Differences in ocular adverse events associated with phosphodiesterase-5 inhibitors: a real-world pharmacovigilance study.

OBJECTIVE: Our study aims to characterize the ocular safety profiles of phosphodiesterase type 5 (PDE5) inhibitors and explore the differences among different PDE5 inhibitors. METHODS: We analyzed reports on ocular adverse events associated with sildenafil, vardenafil and tadalafil submitted to the FDA Adverse Event Reporting System (FAERS) database from the first quarter of 2004 to the first quarter of 2023. Disproportionality analysis was conducted to evaluate reporting risk profiles. RESULTS: Among 61,211 reports qualifying for analysis, 5,127 involved sildenafil, 832 vardenafil, and 3,733 tadalafil. All PDE5 inhibitors showed increased reporting odds ratios (ROR) for ocular adverse events, with vardenafil highest (ROR 4.47) followed by sildenafil and tadalafil. Key ocular adverse events included cyanopsia, optic ischemic neuropathy, visual field defects, unilateral blindness and blindness. Sildenafil showed the highest disproportionality for cyanopsia (ROR 1148.11) while vardenafil and tadalafil showed the highest disproportionality for optic ischemic neuropathy. Time-to-onset analysis also revealed significant differences, with sildenafil having a later median time-to-onset compared to vardenafil and tadalafil. CONCLUSIONS: This comprehensive pharmacovigilance study reveals distinct patterns of ocular adverse events associated with PDE5 inhibitors. These findings contribute to a better understanding of the safety profiles of PDE5 inhibitors and may guide healthcare professionals in clinical decision-making.

Effects of different vardenafil doses on bone healing in a rat fracture model.

OBJECTIVES: We aimed to investigate the radiological, biomechanical, histopathological, histomorphometric, and immunohistochemical effects of different doses of vardenafil on fracture healing. MATERIALS AND METHODS: Fifty-one rats were divided into three groups. Group V5 was given 5 mg/kg/day of vardenafil; Group V10 was given 10 mg/kg/day of vardenafil; and the control group was given the same volume of saline. Six rats from each group were sacrificed on Day 14 (early period) and the remaining rats were sacrificed on Day 42 (late period). Callus/femoral volume and bone mineral density were measured using micro-computed tomography. Five femurs from each group in the late period were examined by biomechanical tests. In addition to the histopathological and histomorphometric evaluations, immunohistochemical analyses were performed to examine the levels of inducible nitric oxide synthase (iNOS), transforming growth factor-3 (TGF-ß3), and nuclear factor kappa B (NF-κB) proteins. RESULTS: Both doses of vardenafil increased primary bone volume and maximal bone fracture strength in late period, compared to the control group (p<0.05). Histological healing scores of vardenafil groups were significantly higher in early period (p<0.001). While cartilaginous callus/total callus ratio in early period was higher, callus diameter/femoral diameter ratio in late period was lower in vardenafil groups (p<0.01). The NF-κB immunopositivity in V10 group decreased in early period, compared to control group (p<0.001). The TGF-ß3 and iNOS immunopositivity increased in both V5 and V10 groups, compared to the control group in early period, but returned to normal in late period. CONCLUSION: During the first period of fracture healing process in which vasodilation is mostly required with increasing inflammation, vardenafil has ameliorating effects on the bone union and supports fracture healing.

Sensitive spectrophotometric determination of vardenafil HCl in pure and dosage forms.

OBJECTIVES: The present work aims to develop and validate a simple, rapid, cost-effective, sensitive and extractive spectrophotometric methods for the determination of phosphodiesterase type 5-inhibitor; vardenafil HCl (VARD) in pure and in dosage forms. METHODS: The developed methods are based on the formation of ion-pair complexes between vardenafil HCl and dyes, namely, bromocresol green (BCG), bromocresol purple (BCP), bromophenol blue (BPB), bromothymol blue (BTB) and eriochrom black T (EBT) in acidic buffer solutions. Different factors affecting the reactions between VARD and the dyes were studied and optimized. RESULTS: The formed complexes were extracted with methylene chloride and measured at 418, 410, 415, 417 and 520nm using BCG, BCP, BPB, BTB and EBT, respectively. The beer's law was obeyed in the ranges 1.0-10, 1.0-16, 0.5-8.0, 2.0-20 and 1.0-14µgmL-1 for BCG, BCP, BPB, BTB and EBT, respectively under the optimum conditions. The composition of the ion-pairs was found 1:1. The molar absorptivity's, Sandell's sensitivity, limits of detection and the limits of quantification were calculated. Other method validation parameters, such as accuracy, intra-day and inter-day precision, robustness, ruggedness and selectivity, have been evaluated. CONCLUSION: The proposed methods have been applied successfully for the analysis of vardenafil HCl in pure and dosage forms. The reliability of the methods was further ascertained by performing recovery studies using the standard addition method. Statistical comparison of the results with the reported method was performed by applying student's t- and F-tests and no significant statistical differences were obtained.

