Feasibility of the determination of plasma vardenafil level in rat by performance liquid chromatography-tandem mass spectrometry / 中华心血管病杂志

Objective: To develope and validate a reliable and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determination of vardenafil concentration in plasma of rat. Methods: Plasma samples of normal Sprague-Dawley rats were collected. A Phenomenex Synergi Polar-RP 80A column (2.0 mm×50 mm, 4 µm) was used. Column temperature was set at 30 ℃. Mobile phase A was 0.1% formic acid in water; mobile phase B was 0.1% formic acid in acetonitrile. The flow rate was 0.4 ml/minutes. Quantitative determination was performed by electrospray ionization, operating in positive ion multiple reaction monitoring (MRM) mode. Cisapride was used as the internal standard. The feasibility of the method was evaluated by examining its specificity, linearity and quantitative range, precision and accuracy, matrix effects, and stability. Results: Under the selected chromatographic and mass spectrometry conditions, the monitoring ions of vardenafil and internal standard were mass-to-charge ratio（m/z) 489.3/151.2 and 466.4/234.2, the retention times of vardenafil and internal standard were 2.62 and 2.80 minutes, respectively, and the peak shape was satisfactory. The method has good linearity in the concentration range of 0.2-200 ng/ml. The intra-batch precision (%CV) and accuracy (%DEV) of vardenafil were 1.5%-9.7% and -6.8%-6.6%, respectively. The inter-batch precision and accuracy of vardenafil were 3.1% -8.4% and -3.7%-4.6%, respectively. In this sample processing method, the extraction recovery rate of vardenafil was obtained at range of 88.2%-104.6%, which met the requirements for the investigation of extraction recovery rate. In this sample processing method, the normalized matrix factor of each quality control concentration of vardenafil was 1.04, 0.85, and 1.04, and the coefficient of variation (%CV) was in the range of 1.7%-10.7%, which met the requirements for the investigation of matrix effects. Variations of short-term stability, long-term stability, and stability of 4 freeze-thaw cycles of vardenafil was within ±15%, and the coefficient of variation were within 5%. Conclusion: The high performance liquid chromatography-tandem mass spectrometry method established in this study is feasible for the measurement of concentration of vardenafil in rat plasma and this method has good specificity and high accuracy, and can be used to detect the concentration of vardenafil in rat plasma.

Validation of an HPLC-MS method for the determinatin of vardenafil in rat urine

A simple and accurate technique of high-performance liquid chromatography with mass spectrometry was developedfor the quantitative determination of vardenafil and its metabolites in urine. Extraction of vardenafil and internalstandard (sildenafil) was performed from 5 ml of urine with 1,2-dichloroethane at pH = 7.5, followed by purificationof samples on Oasis HLB cartridges. Chromatographic separation was carried out on a Zorbax SB-C18 reversedphase column (50 mm × 2.1 mm) in linear gradient mode, at a rate of 0.4 ml/minute. Mobile phase composition: 0.1%aqueous formic acid solution and 0.1% formic acid solution in acetonitrile. Detection of vardenafil and sildenafil insamples was performed using a single quadrupole mass spectrometer with electrospray ionization. Mass spectralanalysis was performed in the m/z range: 50–500 with the fragmentation of 50 m/z under positive ionization. Thelinear dependence for vardenafil was in the range of 7–500 ng/ml; limit of detection and limit of quantification were5 and 7 ng/ml, respectively. The developed method was tested on specimens of rat urine taking vardenafil at a doseof 0.28 mg/kg. 11.27–13.60 ng of vardenafil were detected in 1 ml of daily urine of the animals. This method isrecommended for use in toxicological practice.

