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1.
Nanoscale ; 16(38): 18014-18026, 2024 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-39252581

RESUMEN

In this study a cutting-edge approach to producing accurate and computationally efficient interatomic potentials using machine learning algorithms is presented. Specifically, the study focuses on the application of Allegro, a novel machine learning algorithm, running on high-performance GPUs for training potentials. The choice of training parameters plays a pivotal role in the quality of the potential functions. To enable this methodology, the "Solvated Protein Fragments" dataset, containing nearly 2.7 million Density Functional Theory (DFT) calculations for many-body intermolecular interactions involving protein fragments and water molecules, encompassing H, C, N, O, and S elements, is considered as the training dataset. The project optimizes computational efficiency by reducing the initial dataset size according to the intended application. To assess the efficacy of the approach, the sildenafil citrate, iso-sildenafil, aspirin, ibuprofen, mebendazole and urea, representing all five relevant elements, serve as the test bed. The results of the Allegro-trained potentials demonstrate outstanding performance, benefiting from the combination of an appropriate training dataset and parameter selection. This notably enhanced computational efficiency when compared to the computationally intensive DFT method aided by GPU acceleration. Validation of the produced interatomic potentials is achieved through Allegro's own evaluation mechanism, yielding exceptional accuracy. Further verification is carried out through LAMMPS molecular dynamics simulations. Structural optimization by energy minimization and NPT Molecular Dynamics simulations are performed for each potential, assessing relaxation processes and energy reduction. Additional structures, including urea, ammonia, uracil, oxalic acid, and acetic acid, are tested, highlighting the potential's versatility in describing systems containing the aforementioned elements. Visualization of the results confirms the scientific accuracy of each structure's relaxation. The findings of this study demonstrate strong scaling and the potential for applications in pharmaceutical research, allowing the exploration of larger molecular structures not previously amenable to computational analysis at this level of accuracy The success of the machine learning approach underscores its potential to revolutionize computational solid-state physics.


Asunto(s)
Aprendizaje Automático , Simulación de Dinámica Molecular , Citrato de Sildenafil , Citrato de Sildenafil/química , Algoritmos , Ibuprofeno/química , Aspirina/química , Teoría Funcional de la Densidad , Urea/química , Agua/química
2.
Bioanalysis ; 16(16): 883-894, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39115045

RESUMEN

Aim: The aim was to evaluate drug-plasma binding (DPB).by employing Hollow Fiber-in-Syringe Equilibrium Sampling Through Supported Liquid Membrane (HFiS ESTSLM) and RP-HPLC analysis.Materials & Methods: HFiS ESTSLM and RP-HPLC were used to evaluate DPB of three weak basic drugs (Metoprolol, Diphenhydramine, and Sildenafil) with differing hydrophilicity and binding ability to blood plasma.Results: The results exhibited an increasing drug-dependent magnitude of DPB for the three model drugs. This trend of DPB confirmed that HFiS ESTSLM has the required sensitivity for determining DPB of the drugs. The DPB was drug concentration-dependent within the tested drug concentration range, especially at high concentration.Conclusion: HFiS ESTSLM and RP-HPLC offered a simple, easy and cost-effective procedure to evaluate DPB of these basic drugs.


[Box: see text].


Asunto(s)
Unión Proteica , Cromatografía Líquida de Alta Presión/métodos , Preparaciones Farmacéuticas/sangre , Preparaciones Farmacéuticas/metabolismo , Preparaciones Farmacéuticas/química , Humanos , Citrato de Sildenafil/sangre , Citrato de Sildenafil/química , Citrato de Sildenafil/análisis , Difenhidramina/sangre , Difenhidramina/química , Membranas Artificiales
3.
Int J Pharm ; 661: 124312, 2024 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-38876441

