Characterising the benefit of apomorphine SL (Uprima) as an optimised treatment for representative populations with erectile dysfunction

The clinical profile for apomorphine sublingual (SL), a new centrally active agent for the management of the erectile dysfunction (ED) patient, is described in this article. Apomorphine SL is shown to be rapid in onset (71% of patients within 20 min) with a consistent, predictable response that is independent of severity (mild, moderate or severe), the underlying aetiology or the presence of significant co-morbidities (coronary artery disease, hypertension, etc). Importantly, there is also consistent long-term clinical benefit (>90% of attempts being successful over 18 months), for patients who respond to therapy and a benign side effect profile (<13.4% patients with adverse events). This formulation of apomorphine has a speed of onset and overall clinical profile that may offer particular advantages to the patient in terms of spontaneity and predictability of response. ED is a complex disease of varying aetiologies and severities often associated with a number of co-morbidities that require diverse solutions. Given the need for customisation of therapy to individual patient needs, the clinical profile of apomorphine SL would indicate that it will make a most welcome addition to the physician's armamentarium against ED.     

Cross-Study Review of the Clinical Efficacy of Apomorphine SL 2 and 3 mg:: Pooled Data from Three Placebo-Controlled,Fixed-Dose Crossover Studies

Background: Sublingual (SL) apomorphine is a nonopioid, centrally acting dopamine agonist developed to treat erectile dysfunction (ED). Clinical trials of the drug, using the most stringent and clinically relevant endpoints of “erections firm enough for intercourse”, have demonstrated its benefit in a wide variety of ED patients.Methods: Data were pooled and analyzed from three fixed-dose, placebo-controlled, double-blind, two-period crossover studies in which apomorphine SL 2 or 3 mg was evaluated against placebo for efficacy. Of the 415 patients who received both apomorphine SL (2 or 3 mg) and placebo, 252 received 2 mg and 163 received 3 mg. The clinical endpoints included erections firm enough for intercourse, per attempt intercourse rates and the International Index of Erectile Function (IIEF) criteria including the erectile function domain scores.Results: Apomorphine SL produced statistically significant improvements in a panel of erectile function measures, including erections firm enough for intercourse, total IIEF score, and IIEF domain scores. The proportion of patients achieving erections firm enough for intercourse was statistically significantly greater than placebo for both doses across all studies (p=0.001) and the ability to achieve an erection and have successful intercourse increased with sequential attempts. The percentage of attempts resulting in erections firm enough for intercourse was greatest in patients with mild or moderate ED; 89% of these patients who received at least eight doses of apomorphine SL 3 mg achieved adequate erections during treatment.Conclusions: Apomorphine SL 2 and 3 mg has significant benefit for men with ED as measured by all currently acceptable erectile function endpoints. An erection results as early as 10 minutes after dosing, and nearly 90% of erections occur within 30 minutes. Apomorphine SL is an appropriate first-line therapy for the management of ED, particularly in men presenting with mild to moderate dysfunction.     

Apomorphine: an update of clinical trial results

Apomorphine SL (TAP Holdings, Deerfield, IL) is a centrally acting treatment for erectile dysfunction (ED) that has been undergoing phase III trials. Over 3000 men have received apomorphine SL and over 75,000 doses have been taken. In the first three phase III parallel arm cross-over double-blind studies 854 patients were given a total of 8263 tablets of apomorphine SL in 2 and 4 mg doses. The patients were between 18 and 70 y old and outcome measures included per attempt rates of intercourse and erections firm enough for intercourse as well as psychometric instruments and partner responses. The majority (74.1%) had moderate and severe grades of ED on admission to the studies, 31% had hypertension, 16% had documented coronary artery disease, 16% had dyslipidemia and 16% had diabetes. Erections occurred rapidly (10-25 min) and in 54.4% of attempts at 4 mg (vs 33.8% placebo). A majority of the attempts at intercourse (50.6%) were successful at 4 mg in patients when recorded on a per-attempt basis. The most common but infrequent and mild side effect of nausea decreases with use. The phase III trials of apomorphine SL show that there is a clinically important restoration of erectile function from this new formulation of apomorphine. It has a rapid and safe effect through action in the central nervous system. Apomorphine SL brings a new choice to the management of ED that will further benefit the millions of couples affected. International Journal of Impotence Research (2000) 12, Suppl 4, S67-S73.     