No Causal Link between Phosphodiesterase Type 5 Inhibition and Melanoma

PURPOSE: To examine the association between phosphodiesterase type 5 (PDE5) inhibitor use and melanoma by 1) conducting a systematic review of observational studies; and 2) determining if low PDE5A gene expression in human melanoma correlated with decreased overall survival. MATERIALS AND METHODS: A systematic search of observational studies examining the association between PDE5 inhibitor use and melanoma was performed through ClinicalTrials.gov, the Cochrane Library, EMBASE, PubMed, and Web of Science databases, and seven eligible studies were identified. PDE5A gene expression was analyzed with RNA sequencing data from 471 human melanoma samples obtained from The Cancer Genome Atlas. RESULTS: Four studies reported a positive association between PDE5 inhibitor use and melanoma, and three studies found no correlation. RNA sequencing data analysis revealed that under-expression of the PDE5A gene did not impact clinical outcomes in melanoma. CONCLUSIONS: There is currently no evidence to suggest that PDE5 inhibition in patients causes increased risk for melanoma. The few observational studies that demonstrated a positive association between PDE5 inhibitor use and melanoma often failed to account for major confounders. Nonetheless, the substantial evidence implicating PDE5 inhibition in the cyclic guanosine monophosphate (cGMP)-mediated melanoma pathway warrants further investigation in the clinical setting.

Preparation and Evaluation of Vardenafil Cross-linked Hydrogel Patch / 中国药学杂志

OBJECTIVE: To prepare a vardenafil cross-linked hydrogel patch and evaluate its quality characteristics. METHODS: The vardenafil cross-linked hydrogel patch was prepared by using sodium polyacrylate as the basic matrix material and aluminum hydroxide as the crosslinking agent, which was compared on transdermal permeation properties in vitro with vardenafil hydrochloride cross-linked patch and vardenafil hydrochloride gel. Transdermal permeation properties and drug content were determined by transdermal diffusion cell and HPLC. Then adhesive force was evaluated by initial adhesion tester, adhesion tester and peel tester. Besides, deformation resistance with moisture, heat and cold resistance, formability and skin irritation were also investigated. RESULTS: The vardenafil cross-linked hydrogel patch was a transparent and gelatinous solid with suitable viscidity. The method of content determination was validated in accordance with the requirements. The in vitro permeation rate of vardenafil cross-linked hydrogel patch fitted the zero-order release realation, and its permeation rate was higher than rates of vardenafil hydrochloride cross-linked patch and vardenafil hydrochloride gel in 24 h. And the cross-linked patch has better deformation resistance with moisture, heat and cold resistance, formability and no skin irritation. CONCLUSION: The vardenafil cross-linked hydrogel patch has good transdermal permeation properties and vardenafil is more suitable for transdermal delivery system than vardenafil hydrochloride, which provides theoretical and practical references for further research.

Effect of vardenafil pretreatment on the activity of post-thaw sperm / 上海交通大学学报（医学版）

Objective: To explore the effect of vardenafil pretreatment on the post-thaw sperm activity. Methods: Semen samples were randomly collected from 30 donors in Shanghai Human Sperm Bank. Then, each semen sample was aliquoted into six parts. One was immediately assayed for sperm activity without any treatment as the original control. The other five parts were incubated with vardenafil at 0, 0.4, 4.0, 40.0, and 400.0 μg/mL respectively for five minutes. The protective agent was added according to the semen: protective agent ration (2: 1), and the fumigation method was used for cryopreservation. After thawing, each specimen was examined for various parameters, including progressive motility, total motility and normal sperm morphology. Results: After thawing, the progressive sperm rates were (41.47±9.80)%, (42.57±9.60)%, (47.77±8.55)%, (37.27±8.47)%, and (26.37±6.99)% in the groups treated with 0, 0.4, 4.0, 40.0, and 400.0 μg/mL of vardenafil, respectively. Compared to the control group (0 μg/mL of vardenafil), 4.0 μg/mL of vardenafil could significantly improve the post-thaw sperm motility (P=0.034). Conclusion: Vardenafil pretreatment can improve the activity of the postthaw sperm; however, it may be toxic to sperm at the high concentration.