RESUMEN

HYPOTHESIS: Sildenafil base and bosentan monohydrate are co-administered in a chronic therapy of pulmonary arterial hypertension (PAH). Both drugs are poorly soluble in water, and their bioavailability is limited to ca. 50 %. Since bosentan is a weak acid, whereas sildenafil is a weak base, we assumed that their co-amorphization could: (i) improve their solubility in the gastrointestinal fluids, (ii) enable to reach supersaturation and (iii) ensure stabilization of supersaturated solutions. If successful, this could accelerate the development of new fixed-dose combination drugs. EXPERIMENTS: The co-amorphous formulations were prepared using high energy ball milling. Their solid state properties were assessed using XRD, DSC, FT-MIR, and dielectric spectroscopy. Particle size distribution and surface wetting were also analyzed. Polarizing optical microscopy and scanning electron microscopy were applied to assess the microstructure of these powders. A new HPLC-DAD method was developed for a simultaneous quantification of both drugs. FINDINGS: It was shown that binary formulations in which bosentan was molecularly dispersed in sildenafil base (Tg = 64-78 °C) could be manufactured in the high energy ball milling process. When the sildenafil load was below 50 wt. %, the formulations showed the greatest thermal stability and formed long-lasting bosentan supersaturation in PBS.


Asunto(s)
Bosentán , Composición de Medicamentos , Citrato de Sildenafil , Solubilidad , Sulfonamidas , Bosentán/química , Bosentán/administración & dosificación , Citrato de Sildenafil/química , Citrato de Sildenafil/administración & dosificación , Sulfonamidas/química , Sulfonamidas/administración & dosificación , Composición de Medicamentos/métodos , Tamaño de la Partícula , Química Farmacéutica/métodos , Antihipertensivos/química , Antihipertensivos/administración & dosificación , Estabilidad de Medicamentos , Combinación de Medicamentos
4.
Int J Biol Macromol ; 269(Pt 2): 131859, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38728875

RESUMEN

Double-layer dermal substitutes (DS) generally provide more effective therapeutic outcomes than single-layer substitutes. The architectural design of DS incorporates an outer layer to protect against bacterial invasions and maintain wound hydration, thereby reducing the risk of infection and the frequency of dressing changes. Moreover, the outer layer is a mechanical support for the wound, preventing undue tension in the affected area. A 3D-printed polycaprolactone (PCL) membrane was utilized as the outer layer to fabricate DS wound dressing. Simultaneously, a polyvinyl alcohol/chitosan/sildenafil citrate (PVA/CS/SC) scaffold was electrospun onto the PCL membrane to facilitate cellular adhesion and proliferation. Scanning electron microscopy (SEM) analysis of the PCL filaments revealed a consistent cross-sectional surface and structure, with an average diameter of 562.72 ±â€¯29.15 µm. SEM results also demonstrated uniform morphology and beadless structure for the PVA/CS/SC scaffold, with an average fiber diameter of 366.77 ±â€¯1.81 nm for PVA/CS. The addition of SC led to an increase in fiber diameter while resulting in a reduction in tensile strength. However, drug release analysis indicated that the SC release from the sample can last up to 72 h. Animal experimentation confirmed that DS wound dressing positively accelerated wound closure and collagen deposition in the Wistar rat skin wound model.


Asunto(s)
Vendajes , Quitosano , Poliésteres , Alcohol Polivinílico , Impresión Tridimensional , Citrato de Sildenafil , Cicatrización de Heridas , Quitosano/química , Quitosano/farmacología , Alcohol Polivinílico/química , Animales , Poliésteres/química , Cicatrización de Heridas/efectos de los fármacos , Ratas , Citrato de Sildenafil/farmacología , Citrato de Sildenafil/química , Membranas Artificiales , Masculino , Andamios del Tejido/química , Liberación de Fármacos , Resistencia a la Tracción
5.
Eur J Pharm Sci ; 198: 106788, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38705421

RESUMEN

Physiologically based pharmacokinetic (PBPK) models can help to understand the effects of gastric emptying on pharmacokinetics and in particular also provide a platform for understanding mechanisms of food effects, as well as extrapolation between different postprandial conditions, whether standardized clinical or patient-oriented, non-clinical conditions. By integrating biorelevant dissolution data from the GastroDuo dissolution model into a previously described mechanistic model of fed-state gastric emptying, we simulated the effects of a high-calorie high-fat meal on the pharmacokinetics of sildenafil, febuxostat, acetylsalicylic acid, theobromine and caffeine. The model was able to simulate the variability in Cmax and tmax caused by the presence of the stomach road. The main influences investigated to affect the gastric emptying process were drug solubility (theobromine and caffeine), tablet dissolution rate (acetylsalicylic acid) and sensitivity to gastric motility (sildenafil and febuxostat). Finally, we showed how PBPK models can be used to extrapolate pharmacokinetics between different prandial states using theobromine as an example with results from a clinical study being presented.