Ethosome-Derived Invasomes as a Potential Transdermal Delivery System for Vardenafil Hydrochloride: Development, Optimization and Application of Physiologically Based Pharmacokinetic Modeling in Adults and Geriatrics.

AIM: The aim of the current work was to develop vardenafil hydrochloride (VRD)-loaded ethosome-derived invasomes as a possible transdermal system which could be used for patients suffering from pulmonary arterial hypertension. METHODS: VRD-loaded ethosomes were developed at three concentrations of phosphatidylcholine (5, 10 and 15 mg/mL) and three percentages of ethanol (20%, 30% and 40%, v/v). The best achieved VRD-loaded ethosomes (ETH9) were optimized to invasomes via incorporation of terpenes (limonene, cineole and a 1:1 mixture) at three concentrations (0.5%, 1% and 2%, v/v). All systems were evaluated for vesicle size, zeta potential, drug entrapment efficiency (EE%), cumulative drug permeated percentages after 0.5hrs (Q0.5h) and 12hrs (Q12h) and steady-state flux (Jss). The optimized system (ETH9-INV8) was further characterized for morphology, histopathology and confocal laser scanning microscopy (CLSM). Physiologically based pharmacokinetic (PBPK) modeling was employed to estimate VRD pharmacokinetic parameters from the optimized transdermal system and an oral aqueous drug dispersion, in adults and geriatrics. RESULTS: The optimized invasomal system (ETH9-INV8) was characterized with spherical vesicles (159.9 nm) possessing negative zeta potential (-20.3 mV), promising EE% (81.3%), low Q0.5h (25.4%), high Q12h (85.3%) and the largest steady-state flux (6.4 µg.cm-2h-1). Following a leave-on period of 12hrs in rats, it showed minor histopathologic changes. CLSM studies proved its ability to deeply permeate rat skin. Lower Cmax values, delayed Tmax estimates and greater AUC0-24h folds in adults and geriatrics (≈ 2.18 and 1.69, respectively) were estimated following the transdermal application of ETH9-INV8 system. CONCLUSION: ETH9-INV8 is a promising transdermal system for VRD.

Polyamidoamine (PAMAM) dendrimers as potential release modulators and oral bioavailability enhancers of vardenafil hydrochloride.

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.

Ocular side effects of Levitra® (vardenafil) - results of a double-blind crossover study in healthy male subjects.

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.

Development and single dose clinical pharmacokinetics investigation of novel zein assisted- alpha lipoic acid nanoencapsulation of vardenafil.

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.

Could chronic Vardenafil administration influence the cardiovascular risk in men with type 2 diabetes mellitus?

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.

Sexual habits of men with ED who take phosphodiesterase 5 inhibitors: a survey conducted in 7 countries.