Preparation and Quality Evaluation of Vardenafil Hydrochloride Orally Disintegrating Tablets / 医药导报

Objective To prepare vardenafil hydrochloride orally disintegrating tablets and evaluate their quality. Methods The tablets were prepared by direct power compression method, using crosslinking povidone ( PVPP ) as disintegrants. The preparation method was optimized by response surface test using amount of PVPP, menthol and taste-masking agents as factors with disintegrating time and distance of bitterness as index. The results of taste of orally disintegrating tablets were determined by electronic tongue, comparing to the results of taste tests. At the same time, the properties of the tablets were evaluated using appearance, content uniformity, disintegrating time, et al. as index. Results The optimal formula was as follows:PVPP 13. 26%, menthol 0. 43%, taste-masking agent SGxj 1. 26%. The results on evaluation of electronic tongue were consistent with the results of taste tests. The quality of the prepared tablets was in line with standard. The disintegrating time was (22. 34 ± 0. 34 ) s. Conclusion The preparation technology of orally disintegrating tablets is simple, and controllable in quality.

Rapid determination of phosphodiesterase 5 inhibitors in invigorative health food by paper spray ionization mass spectrometry method / 中国食品卫生杂志

Objective A rapid method was constructed for detection of 3 kinds of phosphodiesterase 5 (PDE5) inhibitors (sidenafil,vardalafil,tadalafil) in invigorative health food by paper spray ionization mass spectrometry (PSI-MS method).Methods The characteristic ions of the PDE5 inhibitors could be used for preliminary identification and semiquantitative analysis with internal standard method using PSI-MS method.Results The 24 kinds of commercially available health-care products includes capsule,tablet,pill,powder,wine,syrup and liquid were tested.Results from PSI-MS were consistent with the HPLC-UV date.The calibration curves of PSI-MS has a good linearity in a given range.The linear coefficients of analytes were higher than 0.99.The LODs of 3 kinds of PDE5 inhibitors were lower than 1.0 mg/L.The RSDs of this method ranged from 20％ to 24％.Conclusion The PSI-MS method was rapid,accurate and targeted,which is compliant for quickly screening the PDE5 inhibitors in large complex matrix samples.

Clinical effect of Bosentan combined with Vardenafil on postoperative pulmonary hypertension associated with congenital heart and its influence on function of vascular endothelium / 药物评价研究

Objective To explore the clinical effect of bosentan combined with vardenafil on postoperative pulmonary hypertension associated with congenital heart and its influence on function of vascular endothelium.Methods 80 congenital heart disease patients with postoperative pulmonary hypertension,who were treated in our hospital from November,2011 to December,2015 were enrolled in the present study.They were randomly divided into observation group and control group,with each group of 40 cases.Both group received conventional therapy of oxygen and dieresis.The clinical effect,clinical symptom improvement,cardiac function were compared between the two groups.Results The clinical effect of control group was 80.0％ (32/40),which was significantly lower than that of observation group (90.0％,P ＜ 0.05).The sPAP,mPAP in both group were significantly decreased,and the Qp/Qs level was obviously increased (P ＜ 0.05);Borg score and NYHAFC score as well as the level of VEGF were largely decreased,and those of observation group were significantly lower than control group (P ＜ 0.05).In the terms of adverse reactions,there was no statistical difference between the two groups.Conclusion Bosentan combined with vardenafil was effective on postoperative pulmonary hypertension associated with congenital heart,which can significantly improve the clinical symptoms of patients with dyspnea,improve the cardiac function,worthy of clinical promotion.

Quantitative analysis of impurities in vardenafil hydrochloride orally disintegrating tablets / 中国药学杂志

OBJECTIVE: To establish a method for quantitative analysis of the impurities in vardenafil hydrochloride orally disintegrating tablets. METHODS: Gradient elution at the flow rate of 1.0 mL·min-1 was used for the determination of known impurities A-E and the unknown impurities simultaneously. The separation was performed on Athena C18-WP column (4.6 mm×250 mm,5 μm) with acetate solution containing 0.8g ammonium acetate in 900 mL of water-acetonitrile (90:10) as mobile phase A and acetate solution containing 0.8g ammonium acetate in 100 mL of water-acetonitrile (10: 90) as mobile phase B. The UV detection was carried out at 245 nm, and the column temperature was maintained at 40℃. RESULTS: After being treated with oxidation, heat, and light, vardenafil underwent more or less degradation. The degradation products were effectively separated and detected using this method. Meanwhile, the method showed good specificity, linearity, and ruggedness. CONCLUSION: The method is selective, sensitive, and accurate, and it is suitable for the quality control of vardenafil hydrochloride orally disintegrating tablets.

