Oral Pharmacotherapy and the Contemporary Evaluation and Management of Erectile Dysfunction

TREATING ERECTILE DYSFUNCTION Oral Pharmacotherapy and the Contemporary Evaluation and Management of Erectile Dysfunction Gregory A. Broderick, MD Department of Urology, Mayo Clinic, Jacksonville, FL The introduction of phosphodiesterase-5 (PDE-5) inhibitor therapy for the treatment of erectile dysfunction (ED) marked the beginning of a much greater awareness of this condition and its effects on quality of life. Resulting research has provided much data on the etiologies of ED, the risk factors involved, and the connection between ED and atherosclerotic disease. With the ED patient more frequently seeking treatment from his primary care physician, it behooves both urologists and non-urologist physicians to be familiar with the properties of the PDE-5 inhibitors, as well as those of other oral, sublingual, intracavernosal, and intraurethral ED drugs. This article reviews the diagnostic approach to the ED patient and the mechanisms of PDE-5 inhibition and discusses data from trials of PDE-5 inhibitors and the erectogenic dopaminergic agonist apomorphine. [Rev Urol. 2003;5(suppl 7):S9-S20] © 2003 MedReviews, LLC Key words: Erectile dysfunction • Sildenafil • Tadalafil • Vardenafil • Apomorphine he US Food and Drug Administration (FDA) approval and subsequent marketing of the first oral phosphodiesterase (PDE) inhibitor, sildenafil, in 1998 increased public awareness about male sexual dysfunction and enlightened perceptions about erectile dysfunction (ED) as a medical condition associated with distinct risk factors. A dramatic change in practice patterns concerning the evaluation and management of ED followed. Since that time, sildenafil has dominated the marketplace. T VOL. 5 SUPPL. 7 2003 REVIEWS IN UROLOGY S9 Evaluation and Management of ED continued Two new PDE-5 inhibitors, tadalafil and vardenafil, have been approved by the European Committee for Proprietary Medicinal Products and were launched in various countries of the European Union in the spring of 2003. Both of these drugs have “approvable" letters from the FDA and, at the time of publication of this supplement, vardenafil has been marketed in the United States for less than 1 month. Also recently available in Europe is apomorphine, a unique, sublingually active drug with erectogenic neural pharmacology. Apomorphine is entirely different from the PDE-5 inhibitors; PDE-5 inhibitors act on penile vascular tissues and have no known central neuropharmacologic effects. The new PDE-5 inhibitors will provide physicians with a choice when prescribing therapy for the ED patient, but it remains to be determined whether these agents will provide the opportunity to treat more patients or to treat the same patients more effectively or safely. Pharmacologic management of ED now includes oral, sublingual, intracavernosal, and intraurethral drugs that, respectively, amplify vascular penile responses to sexual stimulation; enhance neural signaling for erection; or, in the case of injectables and intraurethral agents, can induce erection to varying degrees regardless of sexual stimulation. The aim of this article is to review the epidemiology and risk factors for ED; summarize the evaluation of the typical ED patient, with special emphasis on what testing is reasonable at the time of presentation and what additional diagnostics have shown us about patients in whom PDE-5 inhibitor therapy fails; familiarize the urologist with the pharmacology of PDE-5 inhibitors; and review the clinical trials data on new orally active drugs for the management of ED. S10 VOL. 5 SUPPL. 7 2003 Epidemiology and Impact of ED Life expectancies worldwide are increasing, and the prevalence of ED is predicted to increase dramatically over the next 20 years.1 The World Health Organization anticipates that, by 2025, over 15% of the world population will be older than 65 years. In the Massachusetts Male Aging Study (MMAS), the prevalence of impotence of all degrees in men older than 40 years was 52%.2 Between the ages of 40 and 70 years, the proba- LUTS, ED, and ejaculatory complaints, independent of aging. The pathophysiologic mechanism explaining the relationship between LUTS and ED as yet remains elusive, but the epidemiologic data are intriguing. Additional risk factors for ED are depression, neurologic disease, pelvic surgery, and exposure to ionizing therapeutic radiation; these patients vary in their response to oral pharmacotherapy with PDE-5 inhibitors.4 Contrary to classic medical school Contrary to classic medical school teachings, ED resulting from endocrine disease is not common. bility of complete impotence increased from 5.1% to 15%, and of moderate impotence, from 17% to 34%. The National Health and Social Life Survey identified the prevalence and predictors of ED, as well as other sexual dysfunctions, in American men and women.3 Responses to questions about trouble maintaining or achieving an erection revealed the following prevalence rates: 7% for ages 18 to 29 years, 9% for ages 30 to 39 years, 11% for ages 40 to 49 years, and 18% for ages 50 to 59 years. In addition to aging, several distinct medical risk factors are associated with an increased likelihood of ED: heart disease, hypertension, depression, smoking, and low highdensity lipoprotein cholesterol levels. Diabetes and cardiovascular disease are the most common risk factors for ED and, typically, their severity is proportionally linked not only with the occurrence but also with the severity of ED. Recently, several international studies have documented a statistical relationship between male sexual dysfunction and lower urinary tract symptoms (LUTS). There is growing evidence of a correlation among REVIEWS IN UROLOGY teachings, ED resulting from endocrine disease is not common. Only a small percentage of hypogonadal patients with ED respond to testosterone therapy alone. Male sexual dysfunction has a significant impact on quality of life; this adverse impact peaks in midlife, when society considers men most productive. Although a 70-year-old man has a higher statistical likelihood of experiencing ED, quality-oflife studies indicate that it is the younger patient who truly “suffers" with his ED. It is not surprising that men aged 50 to 60 years have predominantly sought treatment with sildenafil since its introduction in 1998. Will changes in social attitudes and the advent of multiple therapies result in more patients seeking treatment? Are gradual changes in male sexual function, especially erection, harbingers of atherosclerotic disease? These societal and epidemiologic concerns will drive sexual