INTRODUCTION: Western cultural perceptions that favour spontaneous sex may create unrealistic expectations for erectile dysfunction (ED) treatment. Little is known about how users of phosphodiesterase type 5 inhibitors (PDE5Is) plan sexual activity and timing of their preactivity PDE5I ingestion. Because various PDE5Is vary in their duration of action and dosage regimen, this may be an important consideration in selecting the optimal agent for the ED patient. AIM: To better understand the sexual habits of PDE5I users. METHODS: Men from 7 countries (Brazil, China, Italy, Japan, Russia, Taiwan, Turkey) were screened online for age, self-reported comorbidities and ED medication use in the prior 3 months. After screening, eligible participants were asked to complete a 7-question, self-administered online survey containing questions regarding sexual habits and behaviours. MAIN OUTCOME MEASURES: Survey questions focused primarily on advanced planning of sexual intercourse and timing of PDE5I ingestion but also addressed the frequency of sexual intercourse and ED medication use. RESULTS: Of the 1458 respondents (response rate: 48%; median age: 48 years [interquartile range (IQR), 44-55]), 83% always/sometimes planned a specific time for intercourse in advance; 72% planned a specific time for sexual intercourse up to several hours in advance. Of respondents who planned in advance, more than half planned specific days of the week (55%) and times of the day (60%) for sexual intercourse. The time to sexual intercourse after dosing was ≤1 hour for 70% and ≤4 hours for 96% of men. The median frequency of sexual intercourse was 6 times/month (IQR, 4-10), with ED medication taken a median of 5 times/month (IQR, 3-8). CONCLUSIONS: Sexual activity is usually planned by ED medication users several hours in advance, and the vast majority are attempting activity within a short time after ingestion of the agent. These data should aid clinicians in the selection of the optimal PDE5I.

Randomized Trial of CPAP and Vardenafil on Erectile and Arterial Function in Men With Obstructive Sleep Apnea and Erectile Dysfunction.

Context: Erectile function is important for life satisfaction and often impaired in men with obstructive sleep apnea (OSA). Uncontrolled studies show that treating OSA with continuous positive airway pressure (CPAP) improves erectile function. Phosphodiesterase type 5 inhibitors (e.g., vardenafil) are the first-line therapy for erectile dysfunction (ED), but may worsen OSA. Objective: To assess the effects of CPAP and vardenafil on ED. Design: Sixty-one men with moderate-to-severe OSA and ED were randomized to 12 weeks of CPAP or sham CPAP, and 10 mg daily vardenafil or placebo in a two-by-two factorial design. Main Outcome Measures: International Index of Erectile Function (primary end point), treatment and relationship satisfaction, sleep-related erections, sexual function, endothelial function, arterial stiffness, quality of life, and sleep-disordered breathing. Results: CPAP increased the frequency of sleep-related erections, overall sexual satisfaction, and arterial stiffness but did not change erectile function or treatment or relationship satisfaction. Vardenafil did not alter erectile function, endothelial function, arterial stiffness, or sleep-disordered breathing, but did improve overall self-esteem and relationship satisfaction, other aspects of sexual function, and treatment satisfaction. Adherent CPAP improved erectile function, sexual desire, overall sexual, self-esteem, relationship, and treatment satisfaction, as well as sleepiness, and quality of life. Adherent vardenafil use did not consistently change nocturnal erection quality. Conclusion: CPAP improves overall sexual satisfaction, sleep-related erections, and arterial stiffness. Low-dose daily vardenafil improves certain aspects of sexual function and did not worsen OSA. Adherent CPAP or vardenafil use further improves ED and quality of life.

Dual-purpose vardenafil hydrochloride/dapoxetine hydrochloride orodispersible tablets: in vitro formulation/evaluation, stability study and in vivo comparative pharmacokinetic study in healthy human subjects.

Erectile dysfunction (ED) is the most important disorder after premature ejaculation for sexual activity in men. Vardenafil hydrochloride (VH) is an oral therapy for the treatment of erectile dysfunction. VH oral disintegrating tablets (ODTs) have been prepared by freeze drying technique to improve its dissolution profile and the overall clinical performance. Dapoxetine hydrochloride (DH) was added to the best three formulae of the prepared VH ODTs to treat premature ejaculation. All the ODTs formulae were evaluated for weight variation, friability, drug content, in vitro disintegration time, wetting time, and the dissolution study. Gelatin as a matrix former with N-methylpyrrolidone as a solubilizer in VH/DH ODTs improved the dissolution rate and extent of release of VH and DH with 100% of drug being dissolved after 15 min. In vivo study results from six healthy male volunteers showed shorter Tmax of VH from VH/DH ODT of 0.583 ± 0.129 h and shorter Tmax of DH from VH/DH ODT of 0.625 ± 0.137 h and showed AUC0-12 of VH from VH/DH ODT of 39.234 ± 10.932 ng/ml h1 and AUC0-12 of DH from VH/DH ODT of 531.681 ± 129.544 ng/ml h1, with relative bioavailability values of 100.9 and 85%, respectively, compared to (Levitra®) and (Priligy®).

