Oral Agents: First-Line Therapy for Erectile Dysfunction

European Urology Supplements

European Urology Supplements 1 (2002) 12±18

Oral Agents: First-LineTherapy for Erectile Dysfunction Gerald Brock* Division of Urology, Faculty of Medicine and Dentistry, University of Western Ontario, 1151 Richmond Street, London, Ont., Canada N6A 5B8

Abstract Oral agents are relatively non-invasive, reversible, readily administered and well tolerated; hence, they are emerging as ®rst-line treatments for patients with erectile dysfunction. Two medications have been licensed in Europe: the dopamine agonist sublingual apomorphine, which in¯uences central regulatory mechanisms, and the phosphodiesterase type 5 (PDE5) inhibitor sildena®l citrate, which affects local regulation of erectile function by potentiating the effects of nitric oxide. Two other potent, selective, reversible PDE5 inhibitors (tadala®l and vardena®l) are under regulatory review in Europe, the United States and other countries. In double-blind, placebocontrolled trials, these compounds signi®cantly enhanced erectile function and increased the likelihood of successful sexual intercourse largely irrespective of etiology or severity of erectile insuf®ciency. Apomorphine and PDE5 inhibitors also signi®cantly 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 ¯ushing. 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 sildena®l and tadala®l patients are similar to those in placebo controls. # 2002 Published by Elsevier Science B.V. Keywords: Apomorphine; Erectile dysfunction; Phosphodiesterase type 5 inhibitors; Sildena®l; Tadala®l; Vardena®l 1. Introduction The advent of phosphodiesterase type 5 (PDE5) inhibition as oral therapy for erectile dysfunction (ED) ushered in a revolution in the clinical management of this condition. The ®rst PDE5 inhibitor to market, sildena®l citrate, has become a therapeutic mainstay, largely ful®lling the prediction by a 1999 World Health Organization (WHO) expert panel that, ``when indicated, oral therapies will probably become ®rst-line treatment for the majority of men (with ED) because of potential bene®ts and lack of invasiveness'' [1]. Both sildena®l and oral (sublingual) apomorphine are relatively non-invasive, reversible, easily administered, well tolerated and, consequently, more acceptable to many patients than other treatment modalities, * Tel. ‡1-519-646-6042; Fax: ‡1-519-646-6037. E-mail address: [email protected] (G. Brock).

including intracavernosal or intraurethral injection of vasoactive substances; vacuum devices; and prosthetic implants or other surgical approaches. Oral ED medications in¯uence the complex neurological, vascular and humoral processes underlying penile erection. Phosphodiesterase type 5 inhibitors in¯uence local regulatory mechanisms, potentiating the smooth muscle-relaxing effects of nitric oxide (NO) on resistance arteries and trabecular smooth muscle within the corpus cavernosum. On the other hand, apomorphine in¯uences central regulatory mechanisms, promoting dopaminergic, proerectile input from hypothalamic nuclei to the erection center in the spinal cord [2,3]. Either of these agents or groups of agents effectively shift the dynamic equilibrium of erectile function from prevailing sympathetic, adrenergic (antierectile) input, which maintains the penis in a ¯accid state, toward cholinergic (proerectile) input, which fosters erection.

1569-9056/02/$ ± see front matter # 2002 Published by Elsevier Science B.V. PII: S 1 5 6 9 - 9 0 5 6 ( 0 2 ) 0 0 1 1 3 - 6

