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1.
Medicine (Baltimore) ; 99(3): e18712, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32011446

RESUMO

BACKGROUND: Drug therapy for lower urinary tract symptoms (LUTS) secondary to benign prostate hyperplasia (BPH) is a major and popular method. However, the therapeutic strategy is still not clear enough up to now. The purpose of this study was to compare the relative safety and efficacy of different types of phosphodiesterase type 5 inhibitors (PDE5-Is) with tamsulosin for the treatment of LUTS secondary to BPH. METHODS: Databases including PubMed, OpenGrey, Embase, Cochrane Library, and Web of Science will be searched to identify qualified studies. We will use the Stata version 13.0 to conduct the network meta-analysis (NMA) with a random or fixed effects model of Bayesian framework. International prostate symptom score (IPSS), maximum urinary flow fate (Qmax) and their credible intervals (CI) will be used to compare every medical intervention with the efficacy and safety, including sildenafil plus tamsulosin, tadalafil plus tamsulosin, vardenafil plus tamsulosin. And the ranking of probability of different interventions will be estimated by comparing the surface under the cumulative ranking curve (SUCRA). RESULTS: A high quality-synthesis of the current evidence for comparing with different doses or types of PDE5-Is combined with tamsulosin to the treatment of LUTS secondary to BPH will be provided. CONCLUSIONS: This NMA and systematic review will generate evidence to help choose the best combination for treatment of LUTS secondary to BPH.PROSPERO registration number: PROSPERO CRD 42019139062.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/uso terapêutico , Inibidores da Fosfodiesterase 5/uso terapêutico , Hiperplasia Prostática/tratamento farmacológico , Tansulosina/uso terapêutico , Antagonistas de Receptores Adrenérgicos alfa 1/administração & dosagem , Antagonistas de Receptores Adrenérgicos alfa 1/efeitos adversos , Teorema de Bayes , Quimioterapia Combinada , Humanos , Masculino , Metanálise em Rede , Inibidores da Fosfodiesterase 5/administração & dosagem , Inibidores da Fosfodiesterase 5/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Citrato de Sildenafila/uso terapêutico , Tadalafila/uso terapêutico , Tansulosina/administração & dosagem , Tansulosina/efeitos adversos , Dicloridrato de Vardenafila/uso terapêutico
2.
Artigo em Inglês | MEDLINE | ID: mdl-31978742

RESUMO

Vardenafil, a remedy for erectile dysfunction, is easily modified, facilitating the creation of analogues that have been illegally added to functional foods and counterfeit medications. However, the medical profile of these analogues, including their safety, efficacy, safe drug combinations, metabolism and excretion, has not been completely evaluated, which could cause serious health problems. In this study, two representative vardenafil analogues, pseudovardenafil and hydroxyvardenafil, were metabolized with in-vitro model (human liver microsome) and in-vivo model (rats). The metabolized samples were extracted and characterized, using liquid chromatography quadrupole-time of flight mass spectrometry (LC-Q-TOF-MS). Some imprecise interpretations were evaluated with tandem mass spectrometry (LC-Q-TOF-MS/MS) for mass fragmentation analysis. A total of 11 metabolites of pseudovardenafil and 13 metabolites of hydroxyvardenafil that were identified have never been reported. These new metabolites could be usefully applied to forensic science and other metabolic fields. Furthermore, they could serve as principal references for the toxicity, danger, and side effects of unlawful vardenafil counterfeits.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas em Tandem/métodos , Dicloridrato de Vardenafila , Animais , Humanos , Masculino , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-Dawley , Dicloridrato de Vardenafila/análogos & derivados , Dicloridrato de Vardenafila/análise , Dicloridrato de Vardenafila/metabolismo
3.
J Pharm Biomed Anal ; 177: 112872, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31525574

RESUMO

It is often reported that falsified medicines have harmful effects on patients both Japan and abroad. In this study, we purchased vardenafil tablets on the internet and investigated their quality and authenticity using visual observations, authenticity investigations, non-destructive tests (handheld NIR and Raman spectroscopy), and quality analyses (active ingredient content and tablet dissolution rate). We used genuine 20-mg Levitra tablets that were sold in Japan and tablets from Bayer AG (Germany) as controls. In April 2015, we obtained 28 samples from 15 websites on the internet. Our authenticity investigations revealed that 11 (40%) were genuine products and 17 (60%) were falsified products. Handheld NIR and Raman results revealed that the falsified products had different spectra to the genuine products. Principal component analysis of the NIR and Raman spectra showed variation among the falsified products. The 11 genuine products were of good quality, and the 17 falsified products were of poor quality. The falsified products contained sildenafil (the active ingredient of Viagra) or tadalafil (the active ingredient of Cialis) instead of vardenafil. Our results show that falsified Vardenafil tablets are sold on the internet and that it is important to prevent illegal internet sales and increase consumer awareness of the presence of falsified medicines.