Preparation and characterization of intravaginal vardenafil suppositories targeting a complementary treatment to boost in vitro fertilization process.

Vaginal route has been recently considered as a potential route for systemic delivery of drugs with poor oral bioavailability. Vardenafil (VDF) is a relatively new phosphodiesterase-5 inhibitor that exhibits a limited oral bioavailability (≈15%) due to extensive first-pass metabolism. In this study, we attempted to enhance the systemic bioavailability of VDF via its formulation within vaginal suppositories. Witepsol H15 and Suppocire NA50 were adopted as lipophilic suppository bases while polyethylene glycol 4000/400 and glycerogelatin were used as hydrophilic suppository bases. The effect of different base types and/or the incorporation of bioadhesive polymer on in vitro release of VDF were evaluated. The in vivo fate and organ biodistribution of VDF following intravaginal (IVG) administration were also investigated. VDF release from water-soluble bases was higher than that from lipophilic bases. The incorporation of bioadhesive polymers, such as Na alginate, remarkably sustained drug release from suppository base. The organ biodistribution study showed a higher Cmax (32 times) and AUC0-4h (20 times) of VDF in uterus following IVG administration of conventional suppositories, compared to oral administration of VDF suspension. In addition, cyclic guanosine monophosphate (cGMP) serum levels, used as an indicator of the in vivo activity of VDF, in animals were higher following IVG administration rather than oral administration. This study suggests that IVG administration of VDF might represent a potential alternative to oral route with superior therapeutic benefits especially when targeting the uterus.

Audiometry results and TEOAE and DPOAE amplitudes in men taking a phosphodiesterase type 5 inhibitor for erectile dysfunction.

We conducted a prospective study of transient evoked otoacoustic emissions (TEOAEs) and distortion-product otoacoustic emissions (DPOAEs) in men who were taking an oral phosphodiesterase type 5 (PDE5) inhibitor for erectile dysfunction. Our study group was made up of 30 men (60 ears), aged 34 to 60 years (mean: 50.9). They were randomly divided into three groups; 10 men were given sildenafil (Viagra) at 50 mg twice a week, 10 were given tadalafil (Cialis) at 20 mg twice a week, and 10 were given vardenafil (Levitra) at 20 mg twice a week. All patients took their drug for 3 weeks, for a total of 6 tablets for each patient. Audiometric tests and TEOAE and DPOAE measurements were performed before and after treatment. Post-treatment audiometry demonstrated improvement in hearing in all three groups. However, post-treatment TEOAE amplitudes and DPOAE amplitudes differed among the three groups; they were significantly higher in the sildenafil group at 1.0 kHz and the same in the tadalafil group; in the vardenafil group, the DPOAE amplitude was significantly lower at 3.0 kHz while there was no change in the TEOAE amplitude. We speculate that the possible mechanism for these findings is that PDE5 inhibitors block degradation of cyclic guanosine monophosphate (cGMP) and induce dilation of the cochlear microcirculation, resulting in an increase in cochlear blood flow. We also believe that the decrease in DPOAE amplitudes at 3.0 kHz seen in the vardenafil group may be related to an accumulation of nitric oxide/cGMP complex, which is toxic to the cochlea; however, since there was no change in TEOAE amplitude in the vardenafil group, this influence may be minimal. Further studies are needed to obtain a more comprehensive assessment of the effects of PDE5 inhibitors on hearing with the use of higher doses and longer durations of therapy.

Superior vasodilation of human pulmonary vessels by vardenafil compared with tadalafil and sildenafil: additive effects of bosentan.