Safety and Tolerability of Apomorphine SL in Men with Cardiovascular Disorders

Objective: Since many men with erectile dysfunction (ED) also have cardiovascular (CV) disease and are likely to be taking antihypertensive medications, nitrates, or other medications, the risk of side effects of oral drug therapy for ED in the presence of these conditions was evaluated.Methods: Clinical trials involving apomorphine SL for ED were evaluated to determine the safety and tolerability profile in men with coronary artery disease, hypertension, hyperlipidemia, and diabetes mellitus in comparison to other oral agents.Results: None of the subpopulations of men, whether analyzed by specific CV disease, presence of diabetes, or any concomitant medication were at increased risk for side effects and adverse events associated with apomorphine SL treatment. In particular, there were no substantive changes in the adverse event rates in those patients concurrently receiving antihypertensive medications nor in those men treated with short- or long-acting nitrates.Conclusions: Apomorphine SL is well tolerated and safe in men with ED associated with concomitant CV disorders or risk factors. Furthermore, apomorphine SL is not contraindicated in men with stable coronary artery disease who take nitrate medication and is well tolerated and safe in men concurrently receiving CV medications including nitrates and various classes of antihypertensives.     

Oral treatment of erectile dysfunction with apomorphine SL.

Apomorphine SL (Ixense, Uprima) is a new oral medication shown to be effective in the treatment of erectile dysfunction. This compound is a dopaminergic agonist with affinity for dopamine receptor sites - mostly D(2) - within the brain known to be involved in sexual function. Apomorphine induces selective activation in the nucleus paraventricularis leading to erectogenic signals. More than 5,000 men with erectile dysfunction participated in phase II/III clinical trials assessing the safety and efficacy of doses ranging from 2 to 6 mg. The most favorable risk/benefit ratio is seen with a dose-optimization regimen of 2-3 mg: the 3-mg dose provides efficacy comparable to that of 4 mg but with fewer side effects. Consequently, review of clinical studies focuses on data with the 2- to 3-mg dose, the registered dose for use in clinical practice. The primary efficacy endpoint in most clinical trials with apomorphine SL was the percentage of attempts resulting in erections firm enough for intercourse - one of the most rigorous endpoints used in ED trials to date. These data were collected from both patients and their partners by reviewing entries in patient diaries and partner BSFI questionnaires. Secondary endpoints included percentage of attempts resulting in intercourse and improvement in ED severity based on the International Index of Erectile Function (IIEF). The proportion of attempts resulting in erections firm enough for intercourse was 49.4% with 3 mg compared with the baseline value of 24.3%. Partner evaluations corresponded with those of the patients. Erections occurred between 18 and 19 min after taking apomorphine SL 2 or 3 mg. The most common side effect was nausea which declined with continued use. Vasovagal syncope was reported in <0.2% of men, and was preceded by clear prodromal symptoms. Thus, apomorphine SL is an effective, well-tolerated drug for erectile dysfunction.     