Assuntos
Medicamentos Falsificados/análise , Disponibilidade de Medicamentos Via Internet/normas , Controle de Qualidade , Agentes Urológicos/análise , Dicloridrato de Vardenafila/análise , Medicamentos Falsificados/química , Medicamentos Falsificados/economia , Humanos , Japão , Disponibilidade de Medicamentos Via Internet/economia , Análise de Componente Principal , Citrato de Sildenafila/análise , Análise Espectral Raman , Comprimidos , Tadalafila/análise , Agentes Urológicos/química , Agentes Urológicos/economia , Agentes Urológicos/normas , Dicloridrato de Vardenafila/química
4.
Medicine (Baltimore) ; 98(51): e18361, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31860994

RESUMO

BACKGROUND: Diabetic mellitus erectile dysfunction (DMED) refers to erectile dysfunction (ED) secondary to diabetes. As people's lifestyle changes and the population ages, the incidence of DMED continues to increase. Many clinical trials have proven that PDE5-inhibitors-vardenafil has a significant effect in the treatment of Diabetic mellitus erectile dysfunction. In this systematic review, we aim to evaluate the effectiveness and safety of PDE5-inhibitors-vardenafil for Diabetic mellitus erectile dysfunction. METHODS: We will search PubMed, Cochrane Library, AMED, EMbase, WorldSciNet; Nature, Science online and China Journal Full-text Database (CNKI), China Biomedical Literature CD-ROM Database (CBM), and related randomized controlled trials included in the China Resources Database. The time is limited from the construction of the library to February 2019.We will use the criteria provided by Cochrane 5.1.0 for quality assessment and risk assessment of the included studies, and use the Revman 5.3 and Stata13.0 software for meta-analysis of the effectiveness, recurrence rate, and symptom scores of Diabetic mellitus erectile dysfunction. ETHICS AND DISSEMINATION: This systematic review will evaluate the efficacy and safety of PDE5-inhibitors-vardenafil for treating Diabetic mellitus erectile dysfunction. Because all of the data used in this systematic review and meta-analysis has been published, this review does not require ethical approval. Furthermore, all data will be analyzed anonymously during the review process Trial. TRIAL REGISTRATION NUMBER: PROSPERO CRD42018095185.


Assuntos
Complicações do Diabetes , Disfunção Erétil/tratamento farmacológico , Inibidores da Fosfodiesterase 5/uso terapêutico , Dicloridrato de Vardenafila/uso terapêutico , Humanos , Masculino , Metanálise como Assunto , Revisões Sistemáticas como Assunto
5.
Sci Justice ; 59(4): 433-441, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31256815

RESUMO

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.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Medicamentos Falsificados , Espectrometria de Massas/métodos , Inibidores da Fosfodiesterase 5/química , Vasodilatadores/química , Suplementos Nutricionais , Contaminação de Medicamentos , Contaminação de Alimentos , Citrato de Sildenafila/análogos & derivados , Tadalafila/análogos & derivados , Dicloridrato de Vardenafila/análogos & derivados
6.
J Health Polit Policy Law ; 44(5): 765-787, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31199865

RESUMO

CONTEXT: Spending on direct-to-consumer advertising (DTCA) for prescription pharmaceuticals has risen to record levels, five times as much as in 1996 in inflation-adjusted dollars. Major health care provider organizations have called for additional regulation of DTCA. These organizations argue that the negative impact of such advertising outweighs the informational value claimed by the pharmaceutical industry. The industry maintains that further restrictions on DTCA are not warranted because it is successfully self-regulating via "guiding principles" for DTCA as certified by firm executives. METHODS: The authors measured recent industry spending on DTCA and used regression models of Nielsen Monitor-Plus data to assess pharmaceutical firm self-regulation after the public disclosure of noncompliance with industry self-regulatory principles, specifically regarding the exposure of children and adolescents to broadcast advertisements for erectile dysfunction drugs. FINDINGS: Public disclosure of noncompliance with self-regulatory DTCA standards did not bring advertising into compliance. Results demonstrate that firms failed to meet the industry standard during every quarter of the six-year period of this study. CONCLUSIONS: Results support previous research findings that pharmaceutical self-regulation is a deceptive blocking strategy rather than a means for the industry to police itself. Policy recommendations include broadcast restrictions on adult content and deincentivizing DTCA via tax reform.