OBJECTIVES: Pulmonary arterial hypertension is characterized by pulmonary vascular proliferation and remodelling, leading to a progressive increase in pulmonary arterial resistance. Vasodilator properties of 3 different phosphodiesterase (PDE)-5 inhibitors alone and in combination with an endothelin (ET) receptor antagonist were compared in an ex vivo model. METHODS: Segments of human pulmonary arteries (PAs) and pulmonary veins (PVs) were harvested from lobectomy specimens. Contractile forces were determined in an organ bath. Vessels were constricted with norepinephrine (NE) to determine the effects of sildenafil, tadalafil and vardenafil and with ET-1 to assess the effects of bosentan. RESULTS: All 3 PDE-5 inhibitors had no relevant effect on the basal tone of the vessels. Both sildenafil and vardenafil significantly (P < 0.0001) reduced the responses of the vessels to NE, whereas tadalafil was effective only in PA (P = 0.0009) but not in PV (P = 0.097). Sildenafil relaxed NE-preconstricted PV (P < 0.0001) but not PA (P = 0.143). Both tadalafil and vardenafil relaxed PA and PV significantly. Vardenafil appears to be the most potent of the PDE-5 inhibitors tested. Furthermore, we analysed the combination of bosentan and vardenafil in PA. Bosentan and vardenafil reduced ET-1 and NE induced vasoconstriction stronger than vardenafil alone (P ≤ 0.049). CONCLUSIONS: Vardenafil caused the most consistent antihypertensive response in this ex vivo model. However, ET receptor antagonism appears to be an even more potent mechanism. A combination therapy using vardenafil and bosentan turned out to be an effective combination to lower vessel tension in PA.

The effect of PDE5 inhibitors on bone and oxidative damage in ovariectomy-induced osteoporosis.

Osteoporosis is a major public health problem associated with many factors, and it affects more than 50% of women over 50 years old. In the current study, our purpose was to investigate the effects of phosphodiestarase-5 inhibitors on osteoporosis via the nitric oxide/3',5'-cyclic guanosine monophosphate/protein kinase G signalling pathway. A total of 50 female albino Wistar rats were separated into five groups. The first group was appointed as the healthy control group with no ovariectomy. All animals in the other groups underwent a bilateral ovariectomy. Six months after the ovariectomy, vardenafil, udenafil and tadalafil were given to the third, fourth and fifth groups, respectively, but were not administered to the positive control group (10 mg/kg per day for two months). The bone mineral density values were determined using a densitometry apparatus for all groups pre- and post-ovariectomy as well as after treatment. The levels of nitric oxide, endothelial nitric oxidesynthase, asymmetric dimethylarginine, 3',5'-cyclic guanosine monophosphate, protein kinase G, phosphodiestarase-5, pyridinoline, deoxypyridinoline, carboxyterminal telopeptide fragments and plasma carboxy terminal propeptide of type I collagen were determined using an enzyme linked immunosorbent assay. The levels of malondialdehyde, 8-hydroxy-2-deoxy guanosine, deoxyguanosine and coenzyme Q10 were determined by a high-performance liquid chromatography assay. Additionally, the right femoral trabecular bone density and the epiphyseal plate were measured in all groups. Angiogenesis was histologically observed in the bone tissue. In addition, we determined that the inhibitors may have caused a positive impact on the increased bone mass density and reduction of bone resorption markers. We also observed the positive effects of these inhibitors on oxidative stress. In conclusion, these phosphodiestarase-5 inhibitors increase angiogenesis in bone tissue and improve the re-formation rate of bone in rats with osteoporosis. Chemical compounds studied in this article Udenafil (PubChem CID: 6918523); Tadalafil (PubChem CID: 110635); Vardanafil (PubCham CID: 110634). Impact statement The results in our study appear to establish the osteoporosis model and provide evidence of the positive effects of three separate PDE5 inhibitors (vardenafil, udenafil, and tadalafil). The positive effects of these PDE5 inhibitors are investigated and demonstrated by the bone mass density and bone resorption markers. These effects are associated with significant demonstrated antioxidant activities. Osteoporosis is a significant major public health problem especially in more aged populations. Advances in identifying and understanding new potential therapeutic modalities for this disease are significant. This study provides such an advance.

Time of onset of vardenafil orodispersible tablet in a real-life setting - looking beyond randomized clinical trials.

