Abstract. Introduction. Vascular and cavernosal smooth muscle in the penis

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1 RBMOnline - Vol 7. No Reproductive BioMedicine Online; on web 9 October 2003 Article Novel PDE5 inhibitors for the treatment of male erectile dysfunction Jas Kalsi (BSc, MRCSEd, MRCSEng) is a research fellow in urology and andrology at the Institute of Urology and The Wolfson Institute for Biomedical Research, London, UK. He has just completed an MD looking at the novel ways of treating severe erectile dysfunction. Dr Jas Kalsi JS Kalsi 1,2,4, G Bahadur 3, A Muneer 1,2, O Ozturk 3, N Christopher 1, DJ Ralph 1, S Minhas 1 1 The Institute of Urology, The Middlesex Hospital, Mortimer Street, London W1N 7AA, UK; 2 The Wolfson Institute of Biomedical Research, University College London, London, UK; 3 The Fertility and Reproductive Medicine Laboratories, University College London, 25 Grafton Way, London WC1E 6DB, UK 4 Correspondence: Tel: ; Fax: ; j.kalsi@ucl.ac.uk Abstract Erectile dysfunction (ED) affects the lives of approximately 150 million men worldwide. ED may be a cause of male subfertility in a significant proportion of patients. There is now an expanding armamentarium for the management of ED, including oral agents such as phosphodiesterase type 5 (PDE5) inhibitors. PDE5 inhibitors may also be useful in situations of temporary ED in couples undergoing IVF. Two novel PDE5 inhibitors have been commercially launched in the European Union in the first quarter of This article reviews the pharmacology and clinical efficacy of these new agents and their potential role in treating patients with male sub-fertility. Keywords: erectile dysfunction, male infertility, sildenafil, tadalafil, vardenafil 456 Introduction In 1992, the National Institutes of Health, USA defined erectile dysfunction (ED) as the inability to achieve and maintain a penile erection adequate for satisfactory sexual intercourse (NIH, 1992). It has since been recognized to be a significant male health problem affecting approximately 150 million men worldwide (Aytac et al., 1999). However, epidemiological studies may underestimate the problem because of the stigma associated with ED. Furthermore, ED may be associated with male sub-fertility in a significant number of patients (Lenzi et al., 2003). There is now an expanding range of options available for the management of ED. They include oral agents such as phosphodiesterase type 5 (PDE5) inhibitors, dopamine agonists, and alpha-receptor blocking drugs. Other options include intracavernosal injection, transurethral vasoactive agents, vacuum erection devices and penile prostheses. Oral therapy is used as the first line therapy in the majority of cases and is generally the most acceptable form of treatment. PDE5 inhibitors may be particularly useful in cases of temporary ED in couples undergoing IVF or other forms of assisted conception (Lenzi et al., 2003). During assisted conception treatment, the male partner is under stress and consequently can fail to produce semen sample prior to egg collection (Tur- Kaspa et al., 1999). Failure to produce spermatozoa at a given time can lead to cancellation of the procedure. Under these circumstances, PDE5 inhibitors may prevent the need for surgical intervention, e.g. percutaneous epididymal sperm aspiration (PESA) (Ojha et al., 2001). Two novel PDE5 inhibitors were launched in the European Union in the first quarter of This article reviews the pharmacology and clinical efficacy of these new agents and their role in the management of patients with male subfertility. Vascular and cavernosal smooth muscle in the penis In order for an erection to occur, relaxation of penile smooth muscle is required to allow blood to flow into the penis. An increase in intra-cavernosal pressure is produced by compression of the subtunical venules against the tunica albuginea (the corporeal veno-occlusive mechanism)

2 (Andersson and Wagner, 1995). This simultaneously reduces venous drainage from the corpora cavernosa and increases pressure within the corpora, producing an erection (Nitahara and Lue, 1999). Relaxation of penile smooth muscle is mediated mainly by nitric oxide (NO), which exerts its action on smooth muscle by activating soluble guanylate cyclase (sgc), which in turn results in an elevated intracellular cgmp concentrations (Figure 1) (Schmidt et al., 1993). Cyclic nucleotides cgmp and camp are metabolized to GMP and AMP respectively by a super-family of enzymes called phosphodiesterases (PDE) (Francis et al., 2001). Eleven families of PDE (PDE1 PDE11) with varying selectivities for cgmp or camp have been identified in mammalian tissues (Francis et al., 2001). Within these families, multiple isoforms are expressed either as products of different genes or as products of the same gene through alternative splicing (Francis et al., 2001). Among all the PDE, PDE5, 6 and 9 are specific for cgmp and among these three isoenzymes, PDE5 is the predominant PDE in the corpus cavernosum (Francis et al., 1980, 