Assuntos
Publicidade Direta ao Consumidor/normas , Indústria Farmacêutica/legislação & jurisprudência , Disfunção Erétil/economia , Fidelidade a Diretrizes , Guias como Assunto , Adolescente , Criança , Disfunção Erétil/tratamento farmacológico , Humanos , Masculino , Medicamentos sob Prescrição , Citrato de Sildenafila , Tadalafila , Dicloridrato de Vardenafila , Vasodilatadores
7.
Life Sci ; 229: 67-79, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31085245

RESUMO

Endothelial dysfunction and vascular reactivity defects secondary to metabolic and immunological disorders carry risk of serious cardiovascular complications. Here, the effects of the phosphodiesterase (PDE) inhibitors vardenafil and cilostazol were examined against rheumatoid arthritis (RA)/diabetes mellitus (DM)-co-morbidity-induced endothelial dysfunction and vascular reactivity defects. After setting of RA/DM-co-morbidity model, rats were divided into a normal control group, an RA/DM-co-morbidity group, and two treatment groups receiving oral vardenafil (10 mg/kg/day) and cilostazol (30 mg/kg/day) for 21 days after RA/DM-co-morbidity induction. Aorta was isolated for biochemical estimations of the pro-inflammatory vasoconstrictor molecules angiotensin-II (Ang-II) and endothelin-1 (ET-1), the adhesion molecules P-selectin and vascular cell adhesion molecule-1 (VCAM-1), the energy sensor adenosine-5'-monophosphate-activated protein kinase (AMPK), and the vasodilator anti-inflammatory molecule vasoactive intestinal peptide (VIP) using enzyme-linked immunosorbent assay (ELISA) and western blot analysis. Immunohistochemical estimations of endothelial nitric oxide synthase (eNOS) and matrix metalloproteinase (MMP)-2 were performed coupled with histopathological examination using routine hematoxylin and eosin (H&E) and special Masson trichrome staining. The in vitro study was conducted using aortic strips where cumulative concentration response curves were done for the endothelium-dependent relaxing factor acetylcholine and the endothelium-independent relaxing factor sodium nitroprusside after submaximal contraction with phenylephrine. Vardenafil and cilostazol significantly improved endothelial integrity biomarkers in vivo supported with histopathological findings in addition to improved vasorelaxation in vitro. Apart from their known PDE inhibition, up-regulation of vascular AMPK and eNOS coupled with down-regulation of Ang-II, ET-1, P-selectin, VCAM-1 and MMP-2 may explain vardenafil and cilostazol protective effect against RA/DM-co-morbidity-induced endothelial dysfunction and vascular reactivity defects.


Assuntos
Artrite Experimental/complicações , Artrite Reumatoide/complicações , Doenças Cardiovasculares/tratamento farmacológico , Cilostazol/farmacologia , Diabetes Mellitus Experimental/complicações , Endotélio Vascular/efeitos dos fármacos , Dicloridrato de Vardenafila/farmacologia , Vasodilatadores/farmacologia , Animais , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Comorbidade , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Feminino , Ratos
8.
J Pediatr Surg ; 54(10): 2172-2177, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30885562

RESUMO

AIM: An experimental study was performed to evaluate the effects of Vardenafil on ischemia-reperfusion (I/R) injury in an experimental volvulus model by histochemical and biochemical methods. MATERIALS AND METHODS: Thirty-five male Wistar rats were divided in five groups (n = 7). In Group 1, a 5 cm segment of small intestine 2 cm proximal to cecum was excised to have a control group. In the second group, 5 cm segment of small intestine 2 cm proximal to cecum was rotated 360° clockwise direction and sutured with 4/0 polyglactin to generate an experimental model of volvulus. At the end of 2 h of ischemia, the same intestinal segment was sampled. In group 3, after achieving ischemia similar to group 2, two hours of reperfusion injury was obtained by removing the sutures. Rats in Group 4 received vardenafil after 1.5 h of ischemia and then 2 h of reperfusion. And finally, in Group 5, vardenafil was administered 2 h before laparotomy and 5 cm of intestine was removed without I/R injury. Intestinal segments were evaluated for total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI) with biochemical and histopathological analysis. RESULTS: Serum TOS levels and OSI were not significantly different between groups (p = 0.910, P = 0,43 respectively). The serum TAS level was decreased in group 3 as compared to vardenafil groups 4 and 5, without a statistical significance (p = 0.428). In histopathologic analysis, we found that vardenafil, partially reduced I/R injury. The villus structure was preserved but, congestion and inflammation were moderate. CONCLUSION: Vardenafil partially reduced I/R injury histopathologically on intestine. Our study shows that it does not have statistically antioxidant effect on intestinal I/R injury in experimental model of volvulus. However, effects of vardenafil in I/R injury of liver, kidney, heart, testis, over and brain which were cited in literature were not confirmed with I/R injury on intestine.


Assuntos
Volvo Intestinal/cirurgia , Complicações Pós-Operatórias/prevenção & controle , Traumatismo por Reperfusão/prevenção & controle , Dicloridrato de Vardenafila/uso terapêutico , Vasodilatadores/uso terapêutico , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Intestino Delgado/patologia , Intestino Delgado/cirurgia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Complicações Pós-Operatórias/patologia , Ratos , Ratos Wistar , Traumatismo por Reperfusão/patologia , Dicloridrato de Vardenafila/farmacologia , Vasodilatadores/farmacologia
9.
J Sep Sci ; 42(2): 475-483, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30358113