BACKGROUND: A rapid onset of action for phosphodiesterase type 5 inhibitors (PDE5is) emerged to be of clinical importance in men treated for erectile dysfunction (ED). Data from randomized clinical trials (RCTs) showed a rapid onset of action for vardenafil 10 mg orodispersible tablet (ODT). However, the effectiveness of vardenafil ODT has never been tested in a real-life setting. We assessed the efficacy and time to onset of action of vardenafil ODT in men seeking medical help for ED in the everyday real-life clinical practice. RESEARCH DESIGN AND METHODS: Patients completed a baseline and follow-up International Index of Erectile Function (IIEF), along with a 8-item self-administered questionnaire about onset of action and overall treatment outcomes. Descriptive statistics tested efficacy rates, patient timing of drug intake and time to post-dosing onset of action. RESULTS: Overall, 118(59.9%) patients used vardenafil ODT. Satisfactory erections for vaginal penetration were reported in 39(34.5%) and 26(21.8%), patients in =15 and =30, minutes post-dosing, respectively. Minimal Clinically Important Differences (MCIDs) criteria and Yang's criteria for responders were obtained in 80(67.8%) and 72(60.8%) patients. CONCLUSIONS: This study showed that one in three patients had satisfactory erection for vaginal penetration in less than 15 min post-dosing in the real-life setting.

Effects of chronic administration of the phosphodiesterase inhibitor vardenafil on serum levels of adrenal and testicular steroids in men with type 2 diabetes mellitus.

To investigate whether long-term, chronic treatment with the phosphodiesterase-5 inhibitor vardenafil affects adrenal and testicular steroidogenesis in diabetic men, using liquid chromatography-tandem mass spectrometry. A longitudinal, prospective, investigator-started, randomized, placebo-controlled, double-blind, clinical-trial was carried out, enrolling 54 male patients affected by type 2 diabetes mellitus diagnosed within the last 5 years. In total, 26 and 28 patients were followed for 1 year and assigned to the study and placebo group, respectively. Progesterone, 17-hydroxyprogesterone, androstenedione, testosterone, dehydroepiandrosterone, dehydroepiandrosterone sulfate, corticosterone, 11-deoxycortisol and cortisol, were evaluated using liquid chromatography-tandem mass spectrometry. No differences were seen in sex testicular steroids between study and control group. As for the adrenal gland, steroids were considered according to the zona in which they are produced. No significant differences were seen in steroid produced in zona fasciculata. For the zona reticularis, dehydroepiandrosterone significantly decreased during treatment only in the study group (p = 0.007), with higher levels at visit 2 and 8 than other visits. The dehydroepiandrosterone sulfate/dehydroepiandrosterone ratio significantly increased during treatment only in the verum group. Considering the adrenal zona glomerulosa, corticosterone significantly changed among visits both in both groups (p < 0.001), with higher levels at visit 2 (p = 0.028), 8 (p = 0.003), and 10 (p = 0.044), i.e., in coincidence with the complete clinical and instrumental examination performed only at these visits according to the study protocol. Chronically administered vardenafil reduces dehydroepiandrosterone levels and increases dehydroepiandrosterone sulfate/dehydroepiandrosterone ratio as possible consequences of modulation of steroidogenic enzymes by tissue changes in cyclic adenosine monophosphate and cyclic guanosine monophosphate availability. A possibly stress-related increase in corticosterone is suggested for the first time.

Hepatoprotective role of vardenafil against experimentally induced hepatitis in mice.

Vardenafil is a selective phosphodiesterase-5 inhibitor used for erectile dysfunction treatment. The hepatoprotective role of vardenafil against acute hepatitis is not reported yet. Hence, this study aims to explore the protective role of vardenafil against concanavalin A (Con A) induced acute liver injury. Mice were pretreated with vardenafil (0.17 mg/kg/day) for seven consecutive days, and then subjected to a single IV injection of Con A. The results demonstrated that the vardenafil pretreatment significantly reduced the elevated serum levels of transaminases and alkaline phosphatase. Histopathological examination showed marked necrosis and inflammation in Con A-treated mice which was significantly ameliorated in vardenafil pretreated animals. Vardenafil pretreatment significantly alleviated the expression of nuclear factor kappa-B and inducible nitric oxide synthase in the hepatic tissue. Additionally, serum levels of nitric oxide and tumor necrosis factor-alpha were decreased in vardenafil pretreated animals compared to the Con A group. Therefore, our results demonstrate that vardenafil has hepatoprotective effect and this could be linked to decrease inflammatory mediators.

The correlation between high sensitivity C-reactive protein and erectile dysfunction patients with hypertension treated with vardenafil.