medicine research over the next decade. Given population projections and the incidence of ED derived from the MMAS, the number of men in the United States at risk for ED is expected to increase from 12 million to 21 mil- Evaluation and Management of ED lion by the year 2025.1 This aging male population represents a vast potential market for new therapies. In the past, ED patients relied on the urology specialist for his or her surgical implantation skills; in the future, a physician’s familiarity with new medical therapies will be called upon more often than his or her surgical skills. Successful management of ED requires a new knowledge base, which begins with a thorough understanding of the pharmacology of PDE-5 inhibitors and efficacy and safety data from clinical trials. Diagnosis and Evaluation of Erectile Dysfunction The evaluation of ED requires a thorough medical and sexual history taking to identify physical and emotional risk factors for ED. Medical and sexual histories are the most important elements of the first evaluation. The sexual history must be elicited in a nonthreatening, permissive manner; attention must be given to defining the problem, distinguishing complaints about ejaculation and/or orgasm from ED, and establishing the chronology and severity of symptoms. The second element of the evaluation is an assessment of the patient’s needs and expectations for treatment. The First International Consultation on ED, held in Paris on July 1-3, 1999, correctly noted that, with the proliferation of oral pharmacotherapy, most men will initially consult a primary care provider regarding their complaints. The Consultation also identified the most important elements in the patient’s medical and sexual history (Tables 1 and 2).5 The cornerstone of diagnosis rests on the patient-physician dialogue and the ability to elicit and qualify the complaint of ED. The diagnostic evaluation is stratified into recommended tests, optional tests, and specialized tests (Table 3).6 The rationale is to identify potentially modifiable risk factors and initiate therapy that might reverse the ED. A focused physical examination is recommended for all patients to assess blood pressure, body habitus, secondary sexual characteristics, and the cardiovascular, neurologic, and genitourinary systems. The indications for referring a patient to a specialist include the following: failure of firstline oral therapy, patient request, primary ED, pelvic/perineal/penile trauma or surgery, Peyronie’s disease, depression or psychosexual disorder, endocrinopathy, relationship problems, and a history and physical examination suggestive of the need for vascular, neurologic, or cardiology evaluations. The quality of patient-physician dialogue depends heavily on the physician’s knowledge of the physiologic, anatomic, and biochemical properties of erection—as well as the physician’s appreciation of the patient’s cultural, ethnic, and religious background. Recently, a variety of self-report measures for assessment of male sexual function and dysfunction have been described. These sexual inventories are subjective measures investigating the domains of interest, performance, and satisfaction. Because they are cost-effective and their results quantifiable, sex questionnaires have become the primary method of measuring efficacy end points in clinical trials of ED pharmacotherapy. In clinical practice, limitations of both time and expertise make sex questionnaires an attractive option in the evaluation of ED. There is an increasing number of choices available, such as the validated International Index of Erectile Function (IIEF), the Brief Male Sexual Function Inventory, and the Center for Marital and Sexual Health Questionnaire.6,7 Assessing Efficacy in Drug Trials All recent randomized, placebo-controlled clinical trials of ED drugs have made an effort to define the etiology of ED (organic, psychological, or mixed), evaluate subpopulations based on medical risk factors (hypertension, diabetes, coronary artery disease, prostatectomy, etc), and quantify ED severity. The most commonly ref- Table 1 Risk Factors for Erectile Dysfunction • Aging • Hypertension • Atherosclerosis • Diabetes mellitus • Hyperlipidemia • Smoking • Depression • Pelvic, perineal, or penile trauma or surgery • Neurologic disease • Endocrinopathy • Prescription or recreational drug use Table 2 Essential Components of Sexual History • Erectile insufficiency (onset, duration, progression, severity, penile bending) • Alteration of sexual desire (libido) • Ejaculation • Orgasm • Genital pain • Lifestyle factors (sexual orientation, presence of a spouse or partner) • Partner sexual function VOL. 5 SUPPL. 7 2003 REVIEWS IN UROLOGY S11 Evaluation and Management of ED continued Table 3 Diagnostic Tests for Evaluation of Erectile Dysfunction Recommended • Fasting glucose level • Glycosylated hemoglobin level • Lipid profile • Testosterone level (preferably morning) Optional • Prolactin, free and total testosterone, and luteinizing hormone levels • Thyroid-stimulating hormone level • Complete blood cell count • Prostate-specific antigen level Specialized • Vascular evaluations – In-office penile injection: pharmacotest (alprostadil or other injectable) – Penile color duplex Doppler ultrasonography and pharmacotest – Dynamic infusion pharmacocavernosometry and cavernosography – Penile arteriography (CT angiography, MRI angiography) • Visual erotic stimulation • Nocturnal penile tumescence and rigidity test • Neurophysiologic testing • Psychological testing CT, computed tomography; MRI, magnetic resonance imaging. erenced self-administered questionnaire (SAQ) for defining ED severity and documenting treatment end points is the IIEF,7,8 which was employed in the worldwide sildenafil citrate clinical trials and is being used in clinical trials of tadalafil and vardenafil.9,10 Efficacy is reported with consideration to the various domains of the IIEF. The IIEF is a 15-item SAQ that addresses and quantifies 5 domains: erectile function (EF) (questions 1-5 and 15), intercourse satisfaction (questions 6, 7, and 8), orgasmic function (questions 9 and 10), sexual desire (questions 11 and 12), and overall satisfaction (questions 13 and 14).7 The EF domain score is a subset of the IIEF that distinguishes subjects based on perceived degrees of ED severity: no ED, 26-30; mild ED, 2225; mild to moderate ED, 17-21; moderate ED, 11-16; and severe ED, 0-10.11 S12 VOL. 5 SUPPL. 