Evaluating the safety and potential activity of URO-902 (hMaxi-K) gene transfer by intravesical instillation or direct injection into the bladder wall in female participants with idiopathic (non-neurogenic) overactive bladder syndrome and detrusor overactivity from two double-blind, imbalanced, placebo-controlled randomized phase 1 trials.

AIMS: Two phase 1 trials were performed in healthy women with the overactive bladder (OAB) syndrome and urodynamically demonstrated detrusor overactivity (DO), with the aim to demonstrate the safety and potential efficacy of URO-902, which comprises a gene therapy plasmid vector expressing the human big potassium channel α subunit. METHODS: ION-02 (intravesical instillation) and ION-03 (direct injection) were double-blind, placebo-controlled, multicenter studies without overlap in enrollment between studies. Active doses were administered and evaluated sequentially (lowest dose first) for safety. ION-02 participants received either 5000 µg or 10 000 µg URO-902, or placebo. ION-03 participants received either 16 000 or 24 000 µg URO-902, or placebo, injected directly into the bladder wall using cystoscopy. Primary outcome variables were safety parameters occurring subsequent to URO-902 administration; secondary efficacy variables also were evaluated. RESULTS: Among the safety outcomes, there were no dose-limiting toxicities or significant adverse events (AEs) preventing dose escalation during either trial, and no participants withdrew due to AEs. For efficacy, in ION-02 (N = 21), involuntary detrusor contractions on urodynamics at 24 weeks in patients receiving URO-902 (P < .0508 vs placebo) and mean urgency incontinence episodes in the 5000 µg group (P = .0812 vs placebo) each showed a downward trend. In ION-03 (N = 13), significant reduction versus placebo in urgency episodes (16 000 µg, P = .036; 24 000 µg, P = .046) and number of voids (16 000 µg, -2.16, P = .044; 24 000 µg, -2.73, P = .047) were observed 1 week after injection. CONCLUSION: Promising safety and efficacy results in these preliminary phase 1 studies suggest gene transfer may be a promising therapy for OAB/DO, warranting further investigation.

A pilot study to determine penile oxygen saturation before and after vacuum therapy in patients with erectile dysfunction after radical prostatectomy.

INTRODUCTION: Provoked and spontaneous nocturnal erections are thought to play a role in maintenance of male sexual health through oxygenation of the corpus cavernosa. Conversely, hypoxia is thought to be an etiological factor in the pathogenesis of cavernosal fibrosis and long-term erectile dysfunction. It has been hypothesized that the early penile hypoxia after radical prostatectomy (RP) may lead to fibrosis and consequently a decrease in stretched penile length and long-term erectile dysfunction. AIM: The aim of this study was to assess the changes in penile tissue oxygenation with vacuum erection device (VED) use. METHODS: Twenty men between 2 and 24 months following RP were enrolled prospectively. Each man cycled a VED to achieve full erection 10 consecutive times over a period of approximately 2 minutes without constriction ring. MAIN OUTCOME MEASURES: Tissue oximetry was measured at baseline and immediately after VED using a tissue oximeter at five sites: right thigh, right corpora, glans, left corpora, and left thigh. Additional measurements were captured over the course of an hour. RESULTS: Mean age and time from surgery was 58.2 years and 12.6 months, respectively, and the average Sexual Health Inventory for Men score was 7. Use of the VED significantly increased both glanular and corporal oximetry relative to the baseline values for the entire 60 minutes. An initial increase of 55% was seen in corporal oxygenation with VED use. CONCLUSIONS: This is the first study demonstrating that a single, brief application of the VED without a constriction ring results in significant improvement in penile oxygen saturation. The use of a VED has significant benefits for patients both with regard to cost and invasiveness when compared with other penile rehabilitation protocols.

A randomized, double-blind, placebo-controlled evaluation of the safety and efficacy of avanafil in subjects with erectile dysfunction.