We evaluate the correlation between the plasma level of C-reactive protein (CRP) in patients with erectile dysfunction (ED) and hypertension and to set up whether the CRP level affected by the treatment of vardenafil 10 mg orally once daily. A total of 116 male patients with ED and hypertension were enrolled in this prospective study. The patients were divided into two groups, group 1 (ED patients with Not controlled hypertension) and group 2 (ED patients with controlled hypertension). All patients completed the International Index of Erectile Function (IIEF) scores, performed a penile color Doppler ultrasound examination and high sensitivity (hs-CRP) levels. The patients were given vardenafil 10 mg once daily for 3 months and reassessed again. According to the IIEF-EF domain score, there were statistically significant differences between the two groups (P=0.012) with a median value 10.0 (4.0-14.5) and 15.0 (9.0-16.5) between group 1 and group 2, respectively. Regarding to the severe (score<11), moderate (score 11-16) and mild (score 17-25) there were statistically significant differences between the two groups (0.023), (0.001) and (0.001), respectively. The hs-CRP showed statistically significant difference between the two groups (P=0.050) with a median value 2.4 (1.5-3.1) and 1.8 (1.1-2.4) between group 1 and group 2, respectively. The peak systolic velocity (PSV) and end diastolic velocity (EDV) showed statistically significant differences between the two groups (P=0.011) and (P=0.046), respectively. After treatment, there were improvements in the IIEF-EF domain score, severe (score<11), moderate (score 11-16), mild (score 17-25), PSV and EDV in both groups and these improvement were more obvious in (group 2) than (group 1) with a statistically significant differences between the two groups (P<0.05) (except in moderate (score 11-16), no statistically significant difference). The hs-CRP showed statistically significant differences between the two groups after treatment (P=0.049) with a median 2.1 (1.6-2.9) and 1.2 (0.9-2.4) between group 1 and group 2, respectively. Serum hs-CRP was significantly elevated in patients with ED and not controlled hypertension than in ED patients with controlled hypertension. ED patients with controlled blood pressure gave better results with penile duplex than those with not controlled blood pressure. Serum hs-CRP level could be a marker for an endothelial condition in men with ED and hypertension.

Comparison of Pharmacokinetics of Vardenafil Administered Using an Ultrasonic Nebulizer for Inhalation vs a Single 10-mg Oral Tablet.

INTRODUCTION: Delivery of vardenafil (for improvement of erectile function) via the inhaled route of administration may be advantageous in that this avoids extensive first pass metabolism and may therefore increase the bioavailability (hence the reliability of absorption) and shorten the time of pharmacological onset of activity. A unique nebulizer design has been developed by the sponsor (Advanced Medical Institute Pty Ltd) that is capable of delivering relatively large volumes of drug. AIM: The primary objective of the Phase 1 study was to assess and compare the pharmacokinetics of a single dose of vardenafil 10-mg tablet and a single dose of vardenafil solution administered via inhalation using an ultrasonic nebulizer device. Secondary objective was to assess the safety of vardenafil administered via inhalation using an ultrasonic nebuliser device. METHODS: Two-part study in healthy volunteers. Dose-ranging study was performed in two subjects to determine the appropriate inhalational dose, followed by an open, randomized, crossover, single dose pharmacokinetic study in 12 subjects, which compared a single 10-mg oral dose to the inhalation dose. MAIN OUTCOME MEASURES: Cmax, Cmax/Dose, Tmax, ke, t1/2, AUC0-t, AUCt-∞, AUC0-∞, AUC0-∞, AUC0-∞/Dose, and % area extrapolated. RESULTS: The two treatments are not bioequivalent, with vardenafil absorbed and eliminated faster and with less variability using the nebulizer for drug delivery. Administration via the inhalational route was not associated with any clinically significant changes in blood pressure or heart rate, and no serious adverse events were recorded, demonstrating an acceptable safety profile. CONCLUSION: To our knowledge, this is the first report of the administration of vardenafil HCl via the pulmonary route of administration. This trial demonstrates that vardenafil HCl may be administered using the ultrasonic nebulizer to reach blood levels comparable with those produced by a vardenafil 10-mg oral tablet, faster and using less drug. This new route of administration may potentially improve the onset of action, reliability, and safety for this class of drug.