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Purpose: We assessed urodynamic changes after vardenafil administration in spinal cord injured male patients on oxybutynin treatment. Materials and Methods: We performed a single center, randomized, double-blind, placebo controlled trial in 25 patients with spinal cord injury who had erectile dysfunction and micturition disorders. A baseline urodynamic test was performed as well as a second urodynamic test 1 to 3 hours after the administration of 20 mg vardenafil and placebo in 15 and 10 cases, respectively. In all patients standard oral oxybutynin administration was not discontinued. Statistical assessment included the 3 urodynamic parameters maximum detrusor pressure during voiding, maximum cystometric capacity and detrusor overactivity volume. Results: Placebo administration did not affect urodynamic parameters. After vardenafil administration maximum detrusor pressure was significantly decreased (59.3 vs 52.1 cm H2O, p <0.001) and maximum cystometric capacity considerably improved (233.5 vs 272 ml, p <0.001). The most dramatic variations were observed for detrusor overactivity volume (174 vs 218 ml, p <0.0001). In 7 patients with American Spinal Injury Association classification A and spinal cord injury above T6 we observed the most significant improvement in the evaluated urodynamic items, including maximum detrusor pressure 57 vs 52 cm H2O (p = 0.039), maximum cystometric capacity 253 vs 296 ml (p = 0.004) and detrusor overactivity volume 177 vs 229 ml (p = 0.003). Conclusions: This trial demonstrates that in spinal cord injured patients a single 20 mg vardenafil administration achieved a significant decrease in maximum detrusor pressure, an improvement in maximum cystometric capacity and a remarkable increase in detrusor overactivity volume value. [Copyright &y& Elsevier]

Purpose: We examined the therapeutic effects of avanafil 15 minutes after dosing in men with mild to severe erectile dysfunction., Materials and Methods: This randomized, double-blind, placebo controlled, 12-week study (4-week run-in and 8-week treatment) randomized 145 men to placebo, 147 to avanafil 100 mg and 148 to avanafil 200 mg on demand. The primary efficacy variable was the per subject proportion of sexual attempts during the treatment period in which subjects achieved erection sufficient for vaginal penetration within approximately 15 minutes after dosing as measured by a stopwatch. The attempt had to enable successful completion of sexual intercourse according to SEP question 3., Results: Significantly greater mean per subject percentages of successful intercourse attempts within approximately 15 minutes after dosing were observed for avanafil 100 mg (mean 25.9%, LS mean ± SE 24.7% ± 2.9%) and 200 mg (mean 29.1%, LS mean 28.2% ± 2.9%) vs placebo (mean 14.9%, LS mean 13.8% ± 2.9%, p = 0.001 and <0.001, respectively). After treatment we noted a statistically significant difference between avanafil and placebo in the average per subject proportion of successful intercourse attempts according to SEP question 3 as early as 10 minutes in the 200 mg group and 12 minutes in the 100 mg group. Treatment emergent adverse events included headache, upper respiratory tract infection and nasal congestion, and most such events were mild or moderate in severity., Conclusions: Avanafil was efficacious within approximately 15 minutes of dosing compared to placebo. A statistically significant treatment difference in the percentage of successful sexual attempts was demonstrated as early as 10 minutes after treatment., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We prospectively investigated whether postoperative statin use would contribute to earlier recovery of erectile function in men who underwent bilateral nerve sparing radical retropubic prostatectomy for clinically localized prostate cancer., Materials and Methods: A total of 50 potent men without hypercholesterolemia undergoing bilateral nerve sparing radical retropubic prostatectomy for clinically localized prostate cancer were prospectively randomized into 2 equal groups. Group 1 patients were instructed to ingest only 50 mg sildenafil per day if needed following hospital discharge after radical retropubic prostatectomy. Group 2 patients were prescribed atorvastatin at a dose of 10 mg daily from postoperative days 1 to 90 and they were also instructed to ingest sildenafil, as in group 1. Patient status regarding potency and adverse events were assessed 6 months after surgery., Results: The 2 groups demonstrated no significant differences regarding various baseline factors, including International Index of Erectile Function-5 scores. Group 2 had a significantly higher postoperative International Index of Erectile Function-5 score than group 1 at 6 months postoperatively (p = 0.003). Meanwhile, as judged by a preset definition, the incidence of potent patients 6 months after prostatectomy was 26.1% in group 1 and 55% in group 2 (p = 0.068). Also, 17.4% and 40% of the men reported achieving intercourse by vaginal penetration without a phosphodiesterase 5 inhibitor in groups 1 and 2, respectively (p = 0.172). No serious adverse events associated with medication were reported., Conclusions: Postoperative treatment with atorvastatin in men who report normal erectile function preoperatively may contribute to earlier recovery of erectile function after nerve sparing radical retropubic prostatectomy.

