Randomized, double-blind, placebo-controlled study of postoperative nightly sildenafil citrate for the prevention of erectile dysfunction after bilateral nerve-sparing radical prostatectomy.

Four weeks after bilateral nerve-sparing radical retropubic prostatectomy, men with normal erectile function before surgery were randomized to double-blind sildenafil (50 or 100 mg) or placebo nightly for 36 weeks, followed by an 8-week drug-free period before assessment of erectile function. Enrollment was prematurely ceased and only 76 men completed because, assuming a placebo response rate similar to the published literature (for example, 34% in meta-analysis), the 25% response at blinded interim review suggested a lack of treatment effect. On the contrary, spontaneous erectile function (a combined score of >or=8 for questions 3 and 4 of the International Index of Erectile Function and a positive response to 'Were erections good enough for satisfactory sexual activity?') occurred in only 4% of the placebo group (n=1 of 25) versus 27% (n=14 of 51, P=0.0156, Fisher's exact test) of the sildenafil group. Nightly sildenafil administration for 36 weeks after surgery markedly increased the return of normal spontaneous erections.

Randomized study of testosterone gel as adjunctive therapy to sildenafil in hypogonadal men with erectile dysfunction who do not respond to sildenafil alone.

PURPOSE: We compare the efficacy of testosterone gel (T-gel) versus placebo as adjunctive therapy to sildenafil in hypogonadal men with erectile dysfunction who do not respond to sildenafil alone. MATERIALS AND METHODS: A randomized, placebo controlled, double-blind, parallel group, multicenter study was performed. A total of 75 hypogonadal men (18 to 80 years old, morning serum total testosterone 400 ng/dl or less) with confirmed lack of response to sildenafil monotherapy were randomized (1:1) to receive a daily dose of 1% T-gel or 5 gm placebo gel as adjunctive therapy to 100 mg sildenafil during a 12-week period. Subjects were evaluated for sexual function, primarily based on the International Index of Erectile Function (IIEF), quality of life and serum testosterone levels at baseline and weeks 4, 8 and 12. RESULTS: Testosterone treated subjects had greater improvement in erectile function compared to those who received placebo, reaching statistical significance at week 4 (4.4 vs 2.1, p = 0.029, 95.1% CI 0.3, 4.7). Similar trends were observed for improvements in orgasmic function, overall satisfaction, total IIEF score and percentage of IIEF responders. T-gel significantly (p < or = 0.004) increased total and free testosterone levels throughout the study, although no significant correlations were made between testosterone levels and the IIEF at end point. CONCLUSIONS: T-gel taken with sildenafil may be beneficial in improving erectile function in hypogonadal men with erectile dysfunction who are unresponsive to sildenafil alone.

Erectile dysfunction as a harbinger for increased cardiometabolic risk.

In August 2003, the Minority Health Institute (MHI) convened an Expert Advisory Panel of cardiologists and urologists to design a new practice model algorithm that uses erectile dysfunction (ED) as a clinical tool for early identification of men with systemic vascular disease. The MHI algorithm noted ED as a marker for the presence of cardiovascular disease and suggested that ED may well be a cardiovascular risk equivalent warranting aggressive secondary prevention management strategies, even in the absence of other cardiac or peripheral vascular symptoms. The MHI algorithm stipulates that all men 25 years of age and older should be asked about ED as a routine part of the cardiovascular history during any office visit. The presence of ED should prompt an aggressive assessment for occult vascular disease; many men with erectile difficulty would benefit from early, aggressive management of cardiovascular risk factors with both lifestyle modification and pharmacotherapy to achieve optimal target goals under the existing treatment guidelines. Since publication of the algorithm in 2005, additional research studies have further supported the advisory panel recommendations.

Efficacy and safety of pomegranate juice on improvement of erectile dysfunction in male patients with mild to moderate erectile dysfunction: a randomized, placebo-controlled, double-blind, crossover study.