2001). By inhibiting the degradation of cgmp, PDE5 inhibitors prolong the activity of this cyclic nucleotide within the penile vascular and cavernosal smooth muscle, thus potentiating the erectile response (Ballard et al., 1998). PDE5 inhibitors The PDE5 inhibitors sildenafil, tadalafil and vardenafil share the same mechanism of action. However, they differ in their efficacy for inhibition of the enzyme, selectivity for PDE5 over other isoenzymes and duration of action (Table 1). Sildenafil and vardenafil (Livetra TM ; Bayer, Newbury, UK) have a similar chemical structure to cgmp (Figure 2), whereas that of tadalafil (Cialis TM ; Lilly-Icos, Indianapolis, IN, USA) is significantly different. Tadalafil Tadalafil has been approved by the FDA in the United States with conditions attached and was launched in the European Union in February Tadalafil is a potent, reversible and selective PDE5 inhibitor. In in-vitro studies, it has an IC 50 of 0.9 nmol/l for inhibition of PDE5 (Angulo et al., 2001; Patterson et al., 2002). A 780-fold higher concentration is needed to inhibit the retinal enzyme PDE6, with even greater concentrations needed to obtain any appreciable inhibition of other human PDE (Patterson et al., Figure 1. Nitric oxide (NO) released from nitrergic nerves and endothelium stimulates smooth muscle relaxation by activation of soluble guanylate cyclase, which in turn catalyses the conversion of GTP to the active intracellular second messenger cgmp. cgmp is then metabolized by PDE5 to GMP. Table 1. Properties of the PDE5 inhibitors. IC 50 is the concentration of drug required to achieve 50% inhibition of enzyme; the lower the value the more efficacious the drug. The selectivity ratio is represented for PDE5 over the other PDE isoenzymes; the higher the value the more specific the drug is for PDE5 over the other isoenzymes. Properties Sildenafil Tadalafil Vardenafil Time to onset (min) Duration of action (h) IC 50 PDE5 (nmol/l) Selectivity ratio PDE1 80 >10, PDE >10,000 >10,000 PDE >10,000 >10,000 PDE4 >10,000 >10,000 >10,000 PDE PDE Figure 2. Chemical structures of the PDE5 inhibitors and cyclic GMP. 457

3 2002; Brock et al., 2002a). This suggests that the side effect profile of tadalafil may be less extensive compared with sildenafil. Tadalafil significantly potentiates relaxant responses of human corporal smooth muscle tissues to sodium nitroprusside, acetylcholine, and electrical stimulation (Angulo et al., 2001; Patterson et al., 2002). Similar potentiating effects were observed when human penile resistance arteries were exposed to sodium nitroprusside or acetylcholine in the presence of tadalafil (Angulo et al., 2001; Patterson et al., 2002). Consistent with the mechanism of action for PDE5 inhibitors, tadalafil induces no physiological erection in the absence of sexual stimulation. In a pharmacokinetic study, tadalafil at a dose of 20 mg was administered to normal volunteers. It was found to be rapidly absorbed, predominantly eliminated by the liver and is distributed widely in tissues. A half-life of 17.5 h was seen and there were no serious adverse effects (Patterson et al., 2002). Integrated efficacy and safety analyses concerning the use of tadalafil were conducted in five randomized, double-blind, placebo-controlled trials lasting at least 12 weeks (Brock et al., 2002a). A total of 1112 men with mild-to-severe ED of various aetiologies, and no evidence of unstable cardiovascular disease received placebo or tadalafil at fixed daily doses ranging from 2.5 to 20 mg. Men were instructed to administer treatment at any time prior to sexual activity, without restrictions on food or alcohol intake. Compared with placebo, tadalafil significantly enhanced erectile function (Figure 3). The international index of erectile function (IIEF) erectile function domain score in the 20 mg group approached a categorization of no ED (Brock et al., 2002a). There was also a significant improvement in the proportion of affirmative responses to the sexual encounter profile (SEP) question 2 (ability to penetrate) and SEP question 3 (ability to maintain erection and complete intercourse) in tadalafil-treated men compared with placebo. When the SEP-Q3 was analysed for selected intervals, a total of 73 80% of intercourse attempts between 30 min and 36 h post-dose resulted in successful completion in the 20 mg tadalafil group (Figure 4) (Brock et al., 2002a). Tadalafil has been found to be equally efficacious irrespective of baseline diabetes status or age (Saenz de Tejada et al., 2001a). Side effects Tadalafil has been found to be well tolerated, with headache (7 21%) and dyspepsia (1 17%) the most common side effects, followed by back pain (4 9%), nasal congestion (4 6%), myalgia (1 7%), and flushing (1 5%) (Saenz de Tejada et al., 2001a; Brock et al., 2002a; Kloner, 2002; Patterson et al., 2002). Tadalafil-related side effects decreased in frequency with continued administration (Saenz de Tejada et al., 2001a; Brock et al., 2002a; Kloner, 2002; Patterson et al., 2002). Less than 3% of patients