PhosphodiesteraseType-5 Inhibitors: A Critical Comparative Analysis

Transcription

1 EAU Update Series 2 (2004) PhosphodiesteraseType-5 Inhibitors: A Critical Comparative Analysis Hartmut Porst * Private Urological Practice, Neuer Jungfernstieg 6a, D Hamburg, Germany Abstract All three PDE5 inhibitors are targeting the same site of action e.g. PDE5 and this is why a quite similar efficacy and safety profile could be expected and was finally proven in many controlled studies. The efficacy as assessed by the endpoint successful intercourse with maintenance of erection (SEP3) ranges between 65 and 75% in broadspectrum ED populations with clearly lower success-rates of 40 50% in patients with involvement of the penile nerve supply such as diabetics or patients after pelvic surgery. Generally speaking the drug-related adverse events are principally comparable except visual disturbances being more frequently reported after sildenafil and back pain/myalgia more often occurring after tadalafil. Considering the pharmacokinetic profile tadalafil distinguishes itself from sildenafil and vardenafil by its long half-life (T 1=2 ¼ 17:5 h) resulting in the majority of patients in successful coitus attempts even after days. As a rule of thumb the clinical efficacy of the respective PDE5 inhibitors corresponds pretty well to the fold halflife time. In terms of onset of action as mirrored by the T max vardenafil has the shortest one (40 min) followed by vardenafil (60 min) and tadalafil (120 min) As efficacy and side-effects may be differently perceived in the same individual patient with each of the three PDE5 inhibitors it seems reasonable to grant the couples the opportunity to try all drugs sequentially. # 2004 Published by Elsevier B.V. Keywords: Erectile dysfunction; Impotence; Phosphodiesterase (PDE) 5 inhibitors; Sildenafil; Tadalafil; Vardenafil 1. The phosphodiesterase (PDE): system Currently the PDE system includes 11 families with a total of more than 50 splice variants (isoforms) [1 5]. The distribution and density of PDEs varies among the different tissues. The PDEs catalyse the breakdown either of cyclic guanosine monophosphate (cgmp) or of cyclic adenosine monophosphate (camp), which are both second messengers with specific physiologic functions. By hydrolysing the phosphodiesterase bond of camp or cgmp, respectively, these second messengers are converted to the biologically inactive monophosphates with subsequent termination of their physiological functions. In addition to PDE5, which is the most abundant one in the corpus cavernosum, to date at least 13 other * Tel. þ (practice)/ (private); Fax: þ address: porst20354@aol.com (H. Porst). PDEs were identified in the cavernous bodies: PDE1A, PDE1B, PDE1C, PDE2A, PDE3A, PDE4A, PDE4B, PDE4C, PDE4D, PDE7A, PDE8A, PDE9A, PDE10A [6]. 2. The three phosphodiesterase-5 inhibitors: sildenafil, tadalafil and vardenafil 2.1. Pharmacodynamics, potency, selectivity, pharmacokinetics General considerations A head to head comparison of the different PDE5 inhibitors is only possible and provides valuable and comparable data when all the three drugs were assessed under the same conditions. The IC 50 values are in particular dependent on the following parameters: Species and tissue being investigated, enzyme assay applied, substrate concentration (should be 10-fold /$ see front matter # 2004 Published by Elsevier B.V. doi: /j.euus