G. Brock / European Urology Supplements 1 (2002) 12±18

13

The PDE5 inhibitor sildena®l citrate has been approved in the United States and Europe, and sublingual (SL) apomorphine in Europe. Two other PDE5 inhibitors, vardena®l and tadala®l, are currently under regulatory review in the United States and other countries. 2. Oral agents 2.1. Apomorphine The ®rst effective and well-tolerated centrally acting therapy for ED, apomorphine augments neural proerectile signaling within the central nervous system, stimulating dopamine receptors in the paraventricular nucleus of the hypothalamus. The selective D1/D2-like dopamine agonist functions at an early stage within the neurovascular cascade that culminates in enhanced vasodilation and reduced vasoconstriction within corporal smooth muscle [2±6]. As a centrally acting agent, apomorphine can augment sexual desire, and certain patients have reported increased libido with self-administered subcutaneous apomorphine [3]. Sublingual apomorphine is a rapidly acting oral ED treatment whose half-life (t1/2) is 2±3 hours [6]. Absorption across the sublingual mucosa is ef®cient and unaltered by food intake [5]. The desired central dopaminergic effects are achieved at low doses; in both healthy men and ED patients, apomorphine induced erections at subcutaneous doses of less than 1 mg [3]. In a multicenter, open-label, phase 3 dose-optimization study of 849 men with ED (mean age, 58 years), the median time to penile erection was 23 minutes, and the median duration of erection was 13 minutes [6]. A double-blind, placebo-controlled, crossover study [5] involving 194 men (mean age, 57 years) with mildto-severe ED ascribed to various factors, such as hypertension, coronary artery disease and diabetes, demonstrated that apomorphine SL 3 mg was effective in restoring erectile function. The primary ef®cacy outcome measure was the proportion of attempts leading to erections that were suf®ciently ®rm for sexual intercourse. Among patients treated for 4 weeks with apomorphine SL 3 mg, approximately 47% of intercourse attempts resulted in erections ®rm enough for intercourse compared with 32% for placebo ( p < 0:001) and 22% at baseline (Fig. 1) [5]. These data were supported by partners' perceptions based on the Brief Sexual Function Inventory. Apomorphine patients also exhibited signi®cant increases in four of the ®ve International Index of Erectile Function (IIEF) assessment domains: erectile function, intercourse satisfaction, overall satisfaction and orgasmic function. However,

Fig. 1. Percentages of attempts resulting in erections ®rm enough for sexual intercourse in patients receiving apomorphine SL 3 mg and placebo in a crossover study. Adapted from [5], copyright 2001, with permission from S. Karger AG.

the dopamine agonist exerted no effect on the sexual desire domain [5]. Apomorphine was also effective irrespective of comorbid factors or ED severity. Findings from three double-blind phase 3 crossover trials involving 854 patients further supported the effectiveness of apomorphine in enhancing erectile function. During 4-week treatment intervals, among men who received apomorphine 2 or 4 mg, 42% and 51% of attempts, respectively, led to successful intercourse compared with 31% for placebo ( p < 0:001) [4]. Adverse events observed with apomorphine SL included nausea, yawning, dizziness, headache and somnolence [5,7]. In clinical trials, nausea tended to be mild, self-limiting and infrequently associated with either premature study discontinuation or antiemetic use [6,7]. The sublingual formulation has no ®rst-pass through the liver and rapidly achieves therapeutic blood levels, and the sublingual administration route was selected largely to reduce the incidence of adverse effects that might otherwise compromise compliance [7]. To further assess the occurrence of adverse events, a cross-study safety analysis [7] involving more than 5000 patients who had received more than 120,000 doses of apomorphine SL 2 to 6 mg was conducted [7]. Of apomorphine SL patients who received 2 or 3 mg doses of apomorphine, approximately 7% or fewer were affected by any single complaint, and most adverse events were mild, transient and self-limiting. Adverse events did not signi®cantly affect apomorphine compliance: only 2.3% of patients treated with apomorphine SL 2 or 3 mg discontinued treatment because of adverse events [7]. The safety pro®le of apomorphine SL 2 to 3 mg was not signi®cantly affected by either comorbidities or a number of concomitant therapies, including nitrates. In

