained undeclared vardenafil. Of all sexual enhancement supplements, 13.9% (95% CI: 8.5-19.4) contained significant concentrations of sildenafil, tadalafil or vardenafil. While the study found relatively low levels of undeclared pharmaceutical ingredients in the sexual enhancement dietary supplements available on the UAE market, it is likely that patients with ED tend to consume multiple such supplements daily, thereby exposing themselves to highly elevated cumulative levels.


Asunto(s)
Inhibidores de Fosfodiesterasa 5 , Espectrometría de Masas en Tándem , Suplementos Dietéticos/análisis , Contaminación de Medicamentos/prevención & control , Humanos , Preparaciones Farmacéuticas , Inhibidores de Fosfodiesterasa 5/química , Citrato de Sildenafil , Tadalafilo , Diclorhidrato de Vardenafil
3.
J Chromatogr Sci ; 60(10): 953-962, 2022 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-35535451

RESUMEN

Consumption of foods and dietary supplements (DS) adulterated with unprescribed or non-permitted phosphodiesterase-5 inhibitors (PDE-5i) and their analogs can cause serious risk to human health. This study aims to analyze 93 PDE-5i and their analogs present in adulterated foods and DS using an established and validated method involving high-performance liquid chromatography (HPLC). The method was validated in solid and liquid samples, resulting in a limit of detection and quantitation of 0.03-0.5 and 0.08-1.6 µg/mL, respectively. Using the validated method, a total of 404 samples were screened. It was found that 32% of 404 samples were illegally adulterated with PDE-5i and their analogs; moreover, 16.9% of the adulterated samples were found to contain more than three compounds. HPLC-quadrupole-time-of-flight (TOF)/mass spectrometry (MS) analysis was conducted on all the samples to confirm the detected compounds accurately based on fragmentation ion patterns. In addition, sildenafil and tadalafil were detected from the capsule shells of DS unusually. Subsequently, the detected compounds were identified and quantified using HPLC at concentrations ranging from 0.007 to 370.0 mg/g. NMR analysis was carried out to confirm the accurate chemical structure of a compound found during the TOF/MS analysis, which did not match with the 93 reference standards.; it was identified to be N-desmethylthiosildenafil. In this study, various PDE-5i compounds and their analogs were detected from low to high concentrations in a sample. Therefore, the study sheds light on the misuse of PDE-5i and their analogs in consumable products, which pose a severe threat to public health.


Asunto(s)
Suplementos Dietéticos , Inhibidores de Fosfodiesterasa 5 , Humanos , Cromatografía Líquida de Alta Presión , Inhibidores de Fosfodiesterasa 5/análisis , Inhibidores de Fosfodiesterasa 5/química , Tadalafilo , Citrato de Sildenafil/análisis , Suplementos Dietéticos/análisis , Contaminación de Medicamentos
4.
Molecules ; 26(4)2021 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-33670094

RESUMEN

Unapproved ingredients included in herbal medicines and dietary supplements have been detected as adulterated synthetic drugs used for erectile dysfunction. Extraction from a dietary supplement was performed to isolate the compounds by HPLC analysis. The structural characterization was confirmed using mass spectrometry (ESI-TOF/MS and LC-MS/MS), 1H NMR, and 13C NMR spectroscopy techniques. Results identified the thus-obtained compound to be sulfoaildenafil, a thioketone analogue of sildenafil. The biological activities of this active compound have been focused for the first time by the experimental point of view performance in vitro. The results revealed that sulfoaildenafil can affect the therapeutic level of nitric oxide through the upregulation of nitric oxide synthase and phosphodiesterase type 5 (PDE5) gene expressions. This bulk material, which displays structural similarity to sildenafil, was analyzed for the presence of a PDE5 inhibitor using a theoretical calculation. These unique features of the potential activity of PDE5 protein and its inhibitors, sildenafil and sulfoaildenafil, may play a key consideration for understanding the mode of actions and predicting the biological activities of PDE5 inhibitors.


Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/genética , Suplementos Dietéticos , Disfunción Eréctil/tratamiento farmacológico , Inhibidores de Fosfodiesterasa 5/química , Cromatografía Líquida de Alta Presión , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/efectos de los fármacos , Disfunción Eréctil/patología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Medicina de Hierbas , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Espectrometría de Masas , Modelos Moleculares , Estructura Molecular , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Piperazinas/química , Piperazinas/uso terapéutico , Citrato de Sildenafil/química , Citrato de Sildenafil/uso terapéutico , Sulfonas/química , Sulfonas/uso terapéutico
5.
Molecules ; 26(4)2021 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-33546456

RESUMEN

Phosphodiesterase 5 (PDE5) is one of the most extensively studied phosphodiesterases that is highly specific for cyclic-GMP hydrolysis. PDE5 became a target for drug development based on its efficacy for treatment of erectile dysfunction. In the present study, we synthesized four novel analogues of the phosphodiesterase type 5 (PDE5) inhibitor-tadalafil, which differs in (i) ligand flexibility (rigid structure of tadalafil vs. conformational flexibility of newly synthesized compounds), (ii) stereochemistry associated with applied amino acid building blocks, and (iii) substitution with bromine atom in the piperonyl moiety. For both the intermediate and final compounds as well as for the parent molecule, we have established the crystal structures and performed a detailed analysis of their structural features. The initial screening of the cytotoxic effect on 16 different human cancer and non-cancer derived cell lines revealed that in most cases, the parent compound exhibited a stronger cytotoxic effect than new derivatives, except for two cell lines: HEK 293T (derived from a normal embryonic kidney, that expresses a mutant version of SV40 large T antigen) and MCF7 (breast adenocarcinoma). Two independent studies on the inhibition of PDE5 activity, based on both pure enzyme assay and modulation of the release of nitric oxide from platelets under the influence of tadalafil and its analogues revealed that, unlike a reference compound that showed strong PDE5 inhibitory activity, the newly obtained compounds did not have a noticeable effect on PDE5 activity in the range of concentrations tested. Finally, we performed an investigation of the toxicological effect of synthesized compounds on Caenorhabditis elegans in the highest applied concentration of 6a,b and 7a,b (160 µM) and did not find any effect that would suggest disturbance to the life cycle of Caenorhabditis elegans. The lack of toxicity observed in Caenorhabditis elegans and enhanced, strengthened selectivity and activity toward the MCF7 cell line made 7a,b good leading structures for further structure activity optimization and makes 7a,b a reasonable starting point for the search of new, selective cytotoxic agents.


Asunto(s)
Caenorhabditis elegans/enzimología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Inhibidores de Fosfodiesterasa 5 , Piperazinas , Tadalafilo , Animales , Evaluación Preclínica de Medicamentos , Células HEK293 , Humanos , Células MCF-7 , Inhibidores de Fosfodiesterasa 5/síntesis química , Inhibidores de Fosfodiesterasa 5/química , Inhibidores de Fosfodiesterasa 5/farmacología , Piperazinas/síntesis química , Piperazinas/química , Piperazinas/farmacología , Tadalafilo/análogos & derivados , Tadalafilo/síntesis química , Tadalafilo/química , Tadalafilo/farmacología
6.
Nat Prod Res ; 35(1): 92-98, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31137981

RESUMEN

Phosphodiesterase 5A enzyme has been the upcoming and promising target in hypertension management. In this research, reported 270 bioactive natural products having antihypertensive potential were selected and docked against PDE5A using vLife MDS 4.6 software. Based on docking score, π-stacking, H-bond and ionic interactions with PDE5A, 82 tricyclic compounds were selected for further study. Protein residue Gln817A was associated in H-boding, Leu804A in ionic interaction whereas Val782A and Phe820A were associated in π-stacking interaction with ligand. In silico docking studies resulted in discovery of oxygen containing naphthofuran and nitrogen and oxygen containing pyrano quinolizine tricyclic lead scaffolds as novel PDE5A inhibitors. Additionally, developed pharmacophore model suggested that one centre of hydrogen bond acceptor, one aromatic centre and two aliphatic centres are minimum pharmacophoric features required in the molecule so as to show sildenafil like activity. The identified lead scaffolds would provide novel platform for drug discovery of bioactive natural products.


Asunto(s)
Productos Biológicos/química , Productos Biológicos/farmacología , Inhibidores de Fosfodiesterasa 5/química , Inhibidores de Fosfodiesterasa 5/farmacología , Simulación por Computador , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos/métodos , Humanos , Enlace de Hidrógeno , Ligandos , Simulación del Acoplamiento Molecular , Nitrógeno/química , Oxígeno/química , Quinolizinas/química , Citrato de Sildenafil/química , Programas Informáticos
7.
Nat Prod Res ; 35(10): 1648-1653, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-31140295

RESUMEN

In 1998, sildenafil was marketed as the first FDA-approved oral drug for the treatment of erectile dysfunction (ED). During the last two decades, the commercialization of other synthetic phosphodiesterase 5 (PDE5) inhibitors has been paralleled by the rise of remedies based on natural molecules from different chemical classes (flavonoids, polyphenols and alkaloids in general). In this work, a set of in silico tools were applied to study a panel of 30 natural compounds claimed to be effective against ED in the scientific literature or in folk medicine. First, pharmacokinetic properties were analysed to exclude the compounds lacking in specific drug-like features. Estimated binding energy for PDE5 and selectivity towards other PDE isoforms were then considered to highlight some promising molecules. Finally, a detailed structural investigation of the interaction pattern with PDE in comparison with sildenafil was conducted for the best performing compound of the set.