7 2003 These scores detect small changes in erectile performance in response to drug and placebo. The EF domain score is also used to identify the percentage of patients “returning to normal"; this is a controversial designation, as the IIEF has not been applied to a broad community sample of healthy men, nor have age-specific normal scores ever been established. Additional treatment measures include sexual encounter profiles, which are principally reported as “ability to insert the penis” and “erection lasting long enough to complete sexual intercourse.” Another clinical trial efficacy end point that has become the focus of many marketing strategies is the global assessment question (GAQ), “Has the treatment you have been taking improved your erections?” Increasing attention is being paid to the impact of ED on our patients and their partners; in REVIEWS IN UROLOGY the drug trial environment, this has translated into the development of several treatment satisfaction questionnaires, quality-of-life questionnaires, partner questionnaires, and diaries/event logs. None of these other SAQs has been uniformly employed like the IIEF, nor have any been as extensively validated across cultures. Statistical differences in EF domain scores cannot be interpreted as one drug being more effective than another. Subtle differences in study populations (age, number and severity of ED risk factors, duration of ED) and the exclusion of sildenafil citrate failures from clinical trials of new PDE-5 inhibitors argue against declaring any one drug superior to another. Indeed, head-to-head comparative clinical trials will be needed before a superior drug can be declared. Pharmacokinetics and Clinical Pharmacodynamics of PDE-5 Inhibitor Therapy Erection hemodynamics are regulated by the tone of corporal smooth muscle (CSM) in the arterioles and trabeculae; the relative states of contraction and relaxation of CSM are primarily mediated by the nitric oxide (NO)/ cyclic guanosine monophosphate (cGMP) pathway (Figure 1). Current clinical strategies for improving ED exploit this pathway by inhibiting cGMP-specific PDE (PDE-5).12 PDEs play a key role in the physiology of erection, since they hydrolyze both cGMP and cyclic adenosine monophosphate. Selective inhibition of PDE-5 prevents the breakdown of cGMP, promoting corpus cavernosum smooth muscle relaxation. Physiologically, this potentiates erection induced by sexual stimulation. PDE-5 inhibitors show competitive kinetics with respect to cGMP; inhibitors bind to the catalytic site of the enzyme (Figure 2). Evaluation and Management of ED safety are functions of all of these parameters. Selectivity describes the relative pharmacokinetic activity of a drug between 2 different receptors or enzymes. Selectivity is expressed as a ratio of 2 drugs’ relative affinity for the same PDE (Table 4). In vitro potency is expressed as the IC50—the concentration of a drug needed to inhibit 50% of the activity of a particular PDE. Published IC50 values for sildenafil, tadalafil, and vardenafil vary because of different tissue sources of the PDE enzymes, varying purity of the preparations, and other assay conditions (Table 5). The lower the IC50 value of a drug, the better that agent acts in vitro as a competitive inhibitor of PDE. In vivo potency is further affected by dose, extent of absorption, protein binding, and tissue distribution. Bioavailability refers to the fraction of drug administered that reaches the central circulation. The bioavailability of sildenafil is approximately 40%; the bioavailability of vardenafil is around 15%.13,14 Pharmacokinetic parameters are used to model and describe the Figure 1. Erection hemodynamics are regulated by the tone of corporal smooth muscle (CSM) in the arterioles and trabeculae; the relative states of contraction and relaxation of CSM are primarily mediated by nitric oxide (NO)/cyclic guanosine monophosphate (cGMP). Selective inhibition of phosphodiesterase-5 (PDE-5) prevents the breakdown of cGMP, promoting corpus cavernosum smooth muscle relaxation. Physiologically, this potentiates erection induced by sexual stimulation. GTP, guanosine triphosphate; eNOS, endothelial nitric oxide synthase. Adapted from Lue TF. N Engl J Med. 2000;342:1802-1813.43 By reducing the breakdown of cGMP, PDE-5 inhibitors can enhance, improve, and/or prolong erection, but they cannot initiate erection. PDE-5 inhibitors are the first class of oral agents to provide effective therapy for ED. Because selective inhibition of PDE-5 enhances the effects of natural sexual stimulation, an intact lower motor neuron system is essential for effectiveness. (Reflexogenic erection in patients with upper motor neuron lesions can be enhanced, but patients with lower motor neuron lesions will not respond.) Eleven families of PDEs have been identified. PDEs are present in all human tissues; accordingly, both the efficacy and side effects of PDE-5 inhibitor therapy are a function of pharmacologic specificity and bioavailability.12 PDE-2, -3, -4, -5, and -11 are all found in penile tissues, with PDE type 5 predominating. Sildenafil, tadalafil, and vardenafil are potent reversible competitive inhibitors of cGMP-specific PDE type 5. The differences among sildenafil, tadalafil, and vardenafil can be characterized by the pharmacologic characteristics of selectivity, potency, and bioavailability. Clinical efficacy and Figure 2. Chemical structure of the phosphodiesterase-5 inhibitors. O O N H3C HN O S CH3 N N N N H O N H O N N Vardenafil O N N H CH3 HN S CH3 O O H3C N CH3 CH3 Sildenafil O N N O CH3 O O CH3 VOL. 5 SUPPL. 7 2003 Tadalafil REVIEWS IN UROLOGY S13 Evaluation and Management of ED continued Table 4 Comparison of Selectivity Ratios of PDE-5 Inhibitors PDE Family PDE-1 PDE-2 PDE-3 PDE-4 PDE-5 PDE-6 PDE-7 PDE-8 PDE-9 PDE-10 PDE-11 Sildenafil 80 >7500 4400 1800 1 10 5160 >10,000 2796 1123 346 Selectivity Ratio Vardenafil 257 >10,000 3600 5700 1 224 No data No data No data 447 203 Tadalafil >10,000 >10,000 >10,000 >10,000 1 780 >10,000 >10,000 >10,000 >10,000 5.5 PDE, phosphodiesterase. Data from Corbin JD, Francis SH. Int J Clin Pract. 2002;56:453-45944; Bischoff E et al. Int J Impot Res. 2001;13(suppl 4):S4145; Eardley I et al. Int J Clin Pract. 2002;56:300-30446; Omrod D et al. Drugs Aging. 2002;19:217-227.47 Table 5 Comparison of IC50 Values of PDE-5 Inhibitors PDE Family PDE-1 PDE-2 PDE-3 PDE-4 PDE-5 PDE-6 PDE-7 PDE-8 PDE-9 PDE-10 PDE-11 Sildenafil 280 68,000 16,200 7200 0.5-4.0 38 21,000 29,800 2610 9800 2730 IC50 Value, nM Vardenafil 69 6200 4000 4000 0.1-0.7 157 <30,000 >30,000 580 3000 162 Tadalafil <30,000 >30,000 >30,000 >30,000 0.9-6.7 780 >100,000 >100,000 >100,000 >100,000 37 IC50, concentration needed to inhibit 50% of PDE activity; PDE, phosphodiesterase. Data from Corbin JD, Francis SH. Int J Clin Pract. 