The effects of vardenafil on high altitude pulmonary hypertension in rats / 天津医药

Objective To investigate the effect of vardenafil on high altitude pulmonary hypertension in rats, and the possible mechanism thereof. Methods Thirty rats were randomly divided into three groups:control group with normal-pres?sure and normal-oxygen (group C), pulmonary hypertension group with low-pressure and low-oxygen (group P), and the group treated by vardenafil in low-pressure and low-oxygen condition (group V). The rats of group P and group V were ex?posed to low-pressure and low-oxygen condition in an auto-modulating hypobaric and hypoxic cabin to simulate 5 000 m high altitude environment (air pressure 50 kPa, oxygen concentration 10%) for 8 hours daily. Vardenafil (1 mg/kg) was given by gastrogavage to rats in group V once daily for 4 weeks, while the isodose distilled water was given by gastrogavage to rats in group C and group P. The mean pulmonary arterial pressure and right ventricular mass index were measured respectively after 4-week treatment. Morphologic changes of peripheral pulmonary artery were detected by light microscope. The serum levels of nitric oxide (NO) and endothelin-1 (ET-1) were detected as well. Results The pulmonary arterial pressure and right ventricular mass index were significantly higher in group P than those of group C and group V (P<0.05). The ratio of vascular medial wall thickness to external diameter (WT%) and the ratio of pulmonary artery wall area to tube area (WA%) were significantly increased in group P than those of group C and group V (P<0.05). Furthermore, the serum level of NO was significantly lower in group P than that of group C and group V, but the serum level of ET-1 was significantly increased compared with that of group C and group V (P<0.05). Conclusion Vardenafil can effectively reduce the pulmonary arteri?al pressure, and attenuate pulmonary vessels and right ventricle remodeling induced by high altitude pulmonary hypertension.

The effects of vardenafil and pentoxifylline administration in an animal model of ischemic colitis

OBJECTIVES: Vardenafil enhances dilatation of vascular smooth muscle and inhibits platelet aggregation. The purpose of this study was to evaluate the clinical effects of vardenafil and pentoxifylline administration in an experimental model of ischemic colitis. METHODS: Forty female Wistar albino rats weighing 250-300 g were randomized into five experimental groups (each with n = 8) as follows:1) a sham group subjected to a sham surgical procedure and administered only tap water; 2) a control group subjected to a standardized surgical procedure to induce ischemic colitis and administered only tap water; 3) and 4) treatment groups subjected to surgical induction of ischemic colitis followed by the postoperative administration of 5 mg/kg or 10 mg/kg vardenafil, respectively; and 5) a treatment group subjected to surgical induction of ischemic colitis followed by postoperative administration of pentoxifylline at 50 mg/kg/day per day as a single dose for a 3-day period. All animals were sacrificed at 72 h post-surgery and subjected to relaparotomy. We scored the macroscopically visible damage, measured the ischemic area and scored histopathology to determine the severity of ischemia. Tissue malondialdehyde levels were also quantified. RESULTS: The mean Gomella ischemic areas were 63.3 mm2 in the control group; 3.4 and 9.6 mm2 in the vardenafil 5 and vardenafil 10 groups, respectively; and 3.4 mm2 in the pentoxifylline group (p = 0.0001). The mean malondialdehyde values were 63.7 nmol/g in the control group; 25.3 and 25.6 nmol/g in the vardenafil 5 and vardenafil 10 groups, respectively; and 22.8 nmol/g in the pentoxifylline group (p = 0.0001). CONCLUSION: Our findings indicate that vardenafil and pentoxifylline are effective treatment options in an animal model of ischemic colitis. The positive clinical effects produced by these drugs are likely due to their influence on the hemodynamics associated ...