Key issues from the clinical trials of apomorphine SL

The central nervous system has the capacity to enhance the activity of dysfunctional penile tissue in men with erectile dysfunction (ED). Phase III clinical trials have been conducted using Apomorphine SL (TAP Pharmaceuticals, Deerfield, IL) as a centrally acting treatment for ED. Apomorphine SL has been administered to over 3000 men in over 75,000 doses. In three phase III crossover double blind studies 854 patients were given a total of 8263 tablets of apomorphine SL in 2 and 4 mg doses. The patients were between 18 and 70 years old and had multiple co-morbid conditions. Outcome measures included intercourse rates and erection rates on a per attempt basis as well as psychometric instruments and partner response evaluations. The results show that 74.1% of patients had moderate or severe grades of ED on inclusion into the studies, 31% had hypertension, 16% had documented coronary artery disease, 16% had dyslipidemia, and 16% had diabetes. Erections occurred rapidly (10–25 min). In 54.4% of attempts at 4 mg (vs 33.8% placebo, P < 0.001) erections suitable for intercourse were documented. A majority of the attempts at intercourse (50.6%, P < 0.001) were successful at 4 mg – a doubling of baseline rates. Mild nausea was the most common but infrequent side effect and the rare occurrence of syncope was the most significant. No cardiac deaths were attributed. It is concluded that the clinical trials of apomorphine SL demonstrate a safe and significant rate of restoration of erectile function by means of a central mode of action. Efficacy has been shown in men with cardiovascular disease and severe grades of ED.     

Tolerability and safety of apomorphine SL (Ixense (TM) )

Apomorphine SL (Ixense (TM) ) (apo SL) is a dopamine receptor agonist that can enhance sexual function in patients with erectile dysfunction (ED). For a patient, the ability to achieve a physiological erection, tolerability, efficacy and the speed of onset of the therapy are of considerable importance when considering ED treatment. Recent studies have focused on determining the patient's tolerability to apo SL as a therapy for ED. In addition, the cardiovascular profile of those patients that would be likely to receive apo SL in the clinic has been assessed. These studies have shown that apo SL is safe and effective in the treatment of ED and offers a new therapeutic option for the first-line treatment of patients with different concomitant diseases including cardiovascular disease and diabetes. The most frequently reported adverse events were nausea and dizziness, but no major adverse events have been noted in any of the clinical trials.     

Effects of visual sexual stimuli and apomorphine SL on cerebral activity in men with erectile dysfunction

PURPOSE: The present study investigates whether cerebral activation during visually evoked sexual arousal is different in patients with erectile dysfunction (ED) compared to the known pattern observed in healthy men, and additionally how cerebral activity during visual sexual stimulation is modified by treatment with apomorphine SL and whether the observed cerebral activity correlates with penile rigidity. PATIENTS AND METHODS: Cerebral activity was measured before and after treatment in 12 patients with erectile dysfunction randomised to receive either apomorphine SL or placebo using [15O]H(2)O-PET. Two PET scans were performed prior to administration of the study medication, the first after a neutral audiovisual stimulus and the second following a sexually stimulating audiovisual presentation. After receiving the study medication, patients were subjected to two additional scans each preceded by a sexually stimulating stimulus. Penile rigidity was assessed with the RigiScan device. Evaluation for significant regional cerebral activation was performed using statistical parametric mapping (SPM99). RESULTS: Cerebral activity increased significantly after the sexually stimulating video sequence compared to the neutral one in the inferior frontal cortex (Brodmann areas [BA] 47, 10, 11) and the rostral anterior cingulate (BA 32), and cerebral activity was observed to decrease in both inferior temporal cortices (BA 20). 4 out of 6 patients showed significant penile rigidity after apomorphine SL and in none of those receiving placebo. Apomorphine SL was observed to increase cerebral activity in the right superior prefrontal area (BA 6) that was not seen with placebo, while neither apomorphine SL nor placebo produced decreased cerebral activity. Penile rigidity correlated with increased cerebral activity in the anterior cingulum and right prefrontal cortex, and with decreased activity in the temporal cortex. CONCLUSIONS: In patients with erectile dysfunction, the pattern of increased and decreased cerebral activity in response to visual sexual stimuli in this study is similar to that reported in the literature in healthy men. Apomorphine SL appears to induce additional cerebral activity in the right prefrontal cortex, an area previously shown to be associated with sexual arousal in male volunteers during orgasm. This increased cerebral activity was associated with penile rigidity, further supporting the conclusion that apomorphine SL improves erectile function in men with ED by enhancing the natural central erectile signals that normally occur during sexual stimulation.     