14

G. Brock / European Urology Supplements 1 (2002) 12±18

the safety analysis of more than 5000 patients taking apomorphine SL at doses of up to 5 mg (a supratherapeutic dose), the mean maximum reduction in blood pressure compared with placebo was 2±3 mmHg. Hypotensive effects with concurrent apomorphine SL and nitrates (n ˆ 20) were additive rather than synergistic, inducing much less marked declines in standing systolic blood pressure compared with sildena®l-nitrates (n ˆ 16) [7]. Although syncope was observed in some patients at higher doses, this adverse event occurred in fewer than 0.2% of patients receiving apomorphine 2 to 3 mg, and not without prodromal symptoms (e.g. nausea, dizziness and sweating) [7]. There were no deaths, myocardial infarctions (MI) or cerebrovascular accidents (CVA) attributed to the study drug in this large patient group and also no reports of priapism [7]. 2.2. Phosphodiesterase type 5 inhibitors Prescribing data from the United States, Canada and Europe indicate that the vast majority of ED patients prefer PDE5 inhibitors over other therapies. Sildena®l has become a clinical mainstay, and the PDE5 inhibitor class is likely to assume a more central treatment role as the physiology of erections is further delineated. By competitively inhibiting enzymatic degradation of second-messenger cyclic nucleotides, PDE5 inhibitors potentiate the smooth muscle-relaxing effects of NO through a complex biochemical cascade [8,9]. First, sexual arousal stimulates release of NO from non-adrenergic, non-cholinergic cavernous nerve terminals and endothelial cells within the penis. Nitric oxide traverses cell membranes of smooth muscle cells within the penile vasculature and trabecular erectile tissues and binds with soluble guanylate cyclase (sGC), which converts guanosine triphosphate to cyclic guanosine monophosphate (cGMP). This cyclic nucleotide in turn facilitates changes in ion channel permeability, with hyperpolarization and reduced in¯ux of ionized calcium (Ca2‡) across the cell membrane, as well as energy-dependent sequestration of Ca2‡ by cellular organelles (e.g. sarcoplasmic reticulum). Reduced intracellular Ca2‡ levels and actin±myosin complex formation are associated with diminished smooth muscle tone. Smooth muscle relaxation within penile arteries and erectile tissues, which elevates regional blood ¯ow and tissue expansion within the corpora cavernosa, is central to the development of penile erection [8,9]. Cyclic nucleotides such as cGMP are inactivated by phosphodiesterases, of which PDE5 is thought to be the predominant form within penile vascular and erectile

smooth muscle tissues. Inhibitors of PDE5 thus function by potentiating the physiologic erectile response to NO after sexual arousal rather than triggering erection per se. By targeting the PDE5 isoenzyme [10], these agents amplify the NO±sGC±cGMP signaling pathway underlying ED largely irrespective of etiology. Numerous phosphodiesterase isoenzymes mediating a number of putative physiologic roles have been identi®ed in a wide array of organs and tissues, including the heart, lung, brain, aorta (and other arteries), adrenal gland and retina [11]. Phosphodiesterases exhibit enormous functional diversity with regard to substrate speci®city and putative regulatory roles. These functions and biochemical properties are at present better characterized for PDE families 1±6 (PDE1±6) than PDE7±11. Tadala®l is approximately 780 times more selective for PDE5 than PDE6, which is expressed in the outer segments of photoreceptor neurons in both rods and cones within the retina [11]. On the other hand, vardena®l and sildena®l are, respectively, only 2.9 and 6.8 times more selective for PDE5 than PDE6 (Data on ®le, Lilly ICOS LLC). Although these in vitro selectivity ratios cannot be extrapolated to clinical ®ndings with each PDE5 inhibitor, disturbances in color vision, including transient blue-green aura and discrimination dif®culties, occurred in up to 11% of sildena®l patients [12,13]. Changes in brightness and haziness also occurred in a small minority of vardena®l patients [14], and color visual disturbance in only 1 (0.1%) tadala®l patient [15]. On the other hand, tadala®l is less selective than sildena®l or vardena®l for PDE11, a recently discovered isoenzyme that has been isolated in vivo from the heart, pituitary, prostate, testes and muscle tissue. Until the physiologic functions of PDE11 have been delineated, the implications of this disparity in selectivities will remain equivocal. 2.2.1. Sildenafil Sildena®l is rapidly absorbed, with a time to maximum plasma concentration (tmax) of 30 to 120 minutes (median, 60 minutes). Meal intake, especially of fatty foods, decreases the rate and extent of absorption. The compound and its metabolite have t1/2 values of about 4 hours [16]. Treatment with sildena®l is effective in patients with ED largely irrespective of baseline disease severity or etiology, according to ®ndings from a 12-week, randomized, double-blind, placebo-controlled ®xed-dose study [12]. The study included 514 men (mean age, 56 years) with ED of various etiologies: 32% organic