This randomized-controlled trial examined the efficacy of wonderful variety pomegranate juice versus placebo in improving erections in 53 completed subjects with mild to moderate erectile dysfunction. The crossover design consisted of two 4-week treatment periods separated by a 2-week washout. Efficacy was assessed using International Index of Erectile Function (IIEF) and Global Assessment Questionnaires (GAQ). Of the 42 subjects who demonstrated improvement in GAQ scores after beverage consumption, 25 reported improvement after drinking pomegranate juice. Further, 17 subjects showed preference of one beverage to the other. Subjects were more likely to have improved scores when pomegranate juice was consumed (P=0.058). Although overall statistical significance was not achieved, this pilot study suggests the possibility that larger cohorts and longer treatment periods may achieve statistical significance.

Sildenafil citrate (Viagra) treatment for erectile dysfunction: An updated profile of response and effectiveness.

In the 7 years since sildenafil citrate (VIAGRA) was introduced as the first oral phosphodiesterase type 5 inhibitor therapy for erectile dysfunction, it has been used to treat nearly 27 million men with erectile dysfunction worldwide. Patient populations with erectile dysfunction of varying etiologies and with diverse comorbidities have benefited from sildenafil treatment. This update focuses on relatively recent research that further defines the response and effectiveness profiles of sildenafil and provides additional insight into optimizing treatment. In addition to providing recent data on sildenafil efficacy and safety/tolerability, the update provides data on assessments of erection hardness, measures of psychosocial outcomes (e.g., emotional well-being and treatment satisfaction), and treatment approaches to maximize response and effectiveness (e.g., by titrating to the maximum tolerated dose). Increased understanding of the sildenafil response and effectiveness profiles and optimal sildenafil treatment are central to the appropriate management of erectile dysfunction using sildenafil.

Erectile dysfunction in patients with coronary artery disease.

Recent studies suggest that erectile dysfunction (ED) may be an early marker of endothelial dysfunction and coronary artery disease (CAD). Conversely, patients with CAD commonly have ED. The phosphodiesterase 5 (PDE5) inhibitors are very effective for the treatment of ED in patients with CAD. Numerous studies show that this class of drugs is in general safe in patients with stable CAD and these agents do not exacerbate ischemia in men with CAD undergoing exercise stress testing. Analysis of placebo-controlled trials did not show an increase in cardiovascular events among men receiving PDE5 inhibitors, and post-marketing surveillance studies with sildenafil did not observe an increase in cardiovascular events compared to expected age-matched rates. Organic nitrates remain a contraindication for PDE5 inhibitors and alpha blockers have precautions/contraindications depending upon specific drugs. The Princeton Consensus Guidelines (soon to be updated) suggest a logical approach to the patient with CAD seeking therapy for sexual dysfunction.

Randomized study of testosterone gel as adjunctive therapy to sildenafil in hypogonadal men with erectile dysfunction who do not respond to sildenafil alone.

PURPOSE: We compare the efficacy of testosterone gel (T-gel) versus placebo as adjunctive therapy to sildenafil in hypogonadal men with erectile dysfunction who do not respond to sildenafil alone. MATERIALS AND METHODS: A randomized, placebo controlled, double-blind, parallel group, multicenter study was performed. A total of 75 hypogonadal men (18 to 80 years old, morning serum total testosterone 400 ng/dl or less) with confirmed lack of response to sildenafil monotherapy were randomized (1:1) to receive a daily dose of 1% T-gel or 5 gm placebo gel as adjunctive therapy to 100 mg sildenafil during a 12-week period. Subjects were evaluated for sexual function, primarily based on the International Index of Erectile Function (IIEF), quality of life and serum testosterone levels at baseline and weeks 4, 8 and 12. RESULTS: Testosterone treated subjects had greater improvement in erectile function compared to those who received placebo, reaching statistical significance at week 4 (4.4 vs 2.1, p = 0.029, 95.1% CI 0.3, 4.7). Similar trends were observed for improvements in orgasmic function, overall satisfaction, total IIEF score and percentage of IIEF responders. T-gel significantly (p < or =0.004) increased total and free testosterone levels throughout the study, although no significant correlations were made between testosterone levels and the IIEF at end point. CONCLUSIONS: T-gel taken with sildenafil may be beneficial in improving erectile function in hypogonadal men with erectile dysfunction who are unresponsive to sildenafil alone.