Pharmacological management of erectile dysfunction

Erectile dysfunction (ED) is a common medical condition that affects the sexual life of millions of men worldwide. Many drugs are now available for treating ED; oral pharmacotherapy represents the first-line option for most patients with ED. Sildenafil, an inhibitor of the enzyme phosphodiesterase type 5, is currently the most widely prescribed oral agent and has a very satisfactory efficacy-safety profile in all patient categories. Apomorphine SL is a dopamine D1- and D2-receptor agonist which has recently been approved for marketing in Europe. It is best selected for treating patients with mild to moderate ED. Vardenafil and tadalafil are new phosphodiesterase type 5 inhibitors which are expected to be approved this year. Both of them have significant positive efficacy-safety profiles. Patients who do not respond to oral pharmacotherapy or who cannot use it are good candidates for intracavernosal and intraurethral therapy. Alprostadil is the most widely used drug, both for injection therapy and for the intraurethral route. The efficacy of second-line treatment is high but the attrition rate remains significant.     

Apomorphine sublingual as primary or secondary treatment for erectile dysfunction in patients with spinal cord injury

OBJECTIVES: To evaluate the effectiveness of apomorphine sublingual (SL) 3 mg, as a primary or secondary treatment for erectile dysfunction (ED) in patients with spinal cord injury (SCI), and to determine possible differences in efficacy considering clinical, urodynamic and neurophysiological findings. PATIENTS AND METHODS: The study included 22 patients with chronic SCI and neurogenic ED who were examined physically and by a video-urodynamic evaluation. A neurophysiological evaluation included somatosensory evoked potentials of the pudendal nerve, palmar and plantar sympathetic skin responses and bulbocavernous reflex recordings. Thereafter the patients received 8 tablets of apomorphine SL 3 mg and were asked to complete the International Index of Erectile Function questionnaire before and after treatment. Side-effects, subjective efficacy compared with other treatments and satisfaction with the SL administration were recorded. RESULTS: Of the 22 men, 11 had upper motor neurone lesions (six complete, five incomplete), eight lower motor neurone lesions (seven complete, one incomplete) and three had mixed lesions. In all, 12 patients took sildenafil citrate and five alprostadil intracavernosally beforehand, and five had used nothing to treat their ED. Seven patients had some response and reported that the drug helped them to obtain an erection, but only two reported erections sufficient for intercourse and would agree to continue apomorphine SL as their standard treatment; all the others reported being disappointed. Nine patients reported side-effects. There were no significant correlations for electrophysiological or urodynamic findings and treatment success. Of the 22 patients 20 preferred SL rather than the normal administration. CONCLUSIONS: Apomorphine SL, a D1/D2 dopamine agonist, facilitates erectile function in a heterogeneous group of patients with no significant relationship with any of the assessed urodynamic or electrophysiological variables. The overall low rates of response either for primary or secondary treatment suggests that apomorphine will have limited applicability in patients with SCI.     

Clinical efficacy of Apomorphine SL in erectile dysfunction of diabetic men

Although subgroup analyses from large randomised premarketing studies have shown that Apomorphine SL enhances the percentage of erections firm enough for sexual intercourse in diabetic men, the clinical role of the drug in this patient population remains to be elucidated. The aim of the present study was to assess the efficacy of Apomorphine SL in diabetic males with erectile dysfunction (ED) and to identify factors predicting those who may benefit from the treatment. A total of 130 diabetic patients were randomised to receive either four tablets of 3 mg Apomorphine or a matching placebo. Assessments of efficacy comprised the erectile function (EF) domain of the International Index of Erectile Function (IIEF) and the one-item global efficacy question (GEQ). Patients with both a positive response to the GEQ and an improvement of at least 5 points in the EF domain of the IIEF were considered responders and subanalysed by several parameters indicative of the severity of both ED and diabetes. Response rate was 17% after placebo and 22% after Apomorphine SL. The EF domain of the IIEF and both questions 3 and 4 scores did not significantly improve in either of the two arms over the baseline. A younger age and a lower Hb1Ac were significantly linked to the status of responder in the Apomorphine arm. Apomorphine SL failed to show a statistically significant benefit over a placebo, but 22% of patients had a clinically significant erectile response. These figures seem to suggest that the drug has a limited use for ED diabetic patients.     