Asunto(s)
Simulación por Computador , Vaciamiento Gástrico , Modelos Biológicos , Periodo Posprandial , Solubilidad , Vaciamiento Gástrico/fisiología , Periodo Posprandial/fisiología , Humanos , Febuxostat/farmacocinética , Febuxostat/química , Teobromina/farmacocinética , Teobromina/química , Cafeína/farmacocinética , Cafeína/química , Cafeína/administración & dosificación , Citrato de Sildenafil/farmacocinética , Citrato de Sildenafil/química , Liberación de Fármacos , Aspirina/farmacocinética , Aspirina/química , Aspirina/administración & dosificación
6.
Bioanalysis ; 16(9): 369-384, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38497721

RESUMEN

This study was conducted to compare dissolution profiles of four Jordanian registered sildenafil (SDF) products to the originator. Dissolution samples were analyzed utilizing a validated and stability-indicating HPLC method in human plasma. Validation was performed for specificity, linearity, limit of detection, lower limit of quantification, precision, trueness and stability. SDF was extracted from plasma samples using liquid-liquid extraction. The analysis was performed utilizing isocratic elution on C18 column with 1.0 ml/min flow rate. The regression value was ∼0.999 over 3 days with drug recovery between 86.6 to 89.8%with 10 ng/ml lower limit of quantitation. This method displayed a good selectivity of SDF with improved stability under various conditions. The method was used for SDF quantification in dissolution medium. Similarity factors for local products varied according to the used mediums, but all SDF local products passed the dissolution in vitro test since all of them showed a released of >85% after 60 min at the dissolution mediums.


[Box: see text].


Asunto(s)
Citrato de Sildenafil , Citrato de Sildenafil/sangre , Citrato de Sildenafil/química , Citrato de Sildenafil/análisis , Cromatografía Líquida de Alta Presión/métodos , Humanos , Medicamentos Genéricos/química , Medicamentos Genéricos/análisis , Solubilidad , Jordania , Estabilidad de Medicamentos , Límite de Detección
7.
Molecules ; 28(6)2023 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-36985604

RESUMEN

Twelve drugs containing sildenafil compounds (sildenafil citrate and sildenafil base) were examined using X-ray studies and thermal analysis. According to the manufacturer's information, the presence of sildenafil was confirmed in all investigated drugs. The positions of diffraction lines (value of 2θ angle) agree with the patterns presented in the ICDD database, Release 2018 (ICDD-International Centre of Diffraction Data). The difference expresses the agreement in the position of the diffraction line between the tested substance and the standard. A good agreement is when this difference is less than 0.2°. The values of interplanar distances dhkl are also compatible with the ICDD database. It indicated that the drug examined was genuine. Because all drugs are mixtures of different substances (API and excipients), the various diffraction line intensities were detected in all observed X-ray images for the tested drugs. The intensity of the diffraction line depends on many factors, like the amount of substance, coexisting phases, and mass absorption coefficient of the mixture. The thermal analysis confirmed the results obtained by the X-ray study. On DSC curves, the endothermic peaks for sildenafil compounds were observed. The determined melting points of sildenafil compounds corresponded to the values available in the literature. The results gathered by connecting two methods, X-ray study and thermal analysis, can help identify irregularities that may exist in pharmaceutical specimens, e.g., distinguishing genuine from counterfeit products, the presence of a correct polymorph, a lack of active substance, an inaccurate amount of the active substance, or excipients in the tested drug.


Asunto(s)
Excipientes , Citrato de Sildenafil/química , Rayos X , Excipientes/química , Radiografía , Difracción de Rayos X
8.
J Pharm Biomed Anal ; 214: 114720, 2022 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-35286987

RESUMEN

Herbal medicines are commonly used in many countries all around the world. In Western countries they are now gaining more and more popularity, whereas in countries like China and India they have been entrenched for millenniums. Some of these perceived herbal medicines claim to help when suffering from erectile dysfunction. Nevertheless, many of these products are adulterated with PDE5 inhibitors like sildenafil or α-blockers. Patients who suffer from high blood pressure sometimes resort to herbal products, as they are not allowed to take sildenafil because of negative drug-drug interactions with nitrates (often utilized as treatment for coronary diseases). Products which are then adulterated with PDE5 inhibitors, can seriously harm patients. Therefore, this study reports the instant screening of alleged herbal products by employing atmospheric pressure solids analysis probe and high-resolution mass spectrometry to determine adulterants. Three out of 12 investigated products contained sildenafil in ranges from 0.5% to 18%. Multivariate analysis of ambient mass spectrometry measurements revealed encouraging outcomes for distinguishing non-sildenafil and sildenafil adulterated samples. Atmospheric pressure solids analysis probe is therefore a promising method for the rapid determination of sildenafil in herbal products with possible downstream semiquantitative analysis.