2 H. Porst / EAU Update Series 2 (2004) lower than the target PDE), ph (buffer used?) of the milieu, in which the investigations were conducted. The differences in the respective IC 50 values and therefore in the selectivity ratios as they were reported by several authors for the same PDE5 inhibitor are due to the fact that the aforementioned investigational conditions were varying among the authors Pharmacodynamics The term pharmacodynamics covers all actions of a drug on the different body organs and in turn their functions (for example, blood pressure, heart rate, vision). The pharmacodynamic interactions of any drug are influenced by the number of receptors available in the target organ and the affinity of the compound to the receptors in question. The most important parameters concerning the pharmacodynamc properties of a drug are its biochemical potency and its organ (PDE) selectivity Biochemical potency In PDE inhibitors the biochemical potency is defined as the inhibitory effect on the enzyme of interest, e.g. in PDE5 inhibitors on the PDE5 which is the main PDE enzyme in the cavernous bodies. The biochemical potency is generally expressed as inhibitory concentration 50, the so-called IC 50. IC 50 is defined as the concentration of a PDE5 inhibitor, required to reduce the activity of PDE5 by 50%. The IC 50 values provide an overview on the efficacy of a PDE5 inhibitor. Generally speaking the lower the IC 50 values the more potent and therefore more effective a compound is for this enzyme. For the clinical setting this means that with a PDE5 inhibitor with low IC 50 values less dosage is needed to yield the same effect namely to inhibit 50% of the enzyme Clinical efficacy The clinical efficacy of a PDE5 inhibitor is related to its ability to produce a rigid and reliable erection enabling the couple to engage satisfactorily in sexual intercourse. In the clinical trials efficacy of the PDE5 inhibitors were measured with the following efficacy tools: General Assessment Question (GAQ): Has the treatment you have been taking improved your erections? This efficacy tool is the weakest one among all the efficacy tools used in ED trials as it does not say anything whether this improvement in erection was sufficient for sexual intercourse or not International Index of Erectile Function (IIEF): In terms of this world-wide mostly accepted and used efficacy tool the following questions are used either as primary or secondary efficacy endpoints: Question 3: When you attempted sexual intercourse, how often were you able to penetrate (enter) your partner? Question 4: During sexual intercourse, how often were you able to maintain your erection after you had penetrated (entered) your partner? Both questions are using the same response options with a score system from 0 to 5: 0 ¼ did not attempt intercourse, 1 ¼ almost never/never, 2 ¼ a few times (much less than half the time), 3 ¼ sometimes (about half the time), 4 ¼ most times (much more than half the time), 5 ¼ almost always/always. EF-domain of IIEF: As mentioned in the chapter diagnosis of ED this domain addresses erectile function and covers Questions 1 5 and 15 of the IIEF [7]. The maximum score achievable in the EF domain is 30 with 26 or more points indicating that erectile function has converted to normal. Sexual encounter profile (SEP): The sexual encounter profile relies on the recordings of the patients in the patient diaries distributed to the patients with the studymedication and collected at each study visit. The SEP comprises the following five questions: Question 1: Were you able to achieve at least some erection (some enlargement of the penis?) Question 2: Were you able to insert your penis into your partner s vagina? Question 3: Did your erection last long enough for you to have successful intercourse? Question 4: Were you satisfied with the hardness of your erection? Question 5: Were you satisfied overall with this sexual experience? Selectivity: profile of the PDE5 inhibitors The selectivity of a drug such as a PDE5 inhibitor provides data on to how selective a compound is in regard to the enzyme (here PDE5), on which the efficacy is desired compared to other enzymes (PDEs 1 4 and 6 11), on which an efficacy has to be regarded undesirable. Therefore the selectivity of a PDE inhibitor is assessed by comparing its potency (IC 50 ) to inhibit a PDE in question (here PDE 1 4 and 6 11) and its potency to inhibit the PDE desired (here PDE5) (see Table 1).