G. Brock / European Urology Supplements 1 (2002) 12±18

etiology (e.g. cardiovascular disease), 25% psychogenic and 43% mixed. Among exclusion criteria were a recent (6-month) history of CVA or MI, regular treatment with nitrates or poorly controlled diabetes. Primary ef®cacy outcome measures were based on responses to IIEF question 3 (IIEF-Q3; ``When you attempted sexual intercourse, how often were you able to penetrate (enter) your partner?'') and IIEF-Q4 (``During sexual intercourse, how often were you able to maintain your erection after you had penetrated (entered) your partner?''). Response scores ranged from 0 to 5, where 0 signi®ed ``never/did not attempt intercourse'' and 5 signi®ed ``almost always/always'' [17]. At week 12, patients who received sildena®l were signi®cantly better able to achieve and maintain erections compared with placebo controls ( p < 0:0001), according to increases from baseline to endpoint in IIEF-Q3 and IIEF-Q4 scores, respectively. In response to a global ef®cacy question, 24%, 67%, 78% and 86% of men receiving placebo or oral sildena®l 25, 50 or 100 mg, respectively, taken as needed approximately 1 hour prior to planned sexual activity, reported that sildena®l had improved their erections ( p < 0:0001 for treatment effect) [12]. The most common adverse events occurring during sildena®l use in studies were headache and facial ¯ushing, with dyspepsia, rhinitis and visual disturbances being reported less frequently. Although the frequencies of most of these events tended to rise with increasing sildena®l doses in the 24-week doseresponse study, most were mild and transient in nature [12,13]. Visual disturbances, including alterations in color perception or brightness, occurred in up to 11% of sildena®l patients. There were no reports of priapism [12,13]. 2.2.2. Vardenafil On the basis of its pharmacokinetic pro®le, vardena®l is similar to sildena®l. Vardena®l has a median tmax of about 40 minutes and a mean t1/2 of 4.4 to 4.8 hours [18]. The ®rst large-scale at-home evaluation of the ef®cacy and tolerability of vardena®l, taken as needed approximately 1 hour prior to planned intercourse at maximum daily doses of 5, 10 and 20 mg, was reported in a 12-week, multicenter, randomized, double-blind, placebo-controlled trial involving 601 men with mildto-severe ED of various etiologies [14]. Approximately 26±34% of men had ED attributed to organic factors; 25±30%, psychogenic; and 36±48%, mixed. Primary ef®cacy outcome variables were based on responses to IIEF-Q3 (penetration) and IIEF-Q4 (maintenance).