Minimal time to successful intercourse after sildenafil citrate: results of a randomized, double-blind, placebo-controlled trial.

OBJECTIVES: To determine the minimal time to successful intercourse after taking sildenafil citrate for erectile dysfunction (ED). METHODS: Male patients with ED (mean age 60 years; mean ED duration 7.0 years) who were successfully treated with sildenafil (100 mg) for 2 months or longer were randomized to sildenafil (n = 115) or placebo (n = 113) for 4 weeks of double-blind treatment. Using a stopwatch, patients recorded the time needed to obtain an erection hard enough for sexual intercourse after taking the study drug at least 2 hours after eating. RESULTS: Within 14 and 20 minutes of sildenafil dosing, 35% and 51% of sildenafil-treated patients, respectively, versus 22% and 30% of placebo-treated patients, respectively, had an erection that led to successful intercourse (P <0.05 for both). The median time to erection leading to successful intercourse after sildenafil dosing was 36 minutes compared with 141 minutes for placebo. CONCLUSIONS: In this study, slightly more than one half of a population of prior sildenafil responders achieved an erection that led to successful sexual intercourse within 20 minutes of sildenafil administration, suggesting that the onset of action of sildenafil can be less than 30 minutes in men with ED.

The efficacy and safety of a topical alprostadil cream, Alprox-TD, for the treatment of erectile dysfunction: two phase 2 studies in mild-to-moderate and severe ED.

In two multicenter, placebo controlled, phase 2 studies, patients with mild-to-moderate (n=161, Study 1) or severe (n=142, Study 2) erectile dysfunction (ED) were randomized to receive placebo, 0.05, 0.1, or 0.2 mg (Study 1) or placebo, 0.1, 0.2, or 0.3 mg (Study 2) of topically applied alprostadil (containing a proprietary skin permeation enhancer). The primary efficacy end point in both studies was the change in erectile function (EF) score from baseline to final visit. The changes from baseline for EF scores were -0.8+/-1.1, 1.8+/-1.1, 0.7+/-1.2, and 3.7+/-1.2 (P<0.01; Study 1) and 2.7+/-1.3, 6.29+/-1.4, 6.49+/-1.5, and 9.44+/-1.5 (P<0.001; Study 2) for ascending dose groups in each study. Topical alprostadil was well tolerated with the most common adverse event being urogenital pain. These results suggest this topical alprostadil formulation may be a potentially useful agent for the treatment of ED.

Long-term safety and efficacy of oral phentolamine mesylate (Vasomax) in men with mild to moderate erectile dysfunction.

The objectives of this study were to evaluate long-term safety and efficacy of phentolamine mesylate, an orally active, rapid-acting alpha-adrenergic receptor antagonist, for the treatment of men suffering from erectile dysfunction (ED). It was an open-label study involving more than 2000 patients. Men received phentolamine mesylate 40 mg or 80 mg (10 tablets/month) as needed for up to 13 months and self-assessed erectile performance using two validated questionnaires. Treatment with phentolamine mesylate was associated with increases in Erectile Function Domain score of the IIEF, successful vaginal penetrations, and in overall satisfaction. Most adverse events were mild or moderate in severity and consistent with the known pharmacodynamic properties of phentolamine. In conclusion, phentolamine mesylate is safe and effective in the long-term treatment of men with mild to moderate ED.

The efficacy and tolerability of vardenafil, a new, oral, selective phosphodiesterase type 5 inhibitor, in patients with erectile dysfunction: the first at-home clinical trial.