PDE5 Inhibitor Treatment Persistence and Adherence in Brazilian Men: Post-hoc Analyses from a 6-Month, Prospective, Observational Study

Purpose Characterize persistence and adherence to phosphodiesterase type - 5 inhibitor (PDE5I) on-demand therapy over 6 months among Brazilian men in an observational, non-interventional study of Latin American men naïve to PDE5Is with erectile dysfunction (ED). Materials and Methods Men were prescribed PDE5Is per routine clinical practice. Persistence was defined as using ≥ 1 dose during the previous 4 - weeks, and adherence as following dosing instructions for the most recent dose, assessed using the Persistence and Adherence Questionnaire. Other measures included the Self - Esteem and Relationship (SEAR) Questionnaire, and International Index of Erectile Function (IIEF). Multivariate logistic regression was used to identify factors associated with persistence/adherence. Results 104 Brazilian men were enrolled; mean age by treatment was 53 to 59 years, and most presented with moderate ED (61.7%). The prescribed PDE5I was sildenafil citrate for 50 (48.1%), tadalafil for 36 (34.6%), vardenafil for 15 (14.4%), and lodenafil for 3 patients (2.9%). Overall treatment persistence was 69.2% and adherence was 70.2%; both were numerically higher with tadalafil (75.0%) versus sildenafil or vardenafil (range 60.0% to 68.0%). Potential associations of persistence and/or adherence were observed with education level, ED etiology, employment status, and coronary artery disease. Improvements in all IIEF domain scores, and both SEAR domain scores were observed for all treatments. Study limitations included the observational design, brief duration, dependence on patient self - reporting, and limited sample size. Conclusion Approximately two-thirds of PDE5I-naive, Brazilian men with ED were treatment persistent and adherent after 6 months. Further study is warranted to improve long-term outcomes of ED treatment. .

Treatment Strategy for Non-Responders to PDE5 Inhibitors

Currently, phosphodiesterase type 5 (PDE5) inhibitors are the initial treatment option for erectile dysfunction. The reported efficacy of PDE5 inhibitors is about 70%, although it is significantly lower in difficult-to-treat subpopulations. Treatment failures might be due to the severity of the underlying pathophysiology, improper use of medication, unrealistic patient expectations, difficult relationship dynamics, severe performance anxiety, and other psychological problems. Physicians must address these issues to identify true treatment failures attributable to the drugs. This article discusses factors that might affect the response to PDE5 inhibitors and develops a strategy to maximize the overall efficacy of PDE5 inhibitors in initial non-responders to PDE5 inhibitors.

Tolerability and Pharmacokinetics Following a Single Dose of Vardenafil in Healthy Korean Volunteers

BACKGROUND: Vardenafil is a phosphodiesterase type 5 inhibitor, used in erectile dysfunction. This study aimed to evaluate the pharmacokinetics and tolerability of vardenafil following a single oral administration in healthy male subjects. METHODS: A randomized, double-blind, placebo-controlled, single dosing, dose-escalation study was conducted in 30 healthy subjects. A single oral dose of vardenafil or placebo was given to 10 subjects (8 active + 2 placebo) in each dose group of 5, 10 and 20 mg. Serial blood and urine samples were obtained up to 48 hours for pharmacokinetic analysis. Vardenafil and its metabolite were detected by high performance liquid chromatography tandem mass spectrometry assay. RESULTS: A total of 45 adverse events (AE) were reported in 22 subjects, including 5 AEs from placebo treatment, and all the AEs were mild, except one case of moderate nasal stuffiness. Vardenafil was absorbed after a single oral dose, with the tmax of 0.5-1.0 hours. The Cmax and AUClast were 10.21 +/- 3.68 ug/L(mean +/- SD) and 18.08 +/- 7.44 ugxh/L in 5 mg dose group, 19.79 +/- 12.13 ug/L and 38.61 +/- 21.04 ugxh/L in 10 mg dose group and 53.16 +/- 37.01 ug/L and 110.05 +/- 69.65 ugxh/L in 20 mg dose group. Dose-linearity on AUClast and Cmax of vardenafil were observed in three dose groups. In all dose groups, the fraction excreted in urine was less than 1%. CONCLUSION: The vardenafil was tolerable over a single dose range of 5 - 20 mg. The pharmacokinetics of vardenfil after a single oral dose was explored and linear pharmacokinetic characteristics were observed over the dose range of 5 - 20 mg in healthy subjects.