2002;56:453-45944; Bischoff E et al. Int J Impot Res. 2001;13(suppl 4):S4145; Eardley I et al. Int J Clin Pract. 2002;56:300-30446; Omrod D et al. Drugs Aging. 2002;19:217-227.47 Table 6 Comparison of Pharmacokinetic Parameters of PDE-5 Inhibitors Indicator Tmax , h T1/2 , h Metabolism Sildenafil <1 3-5 Hepatic Tadalafil 2 17.5 Hepatic Vardenafil <1 3-5 Hepatic PDE, phosphodiesterase; Tmax , time to peak maximum observed plasma concentration; T1/2 , terminal half-life. Data from Corbin JD, Francis SH. Int J Clin Pract. 2002;56:453-45944; Bischoff E et al. Int J Impot Res. 2001;13(suppl 4):S4145; Eardley I et al. Int J Clin Pract. 2002;56:300-30446; Omrod D et al. Drugs Aging. 2002;19:217-227.47 S14 VOL. 5 SUPPL. 7 2003 REVIEWS IN UROLOGY movement of a drug around the body; among these parameters are the maximum observed plasma concentration (Cmax); time to reach peak maximum observed plasma concentration (Tmax); and apparent terminal halflife (T1/2), which is the time it takes to decrease Cmax by 50% (Table 6). The half-life of an agent suggests its duration of clinical activity. The IC50 describes both the potency of the inhibitor and the likelihood it will cause PDE cross-type reactions (the basis for PDE-5 inhibitor side effects). The lower the IC50 , the more potent a drug is for inhibiting a specific PDE; the higher the IC50 , the less likely the drug is to interfere with that particular PDE. Side effects result from the direct but exaggerated effect of a drug on the target tissue or its effects on other tissues not being specifically targeted. For example, a direct side effect of intracavernous therapy is priapism, which has been reported in 4% to 20% of patients, depending on the agent(s) injected. There have been no reports of priapism in the worldwide clinical trials of sildenafil and only rare case reports in postmarketing studies.8,15,16 The common side effects are actually class effects of PDE-5 inhibitors in other tissues: headache, flushing, nasal congestion, dyspepsia, back pain, and visual changes (Table 7). Visual disturbance is caused by cross-reaction with PDE-6; this cross-inhibition affects the cones of the retina and results in the typical transient complaint of blue vision. Theoretically, the higher the IC50 a PDE-5 inhibitor has for PDE-6, the less likely visual disturbance is to occur. All PDE-5 inhibitors are metabolized through the hepatic cytochrome P450 enzyme 3A4 and secondarily through P450 enzyme 2C9. Simultaneous dosing with cytochrome 3A4 inhibitors results in higher plasma Evaluation and Management of ED levels (Cmax). Cimetidine, ketoconazole, erythromycin, and protease inhibitors (ritonavir) prolong the duration of action and raise plasma concentrations of PDE-5 inhibitors. There is a synergistic interaction between organic nitrates and PDE-5 inhibitors, with both acting on the NO/cGMP pathway; one releases NO and the other prevents hydrolysis of the enzyme that eliminates cGMP. Clinically, this produces vasodilation and severe hypotension. Therefore, sildenafil and vardenafil are contraindicated in patients using therapeutic nitrates (oral, sublingual, or topical). It is anticipated that concomitant dosing of tadalafil and nitrates will also be contraindicated, and these patients were routinely excluded from clinical trials. On the other hand, there have been numerous studies suggesting that PDE-5 inhibitor therapy does not have a direct adverse cardiovascular effect.4,15,16 Sildenafil Peak plasma concentrations of sildenafil are reached in 30 to 120 minutes (median, 60 minutes). Postmarketing studies have shown onset of action as soon as 14 minutes after dosing, with an efficacy of 12 hours.17 Table 7 Side Effects of Phosphodiesterase-5 Inhibitors Drug (Dose) Sildenafil* (25 mg, 50 mg, 100 mg) Adverse Event (% Reporting) Headache (7-25) Flushing (7-34) Dyspepsia (1-11) Nasal congestion (4-19) Visual effects (1-6) Tadalafil† (2.5 mg, 5 mg, 10 mg, 20 mg) N = 1561 Headache (11-14) Flushing (4) Dyspepsia (7-10) Nasal congestion (4-5) Back pain (4-6) Myalgia (4-5) Vardenafil‡ (5 mg, 10 mg, 20 mg) N = 1385 Headache (8-17) Flushing (6-13) Dyspepsia (2-6) Nasal congestion (1-8) *Data from Sadovsky R et al. Int J Clin Pract. 2001;55:115-128.18 † Data from Brock G et al. J Urol. 2002;167(suppl 4):178.48 ‡ Data from Godfishcher E et al. J Urol. 2002;167(suppl 4):178.49 with a 25-mg dose.13 Dose-finding and postmarketing studies have shown best results with a maximum dose of 100 mg, with responses maximized after 4 to 6 administrations. At the end of a 12-week, flexible dose-escalation study of sildenafil, 74% of subjects were receiving 100 mg, 23% of subjects were receiving In patients with ED induced by selective serotonin reuptake inhibitor therapy, sildenafil efficacy is high (80%), likely because of the relative absence of vascular risk factors in these patients. Sildenafil can be taken with or without food; however, a high-fat meal will slow the rate of absorption and delay peak plasma concentration of sildenafil and may reduce peak plasma concentration by 29%. The half-life of sildenafil is 3 to 5 hours. Recommended starting dose is 50 mg; patients older than 65 years and those with hepatic impairment or severe renal insufficiency should start 50 mg, and 2% preferred the 25 mg dose. EF domain scores were 22.1 for sildenafil versus 12.2 for placebo.8,16 In terms of the GAQ, treatment with sildenafil improved ED symptoms in 43% to 89% of subjects (organic, psychogenic, and mixed etiologies), compared with 10% to 30% improvement in placebo groups. Similary, based on the GAQ, improvement in erections with sildenafil therapy was dose-related: 63% at 25 mg, 74% at 50 mg, and 82% at 100 mg. Regarding specific etiologies of ED, sildenafil postmarketing studies have demonstrated improved erections in 70% of hypertensive patients, 42% to 72% of radical prostatectomy patients, 66% of external beam radiotherapy patients, 81% of brachytherapy patients, 76% of patients with depression, and 80% of patients with upper motor neuron spinal cord injury.18 In two 12-week, double-blind, placebo-controlled trials, 51% to 56% of sildenafil-treated diabetic men reported improved erections, compared with 10% to 12% of diabetic men randomized to the placebo group. The EF domain score for the placebo group was 10.4 versus 17.5 for the sildenafil group, reflecting the severity of diabetic ED; baseline IIEF scores were highest for men with 1 diabetic complication versus 2 or more complications (retinopathy, nephropathy, cardiovascular disease, neuropathy).19 In patients with ED VOL. 5 SUPPL. 