Asunto(s)
Inhibidores de Fosfodiesterasa 5/química , Inhibidores de Fosfodiesterasa 5/farmacología , Sitios de Unión , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Simulación por Computador , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Disfunción Eréctil/tratamiento farmacológico , Humanos , Masculino , Medicina Tradicional , Inhibidores de Fosfodiesterasa 5/farmacocinética , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Citrato de Sildenafil/farmacología
8.
Artículo en Inglés | MEDLINE | ID: mdl-33136528

RESUMEN

A new tadalafil analogue was detected via high-performance liquid chromatography (HPLC)-diode array detection (DAD) during routine screening of health foods suspected of adulteration with erectile dysfunction drugs. The UV absorption spectrum of the unknown was almost identical to that of tadalafil. The analogue was purified by preparative HPLC and structural elucidation carried out by mass spectrometric and NMR spectroscopic experiments. The spectral data revealed that this tadalafil analogue bears a benzyl group instead of the methyl group. The isolated compound was identified as N-benzyl tadalafil. Considering the risk it poses to public health, this new PDE-5 analogues for ED should be included on the inspection list for illegal products.


Asunto(s)
Café/química , Suplementos Dietéticos/análisis , Contaminación de Medicamentos , Contaminación de Alimentos/análisis , Inhibidores de Fosfodiesterasa 5/aislamiento & purificación , Tadalafilo/aislamiento & purificación , Cromatografía Líquida de Alta Presión , Humanos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Estructura Molecular , Inhibidores de Fosfodiesterasa 5/química , Tadalafilo/análogos & derivados , Tadalafilo/química
9.
Molecules ; 25(12)2020 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-32545673

RESUMEN

An accurate and reliable method based on ion trap-time of flight mass spectrometry (IT-TOF MS) was developed for screening phosphodiesterase-5 inhibitors, including sildenafil, vardenafil, and tadalafil, and their analogs in dietary supplements. Various parameters affecting liquid chromatographic separation and IT-TOF detection were investigated, and the optimal conditions were determined. The separation was achieved on a reversed-phase column under gradient elution using acetonitrile and water containing 0.2% acetic acid at a flow rate of 0.2 mL/min. The chromatographic eluents were directly ionized in the IT-TOF system equipped with an electrospray ion source operating in the positive ion mode. The proposed screening method was validated by assessing its linearity, precision, and accuracy. Sequential tandem MS was conducted to obtain structural information of the references, and the fragmentation mechanism of each reference was proposed for providing spectral insight for newly synthesized analogs. Structural information, including accurate masses of both parent and fragment ions, was incorporated into the MSn spectral library. The developed method was successfully applied for screening adulterated dietary supplement samples.


Asunto(s)
Suplementos Dietéticos/análisis , Espectrometría de Masas/métodos , Inhibidores de Fosfodiesterasa 5/análisis , Cromatografía Líquida de Alta Presión/métodos , Cromatografía Liquida/métodos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Contaminación de Medicamentos , Inhibidores de Fosfodiesterasa 5/química , Citrato de Sildenafil/análogos & derivados , Citrato de Sildenafil/análisis , Tadalafilo/análogos & derivados , Tadalafilo/análisis , Espectrometría de Masas en Tándem/métodos , Diclorhidrato de Vardenafil/análogos & derivados , Diclorhidrato de Vardenafil/análisis
10.
Molecules ; 25(1)2020 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-31906356