RESUMO

The widespread use of phosphodiesterase-5 inhibitors has attracted broad attention of counterfeiters to develop illicit erectile products with inaccurate amounts, unknown toxicity, and purity of active ingredients. Correspondingly, intake of these products endangers consumer health and needs to be screened for precautionary actions to reduce this risk. Therefore, in this study, a sensitive and rapid analytical method has been developed for simultaneous determination of selected phosphodiesterase-5 inhibitors present in illicit erectile medications and human urine. Quantification of the analytes was performed by liquid chromatography coupled with quadrupole-time-of-flight tandem mass spectrometry system. The chromatographic separation was successfully achieved with a run period of 8 min. Low detection limits were obtained in the range of 1.63-9.81 ng/g with relative standard deviations below 7.72% obtained using the replicate measurements of lowest concentration in calibration plots. The analytical performance of the proposed method proved good linearity, low detection limits, good accuracy and precision with high percent recoveries for human urine samples. Developed method was successfully applied to real samples including four different brands of illicit erectile medications. The results obtained revealed the presence of high levels of sildenafil in analyzed samples. The behaviors of selected phosphodiesterase-5 inhibitors were also studied in simulated gastric conditions.


Assuntos
Disfunção Erétil/diagnóstico , Pirimidinas/urina , Citrato de Sildenafila/urina , Tadalafila/urina , Dicloridrato de Vardenafila/urina , Cromatografia Líquida , Humanos , Masculino , Pirimidinas/farmacologia , Citrato de Sildenafila/farmacologia , Estômago/efeitos dos fármacos , Tadalafila/farmacologia , Espectrometria de Massas em Tandem , Dicloridrato de Vardenafila/farmacologia
10.
Eur Urol ; 75(2): 329-340, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30344087

RESUMO

BACKGROUND: Peyronie's disease (PD) is a fibrotic disorder of the penile tunica albuginea, characterised by the formation of a localised fibrous plaque that can lead to deformity and erectile dysfunction. Nonsurgical therapeutic options for PD are limited in efficacy and safety. Myofibroblasts are key cells in the pathogenesis of PD, and inhibition of myofibroblast transformation has been suggested as a therapeutic option. OBJECTIVE: To identify potential drugs using a novel phenotypic assay and then to test them using in vitro and in vivo models of PD. DESIGN, SETTING, AND PARTICIPANTS: We have developed and validated a phenotypic screening assay that measures myofibroblast transformation, by which we tested 21 compounds that were suggested to be efficacious in treating PD. The successful hits from this assay were further tested using in vitro and in vivo models of PD. RESULTS AND LIMITATIONS: The new assay was able to detect transforming growth factor-ß1-induced myofibroblast transformation. Using this assay, phosphodiesterase type 5 inhibitors (PDE5i) and selective oestrogen receptor modulators (SERMs) were identified to significantly inhibit myofibroblast transformation. A PDE5i (vardenafil) and an SERM (tamoxifen) inhibited myofibroblast transformation, collagen gel contraction, and extracellular matrix production in a synergistic fashion. In a rat model of PD, the antifibrotic effect of the combination of vardenafil and tamoxifen was greater than that of each drug alone. This study is limited by not providing a molecular mechanism for the proposed synergy. CONCLUSIONS: This is the first demonstration of a synergistic activity between a PDE5i and an SERM discovered through a phenotypic screening approach. Future clinical trials using a combination of these drugs should be considered during the active phase of PD, given the early evidence of benefit in both in vitro and in vivo models. PATIENT SUMMARY: This report suggests that the combination of a phosphodiesterase type 5 inhibitor and a selective oestrogen receptor modulator may be efficacious in treating Peyronie's disease in its active phase.


Assuntos
Miofibroblastos/efeitos dos fármacos , Induração Peniana/tratamento farmacológico , Pênis/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/farmacologia , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Tamoxifeno/farmacologia , Dicloridrato de Vardenafila/farmacologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Sinergismo Farmacológico , Quimioterapia Combinada , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/enzimologia , Matriz Extracelular/patologia , Fibrose , Ensaios de Triagem em Larga Escala , Humanos , Masculino , Miofibroblastos/enzimologia , Miofibroblastos/patologia , Induração Peniana/enzimologia , Induração Peniana/patologia , Pênis/enzimologia , Pênis/patologia , Fenótipo , Ratos Sprague-Dawley
11.
Ann Pharm Fr ; 77(1): 28-37, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30172351

RESUMO

Alfuzosin and tamsulosin are recently co-administrated with vardenafil to treat symptoms of benign prostatic hyperplasia and erectile dysfunction. A highly sensitive and simple liquid chromatographic method was developed and validated for the simultaneous determination of the three drugs using moxifloxacin as an internal standard. Isocratic separation was achieved within 7.0 min using phenyl-hexyl column (250 × 4.6 mm i.d.) and a mobile phase composed of acetonitrile/0.25% phosphoric acid (30:70, v/v) at pH 3.0. The analysis was performed at a flow rate of 1.2 mL/min with fluorescence detection at 246/450 nm for Alfuzosin and vardenafil, and 226/322nm for tamsulosin using time programming technique. The proposed method was linear over the concentration ranges of 5.0-50.0ng/mL, 10.0-200.0ng/mL and 20.0-400.0ng/mL for alfuzosin, vardenafil and tamsulosin, with limits of detection of 0.56ng/mL, 0.98ng/mL and 2.81 ng/mL in a respective order. The developed method was successfully applied to determine the studied drugs in dosage forms and human plasma samples and the results were satisfactory as revealed by statistical analysis of the data.