Vardenafil, a novel selective phosphodiesterase type 5 inhibitor, was evaluated in its first large-scale at-home trial. A total of 601 men with mild to severe erectile dysfunction (ED) were enrolled in this multi-centre, randomized, double-blind, placebo-controlled trial of 12 weeks of treatment with either placebo or 5, 10 and 20 mg of vardenafil. Primary endpoints were Q3 (vaginal penetration) and Q4 (maintenance of erection) of the International Index of Erectile Function (IIEF). In the intent-to-treat population (n=580), the changes from baseline for 5, 10 and 20 mg vardenafil (1.2, 1.3 and 1.5, respectively) were all improved (P<0.001) over placebo (0.2) for Q3 and were similarly improved for Q4 (1.4, 1.5 and 1.7) compared to placebo (0.5) (P<0.001). All vardenafil doses improved all IIEF domains compared to placebo (P<0.001). The percentage of successful intercourses was between 71 and 75% for the three vardenafil doses. For the 20 mg dose, 80% of the patients experienced improved erections (GAQ) compared to 30% for placebo. Most frequent treatment-emergent adverse events were headache (7-15%), flushing (10-11%) and up to 7% for dyspepsia or rhinitis. Vardenafil treatment resulted in a high efficacy and low adverse-event profile in a population with mixed ED etiologies.

Oral drug therapy for erectile dysfunction.

Oral drugs are a well-established, first-line therapy for erectile dysfunction. As a result of the success of sildenafil, a plethora of new drugs for erectile dysfunction are on the horizon. Apomorphine and IC351 are in late phase III development. Vardenafil (Bayer, New Haven, CT), a PDE5 inhibitor, and the combination of yohimbine and L-arginine (NitroMed, Boston, MA) are in early phase III development. Early clinical and preclinical studies are investigating new phosphodiesterase inhibitors, cyclic AMP activators, alpha-adrenergic antagonists, dopamine agonists, melanocyte-stimulating hormone, potassium channel modulators, endothelin antagonists, and new nitric oxide donors. The future is bright for this infant field of sexual pharmacotherapy.

On-demand IC351 (Cialis) enhances erectile function in patients with erectile dysfunction.

IC351 (Cialis) is a selective inhibitor of PDE5. The efficacy and safety of on-demand dosing of IC351 in men with erectile dysfunction was assessed in a multicenter, double-blind, placebo-controlled study. One hundred seventy-nine men (mean age: 56 y) were randomized to receive placebo or IC351 at doses of 2, 5, 10 or 25 mg, taken on demand over a 3-week period. The primary endpoints were change from baseline in responses to Questions 3 (Q3) and 4 (Q4) of the International Index of Erectile Function (IIEF). IC351 significantly improved IIEF Q3 scores at all doses vs placebo (P < or =0.003). IC351 also significantly improved IIEF Q4 scores in all but the 2 mg group (P < or =0.0003). No significant changes in laboratory values, ECGs, or blood pressure were observed. The most common adverse events were headache and dyspepsia. The conclusion of this study was that on-demand IC351 at doses up to 25 mg was well tolerated and significantly improved erectile function.

Axial penile rigidity as primary efficacy outcome during multi-institutional in-office dose titration clinical trials with alprostadil alfadex in patients with erectile dysfunction. Alprostadil Alfadex Study Group.