7 2003 REVIEWS IN UROLOGY S15 Evaluation and Management of ED continued induced by selective serotonin reuptake inhibitor (SSRI) therapy, sildenafil efficacy is high (80%),20 likely because of the relative absence of vascular risk factors in these patients. There are numerous reports documenting the efficacy and safety of sildenafil; as of 2002, there were 130 clinical trials including more than 13,000 patients. Sildenafil has been effective in patients using other ED pharmacotherapies. In a multicenter European trial, 70% of men using intracavernous alprostadil (ICI) successfully switched to oral therapy. Treatment satisfaction with ICI was 64%; following the switch to oral therapy, satisfaction was 74%.21 Sildenafil is well tolerated in patients with ED. The most commonly reported adverse events occurring more frequently than with placebo were headache, flushing, and rhinitis. For the most part, these adverse events are class effects of PDE-5 inhibitor therapy and reflect the actions of the drug on the PDEs in other tissues. Although sildenafil does potentiate the hypotensive effects of nitrates, in clinical trials, no additional incidence of myocardial infarction compared with placebo was seen.22 Patients at high cardiac risk should defer sexual activity until stabilization and preferably improvement of their heart condition. A consensus panel evaluating cardiac risk and the use of PDE-5 inhibitors has defined high-risk patients as those with: unstable or refractory angina, uncontrolled hypertension, left ventricular dysfunction/ congestive heart failure (NYHA class III or IV), recent myocardial infarction (<2 weeks), cerebral vascular accident, high-risk arrhythmias, hypertrophic obstructive cardiomyopathies, other cardiomyopathies, or moderate/ severe valvular disease. Patients at low risk can be assured that sexual activity is safe, and that PDE-5 inhibitor therapy for ED may be used S16 VOL. 5 SUPPL. 7 2003 as indicated. Low risk is defined as patients with: no symptoms and fewer than 3 risk factors for CAD excluding gender, controlled hypertension, mild stable angina, post–successful coronary revascularization, uncomplicated remote myocardial infarction, mild valvular disease, and congestive heart failure class I.23 Tadalafil Peak plasma concentrations of tadalafil are reached in 2 hours. A high-fat meal does not appear to response to tadalafil as measured by EF domain score: placebo, 15.1; 2.5 mg, 16.6; 5 mg, 17.7; 10 mg, 21.1; and 20 mg, 23.9. Positive responses to the GAQ were as follow: placebo, 35%; 2.5 mg, 42%; 5 mg, 50%; 10 mg, 67%; and 20 mg, 81%. “Normalization" of the EF domain score occurred as follows: placebo, 11%; 2.5 mg, 21%; 5 mg, 23%; 10 mg, 40%; and 20 mg, 59%.9,24,25 In diabetic patients, ED was typically more difficult to treat, as evidenced by lower scores in the placebo Patients at high cardiac risk should defer sexual activity until stabilization and preferably improvement of their heart condition. slow the rate of absorption or delay peak plasma concentration of this agent. Alcohol has no effect on tadalafil plasma concentrations measured 3 hours after dosing, and tadalafil does not influence blood pressure changes induced by alcohol. The half-life of tadalafil is 17.5 hours in young men and may be up to 22.5 hours in the elderly. Its unique chemical structure and longer half-life clearly distinguish tadalafil from the other PDE-5 inhibitors. In phase 2b/3 clinical trials performed at 36 centers in Europe and the United States to evaluate the effects of tadalafil over time, patients were stratified by baseline severity of ED and randomly allocated within severity groups to tadalafil, 20 mg (n = 175), or placebo (n = 173). At 24 hours (>20 hours and <30 hours) post-dosing of tadalafil, 20 mg, 57% of attempts resulted in successful intercourse, compared with 31% with placebo. At 36 hours (>30 hours and <48 hours), 60% of attempts resulted in successful intercourse, compared with 30% with placebo.24,25 The results of 5 phase 3 studies (N = 1112) document a clear dose REVIEWS IN UROLOGY group. EF domain scores for subjects with diabetes were as follow: placebo, 13; 2.5 mg, 12; 5 mg, 17; 10 mg, 19; and 20 mg, 21. The occurrence of “erections lasting long enough to have successful intercourse" was statistically significantly higher in subjects who received tadalafil, 10 mg (49%) or 20 mg (58%), than in those who received placebo (18%).26 Vardenafil The time to maximal plasma concentration for a single oral dose of vardenafil, 10 mg, 20 mg, or 40 mg, ranges from 0.7 to 0.9 hours. As with sildenafil, vardenafil absorption is delayed by a high-fat meal. Two food-effect studies showed that high-fat meals caused a reduction in Cmax of 18% to 50%; median Tmax remained 1 hour. In clinical trials, vardenafil was dosed without regard to meals. Based on the efficacy observed in phase 3 studies that were not restricted with respect to food, the prescribing recommendation is that vardenafil can be taken with or without food. Ethanol had no influence on systemic exposure of vardenafil. Cmax was Evaluation and Management of ED slightly, although not significantly, increased. Ethanol did not influence the T1/2 and Tmax of vardenafil. Vardenafil and ethanol administered concomitantly were generally well tolerated. The half-life of vardenafil is 4 to 5 hours, and Tmax and T1/2 are similar in men aged 18 to 45 years and those older than 65 years.27 In phase 2b and 3 clinical trials, the key efficacy parameter of EF domain score showed statistically significant differences for 5-mg, 10-mg, and 20-mg doses of vardenafil compared with placebo: placebo, 15.0; 5 mg, 18.4; 10 mg, 20.6; and 20 mg, 21.4. The following percentages of subjects responded positively to the GAQ: placebo, 38.6%; 5 mg, 64.5%; 10 mg, 72.9%; and 20 mg, 80.9%.10,28 Again, diabetic men typically had more severe ED: those who received placebo had an EF domain score of 12.6; those who received vardenafil, 10 mg or 20 mg, had scores of 17.1 and 19.0, respectively. “Erection lasting long enough for successful intercourse" occurred in 23% of the placebo group, 49% of the 10-mg vardenafil group, and 54% of the 20-mg vardenafil group.29 In a broad population of men with ED of various etiologies and severity, vardenafil improved all efficacy parameters of erectile function, “normalizing” erectile function in more than 80% of men with mild ED and up to 39% of men with severe ED treated for 26 weeks.30 Vardenafil was evaluated in 4 major double-blind, randomized, placebo-controlled, fixed-dose, parallel design trials in 2431 men aged 20 to 83 years. The recommended starting dose of vardenafil is 10 mg, taken orally approximately 60 minutes before sexual activity. The dose may be increased to a maximum of 20 mg or decreased to 5 mg based