Examination of the Effects of Vardenafil on Esophageal Function Using Multichannel Intraluminal Impedance and Manometry

BACKGROUND/AIMS: To evaluate the effects of the phosphodiesterase type 5 (PDE5) inhibitor vardenafil on esophageal function, including bolus transit, using multichannel intraluminal impedance and esophageal manometry (MII-EM). METHODS: Sixteen healthy volunteers (15 men) underwent an MII-EM study including 10 liquid swallows and 10 viscous swallows in a seated position after fasting. Then, each subject was asked to ingest 50 mL distilled water or 10 mg vardenafil dissolved in 50 mL water, in a double-blind manner. After 25 minutes, the MII-EM study was repeated. RESULTS: Eight men received vardenafil and eight subjects received water. Resting and residual lower esophageal sphincter pressures differed significantly only in the vardenafil group (from 18 +/- 6.7 to 6.6 +/- 5.3 mmHg, P < 0.001 and from 4.9 +/- 2.6 to 2.1 +/- 3.6 mmHg, P = 0.006, respectively). Mean distal esophageal amplitude decreased significantly only in the vardenafil group (from 86.7 +/- 41.6 to 34.0 +/- 38.0 mmHg, P < 0.05). Complete bolus transits of liquid and viscous meals decreased significantly only after vardenafil ingestion (from 80.2% +/- 13.8% to 49.4% +/- 27.9%, P < 0.05 and from 72.8% +/- 33.6% to 21.5% +/- 29.0%, P = 0.01, respectively). CONCLUSIONS: Vardenafil decreased esophageal bolus transit in the seated position, despite decreased lower esophageal sphincter pressure.

Correlação da resposta clínica à vardenafila em dois regimes terapêuticos com parâmetros vasculares e escore de risco cardiovascular em hipertensos com disfunção erétil vasculogênica / Correlation of clinical response of vardenafil in two therapeutic regimens with vascular parameters and cardiovascular risk score in hypertensive patients with vasculogenic erectile dysfunction

A disfunção erétil (DE) tem alta prevalência entre hipertensos e tem sido considerada marcdor precoce de risco cardiovascular. A presença e gravidade da DE bem como a resposta clínica aos inibidores da fosfodiesterase tipo 5 (PDES) parecem depender da biodisponibilidade do óxido nítrico (NO) endotelial e da extensão da doença aterosclerótica. O objetivo deste estudo foi avaliar a resposta clínica da vardenafila usada em dois regimes terapêuticos em hipertensos com DE vasculogênica e sem doença cardiovascular maior, correlacionando a gravidade da DE e a eficácia da vardenafila com dados antropométricos, laboratoriais, escore de risco cardiovascular e parâmetros vasculares funcionais e estruturais. A resposta clínica à vardenafila nos dois regimes foi avaliada conforme o percentual de respostas positivas à questão 3 do Perfil do Encontro Sexual (PES3). Os parâmetros vasculares considerados foram a espessura médio-intimal (EMI) da carótida comum, a dilatação mediada pelo fluxo (DMF) da artéria braquial e a dilatação nitrato-mediada (DNM). Foram incluídos 100 homens hipertensos com idade entre 50 e 70 anos, sendo 74 portadores de DE vasculogênica e 26 com função erétil normal que serviram de grupo controle. Nos pacientes com DE, o índice de massa corporal, relação cintura-quadril, EMI da carótida, níveis séricos de triglicerídeos, colesterol total e LDL foram significativamente maiores que no grupo controle. Após o uso de vardenafila on demand (fase 1), os pacientes com mais de 50% de respostas positivas ao PES3 ou 50% de respostas afirmativas e um incremento de 6 pontos ou mais em relação ao Índice Internacional de Função Erétil (IIEF-FE) basal e/ou resposta positiva a Questão de Avaliação Global (QAG), foram considerados respondedores. O escore do IIEF-FE basal se correlacionou negativamente com a EMI da carótida (r=-0,48, P<0,001) e com o escore de Framingham (r=-0,41, P<0,001) no grupo com DE. Houve forte correlação positiva entre a resposta clínica...