15

Vardena®l treatment signi®cantly enhanced patients' ability to attain and maintain erection, as indicated by signi®cantly more marked increases from baseline in IIEF-Q3 and IIEF-Q4 scores among actively treated patients compared with placebo controls ( p < 0:001) [14]. Increases from baseline to endpoint in all ®ve IIEF domains were signi®cantly more pronounced with vardena®l than placebo ( p < 0:001). Although statistically signi®cant, the increase in the sexual desire domain with vardena®l was modest and may have been an indirect consequence of the favorable psychological effects associated with improved sexual function rather than a direct effect of vardena®l on libido [14]. Among patients randomized to vardena®l, more than 70% of intercourse attempts were successful compared with40% withplacebo ( p < 0:001; Fig.2).Finally, 30%, 66%, 76% and 80% of patients randomized to placebo or vardena®l at 5, 10 or 20 mg, respectively, reported that treatment had improved their erections ( p < 0:001). The most common, dose-dependent adverse events with vardena®l were also headache, ¯ushing, dyspepsia and rhinitis [14]. These treatment-emergent adverse events led to premature treatment discontinuation in 0.7±4.8% of vardena®l patients compared with 1.3% of placebo controls. Minor visual disturbances, consisting mainly of transient increases in brightness or haziness, occurred in six patients taking vardena®l and in no patients taking placebo. 2.2.3. Tadalafil In both chemical structure and PDE subtype selectivity pro®le, tadala®l differs markedly from sildena®l and vardena®l. These disparities are indicated by the respective suf®xes: -dala®l and -dena®l. Compared with sildena®l and vardena®l, tadala®l exhibits a prolonged plasma residence and window of therapeutic response. The t1/2 of tadala®l is 17.5 hours

Fig. 2. Percentages of attempts resulting in successful intercourse in patients receiving vardena®l 5, 10 or 20 mg or placebo. Dashed lines represent baseline percentages. Adapted from [14], copyright 2001, with permission from Nature Publishing Group.

16

G. Brock / European Urology Supplements 1 (2002) 12±18

and the tmax is approximately 2.0 hours (range, 0.5± 12.0 hours; normalized for a 20 mg dose) in healthy volunteers [19]. In men with ED treated with tadala®l, a signi®cantly higher percentage of attempts at sexual intercourse was successful as long as 24±36 hours after dosing compared with placebo [15,20]. The pharmacokinetics of tadala®l are also not clinically signi®cantly in¯uenced by extrinsic factors, such as food or alcohol intake; or intrinsic factors, such as diabetes or renal or hepatic impairment [21]. The foregoing advantages, particularly the reduced need to plan sexual activity around the time of either tadala®l dosing or meal/alcohol consumption, may translate in clinical practice into enhanced convenience and acceptability of tadala®l to the ED patient and/or his partner. Recent integrated analyses [15] of ®ve 12-week randomized, double-blind, placebo-controlled trials demonstrated that tadala®l, taken as needed at maximum daily doses of 5±20 mg without speci®c instructions regarding food/alcohol intake, signi®cantly enhanced erectile function. Over this dose range, tadala®l signi®cantly increased the ability to attain and maintain erections among 1112 men with histories of mild-to-severe ED ascribed to various causes. Approximately 61% of men had organic ED, 9% psychogenic and 31% mixed. Nearly 60% of men had moderate or severe ED at baseline [15]. The co-primary ef®cacy outcome measures were the changes from baseline to endpoint in both the erectile function domain of the IIEF and proportions of ``yes'' responses to two questions on the Sexual Encounter Pro®le (SEP): SEP-Q2, ``Were you able to insert your penis into your partner's vagina (yes/no)?''; and SEPQ3, ``Did your erection last long enough for you to have successful intercourse (yes/no)?'' Tadala®l therapy signi®cantly enhanced scores on the erectile function domain of the IIEF ( p < 0:001 versus placebo) and sharply increased proportions of sexual attempts marked by self-reported ability to penetrate (SEP-Q2) and maintain erection (SEP-Q3) compared with placebo ( p < 0:001). In the tadala®l 20 mg group, 75% of intercourse attempts were successfully completed compared with 32% with placebo ( p < 0:001; Fig. 3). A total of 35%, 50%, 67% and 81% of patients randomized to placebo or tadala®l 5, 10 or 20 mg reported improved erections ( p < 0:001) [15]. Treatment with tadala®l also signi®cantly enhanced erectile function irrespective of ED severity, age or diabetes status at baseline. Among patients who received tadala®l 20 mg, 59% achieved normal erectile function according to scores on the erectile function domain of the IIEF [22] compared with 11% of controls ( p < 0:001) [15]. Finally, 73±80% of attempts made between 30 minutes