Purpose: We determined the differential cyclic guanyl monophosphate catalytic and cyclic guanyl monophosphate binding activity of phosphodiesterase-5 isoforms and the inhibitory effects of sildenafil (Pfizer, New York, New York) and vardenafil (Bayer Pharmaceutical Research, Wuppertal, Germany)., Materials and Methods: Coding sequences of the human phosphodiesterase-5 isoforms A1, A2 and A3 were cloned into pBlueBac4.5/V5-His (Invitrogen, Carlsbad, California), which allows the tagging of histidines at the carboxyl terminal of the expressed protein. Isoforms were expressed with the Bac-N-Blue baculoviral system and purified with the ProBond system. Expression clones were identified by polymerase chain reaction using vector and phosphodiesterase-5 specific primers. Purified proteins were verified by Western blotting. Purified proteins were analyzed for cyclic guanyl monophosphate catalytic and cyclic guanyl monophosphate binding activity, and used to determine the differential potencies of the phosphodiesterase-5 selective inhibitors sildenafil and vardenafil., Results: Cloning and expression of phosphodiesterase-5A1 to A3 isoforms in the baculoviral system resulted in the isolation of purified isoform proteins. Mean cyclic guanyl monophosphate catalytic activity (K(m)) +/- SD was 4.76 +/- 0.37, 4.52 +/- 0.09 and 11.39 +/- 0.22 microM for A1 to A3, respectively. Mean cyclic guanyl monophosphate binding activity (K(d)) was 3.24 +/- 0.47, 1.95 +/- 0.60 and 1.70 +/- 0.47 microM for A1 to A3, respectively. Mean IC(50) of sildenafil against phosphodiesterase-5A1 to A3 was 1.20 +/- 0.34, 2.83 +/- 0.56 and 2.28 +/- 0.38 nM, respectively. Mean IC(50) of vardenafil against phosphodiesterase-5A1 to A3 was 0.41 +/- 0.15, 0.23 +/- 0.08 and 0.45 +/- 0.06 nM, respectively., Conclusions: Phosphodiesterase-5A1 and A2 had similar K(m) values, while phosphodiesterase-5A3 had a much higher K(m) and, thus, lower cyclic guanyl monophosphate catalytic activity. Phosphodiesterase-5A2 and A3 had similar K(d) values, while phosphodiesterase-5A1 had higher K(d) and, thus, lower cyclic guanyl monophosphate binding activity. Vardenafil was more potent (3 to 12-fold) than sildenafil for inhibiting the catalytic activity of all 3 human phosphodiesterase-5 isoforms with phosphodiesterase-5A2 showing the highest differentiation (12-fold).