Erectile dysfunction (ED) is a high prevalent disease in hypertensive subjects and has been considered an early cardiovascular risk marker. ED's presence and severity, as well as clinical response to phosfodiesterase type 5 (PDES5) inhibitors, vary according to nitric oxide (NO) availability and atherosclerosis extension. We investigated whether vasculogenic ED severity and clinical response to vardenafil used on demand or continuously were associated with structural and functional vascular changes in patients with uncomplicated hypertension. Our main efficacy criterion was per patient percentage of positive answers on Sexual Encounter Profile question 3(SEP3). Vascular parameters considered were intima-media thickness (IMT), flow-mediated dilation (FMD) on brachial artery and nitrate-mediated dilation. A total of 100 hypertensive men aging between 50 and 70 years were included. Among these patients, 74 had vasculogenic ED and 26 presented normal erectile function according to erectile domain of International Index of Erectile Function (IIEF-EF). Among those with ED, body mass index, waist-rip ratio, carotid IMT, triglycerides, total cholesterol and LDL-cholesterol were significantly higher than controls. After vardenafil on demand usage during phase 1, patients with more than 50% of positive answers on SEP3 or 50% and more than 6 points on IIEF basal score or positive answer to global evaliation question were considered "responders". IIEF basal score correlated inversely with carotid IMT (r=-0.48, P<0.001) and with Framingham risk score (r=-0.41, P<0.001) in ED group. Clinical response to vardenafil strongly correlated with FMD (r= 0.70, P<0.001), except among diabetics. "Non responders" (n=35) on phase 1 were included on phase 2 when, after randomization, they received vardenafil 10 mg nightly or placebo during five weeks. Open vardenafil on demand were allowed on hour before sexual intercourse, and 38.8% of active group improved and became responders...

Vardenafil Enhances Oxytocin Expression in the Paraventricular Nucleus without Sexual Stimulation / 대한배뇨장애요실금학회지

PURPOSE: Oxytocin is associated with the ability to form normal social attachments. c-Fos is an immediate early gene whose expression is used as a marker for stimulus-induced changes in neurons. The effect of phosphodiesterase-5 (PDE-5) inhibitors on oxytocin activation in the brain without sexual stimuli has not yet been reported. In the present study, we investigated the effects of vardenafil on oxytocin and c-Fos expression in the paraventricular nucleus (PVN) of conscious rats. METHODS: Male Sprague-Dawley rats weighing 300+/-10 g were divided into 6 groups (n=5 in each group): the control group, the 1-day-0.5 mg/kg, the 1-day-1 mg/kg, the 1-day-2 mg/kg, the 3-day-1 mg/kg, and the 7-day-1 mg/kg vardenafil administration group. The experiment was conducted without sexual stimulation. Vardenafil was orally administered. The animals in the control group received an equivalent amount of distilled water orally. The expression of oxytocin and c-Fos in the PVN was detected by immunohistochemistry. RESULTS: Oxytocin expression in the PVN was increased by 1 day administration of 2 mg/kg vardenafil, and this effect of vardenafil appeared in a duration-dependent manner. c-Fos in the oxytocin neurons of the PVN was increased by 1 day administration of 2 mg/kg vardenafil, and this effect of vardenafil also appeared in a duration-dependent manner. These results showed that vardenafil augments the expression of oxytocin with activation of oxytocin neurons in the PVN. CONCLUSIONS: In this study, we showed that the PDE-5 inhibitor, vardenafil directly enhances oxytocin expression and also activates oxytocin neurons in the PVN, which indicates that vardenafil may exert positive effects on affiliation behavior and social interaction.

Vardenafil Increases Cell Proliferation in the Dentate Gyrus through Enhancement of Serotonin Expression in the Rat Dorsal Raphe

This study was conducted to evaluate the effects of vardenafil (Levitra), a phosphodiesterase-5 (PDE-5) inhibitor, on cell proliferation in the hippocampal dentate gyrus and on 5-hyroxytryptamine (5-HT, serotonin) synthesis and tryptophan hydroxylase (TPH) expression in the rat dorsal raphe nucleus. Male Sprague-Dawley rats were divided into 6 groups (n=5 in each group): a control group, a 0.5 mg/kg-1 day vardenafil-treated group, a 1 mg/kg-1 day vardenafil-treated group, a 2 mg/kg-1 day vardenafil-treated group, a 1 mg/kg-3 day vardenafil-treated group, and a 1 mg/kg-7 day vardenafil-treated group. 5-bromo-2'-deoxyuridine (BrdU) immunohistochemistry was then performed to evaluate cell proliferation in the dentate gyrus. In addition, 5-HT and TPH immunohistochemistry was conducted to evaluate serotonin expression in the dorsal raphe. The results revealed that treatment with vardenafil increased cell proliferation in the dentate gyrus and enhanced 5-HT synthesis and TPH expression in the dorsal raphe in a dose- and duration-dependent manner. The findings demonstrate that the increasing effect of vardenafil on cell proliferation is closely associated with the enhancing effect of vardenafil on serotonin expression under normal conditions.