INTRODUCTION: Phosphodiesterase type 5 (PDE5) inhibitors have become standard treatment for erectile dysfunction (ED). AIM: To prospectively evaluate the safety and efficacy of avanafil, a novel PDE5 inhibitor, in men with mild to severe ED. METHODS: In this multicenter, double-blind, Phase 3 trial, 646 subjects were randomized to receive avanafil (50 mg, 100 mg, 200 mg) or placebo throughout a 12-week treatment period. Subjects were instructed to take study drug 30 minutes prior to initiation of sexual activity. At least a 12-hour separation time between doses was required; no restrictions were placed on food or alcohol intake. MAIN OUTCOME MEASURES: Improvement in erectile function (EF) was measured by Sexual Encounter Profile questions 2 and 3 (SEP2 and SEP3) and by the EF domain of the International Index of Erectile Function (IIEF) questionnaire. RESULTS: Mean change in percentage of successful sexual attempts (SEP2 and SEP3) and IIEF-EF domain score significantly favored all doses of avanafil over placebo (P ≤ 0.001). Secondary analyses demonstrated achievement of successful intercourse by subjects within 15 minutes of dosing. Of the 300 sexual attempts made during this interval, 64% to 71% were successful in avanafil-treated subjects compared with 27% in placebo-treated subjects. Successful intercourse was also demonstrated >6 hours post dosing, with 59% to 83% of the 80 sexual attempts successful in avanafil-treated subjects compared with 25% of placebo-treated subjects. The most commonly reported adverse events in subjects taking avanafil included headache, flushing, and nasal congestion; there were no drug-related serious adverse events. CONCLUSION: Following 12 weeks of avanafil treatment without food or alcohol restrictions, significant improvements in sexual function were observed with all 3 doses of avanafil compared with placebo. Successful intercourse was observed as early as 15 minutes and >6 hours after dosing in some subjects. Avanafil was generally well tolerated for the treatment of ED.

A multi-institutional observational study of testosterone levels after testosterone pellet (Testopel(®)) insertion.

INTRODUCTION: Implantable testosterone pellets were approved by the Food and Drug Administration in 1972 for the treatment of testosterone deficiency syndrome (TDS). Clinical use of this testosterone delivery modality has been limited until its recent reintroduction (Testopel(®) , Slate Pharmaceuticals, Durham, NC, USA). Six academic institutions collaborated and combined their databases to more fully characterize serum testosterone levels after the pellet implantations. AIMS: To assess the time-dependent serum testosterone levels after subcutaneous testosterone pellets in clinical practice for the treatment of TDS. METHODS: Data were retrospectively pooled and analyzed from data in six academic institutions. Variables included patient age, total testosterone concentrations before and after implantation, the number of testosterone pellets implanted, and the time from implantation to measurement of serum testosterone concentrations. Three hundred eighty men undergoing 702 insertions were included for analysis using JMP (version 4.0.4; SAS Institute, Cary, NC, USA). MAIN OUTCOME MEASURES: Main outcome measures were postimplantation total testosterone levels and investigator-reported adverse events. Testosterone levels as a function of the number of pellets implanted and time from implantation were assessed. RESULTS: Implantation of six to ≥10 testosterone pellets (450 to ≥750 mg) increased total testosterone into the therapeutic range at 1 month postimplantation and sustained therapeutic levels (>300) for 4-6 months. Higher pellet numbers (10-12 pellets) were associated with higher, more consistent, and longer maintenance of testosterone levels within the therapeutic range. Four extrusions and three hematomas were reported early in our experience; other investigator-reported adverse events were generally mild to moderate in nature and transient in duration. No subjects required analgesics. CONCLUSIONS: Testosterone pellets (Testopel(®) , Slate Pharmaceuticals) provide sustained levels of testosterone for at least 4 months and up to 6 months in men with TDS. Implantation of ≥8 pellets achieved optimal results with respect to peak mean testosterone level and duration of effect. Testosterone pellets were generally well tolerated.

Recovery of erectile function after nerve sparing radical prostatectomy and penile rehabilitation with nightly intraurethral alprostadil versus sildenafil citrate.