Purpose: We investigated whether phosphodiesterase-5 (PDE5) can be down-regulated by a specific small interfering RNA (siRNA) and whether this would improve erectile function., Materials and Methods: A PDE5 siRNA encoding oligonucleotide was inserted into pSUPER-retro vector, resulting in the siRNA expressing construct, pPDE5-silencer. The construct was packaged into oncoretroviral particles and then transduced into rat cavernous smooth muscle cells (CSMCs). Cells were examined for PDE5 expression by reverse transcriptase-polymerase chain reaction, Western blotting and immunofluorescence microscopy. Cells were then treated with 10 microM sodium nitroprusside (SNP) and examined for cyclic guanosine monophosphate (cGMP) at 0, 10, 30, 60 and 240 minutes. The siRNA expressing cassette was transferred from the oncoretrovirus to lentivirus, which was then injected into rat penises. Three months later erectile function was examined by electrostimulation and PDE5 expression in cavernous smooth muscle was determined by immunohistochemistry., Results: CSMCs transfected with pPDE5-silencer (CSMC plus siRNA) showed an 88.2% decrease in PDE5 compared with CSMCs transfected with control vector (CSMCs plus vector). Within 10 minutes of SNP treatment cells (CSMCs, CSMCs plus vector and CSMCs plus siRNA) showed similar sharp increases in cGMP. However, while cGMP levels in CSMCs and CSMCs plus vector returned to almost baseline in 1 hour, the cGMP level in CSMCs plus siRNA remained high even 4 hours after SNP treatment. Rats injected with the siRNA expressing lentivirus showed increased electrostimulated erectile function, as measured by peak intracorporeal pressure and the intracorporeal pressure increase, compared with rats injected with control lentivirus. PDE5 expression was decreased in the siRNA treated cavernous smooth muscle., Conclusions: PDE5 expression could be decreased by siRNA, resulting in prolonged cGMP accumulation and improved erection.

Purpose: Nerve sparing radical retropubic prostatectomy (NS-RRP) results in erectile dysfunction in a significant number of patients. Vardenafil, a potent and selective phosphodiesterase type 5 inhibitor, is generally safe. It improves International Index of Erectile Function erectile function domain scores, and penetration and erection maintenance success rates in patients who have undergone NS-RRP. We report additional parameters important to patient perceptions regarding erection quality and satisfaction with sexual experience following NS-RRP., Materials and Methods: A total of 440 men at 58 centers throughout the United States and Canada participated in this randomized, placebo controlled, double-blind trial with 3 phases, namely baseline (4-week untreated period), treatment (12 weeks) and followup (7 days). Participants received placebo (145), 10 mg vardenafil (146) or 20 mg vardenafil (149) at home on demand but no more than once per calendar day. Efficacy and satisfaction with erection quality and sexual experience were determined during the trial., Results: The 10 and 20 mg vardenafil doses were significantly superior to placebo for the International Index of Erectile Function domains for intercourse satisfaction, orgasmic function and overall satisfaction with sexual experience (vs placebo p <0.0009). Significant improvement in the satisfaction rate with erection hardness were demonstrated for each vardenafil dose compared with placebo (p <0.0001). Vardenafil was generally well tolerated. Common adverse events were headache, vasodilatation and rhinitis., Conclusions: In this difficult to treat population of men with erectile dysfunction subsequent to NS-RRP on demand treatment with vardenafil during a 3-month period significantly improved key aspects of the sexual experience important to patient quality of life.

Purpose: Tadalafil, a phosphodiesterase type 5 inhibitor, is effective therapy for erectile dysfunction (ED). Men with ED have a high incidence of comorbid conditions including cardiovascular disease, diabetes mellitus and benign prostatic hyperplasia. Although phosphodiesterase type 5 inhibitors are safe when administered with most medications, sildenafil given with doxazosin and vardenafil given with terazosin evoke orthostatic hypotension in some patients. We examined the hemodynamic interactions of tadalafil with the alpha-blockers doxazosin and tamsulosin., Materials and Methods: In separate double-blind, placebo controlled, randomized crossover studies (18 patients in each study) we evaluated the hemodynamic effects of doxazosin 8 mg with tadalafil 20 mg, and tamsulosin 0.4 mg with tadalafil 10 and 20 mg. Blood pressure (BP) and heart rate were recorded before dosing and for 24 hours after dosing., Results: Tadalafil 20 mg augmented the hypotensive effect of doxazosin by producing a mean maximal decrease in standing systolic BP (SBP) that was significantly greater than placebo (a mean difference of 9.8 mm Hg). Analysis of BP outliers showed that the number of subjects with a standing SBP of less than 85 mm Hg was greater after doxazosin plus tadalafil (28%) versus doxazosin plus placebo (6%). In subjects on tamsulosin, tadalafil 10 and 20 mg produced mean maximal decreases in standing SBP that were similar to placebo (mean difference of 1.7 and 2.3 mm Hg, respectively). No subject taking tamsulosin had a decrease in standing SBP less than 85 mm Hg., Conclusions: Tadalafil augmented the hypotensive effects of doxazosin but had little hemodynamic interaction with tamsulosin. In patients taking tadalafil for ED, tamsulosin 0.4 mg may be given for the treatment of benign prostatic hyperplasia.