RESUMEN

The crude drug ysypó hû (Adenocalymma marginatum DC., Bignoniaceae) is used traditionally by the Guarani of Eastern Paraguayan as a male sexual enhancer. The aim of the present study was to identify the main constituents of the crude drug and to evaluate the in vitro inhibitory activity towards the enzyme phosphodiesterase-5 (PDE-5). The main compounds were isolated by counter-current chromatography (CCC). The metabolites were identified by spectroscopic and spectrometric means. The chemical profiling of the extracts was assessed by high-performance liquid chromatography coupled to mass spectrometry (HPLC-MS/MS). The crude extract and main isolated compounds were tested for their PDE-5 inhibitory activity using commercial kits. The iridoid theviridoside and 4-hydroxy-1-methylproline were isolated as the main constituent of the crude drug. Four chlortheviridoside hexoside derivatives were detected for the first time as natural products. Chemical profiling by HPLC-MS/MS led to the tentative identification of nine iridoids, six phenolics, and five amino acids. The crude extracts and main compounds were inactive towards PDE-5 at concentrations up to 500 µg/mL. Iridoids and amino acid derivatives were the main compounds occurring in the Paraguayan crude drug. The potential of ysypó hû as a male sexual enhancer cannot be discarded, since other mechanisms may be involved.


Asunto(s)
Bignoniaceae/química , Iridoides/química , Inhibidores de Fosfodiesterasa 5/química , Extractos Vegetales/química , Aminoácidos/análisis , Aminoácidos/química , Aminoácidos/aislamiento & purificación , Bignoniaceae/metabolismo , Cromatografía Líquida de Alta Presión , Mezclas Complejas , Distribución en Contracorriente , Glicósidos Iridoides , Iridoides/análisis , Iridoides/aislamiento & purificación , Paraguay , Fenoles/análisis , Fenoles/química , Fenoles/aislamiento & purificación , Inhibidores de Fosfodiesterasa 5/metabolismo , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/metabolismo , Espectrometría de Masas en Tándem
11.
Sci Justice ; 59(4): 433-441, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31256815

RESUMEN

Recently, adulterated supplements with phosphodiesterase-5 inhibitors (PDE-5i) have frequently observed. New synthetic analogues obtained from the chemical modification of parent compounds are frequently found in illicit products despite continuous efforts to inspect for these adulterants. A rapid and accurate method based on quadrupole-Orbitrap mass spectrometry was developed for simultaneously confirming and quantifying 85 PDE-5i and derived analogues present in illicit products for erectile dysfunction (ED). Common ions of PDE-5i according to their similar structures were proposed based on MS/MS fragmentations. These common ions could be an important diagnosis of their presence targets or new emerging analogues in supplements. Several validation parameters were employed, resulting in a limit of detection and quantification of 0.09-8.55 ng/mL and 0.24-17.10 ng/mL, respectively. The linear correlation coefficient (r2) was higher than 0.995, and mean recoveries of target compounds were in the range of 82-118%. A total of 187 illicit products, obtained from on/offline markets over a period of 3 years (2015-2017), were screened by the established method. Approximately 53% of them were adulterated with PDE-5i or derived analogues at concentrations of 0.1-726.0 mg/g in the illicit products. In the interests of public health, this study describes a rapid and accurate method to determine PDE-5i and new emerging analogues in adulterated products.


Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Medicamentos Falsificados , Espectrometría de Masas/métodos , Inhibidores de Fosfodiesterasa 5/química , Vasodilatadores/química , Suplementos Dietéticos , Contaminación de Medicamentos , Contaminación de Alimentos , Citrato de Sildenafil/análogos & derivados , Tadalafilo/análogos & derivados , Diclorhidrato de Vardenafil/análogos & derivados
12.
J Food Biochem ; 43(3): e12772, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-31353540

RESUMEN

Due to the exceptional wide range in biochemical activities of natural plant products, Spondias mombim L. are attaining a new height because they present great prospects for drug advancement. This research was designed to analyze the pharmaceutical properties of S. mombim L. ethyl acetate fraction (SMEAF) on key enzymes relevant to erectile and cognitive dysfunction. SMEAF inhibitory activities of the specified enzymes were determined spectrophotometrically. Chemical profile of SMEAF were assessed by HPLC/MS analysis. Thereafter, molecular docking of the studied enzymes with chlorogenic acid, lutein, and zeaxanthin were carried out using PATCHDOCK. SMEAF had remarkable enzyme inhibitory effects against phosphodiesterase-5 (PDE-5), arginase, angiotensin I-converting enzyme (ACE), cholinesterase, monoamine oxidase A (MAO), ecto-5' nucleotidase (E-NTDase), tyrosinase, and stimulated sodium-potassium ATPase (Na+/K+-ATPase) activities. HPLC/MS analysis revealed that phenolics and carotenoids were major components in these fraction notably, chlorogenic acid, lutein, and zeaxanthin. Our results suggested that SMEAF could be explored as phytopharmaceuticals. PRACTICAL APPLICATIONS: Spondias mombim L. are cooked as green vegetable with enormous medicinal value probably due to its polyphenols with potent antioxidant activity. Furthermore, the leaves could also be useful for therapeutic purposes against erectile dysfunction and central nervous system disorders.