left studies because of side effects, and no treatment-related serious adverse events were reported (Saenz de Tejada et al., 2001a; Brock et al., 2002a; Kloner, 2002; Patterson et al., 2002). Co-administration of a nitrate with tadalafil is likely to be contra-indicated, because tadalafil relaxes vascular smooth muscle, which augments the hypotensive effects of nitrates. In summary, the available data are encouraging and tadalafil may be particularly useful for patients who require oral therapy to last for a longer period of time. With a broad period of responsiveness, patients and their partners may not need to synchronize their sexual activities according to dosing. Anecdotally, many female partners are particularly averse to planned sexual activity. This dose flexibility, together with the patient s ability to take tadalafil without restrictions on food or alcohol intake, may translate into enhanced patient convenience and regimen simplicity. The improvements in efficacy and flexibility in the timing of the medication, may serve to allow a greater number of patients with male subfertility to be treated in a less invasive manner. Vardenafil hydrochloride Vardenafil hydrochloride is a novel, high affinity PDE5 inhibitor currently being evaluated for the treatment of ED. It was commercially launched in March Figure 3. Effect of tadalafil ( mg) on mean IIEF erectile function domain. Significantly different from baseline. Figure 4. Effects of tadalafil on successful intercourse completion (SEP-Q3) with time after dosing.

4 In in-vitro studies, vardenafil has an IC 50 value of 0.7 nmol/l for the inhibition of PDE5. In comparison to sildenafil, this value is thus 5-fold lower (Kim et al., 2001). The effects of the vardenafil hydrochloride and sildenafil citrate on basal cgmp concentrations were assessed in intact smooth muscle cells. Equimolar concentrations of sildenafil and vardenafil resulted in a dose dependent increase in cgmp concentrations, but to a much lower extent for sildenafil (27 60%) than vardenafil (63 137%) (Kim et al., 2001). Vardenafil has been shown to have a more significant effect than sildenafil in increasing intracavernous pressure in response to pelvic nerve stimulation in anaesthetized rabbits (Choi et al., 2001). Vardenafil is a more potent inhibitor of PDE5 and more effective at lower doses. In addition, vardenafil is 16 times more selective towards PDE5 compared with PDE6 (Saenz de Tejada et al., 2001b). Vardenafil hydrochloride reaches maximum plasma concentrations within 40 min and has a half-life of h (Saenz de Tejada et al., 2001b). Vardenafil at doses of 10 and 20 mg produces a significant increase in the duration of penile rigidity in a dose dependent manner relative to placebo (Saenz de Tejada et al., 2001b; Stark et al., 2001). In a randomized, double-blind, placebo-controlled, dosefinding study involving 601 men with mild-to-severe ED, treatment with vardenafil significantly ameliorated erectile function as compared with placebo (Klotz et al., 2001). With vardenafil at 5 20 mg, changes from baseline to endpoint in responses to IIEF question 2 (ability to penetrate partner) and question 3 (ability to maintain erection) were significantly higher than placebo. Increases in the percentage of intercourse attempts with maintenance of erection and completion (SEP question 3) were also significantly higher in vardenafil-treated patients. With vardenafil, nearly 75% of attempts were successful compared with less than 40% in the placebo group (Klotz et al., 2001). Vardenafil therapy also significantly enhanced the erectile function domain and 80% of men in the 20 mg vardenafil group reported improved erections (Global Assessment Question) compared with 30% of placebo-treated patients (Figure 5) (Klotz et al. 2001). However patients with diabetes, spinal cord injury and those who had had a radical resection of the prostate gland were excluded from the study. The results of ED treatment following a radical prostatectomy have been poor. However vardenafil at doses of 10 and 20 mg significantly improved both erectile function and erection quality following nerve-sparing radical prostatectomy versus placebo (Brock et al., 2002b). The mean erectile function domain score improved from 9.1 to The results were far better for mild rather than severe ED (Brock et al., 2002b). Furthermore, significant improvements in erectile function have been found using 10 and 20 mg of vardenafil in ED associated with diabetes mellitus (Figure 6) (Pryor, 2002). Side effects The side effect profile for vardenafil appears to be similar to that of other PDE5 inhibitors, with headache, flushing, dyspepsia and rhinitis the commonest reported adverse symptoms in 6.8, 10.2, 0.7 and 4.8% respectively of patients taking 5 mg of the preparation (Klotz et al., 2001). A total of 4.8% of patients discontinued treatment due to adverse effects, compared with 1.3% for placebo. No blue colour vision adverse events or serious cardiovascular effects were reported (Klotz et al., 2001). The use