3 58 H. Porst / EAU Update Series 2 (2004) Table 1 Selectivity profile of PDE5 inhibitors for male impotence IC 50 concentrations in nmol PDE isoenzyme Cyclic nucleotide Sildenafil a Tadalafil b Vardenafil c,d PDE1 cgmp > camp 281 >10,000 (>30,000 a ) 180 (70 a ) PDE 2 cgmp ¼ camp >30,000 >10,000 (>100,000 a ) >10,000 (6200 a ) PDE 3 camp/cgmp 16,200 >10,000 (>100,000 a ) 2500 (>1000 a ) PDE 4 camp 7680 >10,000 (>100,000 a ) 4000 (6100 a ) PDE 5 cgmp (6.7) a,e 0.7 (0.14 a ) PDE 6 (rod) a cgmp > camp (1260 a ) 157 c (3.5 a ) PDE 6 (cone) a cgmp > camp a 0.6 a PDE 7 camp 21,300 >10,000 (>100,000 a ) 4600 (>30,000 a ) PDE 8 camp 29,800 >10,000 (>100,000 a ) >10,000 (>30,000 a ) PDE 9 cgmp 2610 >10,000 (>100,000 a ) 3370 (580 a ) PDE 10 cgmp > camp 9800 >10,000 (>100,000 a ) 1000 (3000 a ) PDE 11 cgmp > camp a,d 308 (162 a ) IC 50 : Concentrations at which 50% of the target enzyme is inhibited. a Corbin, JD et al. [3]. b Angulo [8]. c Bischoff [9]. d Bischoff [10]. e Baxendale [11]. Generally speaking the less the concentrations (IC 50 ) are for inhibition of the target enzyme (PDE5) as compared to the PDE in question, or vice versa, the higher the concentrations (IC 50 ) are, requested for inhibition of a PDE in question, compared to the concentrations (IC 50 ) needed to inhibit the target PDE5 the less likely are cross-activities eventually resulting in drug-related adverse events Selectivity ratio IC 50 for a PDE in question IC 50 for PDE5. The selectivity ratio is used for all three PDE5 inhibitors to show how selective they are for PDE5 as compared to anyone of the other ten PDEs. The higher this selectivity ratio is for PDE5 compared to the PDE investigated the more specific the PDE5 inhibitor can be considered. From the clinical point of view of special interest are the selectivity ratios of the three PDE5 inhibitors for the following PDEs: PDE1: this enzyme has an influence on increase of heart rate and on vasodilation. PDE3: this enzyme is said to influence myocardial contractility. PDE6: this enzyme is mainly responsible for color vision and brightness perception. PDE11: to date the physiological function of this enzyme is not specifically investigated and therefore its clinical importance not well understood. PDE11 was found in meaningful concentrations in the testicle, pituitary gland, heart (not cardiomyozyte), prostate, kidney and skeletal muscle Pharmacokinetics of the three PDE5 inhibitors The pharmacokinetic properties of a drug comprise all the different steps from its entry into the body to its elimination out of the body. These steps include absorption rates with special regard to any food and alcohol interaction. In this regard of special interest is the speed of absorption, which can be seen by the T max (time needed to reach the maximum plasma concentration, C max ). C max (maximum plasma concentration of a drug) indicates the value of the highest drug concentrations reached in the plasma. According to the personal experiences in the clinical setting the T max corresponds pretty well with the time needed to get a completely rigid erection and the emphasis is here on the word rigid. Of major importance for the patients and their partners is also the T 1/2 (half-life time), defined as that time it takes for the fall of the plasma concentrations of a drug to half of its C max values. Generally speaking the T 1/2 corresponds very well with the duration of action of a drug. For the three PDE5 inhibitors it can be stated that the period of responsiveness, during which the majority of the responders to the drug are able to get a rigid erection after sexual stimulation, corresponds pretty well to the 2 3-fold half-life time. In this perspective it has to be remembered that the three PDE5 inhibitors are predominantly metabolized in the liver by the low-affinity cytochrome P450 enzyme 3A4 (CYP3A4) and secondarily by the high-affinity CYP2C9. Drugs with known inhibitory activities on CYP3A4 such as the H 2 receptor antagonist cimetidine, the antibiotic erythromycin, the antimykotic drugs keto- and itraconazole or the protease

4 H. Porst / EAU Update Series 2 (2004) Table 2 Comparison of PK parameters between the three PDE5 inhibitors Parameter Vardenafil (20 mg, po) Sildenafil (100 mg, po) Tadalafil (20 mg, po) T max (min) T 1/2 (hrs) C max (mg/l) AUC Protein binding (%) NA Food interaction Low fat no Low fat? No High fat yes High fat yes Alcohol interaction No No No Age T 1/2 " T 1/2 " T 1/2 " Adjust >65 y Adjust >65 y No recommendation Source: Corbin JD et al. [3], European package insert informations of sildenafil, tadalafil and vardenafil. inhibitors indinavir, ritonavir and saquinavir can exert a major influence on the degradation rates of the single PDE5 inhibitor and can increase considerably the C max (up to 7-fold for vardenafil and less marked for sildenafil) and the total exposure to a PDE5 inhibitor in question. In particular the protease inhibitors mentioned before are increasing the plasma concentrations and prolonging the half-life time in a clinically meaningful way that the dosages of the PDE5 inhibitors have to be adjusted (reduced) when patients are on such medications. The same applies for grapefruit juice, a typical CYP3A4 inhibitor. Last but not least in terms of the pharmacokinetic profile of a drug the proteinbinding has to be considered. Both the pharmacokinetic and pharmacodynamic properties of a drug may be influenced by intrinsic factors such as age, kidney or liver function, respectively, and concomitant diseases or medications Sildenafil (Viagra 1 ) The important data on the pharmacokinetics and pharmacodynamics of sildenafil are summarized in Table 2. The drug is subject to a marked first-pass metabolism in the liver dominated by cytochrome P450 CYP3A4 and followed by CYP2C9. With concomitant medication of the CYP3A4 inhibitors erythromycin and keta-and itraconazole the sildenafil exposure increased between 100 and 200% and with the protease inhibitors ritonavir and saquinavir by 2 10-fold. Although the plasma half-life of this drug is about 4 hours our own experience with more than 8000 sildenafil users has shown that especially with the 100 mg dose many of the patients report efficacy also after 6 8 hours. Sildenafil is available in 25, 50 and 100 mg tablets. Sildenafil is meanwhile one of the best investigated drugs world-wide in terms of safety and efficacy (see Table 3). Presently the drug is also investigated in indications different from ED in particular for the treatment of pulmonary hypertension Vardenafil (Levitra 1 ) In in-vitro studies vardenafil showed the highest biochemical potency which is between 9 and 25-fold higher than that of sildenafil and between 13 and 48- fold higher as compared to tadalafil (see Fig. 1) [24 26]. Vardenafil is available in 5, 10 and 20 mg doses. As illustrated in Table 2 vardenafil shows the shortest T max among the three PDE5 inhibitors. The T 1/2 of vardenafil is somewhat longer (3.9 h) than that of sildenafil (3.7 h) but considerably shorter as compared to tadalafil (17.5 h). In the rabbit clinical efficacy of vardenafil lasted up to 4 times of the half-life time even though plasma levels have been dropped after 7 hours to 2.5% [27]. The efficacy of vardenafil has been proven in many placebo-controlled trials. The very first large worldwide phase IIB at home trial, for which the author served as principal investigator, with more than 580 eligible patients confirmed the high efficacy of this drug even in the low 5 and 10 mg doses with successfully completed intercourse-rates of between 71 and 75% [28]. In the large pivotal phase III US/Canada trial with more than 805 patients involved the success rates (completion of intercourse) were 32.7%, 51.7%, 64.7%, and 66.7% for placebo, vardenafil 5, 10 and 20 mg [29]. In a diabetic trial with a total of 452 patients suffering from type 1 (12%) and type 2 (88%) diabetes the mean success rates (successful intercourse with maintenance of erection up to ejaculation) per patient were 36%, 61% and 64% for placebo, 10 and 20 mg of vardenafil [30]. In terms of the side-effect profile the drug-related adverse events were principally similar to those