Purpose: We evaluate the efficacy and safety of tadalafil, taken as needed, in men with mild to severe erectile dysfunction (ED) and assess sexual intercourse attempt patterns., Materials and Methods: In this multicenter, double-blind, placebo controlled, parallel study conducted in the United States and Puerto Rico 207 men with ED were randomized to placebo or 20 mg tadalafil for 12 weeks. The primary efficacy variables were changes from baseline in the mean International Index of Erectile Function erectile function domain score and mean per patient percentage of "yes" responses to Sexual Encounter Profile (SEP) diary questions 2 (successful penetration) and 3 (successful intercourse). The Global Assessment Question was a secondary end point and post hoc analyses on sexual intercourse attempt patterns were conducted., Results: Men treated with tadalafil compared with placebo reported greater mean changes from baseline on the erectile function domain score (9.3 vs 0.3 with placebo, p <0.001) and on the mean per patient percentage of successful penetration (SEP question 2, 31.6% vs 2.3% with placebo, p <0.001) and successful intercourse attempts (SEP question 3, 43.6% vs 3.5% with placebo, p <0.001). The per treatment group percentage of successful intercourse attempts during treatment was higher for tadalafil than placebo (67.6% vs 24.1%, respectively, p <0.001) and most successful intercourse attempts occurred between 4 and 36 hours after taking tadalafil. Of the men treated with tadalafil 82.8% reported improved erections versus 19.6% taking placebo (Global Assessment Question, p <0.001). The most common treatment emergent adverse events were headache (15.7% vs 6.3% with placebo), back pain (8.8% vs 0%), and dyspepsia (7.5% vs 0%)., Conclusions: Tadalafil (20 mg) significantly improved erectile function and patients did not closely temporally link sexual intercourse attempts with taking tadalafil. Tadalafil was also well tolerated in both groups of men with mild to severe ED.

Purpose: We assessed the effects on spermatogenesis of placebo vs 10 or 20 mg tadalafil administered daily for 6 months to healthy men and men with mild erectile dysfunction., Materials and Methods: In 2 studies 421 healthy men or men with mild erectile dysfunction who were 45 years or older and met semen criteria derived from WHO reference values were randomized to 6 months of treatment with placebo (101) or 10 mg tadalafil (103), or to placebo (106) or 20 mg tadalafil (111). Semen samples and serum for reproductive hormones (testosterone, luteinizing hormone and follicle-stimulating hormone) were collected at baseline, after 3 months and at the end of treatment., Results: Tadalafil had no adverse effects on spermatogenesis, as assessed by sperm concentration, sperm count per ejaculate, percent sperm motility, normal morphology or serum reproductive hormones. Tadalafil was well tolerated. Common adverse events were headache, dyspepsia and back pain., Conclusions: Chronic daily administration of tadalafil at doses of 10 and 20 mg for 6 months had no adverse effects on spermatogenesis or on reproductive hormones in men older than 45 years.