on efficacy and side effects. The maximum recommended dosing frequen- cy is once per day. Vardenafil can be taken with or without food. It is well tolerated, with the most common side effects being headache, flushing, dyspepsia, and nasal congestion.14 PDE-5 inhibitors may result in transient decreases in blood pressure in healthy volunteers. PDE-5 inhibitors do potentiate the hypotensive effects of nitrates, and both sildenafil and vardenafil are contraindicated with nitrates administered regularly or intermittently. A safe time interval between PDE-5 inhibitor dosing and nitrates has not been established. -Blockers inhibit pressor effects of naturally circulating epinephrine, leading to a decrease in peripheral vascular resistance. -Blockers are sometimes associated with first-dose postural consistent effects across analyses when compared with moxifloxacin. These observations should be considered in clinical decisions to prescribe PDE-5 inhibitors for patients with a known history of QT prolongation or patients who are taking medicines known to prolong the QT interval, such as class IA (eg, quinidine, procainamide) or III (amiodarone, sotalol) antiarrhythmic medications. Apomorphine Hydrochloride Apomorphine is well known for its positive effect on sexual arousal in rats; intrathecal or subcutaneous injection causes yawning and erection.32 Apomorphine is chemically unrelated to morphine; it is not an opiate. It acts within the paraven- Apomorphine is a nonspecific dopaminergic agonist, activating D1 and D2 receptors. hypotension and syncope. Combining PDE-5 inhibitors and -blockers may increase the risk of postural hypotension. Current prescribing information for sildenafil includes a precaution that doses above 25 mg should not be taken within 4 hours of an -blocker.16 Current prescribing information for vardenafil notes that coadministration of -blockers and vardenafil can produce hypotension.14 Vardenafil is contraindicated in patients taking -blockers. In an electrophysiology study of 59 healthy men, vardenafil, 10 mg and 80 mg, produced small mean increases (4-10 msec) in the corrected QT interval, as did the active control moxifloxacin (400 mg) and the reference PDE-5 inhibitor sildenafil (50 mg and 400 mg).31 Sildenafil and vardenafil have similar effects on QT intervals at both the usual starting doses and at 4-times the maximum recommended dose. Both showed tricular nucleus of the hypothalamus, which may be the brain’s sexual drive center in mammals. Apomorphine is a nonspecific dopaminergic agonist, activating D1 and D2 receptors.32,33 Early reports of patients receiving the drug for the treatment of Parkinson disease noted increased spontaneous erections without increased libido. Apomorphine stimulates central pro-erectile signaling, which is necessary in human sexual arousal. Apomorphine hydrochloride acts through buccal absorption, and erection efficacy is lost if the tablet is swallowed. The drug is highly lipidsoluble and rapidly crosses the blood-brain barrier. Maximal plasma concentrations are reached in 40 to 60 minutes, and the half-life is short at 2.7 hours for a 2-mg sublingual dose. In clinical trials, a rapid onset of action is noted, with a median time to erection of 18 minutes with a 3-mg dose.34 Eating before dosing VOL. 5 SUPPL. 7 2003 REVIEWS IN UROLOGY S17 Evaluation and Management of ED continued has no effect on plasma concentrations, likely because of the agent’s buccal absorption. The primary efficacy end point for double-blind, placebo-controlled, crossover clinical trials of apomorphine SL was neither the IIEF nor the EF domain score, but rather the “percentage of attempts resulting in an erection firm enough for intercourse," with an attempt defined as taking the drug and recording the results in a treatment diary.35,36 Using this definition of efficacy, the Apomorphine SL Study Group evaluated apomophine in 296 men with ED. Results of a study evaluating apomorphine, 2 mg, demonstrated a 45.5% response rate, compared with 34.6% for subjects who received placebo.35 Evaluation of apomorphine, 3 mg, demonstrated a 46.9% response rate, compared with 32.3% for subjects who received placebo.36 Increasing doses beyond 3 mg resulted in no additional pro-erectile efficacy but did increase adverse events. Specifically, there was no statistical difference in benefit between 3-mg and 4-mg doses. The difference in treatment effect compared with placebo was modest for 2-mg, 3-mg, and 4-mg doses of apomorphine.35,36 In order to evaluate a more substantial number of patients, data from 2-mg and 3-mg apomorphine studies were pooled. Baseline severity was rated by IIEF (severe [n = 140], moderate [n = 134], mild [n = 105]). Efficacy in patients with severe ED was 20.1% for placebo versus 28% for active drug; in those with moderate ED, efficacy was 37.2% for placebo versus 53.9% for active drug; and in those with mild ED, efficacy was 56.5% for placebo versus 68% for active drug.36 Patients were instructed to drink water before placing the drug under the tongue, which facilitates dissolving, a process that can take up to 10 minutes. There is no food interaction. S18 VOL. 5 SUPPL. 7 2003 Adverse events described in clinical trials of apomorphine, 3 mg and 4 mg, respectively, were as follow: nausea, 7% and 14.1%; yawning, 8.1% and 13%; dizziness, 6.5% and 5.4%; somnolence, 4.9% and 9.8%; and headache, 2.2% and 6.5%. Syncope occurred in 0.6% of patients and was accompanied by a clear prodrome suggestive of a vasovagal event: nausea, vomiting, sweating, dizziness, and light-headedness.36 The vasovagal events were without cardiac sequelae in clinical trials. The reported severity of nausea was reduced in subjects for risk factor for ED), response rates for sildenafil have averaged 60% to 70%. However, in a study by McCullough and colleagues,37 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 of 8 attempts for efficacy assessment. When several risk factors coexist, efficacy of sildenafil declines. In one postmarketing trial, significant failure rates Two recent studies have concluded that sildenafil nonresponders should be evaluated for androgen status. whom doses were titrated from 2 mg to 3 mg. There were no specifically documented pharmacologic interactions in subjects taking nitrates. Apomorphine SL, 6 mg, in combination with a large intake of alcohol (0.6 g/kg) significantly reduced blood pressure in some subjects.36 Clinical trial data were submitted for FDA review in 2000, voluntarily withdrawn for further studies of efficacy and safety, and resubmitted in 2002. However, since then, apomorphine SL has received a nonapprovable letter from the FDA, and