Asunto(s)
Contaminación de Medicamentos , Inhibidores de Fosfodiesterasa 5 , Presión Atmosférica , Contaminación de Medicamentos/prevención & control , Humanos , Masculino , Espectrometría de Masas/métodos , Medicamentos sin Prescripción , Inhibidores de Fosfodiesterasa 5/análisis , Citrato de Sildenafil/química
9.
Arch Pharm (Weinheim) ; 354(10): e2100145, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34131943

RESUMEN

A series of novel pyrazolo[3,4-d]pyrimidin-4-one derivatives were synthesized and evaluated for their anti-phosphodiesterase-5 (PDE-5) activity. A total of 28 compounds, containing alkyl and aryl groups at the 1-N and 3-C positions on the pyrazole ring, and also bearing different alkyl substituents on the piperazine ring were synthesized. Four compounds (4d, 5d, 6d, and 5o) were found to have better inhibitory activity against PDE-5 (IC50 < 10 nM). All four of the most active compounds contain a phenyl ring at the N1 position. Compounds containing a 3,5-dimethylpiperazinyl group show better activity than others. These results suggest that compound 5o can be used as a lead structure for developing new inhibitors of PDE-5.


Asunto(s)
Inhibidores de Fosfodiesterasa 5/farmacología , Pirazoles/farmacología , Pirimidinas/farmacología , Citrato de Sildenafil/farmacología , Concentración 50 Inhibidora , Inhibidores de Fosfodiesterasa 5/síntesis química , Inhibidores de Fosfodiesterasa 5/química , Pirazoles/síntesis química , Pirazoles/química , Pirimidinas/síntesis química , Pirimidinas/química , Citrato de Sildenafil/química , Relación Estructura-Actividad
10.
Biol Pharm Bull ; 44(5): 691-700, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33952825

RESUMEN

There are many reports of falsified medicines that may cause harm to patients. A rapid and simple method of identifying falsified medicines that could be used in the field is required. Although Raman scattering spectroscopy has become popular as a non-destructive analysis, few validation experiments on falsified medicines that are actually distributed on the market have been conducted. In this study, we validated a discriminant analysis using an ultra-compact, portable, and low-cost Raman scattering spectrometer combined with multivariate analysis. The medicines were three types of erectile dysfunction therapeutic tablet and one type of antifungal tablet: tadalafil (Cialis), vardenafil hydrochloride (Levitra), sildenafil citrate (Viagra), and fluconazole (Diflucan), which is sometimes advertised as female Viagra. For each medicine, the authentic standard product and products obtained by personal import via the internet (genuine or falsified) were used. Discriminant analyses were performed on the Raman spectra combined with soft independent modeling of class analogy (SIMCA) and partial least squares discriminant analysis (PLS-DA). It was possible to identify all falsified samples by SIMCA using the standard product model for all four products. Using the PLS-DA using the PLS models of the four standard products, falsified Levitra and Diflucan samples were classified correctly, although some falsified Cialis and all Viagra samples also belonged to the standard class. In this study, SIMCA might be more suitable than PLS-DA for identifying falsified medicines. A spectroscopic module that combines the low-cost Raman scattering spectroscopy with SIMCA might contribute to the rapid identification of falsified medicines in the field.