Efficacy and safety of fixed-dose and dose-optimization regimens of sublingual apomorphine versus placebo in men with erectile dysfunction. The Apomorphine Study Group

OBJECTIVES: A sublingual (SL) formulation of apomorphine has been developed and found effective in penile erectile dysfunction (ED). This study assessed the efficacy and safety of several doses of apomorphine SL in a dose-optimization schedule compared with placebo. METHODS: In this 8-week, multicenter, double-blind clinical trial, 569 patients were randomized to four groups: a dose-optimization group in which patients began with 2 mg, increased or decreased the dosage as needed for 4 weeks, and thereafter maintained an optimal dose for 4 weeks; two fixed-dose groups of either 5 or 6 mg; and a placebo group. Efficacy was assessed by patient and partner responses to home-use questionnaires about sexual function and activity and by responses to the International Index of Erectile Function and the Brief Sexual Function Inventory. RESULTS: In all apomorphine SL groups, a significantly higher percentage of patients compared with the placebo group achieved and maintained an erection firm enough for intercourse (48% to 53% versus 35% for placebo, P < or =0.001) and a significantly higher percentage of attempts resulted in intercourse (45% to 51% versus 33%, P < or =0.001). The responses to the questionnaires completed by the patients and partners were similar. Apomorphine SL was well tolerated; nausea, the most common side effect, was dose related and diminished substantially during the second 4-week period at all doses. The dose-optimization schedule resulted in fewer adverse events without impacting efficacy. CONCLUSIONS: Apomorphine SL is an effective and safe treatment for ED, with 2 and 4 mg providing the most acceptable therapeutic index.     

Erectile dysfunction prevalence,time of onset and association with risk factors in 300 consecutive patients with acute chest pain and angiographically documented coronary artery disease

OBJECTIVES: The aim of this study was to assess erectile dysfunction prevalence, time of onset and association with risk factors in patients with acute chest pain and angiographically documented coronary artery disease. METHODS: 300 consecutive patients with acute chest pain and angiographically documented coronary artery disease were assessed using a semi-structured interview investigating their medical and sexual histories, the International Index of Erectile Function and other instruments. RESULTS: Patient mean age was 62.5+/-8 years (range 33-86 years). Mean duration of symptoms or signs of myocardial ischaemia prior to enrollment in the study was 49 months (range 1-200). Coronary angiography showed 1-, 2- and 3-vessel disease in 98 (32.6%), 88 (29.3%) and 114 (38%) patients, respectively. The prevalence of ED among all patients was 49% (147/300). Erectile dysfunction was scored as mild, mild to moderate, moderate and severe in 21 (14%), 31 (21%), 20 (14%), and 75 (51%) of patients, respectively. There was no significant difference between patients with ED (n=147) or without ED (n=153) as far as clinical and angiographic characteristics were concerned.In the 147 patients with co-existing ED and CAD, ED symptoms were reported as having become clinically evident prior to CAD symptoms by 99/147 (67%) patients. The mean time interval between the onset of ED and CAD was 38.8 months (range 1-168). There was no significant difference in terms of risk factor distribution and clinical and angiographic characteristics between patients with the onset of ED before vs. after CAD diagnosis. Interestingly, all patients with type I diabetes and ED actually developed sexual dysfunction before CAD onset (p<0.001). CONCLUSIONS: Our study suggests that a significant proportion of patients with angiographically documented coronary artery disease have erectile dysfunction and that this latter condition may become evident prior to angina symptoms in almost 70% of cases. Future studies including a control group of patients with coronary artery disease and normal erectile function are required in order to verify whether erectile dysfunction may be considered a real predictor of ischemic heart disease.     