US approval is no longer being pursued. In 2001, the European Agency for the Evaluation of Medicinal Products approved apomorphine hydrochloride, 2 mg and 3 mg, for the treatment of ED. PDE-5 Inhibitor Therapy: Nonresponders The immediate challenge for urologists is how to evaluate and manage the patient who has ED that does not respond to PDE-5 inhibitor therapy. For the average ED patient (a 50-yearold man with 1 additional medical REVIEWS IN UROLOGY have been noted, not surprisingly, among diabetic men with neuropathy, diabetic men with hypertension, and prostatectomy patients.4 Because the efficacy of apomorphine appears to be highest among men with no vascular risk factors and those with mild vascular ED, it is unlikely that this drug alone will salvage PDE-5 inhibitor nonresponders. In a postmarketing clinical study, pharmacotesting with alprostadil and color duplex Doppler ultrasonography demonstrated that, among 178 patients with ED, the etiologies of sildenafil failure were severe arterial insufficiency (40%), cavernous venous occlusive disease (28%), and mixed vascular insufficiency (21%). Sixty-three percent of nonresponders were aged 61 years or older. The investigators noted that 11% of nonresponders actually had normal penile blood flow with alprostadil, 10 g, and concluded that nonresponders should be further evaluated for improper dosing or psychosexual ED.38 In a smaller study involving 30 sildenafil nonresponders, none Evaluation and Management of ED responded to subsequent challenges with apomorphine SL; 2 of 30 patients had normal penile blood flow with alprostadil, 20 g. Duplex Doppler ultrasonography pharmacotesting documented vascular lesions in 28 of 30 patients; penile biopsy revealed that all had reductions in cavernous smooth muscle content.39 Two recent studies have concluded that sildenafil nonresponders should be evaluated for androgen status. Testosterone replacement alone did not restore erections in hypogonadal patients or those with borderline testosterone levels. However, testosterone replacement coupled with repeated challenge of sildenafil resulted in improved erections in the majority of subjects.40,41 The FDA has neither reviewed nor approved sildenafil in combination with any other pharmacotherapy for penile dysfunction. Therefore, combination treatments should be considered “off-label" and initiated with proper informed consent and clinical precautions. Several studies have documented the efficacy of intracavernous therapy with FDAapproved alprostadil or combinations of papaverine, phentolamine, and alprostadil in men who have failed sildenafil therapy.42 Because published clinical trials on newer PDE-5 inhibitors have, to date, excluded sildenafil failures, one is unable to conclude that these newer agents will more effectively treat the same patient population or help current nonresponders. References 1. 2. 3. Conclusion With the recent awareness that has been shed on the topic of male sexual dysfunction, and with increasing numbers of men seeking treatment for ED, the market for new therapies is rapidly growing. Since its introduction, sildenafil has dominated the marketplace. However, the addition of the new PDE-5 inhibitors tadalafil and vardenafil and the sublingual drug apomorphine to the armamentarium will provide physicians with additional choice when managing the ED patient. It remains to be seen whether these new agents will represent an improvement over current treatments or will result in greater treatment success rates—additional clinical data are eagerly awaited. In the meantime, the best course of action for the physician managing patients with ED continues to be a combination of open communication; careful assessment of risk factors; well-chosen diagnostic testing; and initiation of the most suitable treatment, medical or otherwise. 4. 5. 6. 7. 8. 9. 10. 11. Aytaç IA, McKinlay JB, Krane RJ. The likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. BJU Int. 1999;84:50-56. Feldman HA, Goldstein I, Hatzichristou DG, et al. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol. 1994;151:54-61. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the US: prevalence and predictors. JAMA. 1999;281:537-544. Guay AT, Perez JB, Jacobson J, Newton RA. Efficacy and safety of sildenafil citrate for treatment of erectile dysfunction in a population with associated organic risk factors. J Androl. 2001;22:793-797. Jardin A, Wagner G, Khorui S, et al. Recommendations of the 1st International Consultation on Erectile Dysfunction. In: Jardin A, Wagner G, Khouri S, et al, eds. Erectile Dysfunction. Plymouth, UK: Health Publication Ltd; 2000:709-726. Mueleman E, Broderick G, Meng Tan H, et al. Clinical evaluation and the doctor-patient dialogue. In: Jardin A, Wagner G, Khouri S, et al, eds. Erectile Dysfunction. Plymouth, UK: Health Publication Ltd; 2000:115-138. Rosen RC, Riley A, Wagner G, et al. The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology. 1997;49:822-830. Goldstein I, Lue TF, Padma-Nathan H, et al, for the Sildenafil Study Group. Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med. 1998;338:1397-1404. Padma-Nathan H, McMurray JG, Pullman WE, et al. On-demand IC351 (Cialis) enhances erectile function in patients with erectile dysfunction. Int J Impot Res. 2001;13:2-9. Porst H, Rosen R, Padma-Nathan H, et al. 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. Int J Impot Res. 2001;13:192-199. Cappelleri JC, Rosen RC, Smith MD, et al. Diagnostic evaluation of the erectile function domain of the International Index of Erectile Function. Urology. 1999;54:346-351. Main Points • The broad range of risk factors for erectile dysfunction (ED), the recently expanded awareness about male sexual dysfunction, and the aging of the US male population ensure that the need for new, effective ED therapies will continue to increase at a rapid rate. • In addition to a thorough medical and sexual history and results of diagnostic tests, sex questionnaires, such as the International Index of Erectile Function, the Brief Male Sexual Function Inventory, and the Center for Marital and Sexual Health Questionnaire, are an effective and efficient way for the clinician to assess ED. • Following in the footsteps of sildenafil, 2 new phosphodiesterase-5 (PDE-5) inhibitors, tadalafil and vardenafil, have been developed for the treatment of ED. • The differences among sildenafil, tadalafil, and vardenafil lie in their selectivity, potency, bioavailability, and half-life; it remains to be seen whether the 2 newer agents will be helpful for men in whom sildenafil treatment has failed. • Apomorphine, also newly available in Europe, is entirely different from the PDE-5 inhibitors because of its erectogenic neural pharmacology; it is a nonspecific dopaminergic agonist that stimulates pro-erectile signaling in the brain. VOL. 5 SUPPL. 