Asunto(s)
Enfermedad de Alzheimer/enzimología , Anacardiaceae/química , Disfunción Eréctil/enzimología , Extractos Vegetales/química , Inhibidores de la Enzima Convertidora de Angiotensina/química , Animales , Arginasa/antagonistas & inhibidores , Arginasa/química , Inhibidores de la Colinesterasa/química , Colinesterasas/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/química , Inhibidores Enzimáticos/química , Humanos , Masculino , Simulación del Acoplamiento Molecular , Monoaminooxidasa/química , Inhibidores de la Monoaminooxidasa/química , Monofenol Monooxigenasa/antagonistas & inhibidores , Monofenol Monooxigenasa/química , Peptidil-Dipeptidasa A/química , Inhibidores de Fosfodiesterasa 5/química , Hojas de la Planta/química , Ratas , Ratas Wistar
13.
Forensic Sci Int ; 298: 10-19, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30870700

RESUMEN

The worldwide spread of illegal sexual enhancement products is posing a threat to public health. The aim of this study was to investigate illegal products claiming to be effective in improving sexual performance through the online or offline markets between 2014 and 2017; these products include foods, dietary supplements, counterfeit drugs, and herbal medicines. These samples were analysed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the presence of 80 PDE-5 inhibitors (PDE-5i) and analogues. The developed method was validated as follows: LODs and LOQs spiked in solid- and liquid-type negative samples (0.03-3.33 ng/mL and 0.08-10.00 ng/mL), linearities (R2 > 0.997), recoveries spiked negative samples (82.2-109.3 %), accuracies (81.6-118.9 %), precisions (≥ 6.5%, RSD) of intra-day and inter-day, and stability (≥10.0%, RSD). Out of 362 measured samples, 145 were adulterated samples mostly detected in food (51%). Sildenafil group (50%) was frequently observed, followed by tadalafil group (41%). Although sildenafil and tadalafil were mainly detected in adulterated samples, their analogues were also found. In particular, new analogues have appeared steadily on illicit erectile dysfunction (ED) products even after they were first discovered. The concentration of detected samples ranged from 0.1 to 826.0 mg/g, and sildenafil of them contained a considerable amount in illicit ED products in 2014, posing a potential toxicology risk of public health. The testing method is fast and reliable making it suitable for both routine screening and up-to-date quantitative analysis of PDE-5i and their analogues in suspicious foods, dietary supplements, and counterfeit drugs.


Asunto(s)
Comercio , Medicamentos Falsificados , Inhibidores de Fosfodiesterasa 5/análisis , Cromatografía Liquida , Suplementos Dietéticos , Formas de Dosificación , Contaminación de Alimentos/análisis , Humanos , Internet , Límite de Detección , Espectrometría de Masas , Inhibidores de Fosfodiesterasa 5/química , Fitoterapia
14.
Sci Rep ; 9(1): 4628, 2019 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-30874604

RESUMEN

We used Box-Behnken design-based (BBD) response surface methodology (RSM) in this research to optimize the extraction process of Traditional medicine Majun Mupakhi Ela (MME) and evaluate its effect on hydrocortisone-induced kidney yang deficiency. Three independent parameters were applied to evaluate the maximum phosphodiesterase type 5 (PDE5) inhibition activity of MME extracts in vitro. The optimal processing conditions (extraction time 2 h, solid-liquid ratio 1:16, extraction once) gave a maximum PDE5 inhibition rate of 84.10%, flavonoid content of 0.49 mg/ml, icariin content of 0.028 mg/ml and targeted extraction yield of 26.50%. In animal experiments, MME extracts significantly increased the adrenal mass index, semen weight index, preputial gland weight index, and penis weight index in mice; in the middle and high dose group, the level of serum testosterone increased by 7664.29% and 14207.14% respectively, compared with the model group, and the level of PDE5 decreased by 67.22% and 74.69% respectively compared with the control group. These results indicate that MME has a significant positive effect on the hypothalamus-pituitary-gonadal axis, improve mating ability and not only has inhibits PDE5 activity but also significantly inhibits the expression of PDE5 in penile tissues, potential to become erectile dysfunction (ED) therapies for the clinical management of patients with kidney yang deficiency.