Adverse Events and Patient Tolerability of Apomorphine SL 2 and 3 mg: A Cross-Study Analysis of Phase II and III Studies

Background: In 1999, the World Health Organization (WHO) Consensus Panel recommended orally administered drugs as first-line treatment of erectile dysfunction. Apomorphine SL, a sublingually administered erectogenic agent with a favorable therapeutic index, has been studied extensively in clinical trials.Methods: The safety and tolerability of apomorphine SL 2 and 3 mg was assessed in 14 phase II and III clinical studies, in which 2908 patients received the 2 mg dose and 1331 patients received the 3 mg dose of apomorphine SL. Of the 3183 patients who received at least one dose of the 2 or 3 mg dose of apomorphine SL, 1040 received the 3 mg dose after first having been exposed to the 2 mg dose in a dose-optimizing treatment regimen. Adverse event outcomes from fixed-dose and dose-optimization studies were analyzed.Results: Across all apomorphine SL studies, the adverse events most commonly seen were nausea, headache and dizziness. The incidence of adverse events was lower with the 3 mg dose in those patients who received an initial 2 mg dose in a dose-optimizing regimen, and no individual adverse event was reported by >5% of patients in the dose-optimization cohort. Nausea, headache and dizziness occurred in 4.2%, 3.0% and 1.8% of patients, respectively, in the 3 mg dose-optimization group, and the overall incidence of any adverse event was 12.5% in these patients. Hypotension and vasovagal syncope occurred rarely at the 2 and 3 mg doses, particularly when a dose-optimization regimen was used, where 0.1% of patients reported syncope. No death, stroke, myocardial infarction, priapism, or inappropriate erection has been associated with apomorphine SL at any dose level.Conclusion: The favorable tolerability and safety profile of apomorphine SL 2 and 3 mg suggests that this drug be considered a first choice treatment for the majority of patients with erectile dysfunction.     

The utility of sildenafil citrate for infertile men with sexual dysfunction: a pilot study

OBJECTIVE: To investigate the use the sildenafil citrate, recognized as a first-line therapy for men with erectile dysfunction (ED), and which is safe and effective in men with various causes and severity of ED, including psychogenic ED, in a population of infertile men with sexual dysfunction. PATIENTS AND METHODS: Infertility is a major source of life stress and might be associated with sexual dysfunction through the erosion of self-esteem and self-confidence, and in stimulating discord in a relationship. Men presenting for evaluation of fertility who on questioning by the physician reported the recent onset of sexual dysfunction, had a history taken, a physical examination, hormonal profile, and completed the International Index of Erectile Function (IIEF), a validated inventory for assessing sexual dysfunction. Thirty men with a score of <26 on the erectile function domain of the IIEF, or who complained of new onset rapid or delayed ejaculation, were treated with sildenafil with no randomization or placebo control. The evaluation was repeated and the IIEF completed again > or =3 months after starting treatment. RESULTS: For men complaining of ED, subjective erectile rigidity, duration of erection, and the percentage of successful penetration attempts significantly improved with sildenafil. The mean (sd) IIEF domain scores for erection and satisfaction, at 18 (4) vs 27 (3), and 12 (2) vs 16 (3) (both P = 0.01), and orgasm, at 4 (1) vs 6 (3) (P = 0.001), respectively, significantly improved after treatment. In patients with ejaculatory dysfunction, the function improved in 64% after sildenafil therapy. CONCLUSIONS: We identified the nature of sexual dysfunction associated with male-factor infertility, and showed the efficacy of sildenafil therapy in men with this condition.     