Asunto(s)
Medicamentos Falsificados/análisis , Modelos Químicos , Espectrometría Raman , Medicamentos Falsificados/química , Fluconazol/análisis , Fluconazol/química , Análisis de los Mínimos Cuadrados , Citrato de Sildenafil/análisis , Citrato de Sildenafil/química , Comprimidos , Tadalafilo , Diclorhidrato de Vardenafil/análisis , Diclorhidrato de Vardenafil/química
11.
Artículo en Inglés | MEDLINE | ID: mdl-33938398

RESUMEN

Phosphodiesterase type 5 (PDE-5) inhibitors are commonly used to treat erectile dysfunction. There is a problem with synthesis and illegal use of a wide range of analogues of the licenced drugs and a simple class-wide analytical method is required. In this work, based on structural modelling, we developed an immunological method using norneovardenafil as a hapten as it contains only the general sub-structure and the common features of sildenafil-like adulterants, such as hydrophobic centres, hydrogen-bond donor atoms and hydrogen-bond acceptor atoms. Thus theoretically it could induce production of antibody which could recognise multiple sildenafil-like adulterants. By immunising rabbits, a group-specific polyclonal antibody was obtained with the desired broad-spectrum molecular recognition performance against sildenafil-like adulterants. Then, an indirect competitive enzyme-linked immunosorbent assay (icELISA) was developed for the detection of sildenafil-like adulterants in herbal spirit drinks. Under the optimised conditions, the icELISA method showed broad linear ranges for acetildenafil, sildenafil and vardenafil respectively of 0.7 to 27.7 µg/kg, 1.0 to 70.7 µg/kg and 1.5 to 22.7 µg/kg, with half-maximal inhibition concentration (IC50) values of 4.5 µg/kg, 8.3 µg/kg and 5.7 µg/kg, respectively. For eleven herbal spirit drinks, there was good agreement between total levels of sildenafil-like adulterants measured by icELISA and levels of each of four individual adulterants determined by LC-MS/MS. In short, the developed icELISA can be employed for rapid and simple screening for adulteration of herbal spirit drinks with sildenafil-like compounds.


Asunto(s)
Anticuerpos/química , Bebidas Endulzadas Artificialmente/análisis , Suplementos Dietéticos/análisis , Aditivos Alimentarios/análisis , Contaminación de Alimentos/análisis , Citrato de Sildenafil/química , Animales , Técnicas Biosensibles , Cromatografía Líquida de Alta Presión , Contaminación de Medicamentos , Ensayo de Inmunoadsorción Enzimática , Haptenos/química , Humanos , Límite de Detección , Modelos Moleculares , Conejos , Espectrometría de Masas en Tándem
12.
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
13.
Sci Rep ; 11(1): 4336, 2021 02 22.
Artículo en Inglés | MEDLINE | ID: mdl-33619326

RESUMEN

Pulmonary arterial hypertension (PAH) is an incurable disease, although symptoms are treated with a range of dilator drugs. Despite their clinical benefits, these drugs are limited by systemic side-effects. It is, therefore, increasingly recognised that using controlled drug-release nanoformulation, with future modifications for targeted drug delivery, may overcome these limitations. This study presents the first evaluation of a promising nanoformulation (highly porous iron-based metal-organic framework (MOF); nanoMIL-89) as a carrier for the PAH-drug sildenafil, which we have previously shown to be relatively non-toxic in vitro and well-tolerated in vivo. In this study, nanoMIL-89 was prepared and charged with a payload of sildenafil (generating Sil@nanoMIL-89). Sildenafil release was measured by Enzyme-Linked Immunosorbent Assay (ELISA), and its effect on cell viability and dilator function in mouse aorta were assessed. Results showed that Sil@nanoMIL-89 released sildenafil over 6 h, followed by a more sustained release over 72 h. Sil@nanoMIL-89 showed no significant toxicity in human blood outgrowth endothelial cells for concentrations up to100µg/ml; however, it reduced the viability of the human pulmonary artery smooth muscle cells (HPASMCs) at concentrations > 3 µg/ml without inducing cellular cytotoxicity. Finally, Sil@nanoMIL-89 induced vasodilation of mouse aorta after a lag phase of 2-4 h. To our knowledge, this study represents the first demonstration of a novel nanoformulation displaying delayed drug release corresponding to vasodilator activity. Further pharmacological assessment of our nanoformulation, including in PAH models, is required and constitutes the subject of ongoing investigations.