Fig. 3. Percentages of attempts resulting in successful intercourse in patients receiving tadala®l 2.5, 5, 10 or 20 mg or placebo. Adapted from [15], with permission of Lippincott Williams & Wilkins.

and 36 hours after tadala®l dosing resulted in successful intercourse in the tadala®l 20 mg arm [15]. Additional ®ndings were presented at the 2002 Meeting of the American Urological Association [20]. The most common adverse events with tadala®l were headache and dyspepsia, with back pain, nasal congestion and myalgia occurring less frequently [15]. These treatment-emergent events were generally mild or moderate and decreased in frequency with continued treatment. As with sildena®l and vardena®l, the rate of treatment discontinuation due to adverse events with tadala®l was low, ranging from 0.7% to 3.1% with tadala®l 5±20 mg versus 1.3% with placebo [15]. No clinically signi®cant effects on vision were noted; 1 (0.1%) of 804 tadala®l patients reported an episode of abnormal color vision [15]. Neither age nor baseline diabetes or hypertension status (or concomitant antihypertensive treatment) had any effect on the incidences of treatment-emergent adverse events [15]. No cases of priapism were reported [15]. To assess the effects of tadala®l on semen characteristics and reproductive-hormone levels, a multicenter, randomized, double-blind, placebo-controlled trial has been conducted [23]. In brief, once-daily placebo or tadala®l at a maximum dose of 20 mg per day was administered for 26 weeks to 217 men aged at least 45 years (mean, 51 years) with at least 50% normal sperm motility and morphology and a minimum average sperm concentration of 20 million/ml. The 26-week interval was chosen to encompass two normal human male spermatogenesis cycles and also to accommodate substantial seasonal variability in semen characteristics. Compared with placebo, chronic tadala®l 20 mg had no effect on sperm concentration, percentage of sperm with normal morphology, percentage of motile sperm or numbers of subjects exhibiting decreases below refer-

G. Brock / European Urology Supplements 1 (2002) 12±18

ence levels in these semen parameters [23]. Similarly, serum testosterone, luteinizing hormone and folliclestimulating hormone levels were also not signi®cantly altered with chronic tadala®l therapy. 3. Cardiovascular safety A joint consensus conference to issue recommendations for the use of sildena®l in patients with cardiovascular disease [24] was convened shortly after the launch of sildena®l. This panel con®rmed that use of nitrates or other NO donors is an absolute contraindication to sildena®l administration [24] and reinforced the instructions in the manufacturer's labeling. In 53 open-label and double-blind trials of sildena®l, including 6884 patient-years exposure to drug and 543 patient-years exposure to placebo, the incidences of MI in the sildena®l and placebo groups were 0.80 and 1.11 per 100 patient-years, respectively [25]. Among more than the 4000 patients in clinical studies with tadala®l, the incidence of MI was 0.39 per 100 patient-years compared with 1.1 per 100 patient-years in placebo controls [26]. Tadala®l has also been evaluated extensively for possible effects on the cardiovascular system. More than 4000 patients, some of whom were taking several antihypertensive medications, or who had stable cardiovascular disease, have been evaluated in clinical pharmacology and large-scale clinical trials. In a study speci®cally designed to assess changes in cardiovascular parameters over 8 hours in 80 healthy subjects who received either placebo or tadala®l, tadala®l 20 mg led to no signi®cant changes in blood pressure (or heart rate) compared with placebo, with mean maximal decreases of 0.2/4.6 mmHg on active treatment ([26]; Data on ®le, Lilly ICOS LLC). Moreover, the incidences of cardiovascular adverse events occurring during tadala®l use were low and not signi®cantly different from placebo. Among 949 patients treated with tadala®l, 3.7% experienced ¯ushing, 2.4% dizziness, 1.1% hypertension and 0.1% syncope; corresponding data for the 379 subjects taking placebo were 1.6% (¯ushing), 1.9% (dizziness), 1.6% (hypertension) and 0.5% syncope [26].