Evaluating dose regimens of apomorphine,an open-label study

The aim of the study was to investigate the safety and efficacy of apomorphine SL (apo SL) 2 and 3 mg, using a dose-optimisation regime in 110 Asian men with erectile dysfunction (ED) during a 10-week open-label study. Based on daily diaries kept by each patient, 63% showed an improvement in their sexual life. Patient responses to the International Index for Erection Function 15 questionnaires showed that there was an improvement in erectile function from baseline score after treatment with apo SL (from 15.9 to 20.4), and intercourse satisfaction (from 7.7 to 9.9), as well as slight improvements in orgasmic function (from 6.8 to 7.5) and total satisfaction (from 41.9 to 50.8). There was no marked improvement seen in sexual desire. In conclusion, apo SL is safe and efficacious in the treatment of ED in this patient population, irrespective of underlying diseases and concomitant medications.     

Central nervous system agents in the treatment of erectile dysfunction

In the last two decades, a better understanding of the mechanisms governing erectile function and the pathophysiologies underlying erectile dysfunction (ED) have led re-searchers to investigate novel treatment concepts. Selective type-5 phosphodiesterase inhibitors are recommended as first-line therapy because of their high efficacy, but 30% to 40% of patients who have ED do not respond adequately to these agents and require alternative methods. The central nervous system plays a fundamental role in sexual behavior. Animal models have advanced our understanding of the neuroanatomic and neuropharmacologic basis of centrally induced penile erections. Clinical research with apomorphine has demonstrated efficacy in men who have a range of ED. Recent interest has focused on other centrally acting agents for ED treatment, including the melanocortin receptor agonists.     

A European multicentre study to evaluate the tolerability of apomorphine sublingual administered in a forced dose-escalation regimen in patients with erectile dysfunction

OBJECTIVE: To determine the risk-benefit ratio of a forced dose-escalation regimen (2 to 3 to 4 mg) in a European clinical study evaluating apomorphine sublingual (SL) in treating erectile dysfunction (ED), by evaluating the overall tolerability and efficacy of the regimen compared with placebo in patients with ED, and evaluating efficacy by assessing the proportion of successful attempts resulting in sexual intercourse. PATIENTS AND METHODS: This randomized, double-blind, two-arm, parallel-group study was conducted in 507 patients enrolled at 34 European sites. After a 1-2 week screening period, patients were treated for 8 weeks with either placebo or apomorphine SL administered as a forced dose-escalation regimen. Heterosexual men (aged 18-70 years) were eligible for participation in the study if they were in stable health, a stable relationship of > or = 6 months duration, had a history of erectile inability, and were diagnosed with ED (successful in fewer than half of attempts to attain and maintain an erection firm enough for intercourse during the 30 days before screening). Patients provided information (recorded on diary cards and reviewed at each study visit) about the frequency and success in achieving erections and of sexual intercourse attempts during both the screening and treatment periods. The dosing regimen required patients to take one tablet of apomorphine SL (2 mg for 2 weeks, then 3 mg for 2 weeks and finally 4 mg for the remaining 4 weeks) or placebo 15-25 min before intercourse, and intercourse was to be attempted at least twice a week. Safety data were collected throughout the 8-week study period, and included recording adverse events, vital signs and changes in laboratory test values for standard haematology and biochemistry variables. The primary efficacy variable was the proportion of successful attempts, defined as an erection rigid enough for sexual intercourse, occurring after dosing (successful intercourse rate). The proportion of erections achieved was a secondary efficacy variable. RESULTS: Of the 507 patients, 254 received apomorphine SL and 253 received placebo; 87% of patients in both groups completed the 8-week treatment period. Of the patients receiving apomorphine SL, 24% had hypertension, 11% had coronary artery disease, 10% had diabetes, and 5.5% had benign prostatic hypertrophy; 62.6% of treated patients received concomitant medications for these maladies. The treatment groups were balanced for demographic and baseline variables, including comorbidity factors. Treatment-emergent adverse events, reported by > 5% of patients in the treated group, were nausea (9.8%), dizziness (7.1%) and headache (6.7%), compared with 0.4%, 2.4% and 4.0%, respectively, in the placebo group. Sixty-six patients withdrew from the study, 16 because of study drug-related adverse events (12 from the apomorphine and four from the placebo group). Six patients (three in each group) reported a total of nine serious treatment-emergent adverse events, all of which resolved by the end of the study. In the intention-to-treat population, the proportion of successful attempts at sexual intercourse and of erections were statistically greater in the apomorphine than in the placebo group (P = 0.001 and 0.021, respectively); analysis of the per-protocol population results confirmed this significant difference. CONCLUSION: This European study supports the safety and tolerability of apomorphine SL despite the forced escalation to a 4-mg dose (exceeding the approved 2-3 mg dose). Adverse effects were not treatment-limiting. These results further support the clinically significant efficacy of apomorphine SL for treating ED at all doses used. The risk/benefit ratio supports apomorphine SL as a safe and effective alternative in managing ED.     