PURPOSE: To our knowledge we report the first large, randomized, prospective penile rehabilitation clinical trial to compare the effectiveness of nightly intraurethral alprostadil vs sildenafil citrate after nerve sparing prostatectomy. MATERIALS AND METHODS: We performed a prospective, randomized, open label, multicenter American study in men with normal erectile function who underwent bilateral nerve sparing radical prostatectomy. The International Index of Erectile Function erectile function domain was the primary end point. Subjects initiated nightly treatment within 1 month of surgery with intraurethral alprostadil or oral sildenafil citrate (50 mg) for 9 months. After 1-month washout and before sexual activity subjects self-administered sildenafil citrate (100 mg) for a total of 6 attempts in 1 month. Secondary end points were the global assessment question, sexual encounter profile, Erectile Dysfunction Inventory of Treatment Satisfaction and measured stretched penile length. RESULTS: Of 139 men who started intraurethral alprostadil and 73 who started sildenafil citrate, 97 and 59, respectively, completed the trial. There were no statistically significant differences in International Index of Erectile Function erectile function domain and intercourse success rates to intraurethral alprostadil. The global assessment question was significantly better only at 6 months for intraurethral alprostadil (p <0.028). At completion there were no differences between treatments for any of the end points. CONCLUSIONS: This is the first study to directly compare the ability of alprostadil and a phosphodiesterase-5 inhibitor to enhance penile recovery subsequent to bilateral nerve sparing radical prostatectomy. The use of nightly subtherapeutic intraurethral alprostadil is well tolerated after radical prostatectomy. The benefit to return of erectile function of nightly sildenafil citrate and subtherapeutic intraurethral alprostadil appears to be comparable within the first year of surgery.

Phosphodiesterase type 5 inhibitors in postprostatectomy erectile dysfunction: a critical analysis of the basic science rationale and clinical application.

CONTEXT: Erectile dysfunction (ED) after radical prostatectomy (RP) has a significant negative impact on a patient's health-related quality of life. Phosphodiesterase type 5 inhibitors (PDE5-Is) have recently been utilized not only as a treatment of ED in this population but also as a preventive strategy in penile rehabilitation programs. OBJECTIVE: To elucidate the pathophysiologic mechanisms of post-RP ED, to assess the need for rehabilitation following surgery, and to analyze the basic scientific evidence and clinical applications of PDE5-Is for the prevention and treatment of ED. EVIDENCE ACQUISITION: A systematic review of the literature using Medline, Cancerlit, and the Cochrane Library was conducted for the period between January 1997 and June 2008 using the keywords erectile dysfunction, radical prostatectomy, and phosphodiesterase inhibitors. Efficacy and safety of PDE5-Is in the randomized, placebo-controlled trials are evaluated in this review, and the limitations of the remaining studies are also discussed. EVIDENCE SYNTHESIS: Post-RP ED has many factors. Cavernosal nerve injury induces pro-apoptotic factors (ie, loss of smooth muscle) and pro-fibrotic factors (ie, an increase in collagen) within the corpora cavernosa. Cavernosal changes may also be attributed to poor oxygenation due to hemodynamic changes. Experimental data support the concept of cavernosal damage and suggest a protective role for daily dosage of a PDE5-I; however, similar data have not yet been replicated in humans. Penile rehabilitation programs are common in clinical practice, but there is no definitive evidence to support their use or the best treatment strategy. PDE5-Is are efficacious and safe in young patients with normal preoperative erectile function who have undergone bilateral nerve-sparing radical prostatectomy. On-demand use of a PDE5-I may be at least as efficacious as daily use. PDE5-I use in penile rehabilitation programs is not supported by rigorous level 1 evidence-based medicine. CONCLUSIONS: PDE5-Is are an efficacious and safe treatment for post-RP ED in properly selected patients. The experimental results on the protective role of daily dosages of PDE5-Is, while robust, have not been replicated in humans. With current human data, the role of a PDE5-I alone as a rehabilitation strategy is unclear and deserves further investigation.

Randomized, double-blind, crossover trial of sildenafil in men with mild to moderate erectile dysfunction: efficacy at 8 and 12 hours postdose.