The purpose of the study was to utilize axial penile buckling testing as a primary efficacy variable of erection quality during multi-institutional in-office dose titration testing with alprostadil alfadex, prostaglandin E1 (PGE1)-alpha-cyclodextrin, (EDEX /VIRIDAL, Schwarz Pharma) in patients with erectile dysfunction. In 41 study sites, in three different dose titration studies involving 894 patients with impotence >6 months, a buckling test was performed and repeated every 10 min for up to 60 min, within 30 min following alprostadil alfadex administration, or when two consecutive circumference measurements reached maximum values. The buckling device consisted of a standard weight scale attached to a 2 inch diameter plastic cap with a concavity on its ventral surface (H. Eric Richards, Inc., Canton MA). A positive test was associated with absent penile shaft buckling to a downward force of 1.0 kg, slowly applied to the glans in the axis of the erect shaft. A total of 630 (71%) patients experienced at least one positive buckling test. Three consecutive positive buckling tests, implying a functionally rigid erection for at least 20 min, were noted in 521 (58%) patients. There were high correlations between the presence of three consecutive positive buckling tests following alprostadil alfadex injection and the patient's (83% of cases) and the investigator's (88% of cases) evaluation of adequacy of erection for intercourse. Similarly, there were high correlations between the presence of negative buckling tests and the patient's (95% of cases) and the investigator's (96% of cases) evaluation of inadequacy of erection for intercourse. The axial penile buckling test offers a simple, reliable, and inexpensive method to objectively quantify erectile response following in-office dose titration of intracavernosal alprostadil alfadex. The high correlation to subjective patient/investigator assessment adds to the validity of the test.

Diagnostic and treatment strategies for erectile dysfunction: the 'Process of Care' model. [University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School].

The new era of erectile dysfunction medicine ushered in by the availability of an effective and safe oral medication paves the evolution of the field toward a multi-disciplinary and primary care setting. There exists a paucity of guidelines regarding the assessment and management of the patient with erectile dysfunction in the primary care arena. The 'Process of Care' model for the evaluation and treatment of erectile dysfunction has been developed to advance new guidelines for the diagnosis and management of erectile dysfunction in the primary care and multi-disciplinary setting. This model was developed under the auspices of the University of Medicine and Dentistry of New Jersey (UMDNJ)-Robert Wood Johnson Medical School (chairman: R Rosen) with input from a multi-disciplinary group of experts including representation from primary care, internal medicine, endocrinology, psychiatry, psychology and urology. The methodology employed was a modified delphi-technique (RAND method). The key components of the model are: 1)a rational approach to diagnosis and treatment, 2) emphasis on clinical history-taking and a focused physical examination 3) specialized testing and referral in pre-defined situations 4) step-wise management approach with ranking of treatment options and 5)incorporation of patient and partner needs and preferences in the decision making process when possible (a goal-directed approach). The management algorithm is conceptually organized into progressive stages from Process--> Action--> Outcome. International Journal of Impotence Research (2000) 12, Suppl 4, S119-S121.

Diagnosis and treatment of erectile dysfunction: the process of care model.

The new era of erectile dysfunction (ED) medicine ushered in by the availability of an effective and safe oral medication paves the way toward managing ED in a primary care setting. The Process of Care Model for the Evaluation and Treatment of Erectile Dysfunction was developed to advance new guidelines for the diagnosis and management of ED. This paper discusses these guidelines.

Management of sexual dysfunction in patients with cardiovascular disease: recommendations of the Princeton Consensus Panel.

Sexual dysfunction is highly prevalent in both sexes and adversely affects patients' quality of life and well being. Given the frequent association between sexual dysfunction and cardiovascular disease, in addition to the potential cardiac risk of sexual activity itself, a consensus panel was convened to develop recommendations for clinical management of sexual dysfunction in patients with cardiovascular disease. Based upon a review of the research and presentations by invited experts, a classification system was developed for stratification of patients into high, low, and intermediate categories of cardiac risk. The large majority of patients are in the low-risk category, which includes patients with (1) controlled hypertension; (2) mild, stable angina; (3) successful coronary revascularization; (4) a history of uncomplicated myocardial infarction (MI); (5) mild valvular disease; and (6) no symptoms and <3 cardiovascular risk factors. These patients can be safely encouraged to initiate or resume sexual activity or to receive treatment for sexual dysfunction. An important exception is the use of sildenafil in patients taking nitrates in any form. Patients in the intermediate-risk category include those with (1) moderate angina; (2) a recent MI (<6 weeks); (3) left ventricular dysfunction and/or class II congestive heart failure; (4) nonsustained low-risk arrhythmias; and (5) >/=3 risk factors for coronary artery disease. These patients should receive further cardiologic evaluation before restratification into the low- or high-risk category. Finally, patients in the high-risk category include those with (1) unstable or refractory angina; (2) uncontrolled hypertension; (3) congestive heart failure (class III or IV); (4) very recent MI (<2 weeks); (5) high-risk arrhythmias; (6) obstructive cardiomyopathies; and (7) moderate-to-severe valvular disease. These patients should be stabilized by specific treatment for their cardiac condition before resuming sexual activity or being treated for sexual dysfunction. A simple algorithm is provided for guiding physicians in the management of sexual dysfunction in patients with varying degrees of cardiac risk.