of vardenafil and other PDE5 inhibitors in men with ED and coronary artery disease has given much cause for concern. The safety of vardenafil was investigated in men with stable ischaemic coronary artery disease. The patients had reproducible exercise tests, were not currently on nitrate medication and received single doses of 10 mg vardenafil or placebo. An exercise treadmill test (5 10 METS) was performed 1 h post-dose at the expected time of maximal drug exposure. Vardenafil 10 mg did not affect the ability of patients with stable coronary artery disease to exercise at a level exceeding that usually required for sexual intercourse (Thadani and Mazzu, 2002). This study supports the use of vardenafil in patients with stable cardiovascular disease not on nitrate therapy. Figure 5. Effect of vardenafil (5 20 mg) on mean IIEF erectile function domain. Significantly different from baseline. Figure 6. The effects of vardenafil on the mean IIEF erectile function domain score in diabetic patients. Significantly different from baseline. 459

5 460 Cautions and contra-indications with PDE5 inhibitors As with sildenafil, the novel PDE5 inhibitors are likely to be contra-indicated in patients taking concomitant nitrates, patients with severe hypotension and a recent CVA (Table 2). However, PDE5 inhibitors may be safely used to treat ED in patients with stable angina who are not taking nitrates. The effect of sildenafil (Viagra) on seminal parameters in normal men was recently assessed. In a double-blind, randomized, placebo-controlled crossover study, 20 healthy male volunteers were given sildenafil (100 mg) or placebo (Aversa et al., 2000). All patients were in a stable relationship and had proven fertility. Sildenafil was found to cause no significant effects on seminal parameters (sperm number, motility, abnormal forms). These results indicate there is no acute impact on sperm function and therefore sildenafil or other PDE5 inhibitors may be safely used to treat male sub-fertility secondary to erectile dysfunction. Table 2. Cautions and contra-indications with PDE5 inhibitors. Contra-indications Concomitant use of nitrates Hereditary degenerative retinal disorders Hypotension (systolic pressure <90 mm Hg) Recent cerebrovascular accident (CVA) Table 3. Keypoints. Cautions Significant coronary artery disease (e.g. myocardial infarction, unstable angina), congestive heart failure ED affects approximately 150 million men worldwide ED is associated with male sub-fertility Oral agents include phosphodiesterase type 5 (PDE5) inhibitors, dopamine agonists, and alpha-receptor blocking drugs Sildenafil (PDE5 inhibitor) was the first approved oral treatment for ED The newer PDE5 inhibitors (tadalafil, vardenafil) have greater efficacy in inhibiting the PDE5 enzyme Tadalafil allows improves erections for h post-dose Vardenafil is structurally related to sildenafil PDE5 inhibitors are safe in patients with stable coronary artery disease not on nitrates PDE5 inhibitors do not affect seminal parameters Conclusions The introduction of sildenafil has resulted in a greater awareness regarding the epidemiology and treatment of erectile dysfunction. The emergence of newer and potentially more efficacious PDE5 inhibitors (tadalafil, vardenafil) will serve to treat an even greater number of patients, allowing once daily and more convenient dosing. Tadalafil may be taken as long as 24 h before sexual activity and without restrictions on food or alcohol intake. Vardenafil is a safe and highly effective PDE5 inhibitor structurally related to the chemical structure of sildenafil. Both novel agents should be used with caution in patients with coronary artery disease. It has been proposed that a man who is undergoing fertility assessment is likely to evaluate himself as sexually inadequate, and may experience temporary impotence and decreased libido (Berger, 1980; Slade et al., 1992). Constant worry about the problem may arouse inhibitory nerves and interfere with smooth muscle relaxation in the penis, thus causing partial or complete failure of erection (Kadem et al., 1990). Whether sexual performance in men undergoing initial infertility evaluation is negatively affected by abnormal semen results is not known. It appears now that sexual dysfunction, and in particular erectile dysfunction, is experienced in men undergoing infertility evaluation (Saleh et al., 2003). It is therefore envisaged that continued improvements in the management of ED will serve to allow a greater number of patients with male sub-fertility to be treated in a less invasive manner. The keypoints that emerge from this article are summarized in Table 3. References Andersson K-E, Wagner G 1995 Physiology of penile erection. Physiological Reviews 75, Angulo J, Gadau M, Fernanadez A et al Tadalafil enhances nitric-oxide mediated relaxation of human arterial and trabecular penile smooth muscle. The European Association for the Study of Diabetes (EASD), Glasgow, UK. Aversa A. Mazzilli F. 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