Assuntos
Antagonistas Adrenérgicos alfa/sangue , Anti-Hipertensivos/sangue , Quinazolinas/sangue , Tansulosina/sangue , Dicloridrato de Vardenafila/sangue , Vasodilatadores/sangue , Cromatografia Líquida de Alta Pressão , Composição de Medicamentos , Humanos , Masculino , Hiperplasia Prostática/tratamento farmacológico , Padrões de Referência , Reprodutibilidade dos Testes , Espectrometria de Fluorescência
12.
Acta Neurochir (Wien) ; 161(1): 129-131, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30542775

RESUMO

Vardenafil is a potent phosphodiesterase-5 (PDE-5) inhibitor used in the treatment of erectile dysfunction. Several cases of stroke related to the use of PDE-5 inhibitors have been reported. Here, we describe the case of a 51-year-old man with headache and right ophthalmoplegia subsequent to vardenafil consumption. Computed tomography and magnetic resonance imaging showed a suprasellar mass with hemorrhage suggesting pituitary apoplexy. He underwent transsphenoidal resection of the pituitary mass. Histopathology confirmed the diagnosis of a necrotic pituitary adenoma with hemorrhage. This report suggests a possible association between pituitary apoplexy and vardenafil use. In patients with preexisting pituitary adenoma, vardenafil may enhance the risk of pituitary apoplexy. Although headache is the most commonly reported side effect of vardenafil, pituitary apoplexy should be considered in the differential diagnosis of a patient with headache and ophthalmoplegia subsequent to vardenafil intake.


Assuntos
Adenoma/complicações , Inibidores da Fosfodiesterase 5/efeitos adversos , Apoplexia Hipofisária/etiologia , Neoplasias Hipofisárias/complicações , Dicloridrato de Vardenafila/efeitos adversos , Vasodilatadores/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade
13.
Pharm Dev Technol ; 24(3): 293-302, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29723110

RESUMO

Vardenafil hydrochloride (VAR) is an erectile dysfunction treating drug. VAR has a short elimination half-life (4-5 h) and suffers low oral bioavailability (15%). This work aimed to explore the dual potential of VAR-dendrimer complexes as drug release modulators and oral bioavailability enhancers. VAR-dendrimer complexes were prepared by solvent evaporation technique using four dendrimer generations (G4.5, G5, G5.5 and G6) at three concentrations (190 nM, 380 nM and 950 nM). The systems were evaluated for intermolecular interactions, particle size, zeta potential, drug entrapment efficiency percentages (EE%) and drug released percentages after 2 h (Q2h) and 24 h (Q24h). The results were statistically analyzed, and the system showing the highest desirability was selected for further pharmacokinetic studies in rabbits, in comparison to Levitra® tablets. The highest desirability (0.82) was achieved with D10 system comprising VAR (10 mg) and G6 (190 nM). It possessed small particle size (113.85 nm), low PDI (0.19), positive zeta potential (+21.53), high EE% (75.24%), promising Q2 h (41.45%) and Q24 h (74.05%). Compared to Levitra® tablets, the significantly (p < 0.01) delayed Tmax, prolonged MRT(0-∞) and higher relative bioavailability (3.7-fold) could clarify the dual potential of D10 as a sustained release system capable of enhancing VAR oral bioavailability.


Assuntos
Dendrímeros/química , Sistemas de Liberação de Medicamentos , Inibidores da Fosfodiesterase 5/administração & dosagem , Dicloridrato de Vardenafila/administração & dosagem , Administração Oral , Animais , Disponibilidade Biológica , Química Farmacêutica/métodos , Preparações de Ação Retardada , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Masculino , Tamanho da Partícula , Inibidores da Fosfodiesterase 5/farmacocinética , Coelhos , Solventes/química , Fatores de Tempo , Dicloridrato de Vardenafila/farmacocinética
14.
Drug Des Devel Ther ; 13: 37-43, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30587926

RESUMO

Purpose: To determine ocular side effects of vardenafil with special regard to color vision and retinal function. Methods: This was a single center, randomized, double-blind, placebo-controlled, twofold crossover study with an administration of a single oral dose of two 20 mg tablets of BAY 38-9456 (vardenafil hydrochloride) or corresponding placebo in 24 healthy male subjects. Ocular investigations included Farnsworth-Munsell D100 color vision test, electroretinogram, and basic ophthalmological examinations like visual acuity, visual field, and slit-lamp of anterior segment and fundus. Results: Compared to placebo, administration of vardenafil hydrochloride lead to a temporary significant increase of Farnsworth-Munsell D100 total error score after 1 and 6 hours as well as in error lines 3 and 4 after 1 hour. Twenty-four hours after administration there was no significant alteration of total error score or of any error line. While latency of electroretinogram b-wave remained unaffected, amplitudes showed a significant decrease compared to placebo 1 hour following administration. While other ocular examinations did not reveal any differences in general some mild to moderate but no serious adverse events have been reported. Conclusion: Despite temporary changes in retinal function our study reports good tolerability of vardenafil in regard to ocular side effects.