Asunto(s)
Medicamentos Herbarios Chinos/farmacología , Medicina Tradicional China/métodos , Animales , China , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Medicamentos Herbarios Chinos/química , Disfunción Eréctil/fisiopatología , Hidrocortisona/metabolismo , Masculino , Ratones , Ratones Endogámicos ICR , Pene/metabolismo , Inhibidores de Fosfodiesterasa 5/química , Inhibidores de Fosfodiesterasa 5/aislamiento & purificación , Deficiencia Yang/metabolismo
15.
J Ethnopharmacol ; 229: 167-179, 2019 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-30339977

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Selected Peruvian Amazon plants are macerated into sugar cane distillates to prepare alcoholic beverages used to improve male sexual performance. The tree bark from Campsiandra angustifolia Spruce ex Benth (Fabaceae), Swartzia polyphylla DC (Fabaceae), Minquartia guianensis Aubl. (Olacaceae) and Thynantus panurensis (Bureau) Sandwith (Bignoniaceae) usually are used as crude drugs in mixtures of several ingredients. AIM OF STUDY: Describe the chemical composition of the most traded traditional male enhancer beverages, namely "Levántate Lazaro" and "Siete veces sin sacarla", and their single crude drug constituents, as well as their inhibitory activity towards the enzyme phosphodiesterase-5. The presence of pro-sexual drugs such as Sildenafil® and derivatives was assessed in the samples. MATERIALS AND METHODS: Single plant constituents and the preparation mixtures were purchased in the Mercado Belen (Iquitos, Peru). Chemical profiling was carried out by HPLC-DAD-ESI-MS/MS. The extracts were assessed for phosphodiesterase-5 inhibition. The occurrence of pro-sexual drugs was determined by HPLC-DAD-ESI-MS/MS. RESULTS: Chemical profiling allowed the identification of condensed tannins as the main constituents of C. angustifolia and S. polyphylla, hydrolysable tannins for M. guianensis, and C-glycosides for T. panurensis. The traditional preparations showed similar composition compared to the crude drugs. At 200 µg/mL, the traditional preparation "Levántate Lázaro" and "Siete veces sin sacarla" inhibited the phosphodiesterase-5 by 49.88% and 27.90%, respectively. No adulterations with pro-sexual drugs were found in the samples. From the crude drugs, low effect was found for the extracts of S. polyphylla and T. panurensis and high activity for C. angustifolia which inhibited the enzyme by 89.37% and 81.32% at 200 and 100 µg/mL, respectively. CONCLUSION: The traditional preparations used to improve sexual performance in the Peruvian Amazon showed activity as phosphodiesterase-5 inhibitors. The most active ingredient of the traditional preparations was C. angustifolia, with some contribution from T. panurensis. These results encourage additional studies, including animal models to confirm the male enhancer effect of the preparations.


Asunto(s)
Afrodisíacos/farmacología , Magnoliopsida , Inhibidores de Fosfodiesterasa 5/farmacología , Preparaciones de Plantas/farmacología , Afrodisíacos/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Etanol/farmacología , Humanos , Masculino , Perú , Inhibidores de Fosfodiesterasa 5/química , Fitoquímicos/análisis , Fitoquímicos/farmacología , Corteza de la Planta , Preparaciones de Plantas/química
16.
Rev Int Androl ; 16(4): 147-158, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30286869