OBJECTIVES: To clarify the period of responsiveness to sildenafil. METHODS: Under a double-blind protocol, men with mild to moderate erectile dysfunction (International Index of Erectile Function [IIEF] Erectile Function domain score, 11 to 25) were randomized to sildenafil (100 mg) or placebo and attempted intercourse 8 hours (range, 7 to 9 hours) postdose (first 4-week phase) and 12 hours (11 to 13 hours) postdose (second 4-week phase after treatment crossover). The primary outcome was the per-patient proportion (PPP; least squares means [95% confidence interval]) of affirmative responses to the Sexual Encounter Profile question 3 (SEP3: "Did your erection last long enough for you to have successful intercourse?"). RESULTS: For sildenafil (n = 174) versus placebo (n = 177), baseline values were similar but the PPP of successful intercourse attempts increased to 76% (69% to 82%) versus 50% (43% to 57%) in phase 1 (odds ratio [OR] = 3.2) and 79% (72% to 85%) versus 52% (44% to 60%) in phase 2 (OR = 3.5), and the PPP of Erection Hardness Score 4 erections (completely hard and fully rigid) was 41% (34% to 48%) versus 10% (7% to 15%) in phase 1 (OR = 6.2) and 44% (37% to 51%) versus 17% (12% to 23%) in phase 2 (OR = 4.0). Thus, at 12 hours, the odds of successful intercourse tripled and of a completely hard erection quadrupled. The sildenafil group achieved greater (P <0.001) PPP of successful penetration (SEP2), satisfaction with erection hardness (SEP4), and satisfaction with the sexual experience (SEP5); improvement in IIEF domain scores; and treatment satisfaction on the Erectile Dysfunction Inventory of Treatment Satisfaction. CONCLUSIONS: In men with mild to moderate ED, responsiveness to sildenafil may persist much longer than 4 hours.

Return of nocturnal erections and erectile function after bilateral nerve-sparing radical prostatectomy in men treated nightly with sildenafil citrate: subanalysis of a longitudinal randomized double-blind placebo-controlled trial.

INTRODUCTION: After bilateral nerve-sparing radical retropubic prostatectomy (BNSRRP), nocturnal and sexually mediated erections may help to preserve normal erectile function (EF). AIM: To investigate nocturnal penile tumescence and rigidity (NPTR) in a subset (N = 54 men) from a randomized, double-blind trial (N = 76) of nightly sildenafil after BNSRRP. METHODS: Inclusion required preoperative "normal" EF (defined as a combined score of >/=8 for International Index of Erectile Function questions 3 (penetration) and 4 (maintained erection after penetration) and NPTR testing (>/=10 continuous minutes of >/=55% rigidity [R >/= 55%] at the base). Postoperative assessments were at weeks 4 (pretreatment), 16, 28, 40 (during 36 weeks of nightly prophylaxis: sildenafil 50 mg [N = 17], 100 mg [N = 18] or placebo [N = 19]), and 48 (after 8 weeks of no erectile dysfunction therapy, when "responders" were delineated by the defined normal EF and a "yes" response to "Over the past 4 weeks, have your erections been good enough for satisfactory sexual activity?"). Base and tip rigidity and tumescence were measured using penile plethysmography. MAIN OUTCOME MEASURES: Duration of R >/= 55% and area under the curves for rigidity and tumescence. RESULTS: Postoperatively, rapid profound reduction in nocturnal EF was noted in all groups. There was a gradual dose-dependent improvement in base and tip rigidity in the sildenafil groups but little improvement in the placebo group. Eight weeks after treatment termination (48 weeks postoperatively), 24% (4/17) of 50-mg sildenafil recipients, 33% (6/18) of 100-mg sildenafil recipients, and 5% (1/19) of placebo recipients were responders. Tip R >/= 55% was the most discriminating NPTR measure between nonresponders and responders to sildenafil, in whom it regained baseline (preoperative) levels (whereas base R >/= 55% did not). It was most prolonged in responders to sildenafil 100 mg. CONCLUSIONS: In our subset analysis, nightly sildenafil for 9 months post-BNSRRP objectively improved nocturnal erections and pharmaceutically unassisted EF.

Rehabilitation of erectile function following radical prostatectomy.

The concept of muscle rehabilitation after nerve injury is not a novel idea and is practiced in many branches of medicine, including urology. Bladder rehabilitation after spinal cord injury is universally practiced. The erectile dysfunction (ED) experienced after radical prostatectomy (RP) is increasingly recognized as being primarily neurogenic followed by secondary penile smooth muscle (SM) changes. There is unfortunately no standard approach to penile rehabilitation after RP because controlled prospective human studies are not available. This article reviews the epidemiology, experimental pathophysiological models, rationale for penile rehabilitation, and currently published rehabilitation strategies.