Assuntos
Inibidores da Fosfodiesterase 5/efeitos adversos , Retina/efeitos dos fármacos , Dicloridrato de Vardenafila/efeitos adversos , Administração Oral , Adolescente , Adulto , Visão de Cores/efeitos dos fármacos , Estudos Cross-Over , Método Duplo-Cego , Eletrorretinografia , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Fosfodiesterase 5/administração & dosagem , Retina/fisiopatologia , Fatores de Tempo , Dicloridrato de Vardenafila/administração & dosagem , Adulto Jovem
15.
Sci Rep ; 8(1): 15802, 2018 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-30361675

RESUMO

The aim of this study was to utilize the biocompatibility of the natural ingredients zein and alpha lipoic acid (ALA) as a novel nanosphere matrix formulation that encapsulates vardenafil (VRD) for improved drug delivery and bioavailability. Three formulations were prepared using zein: ALA ratio of 1:1, 2:1 and 3:1 by liquid-liquid phase separation method. Physicochemical characterization and in vitro diffusion evaluation were carried out for the prepared formulations. A single dose clinical pharmacokinetic study was carried out for the selected formulation. Results revealed VRD formulations showed particle size of 836.7 ± 191.3, 179.8 ± 18.4 and 147.3 ± 18.1 nm and encapsulation efficiency of 55.72 ± 4.36, 65.33 ± 7.82 and 69.38 ± 6.83% for F1, F2 and F3, respectively. Single dose clinical pharmacokinetic results, in healthy human volunteers, showed improved VRD bioavailability by 2.5 folds from nanosphere formula (F3) compared with the marketed tablets. The formulation of novel zein-ALA nanospheres offers the possibility for application of a biocompatible nano-carrier system in drug delivery for improved drug delivery and efficacy.


Assuntos
Ácido Tióctico/química , Dicloridrato de Vardenafila/farmacocinética , Zeína/química , Administração Oral , Difusão , Relação Dose-Resposta a Droga , Composição de Medicamentos , Voluntários Saudáveis , Humanos , Masculino , Nanosferas/química , Nanosferas/ultraestrutura , Tamanho da Partícula , Espectroscopia de Infravermelho com Transformada de Fourier , Dicloridrato de Vardenafila/administração & dosagem , Dicloridrato de Vardenafila/química , Difração de Raios X
16.
AAPS PharmSciTech ; 19(8): 3650-3660, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30291543

RESUMO

Vardenafil hydrochloride is commonly used for the curing of erectile dysfunction. VAR suffers certain limitations: (i) short elimination half-life (4-5 h), (ii) low aqueous solubility (0.11 mg/mL), (iii) susceptibility to extensive first-pass metabolism and drug efflux transporters (P-glycoprotein), and (iv) limited (15%) oral bioavailability. The current study focused on the development of VAR lipomers as promising modified release systems able to enhance oral bioavailability. VAR-lipomers (lipid-polymer complexes) were successfully developed by a modified precipitation technique employing a lipid (polyglyceryl-6-distearate or glyceryl tristearate) and an amphiphilic polymer (Gantrez®). Three VAR:lipid ratios [1:1, 1:2, and 1:3] and three VAR:Gantrez® ratios [4:1, 2:1, and 1:1] were investigated. Solid-state characterization studies involved differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Fourier-transform infrared (FT-IR) spectroscopy. The systems were assessed for particle size, polydispersity index (PDI), zeta-potential, VAR entrapment-efficiency (EE%), morphology, and VAR released % after 2 h (Q2h) and 8 h (Q8h). The best-achieved system (the highest desirability) was promoted for pharmacokinetic studies in fasted rabbits. Statistical analysis of data revealed that L9 system (PGDS, VAR, and Gantrez®; 3:1:1, respectively) had the highest desirability (0.85) with respect to spherical particle size (622.15 nm), PDI (0.11), zeta-potential (-27.90 mV), EE% (62.80%), Q2h (43.45%), and Q8h (77.40%). With respect to Levitra® tablets, the significantly higher relative bioavailability (170%), delayed Tmax, and extended MRT(0-∞) clarified the dual ability of L9 system. Lipomers are emerging systems capable of modifying the rate of VAR release and promoting its oral bioavailability.