RESUMEN

OBJECTIVE: Prismatomeris memecyloides Craib (Rubiaceae) is a medicinal plant traditionally used by ethnic minorities in Vietnam for the treatment of erectile dysfunction (ED). The aim of this study was to investigate the chemical compositions and screen in silico its possible inhibitory effect against PDE-5 which reduced cyclic guanosine-3',5'-monophosphate (cGMP) levels and indirectly caused the male ED. METHODS: Separation of natural compounds were carried out on chromatographic column with silica gel or reversed phase materials, eluting with different solvent gradients. The structures of all isolated compounds were elucidated on the basis of spectroscopic data (HR-MS, 1D/2D-NMR). Docking simulation study of compound (1-7) was performed by using flexible side chains protocol based on Iterated Local Search Global Optimizer Algorithm of AutoDock/Vina v.1.1.2. Pharmacokinetic parameters and toxicity prediction were also calculated by appropriate softwares. RESULTS: From the methanol extract of roots of P. memecyloides collected in Vietnam, seven compounds including four anthraquinone/one anthraquinone glycoside namely damnacanthal (1), lucidin-ω-methyl ether (2), 3-methylalizarin (3), rubiadin-3-methyl ether (4), and 1-O-methylrubiadin 3-O-primeveroside (5) along with two iridoid glucosides, asperulosidic acid (6) and aitchisonide A (7) were isolated. The molecular modeling results showed that 5 anthraquinone compounds possess the lowest binding energies to PDE-5. The anthraquinone glucoside 1-O-methylrubiadin 3-O-primeveroside (5) potentially inhibited PDE-5 similarly to commercial PDE-5Is sildenafil (SLD) and tadalafil (TLD). Calculated pharmacokinetic results like pIC50,pred; miLogP, TPSA, enzyme inhibitory of anthraquinone glucoside (5) were similar and even higher to those of the commercial PDE-5 inhibitors. Especially the predictive toxicity of 1-O-methylrubiadin 3-O-primeveroside (5) was even lower than those of SLD and TLD. CONCLUSION: This is the first study to find a scientific-based evidence for the ethnic use of P. memecyloides as medicinal plant for the treatment of ED. The result indicates that the anthraquinones (damnacanthal (1), lucidin-ω-methyl ether (2), 3-methylalizarin (3) and rubiadin-3-methyl ether (4)), especially anthraquinone glycoside (1-O-methylrubiadin 3-O-primeveroside (5)) are compounds of potential novel drug class for the ED treatment.


Asunto(s)
Antraquinonas/farmacología , Inhibidores de Fosfodiesterasa 5/farmacología , Extractos Vegetales/farmacología , Rubiaceae/química , Antraquinonas/química , Antraquinonas/aislamiento & purificación , Simulación por Computador , Espectroscopía de Resonancia Magnética/métodos , Medicina Tradicional de Asia Oriental , Simulación del Acoplamiento Molecular , Inhibidores de Fosfodiesterasa 5/química , Inhibidores de Fosfodiesterasa 5/aislamiento & purificación , Extractos Vegetales/química , Raíces de Plantas , Vietnam
17.
Food Addit Contam Part B Surveill ; 11(3): 214-222, 2018 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-29909756

RESUMEN

Chinese tonic liquor is an important dietary supplement in daily use, but it often happens that illicitly adulterated drugs in Chinese tonic liquor could lead to food safety issues. In this survey, an analytical method consisting of a liquid chromatography-quadrupole-time of flight mass spectrometer (LC-Q-TOF-MS), coupled with quick easy cheap effective rugged safe (QuEChERS) pretreatment, was established for identification of phosphodiesterase type 5 enzyme (PDE-5) inhibitors in Chinese tonic liquors. 86 PDE-5 inhibitors were qualitatively analysed by employing information dependent acquisition mass spectrometry (IDA-MS) in comparison with the accurate mass of the protonated molecular ion, isotopic pattern, library and chemical formula. This method was used to test 28 Chinese tonic liquor samples. The results revealed that the IDA-MS screening method is suitable for qualitative analysis of 86 PDE-5 inhibitors. Four samples were found to be adulterated with sildenafil, tadalafil, vardenafil, isopiperazinoafil, nortadalafil and desmethylsidenafil, which was 14.3% of the tested samples.


Asunto(s)
Bebidas Alcohólicas/análisis , Suplementos Dietéticos/análisis , Contaminación de Alimentos , Inhibidores de Fosfodiesterasa 5/análisis , Calibración , China , Cromatografía Líquida de Alta Presión , Cromatografía de Fase Inversa , Biología Computacional , Bases de Datos Farmacéuticas , Inspección de Alimentos , Humanos , Isomerismo , Límite de Detección , Estructura Molecular , Peso Molecular , Inhibidores de Fosfodiesterasa 5/química , Bibliotecas de Moléculas Pequeñas , Espectrometría de Masas en Tándem
18.
Planta Med ; 84(15): 1134-1140, 2018 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-29702722

RESUMEN

Phosphodiesterase 5 inhibitors have been used as a first-line medicine for the treatment of erectile dysfunction. In the search for new phosphodiesterase 5 inhibitors from natural sources, we found that the 95% ethanol extract of Derris scandens stem showed phosphodiesterase 5 inhibitory activity with an IC50 value of about 7 µg/mL. Seven isoflavones and a coumarin constituent isolated from this plant were investigated for phosphodiesterase 5 inhibitory activity. The results showed that osajin (8: ), 4',5,7-trihydroxybiprenylisoflavone (4: ), and derrisisoflavone A (2: ) had the ability to inhibit phosphodiesterase 5 with IC50 values of 4, 8, and 9 µM, respectively. These compounds exhibited selectivity on phosphodiesterase 5 over phosphodiesterase 1, however, the selectivity on phosphodiesterase 5 over phosphodiesterase 6 was low. In order to quantitatively determine these bioactive constituents in D. scandens extract, LC-QTOF-MS method has been developed and validated. The limit of quantitation values in the range of 0.1 - 5 µg/mL were obtained. The assay showed satisfactory precision and accuracy. The results from our method showed that the 95% ethanol extract of D. scandens stem was comprised of all eight compounds, with derrisisoflavone A (2: ) and lupalbigenin (3: ) presenting as the major constituents.