Penile oxygen saturation in the flaccid and erect penis in men with and without erectile dysfunction.

It is believed that a chronic state of corporal oxygen desaturation or hypoxemia secondary to the loss of nocturnal erections is a fundamental pathophysiological cause of erectile dysfunction (ED). Limited invasive blood gas measurements in human models have shown decreased oxygen tension in vasculogenic impotence. Normative data on flaccid and erect oxygen saturation (StO(2)) levels are lacking due to the invasive nature of blood gas determinations. Our objective was to determine StO(2) in the flaccid and erect penis in men with and without ED using a tissue oximeter. This FDA-approved instrument provides instantaneous, noninvasive, painless local tissue StO(2) measurements, which highly correlate to blood gas data. The study population included 171 men (18-90 years) who presented to one andrologist. They completed the Sexual Health Inventory for Men (SHIM) based on pharmacologically unassisted erectile function and had penile StO(2) measurements taken. 64 of these men had repeat measurements after PGE-1 induced erections. There are significant differences (P<.001) in corporal and glanular StO(2) in the flaccid (right corpora, 45.23%; left corpora, 52.50%) and erect state (right corpora, 76.58; left corpora, 80.42). Men with ED (right corpora, 45.04% vs 53.58%; P=.02; and left corpora, 50.95% vs 58.78%; P=.03) have significantly lower corporal penile StO(2). Future prospective data collection can correlate penile StO(2) in specific populations, such as diabetics and RRP patients. This may help further elucidate the relationship between corporal hypoxia and the development and progression of ED and possibly its treatment and prevention.

A prospective study of the beneficial effects of dose optimization and customized instructions on patient satisfaction with sildenafil citrate (Viagra) for erectile dysfunction.

Our objective was to assess the effects of customized instructions and dose optimization on treatment satisfaction and improvement in erectile function (EF) with sildenafil citrate in men with erectile dysfunction (ED) who had not been previously treated with a phosphodiesterase-5 inhibitor. This 8-week, multicenter, open-label, flexible-dose (25, 50, or 100 mg sildenafil) study included 2 phases. During phase 1, patients took 50 mg sildenafil and followed the sildenafil sample package instructions. In phase 2, sildenafil dose could be adjusted on the basis of efficacy and tolerability, and investigators provided additional customized instructions. The primary efficacy variable was the satisfaction rate (defined as patients responding "very" or "somewhat" satisfied to the Erectile Dysfunction Inventory of Treatment Satisfaction [EDITS] Question 1). Other efficacy assessments included the International Index of Erectile Function (IIEF) and the percentage of successful sexual intercourse attempts. Of 1109 men (mean age, 54+/-13 years) treated, 867 completed the study. In phase 1, 75% of patients were very or somewhat satisfied with treatment. Mean EF domain score on the IIEF increased from 14.3 at baseline to 23.5, and 79% of sexual intercourse attempts were successful. In phase 2, 53% of patients increased their sildenafil dose to 100 mg and 2% decreased to 25 mg. Satisfaction with sildenafil increased to 86%, 91% of sexual intercourse attempts were successful, and mean IIEF EF domain score increased to 25.7. Of the 196 men who were not initially satisfied at the end of phase 1, 64% became very or somewhat satisfied with treatment by the end of phase 2. Initially high levels of efficacy and satisfaction with sildenafil were achieved when patients were provided with only the sample package instructions and the recommended 50-mg starting dose. These results were enhanced with dose optimization, individual patient counseling, and customized instructions.

Sexual dysfunction after radical prostatectomy.

Sexual dysfunction associated with radical retropubic prostatectomy (RRP) may start before the surgery. Men undergoing RRP frequently have some degree of sexual dysfunction. In addition to the psychological stress of the diagnosis, the biopsy may itself have a detrimental effect. After surgery, all men will experience loss of ejaculate, because the organ responsible for ejaculate has been removed. Orgasm quality is adversely affected in many men. Erectile dysfunction is immediate and recovery from it is slow. Initially, phosphodiesterase (PDE)-5 inhibitors do not work, and they take up to 18 months for their effect to be maximized. Younger men who have had bilateral nerve-sparing procedures respond the best. Combination treatment with prostaglandin E1 or high-dose PDE-5 inhibitors may provide salvage therapy when initial PDE-5 inhibitor therapy has failed.