Management of sexual dysfunction in patients with cardiovascular disease: recommendations of The Princeton Consensus Panel.

Sexual dysfunction is highly prevalent in both sexes and adversely affects patients' quality of life and well being. Given the frequent association between sexual dysfunction and cardiovascular disease, in addition to the potential cardiac risk of sexual activity itself, a consensus panel was convened to develop recommendations for clinical management of sexual dysfunction in patients with cardiovascular disease. Based upon a review of the research and presentations by invited experts, a classification system was developed for stratification of patients into high, low, and intermediate categories of cardiac risk. The large majority of patients are in the low-risk category, which includes patients with (1) controlled hypertension; (2) mild, stable angina; (3) successful coronary revascularization; (4) a history of uncomplicated myocardial infarction (MI); (5) mild valvular disease; and (6) no symptoms and <3 cardiovascular risk factors. These patients can be safely encouraged to initiate or resume sexual activity or to receive treatment for sexual dysfunction. An important exception is the use of sildenafil in patients taking nitrates in any form. Patients in the intermediate-risk category include those with (1) moderate angina; (2) a recent MI (<6 weeks); (3) left ventricular dysfunction and/or class II congestive heart failure; (4) nonsustained low-risk arrhythmias; and (5) >/=3 risk factors for coronary artery disease. These patients should receive further cardiologic evaluation before restratification into the low- or high-risk category. Finally, patients in the high-risk category include those with (1) unstable or refractory angina; (2) uncontrolled hypertension; (3) congestive heart failure (class III or IV); (4) very recent MI (<2 weeks); (5) high-risk arrhythmias; (6) obstructive cardiomyopathies; and (7) moderate-to-severe valvular disease. These patients should be stabilized by specific treatment for their cardiac condition before resuming sexual activity or being treated for sexual dysfunction. A simple algorithm is provided for guiding physicians in the management of sexual dysfunction in patients with varying degrees of cardiac risk.

Intracavernous alprostadil alfadex (EDEX/VIRIDAL) is effective and safe in patients with erectile dysfunction after failing sildenafil (Viagra).

OBJECTIVES: Sildenafil (Viagra), an oral treatment for erectile dysfunction, has proved popular since its introduction in 1998. However, not all patients respond to this form of therapy. Consequently, this study investigated the efficacy of intracavernous alprostadil alfadex (EDEX/VIRIDAL) treatment in patients not responding to sildenafil. METHODS: In an open-label, multicenter study, patients with erectile dysfunction were treated with sildenafil for 4 weeks. The initial dose was 50 mg, which was increased to 100 mg if no response was achieved. Patients not responding to treatment, measured using the International Index of Erectile Function (IIEF) questionnaire, entered an alprostadil alfadex in-office titration phase, to determine the optimal dose, up to 40 microgram. A 6-week alprostadil alfadex at-home treatment phase followed. RESULTS: In 67 patients who did not respond satisfactorily to sildenafil, the alprostadil alfadex at-home therapy resulted in improvements in questions 3 and 4 of the IIEF in 60 (89.6%) and 57 (85.1%) patients, respectively. The mean improvement in IIEF score for these patients was 2.75 and 2.63 for questions 3 and 4, respectively. The most common side effect was penile pain in 25 (29. 4%) of 85 patients treated with alprostadil alfadex in-office and at home. CONCLUSIONS: Alprostadil alfadex therapy can be used effectively and safely in men who fail initial therapy with sildenafil.