Assuntos
Lipídeos/química , Polímeros/química , Dicloridrato de Vardenafila/química , Animais , Disponibilidade Biológica , Liberação Controlada de Fármacos , Masculino , Coelhos , Solubilidade , Dicloridrato de Vardenafila/farmacocinética
17.
Analyst ; 143(21): 5202-5209, 2018 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-30265267

RESUMO

The illegal adulteration of natural healthcare products with chemical drugs can result in serious health risks for consumers. Thus there is an urgent need for a fast and precise detection method. In this research, sodium alginate (SA)-silver nanoparticles (AgNPs) were used as a substrate in surface-enhanced Raman scattering (SERS) for determining vardenafil and rosiglitazone maleate (ROS). Sodium alginate can not only reduce silver ions rapidly to AgNPs as reducing agents but can also protect AgNPs from aggregation by its use as a capping agent. The coffee ring effect has also been applied in this research to facilitate the separation and concentration of analytes. A prominent SERS enhancement can be obtained on the ring because of the electromagnetic mechanism. Both of the properties, including the use of SA and the coffee ring effect, make the method more sensitive in detecting the analytes compared to the classical AgNPs, SERS substrate which were produced using the reduction of silver nitrate with sodium citrate. The method displays a linear response for the determination of vardenafil and ROS in the 4.88-488 µg·mL-1 and 4.74-94.7 µg·mL-1 concentration ranges, and the limit of detection is as low as 1.63 µg·mL-1 and 2.20 µg·mL-1, respectively. The method was successfully applied to the detection of vardenafil and ROS in healthcare products, with recoveries between 91.52% to 107.1% and relative standard deviations of less than 4.31%. This method shows good potential for real applications.


Assuntos
Produtos Biológicos/análise , Contaminação de Medicamentos , Preparações Farmacêuticas/análise , Rosiglitazona/análise , Análise Espectral Raman/métodos , Dicloridrato de Vardenafila/análise , Alginatos/química , Calibragem , Química Verde/métodos , Nanopartículas Metálicas/química , Prata/química , Nitrato de Prata/química
18.
PLoS One ; 13(6): e0199299, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29953477

RESUMO

INTRODUCTION: Appropriate algorithms for the prediction of cardiovascular risk are strongly suggested in clinical practice, although still controversial. In type 2 diabetes mellitus (T2DM), the beneficial effect of phosphodiesterase (PDE)-5 inhibitors is demonstrated on endothelial function but not on the estimation of cardiovascular risk. AIM: To study whether the chronic Vardenafil administration to men with T2DM influences variables correlated with the predicted long-term cardiovascular risk calculated by different validated algorithms. METHODS: Per-protocol analysis of a longitudinal, prospective, randomized, placebo-controlled, double-blind, investigator-started, clinical trial. 54 male patients affected by T2DM were assigned to study (26patients) and control-group (28patients), respectively. The study included a treatment phase (24weeks) (Vardenafil/placebo 10mg twice-daily) and a follow-up phase (24weeks). Three time points were considered: baseline(V0), end of treatment(V1) and end of the study(V2). Parameters evaluated: endothelial health-related parameters and cardiovascular risk, assessed by calculating the Framingham (coronary hart disease [CHD], myocardial infarction [MI], stroke and cardiovascular disease [CVD]), ASSIGN and CUORE equations. RESULTS: Predicted cardiovascular risk at ten years resulted different using the three algorithms chosen, without differences between study and control groups and among visits. IL-6 was directly related to CHD, CVD and CUORE scores at V1 and with MI and STROKE at V2. Similarly, hs-CRP was directly related to CHD, MI, STROKE and CUORE only at V1 in the study group. Testosterone serum levels were inversely related to CHD and MI at V1 in study group. DISCUSSION: The predicted cardiovascular risk is different depending on the algorithm chosen. Despite no predictive risk reduction after six months of treatment, a possible effect of Vardenafil could be hypothesized through its action on inflammation markers reduction and through restoration of normal testosterone levels.


Assuntos
Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/complicações , Dicloridrato de Vardenafila/efeitos adversos , Doenças Cardiovasculares/metabolismo , Endotélio/metabolismo , Gônadas/metabolismo , Humanos , Estudos Longitudinais , Masculino , Reprodutibilidade dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Dicloridrato de Vardenafila/administração & dosagem
19.
Neuropharmacology ; 138: 151-159, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29885420