17

Finally, potential interactions between tadala®l and nitrates and sildena®l and nitrates were evaluated in a randomized, double-blind, three-way crossover study of 49 healthy subjects over the age of 55 years [27]. Compared with placebo, treatment with tadala®l 10 mg exerted no signi®cant effect on mean maximal changes in standing systolic blood pressure when administered together with sublingual nitroglycerin (SL NG). However, the frequencies of outliers, or subjects with standing systolic blood pressures of less than 85 mmHg, were higher in the tadala®l SL NG group (n ˆ 23) and sildena®l (50 mg) SL NG group (n ˆ 23) compared with placebo SL NG (n ˆ 12) [27]. 4. Conclusions Evidence from clinical trials indicates that oral agents, which are relatively non-invasive, reversible and well tolerated, signi®cantly enhance erectile function in a broad spectrum of patients with ED of various severities and etiologies. In double-blind, placebocontrolled trials, both the dopamine agonist apomorphine SL and the potent, selective, reversible PDE5 inhibitors sildena®l, vardena®l and tadala®l conferred signi®cant bene®ts in erectile function across a number of ef®cacy endpoints, including proportions of men able to penetrate their partners and maintain erections to completion of intercourse. In studies to date, none of these agents appears to augment sexual desire directly. Both apomorphine SL and PDE5 inhibitors are well tolerated, with adverse events being typically mild to moderate and transient. The principal adverse events observed with apomorphine SL included nausea and headache, and with the PDE5 inhibitors, headache and ¯ushing. In clinical trials, these self-limiting events led to premature treatment discontinuations infrequently (<5%). Finally, a large body of data involving thousands of patients suggests that PDE5 inhibitors do not increase the incidence of MI compared with placebo. However, because of potentially profound hypotensive effects, concomitant administration of nitrates or NO donors with sildena®l, but not apomorphine SL, is contraindicated.

References [1] Jardin A, Wagner G, Khoury S, Giuliano F, Goldstein I, PadmaNathan H, editors. Recommendations of the First International Consultation on Erectile Dysfunction, co-sponsored by the World Health Organization (WHO). Plymouth: Health Publications Ltd., 2000, p. 709±26.

[2] Andersson KE. Neurophysiology/pharmacology of erection. Int J Impot Res 2001;13(3):S8±17. [3] Giuliano F, Allard J. Apomorphine SL (Uprima1): preclinical and clinical experiences learned from the ®rst central nervous systemacting ED drug. Int J Impot Res 2002;14(1):S53±6.