Asunto(s)
Estructuras Metalorgánicas , Inhibidores de Fosfodiesterasa 5/administración & dosificación , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Citrato de Sildenafil/administración & dosificación , Nanomedicina Teranóstica , Animales , Aorta/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Liberación de Fármacos , Humanos , Cinética , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/ultraestructura , Ratones , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Inhibidores de Fosfodiesterasa 5/química , Inhibidores de Fosfodiesterasa 5/farmacocinética , Hipertensión Arterial Pulmonar/etiología , Citrato de Sildenafil/química , Citrato de Sildenafil/farmacocinética , Análisis Espectral , Vasodilatadores/administración & dosificación , Vasodilatadores/química , Vasodilatadores/farmacocinética
14.
J Chromatogr Sci ; 59(1): 30-39, 2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-33107906

RESUMEN

One of the highest incidences of illegal drug products is related to phosphodiesterase-5 inhibitors, used in treatment of erectile dysfunction, including those containing sildenafil citrate and tadalafil. In this context, comprehensive evaluation of the quality of genuine and illegal medicines was performed. A simple and rapid ultra-high performance liquid chromatography (UHPLC-UV) method to quantify sildenafil and tadalafil in the presence of six degradation products was developed and validated. Sildenafil and tadalafil were submitted to forced degradation. The separation was carried out on a Kinetex C18 (50 × 2.1 mm; 1.7 µm) column with mobile phase composed of acetonitrile and aqueous triethylamine solution. The calibration curves were linear in the range of 14-126 µg mL-1 for sildenafil citrate and 4-36 µg mL-1 for tadalafil and the method proved to be selective, precise, accurate and robust. Sildenafil degraded in oxidative media, whereas tadalafil degraded in acidic, alkaline and oxidative environment. The chemical structures and the mechanisms for the formation of the main degradation products were proposed by UHPLC coupled to tandem mass spectrometry. The UHPLC-UV method was applied in the pharmaceutical analysis of genuine and seized medicines. Some of them did not meet quality standards, mainly due to contents below specifications and the large variation on contents between units within a batch.


Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Drogas Ilícitas , Citrato de Sildenafil , Tadalafilo , Medicamentos Falsificados , Drogas Ilícitas/análisis , Drogas Ilícitas/química , Límite de Detección , Modelos Lineales , Reproducibilidad de los Resultados , Citrato de Sildenafil/análisis , Citrato de Sildenafil/química , Citrato de Sildenafil/normas , Tadalafilo/análisis , Tadalafilo/química , Tadalafilo/normas , Espectrometría de Masas en Tándem
15.
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
16.
AAPS PharmSciTech ; 21(8): 310, 2020 Nov 08.
Artículo en Inglés | MEDLINE | ID: mdl-33164131

RESUMEN

Palmar plantar erythrodysesthesia (PPE) is a commonly reported skin toxicity of chemotherapeutic agents that significantly affects patients' quality of life. PPE is described as inflammation, swelling, and even cracks and ulcers in the skin of palms and soles of the feet. Conventional treatment includes topical creams, analgesics, or corticosteroids. However, serious cases are not responding to these medications. PPE has been reported to cause drug cessation or dose reduction if not properly treated. Sildenafil citrate (SC) has a well-documented activity in wound healing through improving blood supply to the affected area. However, SC has poor physicochemical properties limiting its transdermal permeation and deposition. This research endeavored to elaborate novel vesicular system with natural components, phospholipids and oleic acid, loaded with sildenafil citrate for topical management of PPE. Sildenafil-loaded oleosomes were prepared using modified ethanol injection method. Optimized oleosomes had nanometric particle size (157.6 nm), negative zeta potential (- 85.2 mv), and high entrapment efficiency (95.56%). Ex vivo studies on human skin revealed that oleosomes displayed 2.3-folds higher permeation and 4.5-folds more deposition through the human skin compared to drug suspension. Results endorsed SC oleosomes as suitable topical treatment of PPE providing ameliorated sildenafil permeability in addition to acting as a reservoir for gradual release of the drug. Graphical abstract.