Onset of Action of Phosphodiesterase Type 5 Inhibitors in the Treatment of Erectile Dysfunction / 대한남성과학회지

PURPOSE: After the market launch of multiple phosphodiesterase type 5 inhibitors (PDE5Is), a considerable amount of information has emerged regarding the efficacy and the time of initiation of these drugs. In clinical situations, however, many patients with erectile dysfunction (ED) have complained about the onset of erection occurring later than expected or desired. We therefore studied the time course for initiating an erection after usage of PDE5Is. MATERIALS AND METHODS: One hundred forty-one patients who were medicated with PDE5Is > 4 times in the most recent 3 months were included for study. The patients were divided into 3 groups: sildenafil (n=51), vardenafil (n=51), and tadalafil (n=39). The choice of PDE5I was made according to the patient's and/or doctor's preferences. Regardless of the type of drug selected, the patients were recommended to have sexual stimulation 15 minutes after taking the medication. RESULTS: The onset of action of the 3 drug groups were significantly different (sildenafil, 57.0+/-38.5 min; tadalafil, 79.5+/-50.6 min; and vardenafil, 44.4+/-26.6 min; p<0.05). Psychogenic causes of ED resulted in a shorter PDE5I onset of action than organic causes of ED. Other factors, such as body mass index and international index of erectile function erectile function domain score, were shown not to differ with respect to the onset of action of PED5Is. CONCLUSION: In clinical situations, patients need more time for the onset of erections after taking PDE5Is. For restoration of a healthy sexual life, patients needs more time to achieve an erection after taking PDE5Is.

Drug Interaction Study of Vardenafil 20mg and Doxazosin 4mg or Tamsulosin 0.2mg in Patients with Benign Prostatic Hyperplasia and Erectile Dysfunction to Evaluate Changes in Blood Pressure / 대한비뇨기과학회지

Purpose: This study aimed at evaluating the expected additive blood pressure (BP) lowering effect of vardenafil when administered in the background of chronic alpha1-blocker therapy. Materials and Methods: Patients (n=90) with symptomatic benign prostatic hypertrophy (BPH) and erectile dysfunction (ED) took vardenafil 20mg in the morning following repeated doxazosin gastrointestinal therapeutic system (GITS) 4mg (n=60) or tamsulosin 0.2mg (n=30) HS a day for 30 days. The standing and sitting BP at baseline, before taking the vardenafil and 30 minutes and 1 hour post vardenafil were measured 3 consecutive times. The data were analyzed by Student's t-test (paired), repeated measures of two-way ANOVA, chi-square tests and Pearson correlation analysis. Results: Doxazosin produced a significant reduction in systolic/diastolic BP ( 12.3/ 6.7mmHg), but tamsulosin did not. In the doxazosin group, the average reductions in BP from baseline ( 24.7/ 15.8mmHg) were significantly higher than that for the tamsulosin group ( 14.6/ 7.5mmHg). However, the average BP change was not different in both group ( 12.4/ 9.1mmHg in the doxazosin group and 11.3/ 6.4mmHg in the tamsulosin group) following a single dose of 20mg vardenafil. The higher the BP was at baseline, the more the reduction in BP was in both the doxazosin and tamsulosin groups. Two patients of tamsulosin showed a sitting systolic BP <85mmHg, but they didn't experience dizziness. Conclusions: We recommend starting Vardenafil treatment in the background of chronic aalpha1 blocker therapy, including tamsulosin, with a low dose and to increase the dose by monitoring the BP, particularly for the patients with hypertension.