The penis as a barometer of endothelial health.

Erectile dysfunction (ED) has only within the past 25 years been recognized as being largely organic in cause. The introduction of phosphodiesterase-5 inhibitor therapy represents a major breakthrough in the treatment of ED and has resulted in a fast-growing body of knowledge regarding the etiology of the disorder, including its close association with cardiovascular disease. ED symptoms are often an early manifestation of endothelial dysfunction and, as such, should prompt further evaluation of not only the sexual dysfunction but also cardiovascular risk. This article discusses the importance of recognizing ED as much more than a quality-of-life issue.

Achieving treatment optimization with sildenafil citrate (Viagra) in patients with erectile dysfunction.

Since its approval in 1998, sildenafil citrate (Viagra) has been shown to be efficacious in >100 clinical trials involving >8000 men with erectile dysfunction (ED). In clinical practice, however, many men do not continue long-term use of sildenafil for a variety of reasons; thus, 6 different aspects of optimizing treatment with sildenafil are described here. (1) Intercourse success rates, considered a reflection of real-world effectiveness, were assessed in 1276 patients with ED. Results indicated that the cumulative probability of achieving intercourse success with sildenafil increased with the number of attempts, reaching a plateau after approximately 8 attempts. (2) A comprehensive disease management approach that included a medical history, physical examination, educational material about ED, modifications of risk factors/lifestyle changes, and counseling resulted in successful intercourse in 74% of 111 patients taking sildenafil. (3) A survey conducted among primary care physicians revealed that almost 50% did not routinely question their patients about ED symptoms, although it is known that most patients would prefer their physician to take the initiative. (4) Overall, 55% of 137 men who were previously not successful with sildenafil became successful after reeducation and counseling, which included information on patient and partner expectations, how to properly take the drug, titration to maximum dose, and a minimum trial of 8 attempts for efficacy assessment. (5) Many men with ED have underlying comorbidities or take multiple medications that are risk factors for ED. Controlling these risk factors in 521 men from a multispecialty clinic led to an overall intercourse success rate of 82%; patients with multiple risk factors were less likely to have intercourse success than men with only 1 risk factor. (6) Finally, treatment satisfaction is a pivotal factor in maintaining long-term ED therapy. In an open-label trial, 82% of 443 subjects reported treatment satisfaction with sildenafil. In summary, these findings highlight how important it is for physicians to take a more comprehensive, proactive approach when treating men with ED, including control of risk factors, instructions on how to properly take the drug, partner involvement, and follow-up visits. Using these recommended measures, most men with ED, including those whose treatment was previously unsuccessful, can be treated successfully with sildenafil.

Four-year review of sildenafil citrate.

Within 6 months of approval by the U.S. Food and Drug Administration (FDA), 5.3 million prescriptions were written for sildenafil citrate. It represented the first clearly effective and FDA-approved oral therapy for the treatment of ED. The chemical structure of sildenafil is very similar to the cyclic guanosine monophosphate molecule with which it competes, in the enzyme phosphodiesterase type-5. Sildenafil binds to the phosphodiesterase-5 enzyme, preventing the breakdown of cyclic guanosine monophosphate through competitive inhibition. The onset of action for sildenafil can be as short as 20 minutes and the duration of action may be as long as three half-lives (18 hours). Anecdotal evidence suggests that many men describe an erectogenic effect for almost 24 hours. The safety of sildenafil has been established in many pre- and postapproval studies at doses as high as eight times the maximum recommended dose. It is likely that the rare instance of myocardial infarction after taking sildenafil as directed, is due more to the activity of sexual intercourse rather than the medication itself. Efficacy have been established in patients with diabetes, parkinsonism, spinal cord injury, and those on antihypertensive (single- and multiple-therapy) agents. It has also been shown to be effective in reversing selective serotonin reuptake inhibitor-induced sexual side effects. Initial concerns about sildenafil with respect to ocular safety were based on misinterpretation of the FDA submission data. The two most common side effects are headache and flushing, both of which are short-lived and easily treated.