18

G. Brock / European Urology Supplements 1 (2002) 12±18

[4] Heaton JPW. Key issues from the clinical trials of apomorphine SL. World J Urol 2001;19:25±31. [5] Dula E, Bukofzer S, Perdok R, George M, Apomorphine SL Study Group. Double-blind, crossover comparison of 3 mg apomorphine SL with placebo and with 4 mg apomorphine SL in male erectile dysfunction. Eur Urol 2001;39:558±64. [6] Mulhall JP, Bukofzer S, Edmonds AL, George M, Apomorphine SL Study Group. An open-label, uncontrolled dose-optimization study of sublingual apomorphine in erectile dysfunction. Clin Ther 2001;23: 1260±71. [7] Bukofzer S, Livesey N. Safety and tolerability of apomorphine SL (Uprima1). Int J Impot Res 2001;13(3):S40±4. [8] Lincoln TM. Cyclic GMP and mechanisms of vasodilation. Pharmacol Ther 1989;41:479±502. [9] SaÂenz de Tejada I. Molecular mechanisms for the regulation of penile smooth muscle contractility. Int J Impot Res 2000;12(4): S34±8. È ckert S, Kuthe A, Stief CG, Jonas U. Phosphodiesterase isoenzymes [10] U as pharmacological targets in the treatment of male erectile dysfunction. World J Urol 2001;19:14±22. [11] Beavo JA. Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol Rev 1995;75:725±48. [12] Montorsi F, McDermott TED, Morgan R, Olsson A, Schultz A, Kirkeby HJ, et al. Ef®cacy and safety of ®xed-dose oral sildena®l in the treatment of erectile dysfunction of various etiologies. Urology 1999;53:1011±8. [13] Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildena®l in the treatment of erectile dysfunction. N Engl J Med 1998;338:1397±404. [14] Porst H, Rosen R, Padma-Nathan H, Goldstein I, Giuliano F, Ulbrich E, Bandel T, the Vardena®l Study Group. The ef®cacy and tolerability of vardena®l, a new, oral, selective phosphodiesterase type 5 inhibitor in patients with erectile dysfunction: the ®rst at-home clinical trial. Int J Impot Res 2001;13:192±9. [15] Brock GB, McMahon CG, Chen KK, Costigan T, Shen W, Watkins V, Anglin G, Whitaker S. Ef®cacy and safety of tadala®l in the treatment of erectile dysfunction: results of integrated analyses. J Urol 2002;168:1332±6. [16] Sildena®l citrate (Viagra1) prescribing information. New York: P®zer, 1999.

[17] Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A. The International Index of Erectile Function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 1997;49: 822±30. [18] Stark S, Sachse R, Liedl T, Hensen J, Rohde G, Wensing G, Horstmann R, Schrott KM. Vardena®l increases penile rigidity and tumescence in men with erectile dysfunction after a single dose. Eur Urol 2001;40:181±90. [19] Patterson B, Bedding A, Jewell H, Payne C, Mitchell M. Dosenormalized pharmacokinetics of tadala®l (IC351) administered as a single oral dose to healthy volunteers. Eur Urol Suppl 2002;1(1):152 [abstract 600]. [20] Porst H, Rosen RC, Padma-Nathan H, Varanese L, Anglin G, Giuliano F. Tadala®l allows men with erectile dysfunction to have successful intercourse up to 36 hours postdose. J Urol 2002;167(4): 177 [abstract 709]. [21] Patterson B, Bedding A, Jewell H, Payne C, Mitchell M. The effect of intrinsic and extrinsic factors on the pharmacokinetics of tadala®l (IC351). Int J Impot Res 2001;13(Suppl 4):S43 [abstract 120]. [22] Cappelleri JC, Rosen RC, Smith MD, Mishra A, Osterloh IH. Diagnostic evaluation of the erectile function domain of the International Index of Erectile Function. Urology 1999;54:346±51. [23] Hellstrom WJG, Overstreet JW, Shen WX, Yu A, Beasley CM, Watkins VS. Tadala®l has no effect on spermatogenesis or reproductive hormones. Manuscript in preparation. [24] Cheitlin MD, Hutter Jr AM, Brindis RG, Ganz P, Kaul S, Russell Jr RO, Zusman RM. ACC/AHA expert consensus document. Use of sildena®l (Viagra) in patients with cardiovascular disease. American College of Cardiology/American Heart Association. J Am Coll Cardiol 1999;33:273±82. [25] Mittleman MA, Glasser DB, Orazem J, Collins M. Incidence of myocardial infarction and death in 53 clinical trials of Viagra1 (sildena®l citrate). J Am Coll Cardiol 2000;35(Suppl A):302A [abstract 807-6]. [26] Kloner RA, Watkins VS, Costigan TM, Bedding A, Mitchell MI, Emmick J. Cardiovascular pro®le of tadala®l, a new PDE5 inhibitor. J Urol 2002;167(4):176 [abstract 707]. [27] Kloner RA, Mitchell MI, Bedding A, Emmick J. Pharmacodynamic interactions between tadala®l and nitrates compared with sildena®l. J Urol 2002;167(4):176±177 [abstract 708].