Asunto(s)
Derris/química , Isoflavonas/farmacología , Inhibidores de Fosfodiesterasa 5/farmacología , Extractos Vegetales/farmacología , Cromatografía Liquida , Cumarinas/química , Cumarinas/aislamiento & purificación , Cumarinas/farmacología , Isoflavonas/química , Isoflavonas/aislamiento & purificación , Espectrometría de Masas , Inhibidores de Fosfodiesterasa 5/química , Inhibidores de Fosfodiesterasa 5/aislamiento & purificación , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Tallos de la Planta/química
19.
ACS Chem Neurosci ; 9(2): 328-345, 2018 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-29068218

RESUMEN

Through drug discovery strategies of repurposing and redeveloping existing drugs, a series of novel tadalafil derivatives were rationally designed, synthesized, and evaluated to seek dual-target AChE/PDE5 inhibitors as good candidate drugs for Alzheimer's disease (AD). Among these derivatives, 1p and 1w exhibited excellent selective dual-target AChE/PDE5 inhibitory activities and improved blood-brain barrier (BBB) penetrability. Importantly, 1w·Cit (citrate of 1w) could reverse the cognitive dysfunction of scopolamine-induced AD mice and exhibited an excellent effect on enhancing cAMP response element-binding protein (CREB) phosphorylation in vivo, a crucial factor in memory formation and synaptic plasticity. Moreover, the molecular docking simulations of 1w with hAChE and hPDE5A confirmed that our design strategy was rational. In summary, our research provides a potential selective dual-target AChE/PDE5 inhibitor as a good candidate drug for the treatment of AD, and it could also be regarded as a small molecule probe to validate the novel AD therapeutic approach in vivo.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/farmacología , Inhibidores de Fosfodiesterasa 5/síntesis química , Inhibidores de Fosfodiesterasa 5/farmacología , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/enzimología , Animales , Barrera Hematoencefálica/metabolismo , Permeabilidad Capilar , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacocinética , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/enzimología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Aprendizaje por Laberinto/efectos de los fármacos , Ratones Endogámicos ICR , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de Fosfodiesterasa 5/química , Inhibidores de Fosfodiesterasa 5/farmacocinética , Fosforilación/efectos de los fármacos , Distribución Aleatoria , Ratas , Escopolamina
20.
Artículo en Inglés | MEDLINE | ID: mdl-28580889

RESUMEN

Adulteration of herbal health supplements with phosphodiesterase-5 (PDE-5) inhibitors and their analogues is becoming a worldwide problem. The aim of this study was to investigate herbal and food products sold in the Malaysian market for the presence of these adulterants. Sixty-two products that claim to enhance men's sexual health were sampled between April 2014 and April 2016. These products included unregistered products seized by the Pharmacy Enforcement Division of the Ministry of Health (n = 39), products sent to the National Pharmaceutical Regulatory Agency for pre-registration testing (n = 9) and products investigated under the post-registration market surveillance programme (n = 14). The products were tested against an in-house spectral library consisting of 61 PDE-5 inhibitors and analogues using a validated liquid chromatography-mass spectrometry ion-trap-time-of-flight (LC-MS IT-TOF) method. Thirty-two (82%) of the unregistered products and two (14%) of the registered products were found to be adulterated with at least one PDE-5 inhibitor or analogue, while none of the pre-registration products contained adulterants. A total of 16 different adulterants were detected and 36% of the adulterated products contained a mixture of two or more adulterants. This study has demonstrated that the adulteration of unregistered herbal products in the Malaysian market is an alarming issue that needs to be urgently addressed by the relevant authorities.


Asunto(s)
Contaminación de Medicamentos , Contaminación de Alimentos/análisis , Inhibidores de Fosfodiesterasa 5/análisis , Inhibidores de Fosfodiesterasa 5/química , Humanos , Malasia
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