Oral Agents: First-Line Therapy for Erectile Dysfunction

Oral agents are relatively non-invasive, reversible, readily administered and well tolerated; hence, they are emerging as first-line treatments for patients with erectile dysfunction. Two medications have been licensed in Europe: the dopamine agonist sublingual apomorphine, which influences central regulatory mechanisms, and the phosphodiesterase type 5 (PDE5) inhibitor sildenafil citrate, which affects local regulation of erectile function by potentiating the effects of nitric oxide. Two other potent, selective, reversible PDE5 inhibitors (tadalafil and vardenafil) are under regulatory review in Europe, the United States and other countries. In double-blind, placebo-controlled trials, these compounds significantly enhanced erectile function and increased the likelihood of successful sexual intercourse largely irrespective of etiology or severity of erectile insufficiency. Apomorphine and PDE5 inhibitors also significantly improved scores in the erectile function, orgasmic function, intercourse satisfaction and overall satisfaction domains of the International Index of Erectile Function. Oral agents were well tolerated; adverse events were generally mild or moderate, prompting premature treatment discontinuation in a small minority of patients. The chief adverse effects with apomorphine were nausea and headache, and with PDE5 inhibitors, headache, dyspepsia and flushing. Because of a potential pharmacodynamic interaction between PDE5 inhibitors and nitrates or nitric oxide donors that has been associated with hypotension, concomitant nitrate use is an absolute contraindication. However, the actual incidences of myocardial infarction in sildenafil and tadalafil patients are similar to those in placebo controls.     

Sildenafil test: Changes in the diagnostic and therapeutic management of erectile dysfunction

Objective: To assess the efficacy of sildenafil as a first-step diagnostic and therapeutic tool for erectile dysfunction (ED) and to evaluate the consequent changes in the management of male sexual insufficiency.Materials and methods: Sildenafil in titrating doses up to 100 mg was prescribed to 50 men presenting to a sexual dysfunction clinic with medically documented ED. They had not undergone any specific diagnostic test before starting sildenafil.Results: Of the 50 men, 24 (48%) responded to sildenafil. Of these, 8 (33.3%) responded to 50 mg and 16 (66.7%) to 100 mg of sildenafil. Of the responders, 9 representing 18% of all studied men were discharged achieving spontaneous erections in a mean follow-up of 5.3 months. Men with no medical history, men with hypertension and men with mild coronary artery disease responded better.Conclusions: The sildenafil test revealed that 48% of men responded to this therapy with no requirement for more invasive tests and that 18% of men required no further treatment at all. In addition this test reduced the overall cost of the diagnostic investigation. It is proposed that the sildenafil test should be used in cases with no significant medical history or in men with hypertension or mild coronary artery disease although almost all men with ED could be categorized as sildenafil-responders or sildenafil-resistant. It is also suggested that the sildenafil test would result in the ability for more men with ED to be managed exclusively in the primary care sector.