Purpose: We identify whether tachyphylaxis and priapism effects of sildenafil are related to regulation of phosphodiesterase-5 (PDE-5) expression., Materials and Methods: Cavernous smooth muscle cells (CSMCs) were isolated from young rats and treated with 0, 1, 10 and 25 microM sildenafil with or without 100 microM of sodium nitroprusside for 3 and 7 days. The cells were subjected to reverse transcriptase-polymerase chain reaction and Western blot analysis for PDE-5 expression. Plasmid constructs carrying PDE-5A1 and PDE-5A2 promoters were transfected into COS-7 cells, treated with 25 microM sildenafil and analyzed for promoter activities. To simulate priapism, CSMCs were cultured under anoxia or hypoxia and then analyzed for PDE-5 expression. Furthermore, rats underwent bilateral pudendal arterial ligation for 1 day to 14 weeks, and corpus cavernous tissues were subjected to reverse transcriptase-polymerase chain reaction analysis for PDE-5 expression., Results: Up-regulation of PDE-5 was noted in CSMCs treated with 25 microM sildenafil for 7 days. PDE-5 messenger RNA and protein levels were significantly increased in the 7-day sildenafil treated cultures. Sodium nitroprusside appeared to down-regulate PDE-5 expression. Sildenafil significantly increased the activities of PDE-5A1 promoter. PDE-5 expression was significantly reduced under anoxia and hypoxia. The corpus cavernous tissue showed a gradual decrease in PDE-5 expression under ischemia., Conclusions: Repeated treatment with sildenafil at high concentrations was needed to simulate tachyphylaxis in our cell culture system. Adequate oxygenation was important for PDE-5 expression. Thus, sicklemic patients may express PDE-5 at abnormally low levels, predisposing them at risk of stuttering priapism.

Purpose: We conducted integrated analyses of the efficacy and safety of tadalafil, a potent, selective phosphodiesterase 5 inhibitor, for the treatment of erectile dysfunction., Materials and Methods: A total of 1,112 men with a mean age of 59 years (range 22 to 82) and mild to severe erectile dysfunction of various etiologies were randomized to placebo or tadalafil, taken as needed without food or alcohol restrictions, at fixed daily doses of 2.5 mg, 5 mg, 10 mg, or 20 mg up to a maximum of once daily [DOSAGE ERROR CORRECTED] in 5 randomized, double-blind, placebo controlled trials lasting 12 weeks. The 3 co-primary outcomes were changes from baseline in the erectile function domain of the International Index of Erectile Function and the proportion of "yes" responses to questions 2 and 3 of the Sexual Encounter Profile. Additional efficacy instruments included a Global Assessment Question., Results: Compared with placebo, tadalafil significantly enhanced all efficacy outcomes. Patients receiving 20 mg. tadalafil experienced a significant mean improvement of 7.9 in International Index of Erectile Function erectile function domain score from baseline (p <0.001 versus placebo), 75% of intercourse attempts (Sexual Encounter Profile question 3, a secondary efficacy outcome) were successfully completed (p <0.001 versus placebo) and 81% reported improved erections at end point compared with 35% in the control group (p <0.001). Tadalafil was consistently efficacious across disease severities and etiologies, as well as in patients of all ages. Tadalafil was well tolerated, and headache and dyspepsia were the most frequent adverse events., Conclusions: Tadalafil was effective and well tolerated in this patient population.

Purpose: Cyclic nucleotide phosphodiesterases (PDEs) are important regulators of cAMP/cGMP secondary messenger systems. Fluctuations in the level of cyclic nucleotides control the smooth muscle tone of corpus cavernosum. It had been shown that milrinone, a PDE3 inhibitor, was as potent as sildenafil, a PDE5 inhibitor, in relaxing human corpus cavernosum. However, milrinone is much less effective in relaxing rabbit corpus cavernosum than sildenafil. PDEs in rabbit corpus cavernosum were characterized and organ bath experiments were carried out in an attempt to search for the biochemical basis of this species difference., Materials and Methods: In a biochemical study, PDE isozymes from rabbit corpus cavernosum were isolated by FPLC and characterized by PDE assay. In organ bath experiments, rabbit corpus cavernous tissue strips were precontracted and increasing doses of various inhibitors were added., Results: The major PDE in rabbit corpus cavernosum is PDE5. There are small amounts of PDE2 and PDE1. PDE3, which contributes significantly to the total PDE activity in human corpus cavernosum, is apparently lacking in rabbit corpus cavernosum. Organ bath experiments with isotype-specific inhibitors confirm this conclusion., Conclusion: The distribution of PDE isozymes in corpus cavernosum is different in human and in rabbit. This could be the biochemical basis for the differential effects of milrinone in relaxing rabbit and human corpus cavernosum. Our study emphasizes the importance of a more complete understanding of the tissue distribution of targeted proteins in an animal model before applying the results to humans.