Asunto(s)
Antineoplásicos/efectos adversos , Gotas Lipídicas , Parestesia/tratamiento farmacológico , Citrato de Sildenafil/química , Enfermedades de la Piel/tratamiento farmacológico , Administración Tópica , Humanos , Parestesia/inducido químicamente , Parestesia/complicaciones , Tamaño de la Partícula , Calidad de Vida , Citrato de Sildenafil/administración & dosificación , Citrato de Sildenafil/uso terapéutico , Enfermedades de la Piel/inducido químicamente , Enfermedades de la Piel/complicaciones
17.
AAPS PharmSciTech ; 21(6): 221, 2020 Aug 03.
Artículo en Inglés | MEDLINE | ID: mdl-32748291

RESUMEN

Sildenafil citrate causes vasodilatation, relaxation of the smooth muscle, and reduction of pulmonary arterial pressure. The latter property makes sildenafil citrate efficient for the treatment of cardiovascular diseases, including pulmonary arterial hypertension. Pediatric patients with pulmonary arterial hypertension are more susceptible to errors in drug administration than adults because of a lack of suitable drug dosages. Thus, the purpose of this study was to develop stable (chemically and microbiologically) sildenafil citrate drop liquid formulation, suitable for pediatric patients (including diabetics), ensuring safety during preparation and storing and improving palatability by using milk as a carrier for administration. The significant factors that affect the sildenafil solubility were evaluated by applying a Plackett-Burman design using two levels with six variables. The experiment showed that the type of buffer and glycerin content influenced the sildenafil solubility. The developed formulations proved to be stable for 6 months at all three assayed conditions (40± 2°C, 75 ± 5% RH; 25± 2°C, 60 ± 5% RH; and 4 ± 2°C). The microbiological tests fit with the requirement of the pharmacopeia at day 0 and 90 and even more at day 180. Finally, the palatability assay showed that 0.82 mL of the formulation containing buffer phosphate, 20% glycerin, and 4 mg mL-1 of sildenafil citrate diluted in 4.8 mL milk (which fits the medium pediatric dose) presented similar palatability to milk alone, and no precipitate or turbidity was observed. Graphical abstract.


Asunto(s)
Hipertensión Pulmonar/tratamiento farmacológico , Citrato de Sildenafil/química , Adulto , Niño , Composición de Medicamentos , Estabilidad de Medicamentos , Humanos , Persona de Mediana Edad , Citrato de Sildenafil/uso terapéutico , Solubilidad , Soluciones
18.
Artículo en Inglés | MEDLINE | ID: mdl-32251992

RESUMEN

In this paper, an ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF HRMS) method was developed and validated for screening, confirmation and quantitation of 31 anti-impotence compounds potentially illegally added to herbal-based dietary supplements. The analytes were well separated by the mobile phase consisted of 0.1% formic acid solution and acetonitrile with gradient elution at a flow rate of 0.3 mL/min. The MS analysis was operated in positive mode and the mass error of the 31 compounds were below 2.9 ppm. The method validation showed good linearity with coefficients of determination (r2) higher than 0.9973 for all analytes. LODs and LLOQs ranged from 0.005 to 0.50 µg/g or µg /mL and from 0.02 to 1.24 µg /g or µg/mL, respectively. The accuracy was in the range of 86.6% to 113.7%, while the intra-and inter-day precision were in the ranges of 0.9-7.6% and 0.9-11.4%, respectively. The absolute and relative matrix effect were in the range of 65.8-115.6% and 0.6-13.3%. The mean recoveries were in the range of 80.5-116.9%. The stability ranged from 0.4% to 8.5%. Among 200 batches of herbal-based dietary supplements, sildenafil and/or tadalafil were found to be added illegally in two samples, while not very high concentration of icariin was detected in one sample. The Q-TOF mass spectrometry has been proved to be a very powerful and efficient tool for rapid screening of 31 anti-impotence compounds potentially illegally added to herbal-based dietary supplements, ensuring food safety and public health.


Asunto(s)
Suplementos Dietéticos/análisis , Medicamentos Herbarios Chinos/química , Disfunción Eréctil/inducido químicamente , Disfunción Eréctil/tratamiento farmacológico , Cromatografía Líquida de Alta Presión , Suplementos Dietéticos/efectos adversos , Contaminación de Medicamentos , Medicamentos Herbarios Chinos/metabolismo , Inocuidad de los Alimentos , Humanos , Límite de Detección , Masculino , Estructura Molecular , Citrato de Sildenafil/química , Tadalafilo/química , Espectrometría de Masas en Tándem
19.
Biomater Sci ; 8(11): 3052-3062, 2020 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-32347852