RESUMO

Cyclic nucleotides cAMP and cGMP cooperate to ensure memory acquisition and consolidation. Increasing their levels by phosphodiesterase inhibitors (PDE-Is) enhanced cognitive functions and rescued memory loss in different models of aging and Alzheimer's disease (AD). However, side effects due to the high doses used limited their application in humans. Based on previous studies suggesting that combinations of sub-efficacious doses of cAMP- and cGMP-specific PDE-Is improved synaptic plasticity and memory in physiological conditions, here we aimed to study whether this treatment was effective to counteract the AD phenotype in APPswe mice. We found that a 3-week chronic treatment with a combination of sub-efficacious doses of the cAMP-specific PDE4-I roflumilast (0.01 mg/kg) and the cGMP-specific PDE5-I vardenafil (0.1 mg/kg) improved recognition, spatial and contextual fear memory. Importantly, the cognitive enhancement persisted for 2 months beyond administration. This long-lasting action, and the possibility to minimize side effects due to the low doses used, might open feasible therapeutic strategies against AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Aminopiridinas/farmacologia , Benzamidas/farmacologia , Memória/efeitos dos fármacos , Nootrópicos/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Dicloridrato de Vardenafila/farmacologia , Doença de Alzheimer/enzimologia , Doença de Alzheimer/psicologia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Ciclopropanos/farmacologia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Memória/fisiologia , Camundongos Transgênicos , Distribuição Aleatória
20.
Eur J Vasc Endovasc Surg ; 56(2): 256-263, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29724533

RESUMO

OBJECTIVES: Ischaemia reperfusion (IR) injury occurs during vascular graft harvesting and implantation during vascular/cardiac surgery. Elevated intracellular cyclic guanosine monophosphate (cGMP) levels contribute to an effective endothelial protection in different pathophysiological conditions. The hypothesis that the phosphodiesterase-5 inhibitor vardenafil would protect vascular grafts against IR injury by upregulating the nitric oxide-cGMP pathway in the vessel wall of the bypass graft was investigated. METHODS: Lewis rats (n = 6-7/group) were divided into Group 1, control; Group 2, donor rats received intravenous saline; Group 3, received intravenous vardenafil (30 µg/kg) 2 h before explantation. Whereas aortic arches of Group 1 were immediately mounted in an organ bath, aortic segments of Groups 2 and 3 were stored for 2 h in saline and transplanted into the abdominal aorta of the recipient. Two hours after transplantation, the implanted grafts were harvested. Endothelium dependent and independent vasorelaxations were investigated. TUNEL, CD-31, ICAM-1, VCAM-1, α-SMA, nitrotyrosine, dihydroethidium and cGMP immunochemistry were also performed. RESULTS: Compared with the control, the saline group showed significantly attenuated endothelium dependent maximal relaxation (Rmax) 2 h after reperfusion, which was significantly improved by vardenafil supplementation (Rmax control, 91 ± 2%; saline 22 ± 2% vs. vardenafil 39 ± 4%, p < .001). Vardenafil pre-treatment significantly reduced DNA fragmentation (control 9 ± 1%, saline 66 ± 8% vs. vardenafil 13 ± 1%, p < .001), nitro-oxidative stress (control 0.8 ± 0.3, saline 7.6 ± 1.3 vs. vardenafil 3.8 ± 1, p = .036), reactive oxygen species level (vardenafil 36 ± 4, control 34 ± 2 vs. saline 43 ± 2, p = .049), prevented vascular smooth muscle cell damage (control 8.5 ± 0.7, saline 4.3 ± 0.6 vs. vardenafil 6.7 ± 0.6, p = .013), decreased ICAM-1 (control 4.1 ± 0.5, saline 7.0 ± 0.9 vs. vardenafil 4.4 ± 0.6, p = .031), and VCAM-1 score (control 4.4 ± 0.4, saline 7.3 ± 1.0 vs. vardenafil 5.2 ± 0.4, p = .046) and increased cGMP score in the aortic wall (control 11.2 ± 0.8, saline 6.5 ± 0.8 vs. vardenafil 8.9 ± 0.6, p = .016). The marker for endothelial integrity (CD-31) was also higher in the vardenafil group (control 74 ± 4%, saline 22 ± 2% vs. vardenafil 40 ± 3%, p = .008). CONCLUSIONS: The results support the view that impairment of intracellular cGMP signalling plays a role in the pathogenesis of the endothelial dysfunction of an arterial graft after bypass surgery, which can effectively be prevented by vardenafil. Its clinical use as preconditioning drug could be a novel approach in vascular/cardiac surgery.


Assuntos
Aorta Torácica/efeitos dos fármacos , Aorta Torácica/transplante , Inibidores da Fosfodiesterase 5/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Coleta de Tecidos e Órgãos , Dicloridrato de Vardenafila/farmacologia , Lesões do Sistema Vascular/prevenção & controle , Vasodilatadores/farmacologia , Actinas/metabolismo , Animais , Aorta Torácica/enzimologia , Aorta Torácica/fisiopatologia , Isquemia Fria , GMP Cíclico/metabolismo , Citoproteção , Dano ao DNA/efeitos dos fármacos , Molécula 1 de Adesão Intercelular/metabolismo , Masculino , Estresse Nitrosativo/efeitos dos fármacos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Ratos Endogâmicos Lew , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/fisiopatologia , Transdução de Sinais/efeitos dos fármacos , Coleta de Tecidos e Órgãos/efeitos adversos , Tirosina/análogos & derivados , Tirosina/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Lesões do Sistema Vascular/enzimologia , Lesões do Sistema Vascular/fisiopatologia , Isquemia Quente
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