7 2003 REVIEWS IN UROLOGY S19 Evaluation and Management of ED continued 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. S20 Corbin JD, Francis SH. Cyclic GMP phosphodiesterase-5: target of sildenafil. J Biol Chem. 1999;274:13729-13732. Viagra [prescribing information]. New York: Pfizer Inc; 2003. Levitra [prescribing information]. West Haven, Conn: Bayer Pharmaceuticals Corp; 2003. Hatzichristou DG. Sildenafil citrate: lessons learned from 3 years of clinical experience. Int J Impot Res. 2002;14(suppl 1):S43-S52. Moore RA, Edwards JE, McQuay HJ. Sildenafil (Viagra) for male erectile dysfunction, a meta analysis of clinical trial reports. BMC Urol. 2002;22:6. Padma-Nathan H, Stecher VJ, Sweeney M, et al. Minimal time to successful intercourse after sildenafil citrate: results of a randomized, doubleblind, placebo-controlled trial. Urology. 2003; 62:400-403. Sadovsky R, Miller T, Moskowitz M, Hackett G. Three-year update of sildenafil citrate (Viagra) efficacy and safety. Int J Clin Pract. 2001; 55:115-128. Rendell MS, Rajfer J, Wicker PA, Smith MD, for the Sildenafil Diabetes Study Group. Sildenafil for treatment of erectile dysfunction in men with diabetes. JAMA. 1999;281:421-426. Nurnberg HG, Lauriello J, Hensley PL. Sildenafil for iagtrogenic serotonergic antidepressant medication-induced sexual dysfunction in 4 patients. J Clin Psychiatry. 1999;60:33-35. Giuliano F, Montorsi F, Mirone V, et al. Switching from intracavernous prostaglandin E1 injections to oral sildenafil citrate in patients with erectile dysfunction; results of a multicenter European study. J Urol. 2000; 164:708-711. Mittleman MA, Glasser DB, Orazem J. Clinical trials of sildenafil citrate (Viagra) demonstrate no increase in risk of myocardial infarction and cardiovascular death compared with placebo. Int J Clin Pract. 2003;57:597-600. DeBusk R, Drory Y, Goldstein I, et al. Management of sexual dysfunction in patients with cardiovascular disease: recommendations of The Princeton Consensus Panel. Am J Cardiol. 2000;86:175-181. Padma-Nathan H, Rosen RC, Shabsigh R, et al. Cialis (IC351) provides prompt response and extended period of responsiveness in the treat- VOL. 5 SUPPL. 7 2003 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. REVIEWS IN UROLOGY ment of men with erectile dysfunction (ED). J Urol. 2001;165(suppl):A953. Porst H. IC351 (tadalafil, Cialis): update on clinical experience. Int J Impot Res. 2002;14(suppl 1):S57-S64. Saenz de Tajada I, Emmick J, Anglin G, et al. The effect of as-needed tadalafil (IC351) treatment of erectile dysfunction in men with diabetes. Int J Impot Res. 2001;13(suppl 4):A128. Klotz T, Sachse R, Heidrich A, et al. Vardenafil increases penile rigidity and tumescence in erectile dysfunction patients: a RigiScan and pharmacokinetic study. World J Urol. 2001; 19:32-39. Pryor JP. Vardenafil: update on clinical experience. Int J Impot Res. 2002;14(suppl 1):S65-S69. Goldstein I, Young J, Segerson T, Thibonnier M. Long term efficacy and safety of vardenafil in diabetic men with erectile dysfunction. Diabetes. 2002;51(suppl 2):A98. Hellstrom WJG, Gittelman MC, Shapiro J, et al. Vardenafil improved erectile function in men with a broad range of erectile dysfunction etiologies and severities: a phase III trial. Int J Impot Res. 2001;13(suppl 5):S65. Abstract 25. Briefing document: assessment of the QT prolongation potential of the phosphodiesterase-5 inhibitor vardenafil. Available at: http://www.fda.gov/ohrms/dockets/ac/03/briefing/ 3956B1_05_Bayer-Levitra.pdf. Accessed October 7, 2003. Argiolas A, Hedlund H. The pharmacology and clinical pharmacokinetics of apomorphine SL. BJU Int. 2001;88(suppl 3):18-21. Rampin O. Mode of action of a new oral treatment for erectile dysfunction: apomorphine SL. BJU Int. 2001;88(suppl 3):22-24. Buvat J, Montorsi F. Safety and tolerability of apomorphine SL in patients with erectile dysfunction. BJU Int. 2001;88(suppl 3):30-35. Mirone VG, Stief CG. Efficacy of apomorphine SL in erectile dysfunction. BJU Int. 2001; 88(suppl 3):25-29. Dula E, Bukofzer S, Perdok R, George M, and the Apomorphine SL Study Group. Doubleblind, crossover comparison of 3 mg apomorphine SL with placebo and with 4 mg apomorphine SL in male erectile dysfunction. Eur Urol. 2001;39:558-564. McCullough AR, Barada JH, Fawzy A, et al. Achieving treatment optimization with silde- 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. nafil citrate (Viagra®) in patients with erectile dysfunction. Urology. 2002;60(suppl 2B):28-38. Pinkstaff DM, Broderick GA. Contemporary management of erectile dysfunction: the challenge for second generation PDE inhibitors [abstract]. Int J Impot Res. 2001;13(suppl 5):S63. Wespes E, Rammal A, Garbar C, et al. Viagra non-responders: heamodynamic and morphometric studies. J Urol. 2003;169(suppl 4):244245. Abstract 946. Shabsigh R, Kaufman JM, Steidle C, PadmaNathan H. Testosterone replacement therapy with testosterone gel 1% converts sildenafil nonresponders to responders in men with hypogonadism and erectile dysfunction who failed prior sildenafil therapy. J Urol. 2003; 169(suppl 4):247. Abstract 954. Rosenthal B, Ginsberg PC, Metro M, Harkaway RC. The addition of testosterone replacement therapy to treat erectile dysfunction after failure of sildenafil alone in men with acquired androgen deficiency syndrome. J Urol. 2003; 169(suppl 4):377. Abstract 1408. Shabsigh R, Padma-Nathan H, Gittleman M. Intracavernous alprostadil alfadex (EDEX/VIRIDAL) is effective and safe in patients with erectile dysfunction after failing sildenafil (Viagra). Urology. 2000;55:477-480. Lue TF. Erectile dysfunction. N Engl J Med. 2000;342:1802-1813. Corbin JD, Francis SH. Pharmacology of phosphodiesterase-5 inhibitors. Int J Clin Pract. 2002;56:453-459. Bischoff E, Niewohner U, Haning H, et al. The inhibitory selectivity of vardenafil on bovine and human recombinant phosphodiesterase isoenzymes. Int J Impot Res. 2001;13(suppl 4):S41. Abstract 113. Eardley I, Cartledge J. Tadalafil (Cialis) for men with erectile dysfunction. Int J Clin Pract. 2002;56:300-304. Omrod D, Easthope SE, Figgitt DP. Vardenafil. Drugs Aging. 2002;19:217-227. Brock G, McMahon C, Point P, et al. Efficacy and safety of tadalafil in men with erectile dysfunction: an integrated analysis of registration trials. J Urol. 2002;167(suppl 4):178. Abstract 713. Godfishcher E, Eardley I, Segerson T. Vardenafil improves erectile function in men with significant comorbidities. J Urol. 2002;167(suppl 4): 178. Abstract 714.