RESUMEN

Inefficient nanoparticle accumulation in solid tumors hinders the clinical translation of cancer nanomedicines. Herein, we proposed that sildenafil, a vasodilator ampholyte, could be used to promote nanoparticle accumulation by inducing vasodilation after its tumor acidity-triggered release from the nanocarriers. To confirm this, sildenafil was first encapsulated in a cisplatin-incorporated polymeric micelle. The dense PEG shell of the micelle reduced its endocytosis by cancer cells, which in return resulted in accumulative extracellular release of protonated sildenafil in the acidic tumor microenvironment. The released sildenafil was found to be more effective in enlarging the tumor blood vessels than could be achieved without sildenafil. As a result, we demonstrated considerable improvement in the intratumoral accumulation of the sildenafil-cisplatin co-loaded nanoparticle and its enhanced cancer therapeutic efficacy over the control group. Given the generality of a dense PEG shell and a hydrophobic part in most clinically developed nanomedicines, this work implies the great potential of sildenafil as a simple and universal adjuvant to selectively promote the intratumoral accumulation of nanomedicines, thus improving their clinical translation.


Asunto(s)
Antineoplásicos/administración & dosificación , Cisplatino/administración & dosificación , Melanoma Experimental/metabolismo , Nanopartículas/administración & dosificación , Citrato de Sildenafil/administración & dosificación , Vasodilatadores/administración & dosificación , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Transporte Biológico , Vasos Sanguíneos/fisiología , Línea Celular Tumoral , Cisplatino/química , Cisplatino/farmacocinética , Liberación de Fármacos , Femenino , Concentración de Iones de Hidrógeno , Melanoma Experimental/irrigación sanguínea , Melanoma Experimental/química , Melanoma Experimental/tratamiento farmacológico , Ratones Endogámicos C57BL , Micelas , Nanopartículas/química , Polietilenglicoles/administración & dosificación , Polietilenglicoles/química , Polietilenglicoles/farmacocinética , Ácido Poliglutámico/administración & dosificación , Ácido Poliglutámico/análogos & derivados , Ácido Poliglutámico/química , Ácido Poliglutámico/farmacocinética , Ratas Sprague-Dawley , Citrato de Sildenafil/química , Citrato de Sildenafil/farmacocinética , Distribución Tisular , Vasodilatación , Vasodilatadores/química , Vasodilatadores/farmacocinética
20.
Cell Signal ; 65: 109425, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31689507

RESUMEN

Sildenafil, a phosphodiesterase-5 inhibitor is FDA approved drug against erectile dysfunction. It is currently undergoing many clinical trials, alone or in combinations against different diseases. Treatment of neural progenitor cells with sildenafil is known to regulate their basal cGMP levels and enhance neurogenesis and differentiation. cGMP as well as cAMP are known to play a central role in the maintenance, repair and remodelling of the nervous system. In the present study, we report the neurodifferentiation property of sildenafil in neuroblastoma cancer cell line IMR-32. Sildenafil was found to induce the formation of neurite outgrowths that were found expressing neuronal markers, such as NeuN, NF-H and ßIII tubulin. IS00384, a recently discovered PDE5 inhibitor by our laboratory, was also found to induce neurodifferentiation of IMR-32 cells. The effect of IS00384 on differentiation was even more profound than sildenafil. Both the compounds were found to elevate and activate the Guanine nucleotide exchange factor C3G, which is a regulator of differentiation in IMR-32 cells. They were also found to elevate the levels of cGMP and activate the AMPK-ACC and PI3K-Akt signalling pathways. These pathways are known to play important role in cytoskeletal rearrangements necessary for differentiation. This study highlights the role of phosphodiesterases-5 in neurodifferentiation and use of sildenafil and IS00384 as small molecule tools to study the process of cellular differentiation.


Asunto(s)
Neuroblastoma/metabolismo , Neurogénesis/efectos de los fármacos , Inhibidores de Fosfodiesterasa 5/farmacología , Citrato de Sildenafil/farmacología , Quinasas de la Proteína-Quinasa Activada por el AMP , Antígenos Nucleares/metabolismo , Línea Celular Tumoral , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Factor 2 Liberador de Guanina Nucleótido/metabolismo , Humanos , Proteínas del Tejido Nervioso/metabolismo , Neuroblastoma/enzimología , Proteínas de Neurofilamentos/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Citrato de Sildenafil/química , Tubulina (Proteína)/metabolismo
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