5 60 H. Porst / EAU Update Series 2 (2004) IC 50 (nm) 6 6,6 in vitro Enzyme tests , , ,7 Vardenafil Sildenafil Tadalafil a Bischoff (24) Saenz de Tejada et al(25) a Data on file 2 0 0,14 Vardenafil Sildenafil Tadalafil Gbekor (26) Fig. 1. The biochemical potency of the three PDE5 inhibitors. observed after sildenafil with the exception that color vision disturbances occurred less frequently Tadalafil (Cialis 1 ) Both in terms of its molecular structure and its pharmacokinetic profile (T 1/2 : 17.5 h!) tadalafil distinguishes itself from the two other PDE5 inhibitors. Tadalafil is available in 10 and 20 mg tablets. In a multicenter, randomized, double-blind placebocontrolled, parallel-group trial with tadalafil a statistically significant efficacy against placebo was proven, even after 24 and 36 hours in 348 men [31]. Steady-state plasma concentrations are achieved within 5 days of once daily dosing, that means that no further increase of tadalafil plasma concentrations occurs with continuing of daily dosing. Tadalafil is predominantly metabolized in the liver by the cytochrome P450 enzyme and like sildenafil and vardenafil by the CYP3A4 isoform Efficacy The efficacy data of the integrated analysis of five randomized, double-blind, placebo-controlled, fixed dose, parallel group trials, conducted at 74 centers from April 1999 to April 2001 with 1112 men, aged between 22 and 82 are displayed in Fig. 2 [32]. These data clearly show that the 20 mg has to be considered as the effective dose. Table 3 Efficacy of sildenafil (Viagra 1 ) in various patient groups Author No. of patients Subgroup Improved erections (GAQ) IIEF (change from baseline) Question 3 Question 4 Placebo Active Placebo Active Placebo Active Blonde [12] 152 Diabetes I 18% 59% 11% 78% 20% 100% 822 Diabetes II 17% 63% 31% 100% 20% 100% 1693 Non-diabetes 26% 83% 20% 95% 22% 111% Kloner [13] 1218 Hypertension 20% 70% Not reported Rendell [14] 252 Diabetes I/II 10% 56% 12.5% 82% 33% 93% Olsson [15] 224 CHD 24% 71% 22% 105% 20% 120% Conti [16] 357 CHD 20% 70% Not reported Rosen [17] 146 Depression 20% 82% 37% 131% 43% 179% Giuliano [18] 178 Spinal cord inj. 10% 80% 10% 95% 9% 134% Schmid [19] 41 Spinal cord inj. NA 93% Not reported Maytom [20] 27 Spinal cord inj. 7% 75% Not reported Wagner [21] 2240 Non-elderly <65 y 23% 75% 10% 80% 12% 100% 742 Elderly >65 y 17% 67% 6% 82% 14% 114% Fowler [22] 217 Multiple scleros. 24% 89% Not reported Chen [23] 35 Dialysis NA 80% Not reported

6 H. Porst / EAU Update Series 2 (2004) double blind, placebo-controlled trials (n=1112) Diabetes mellitus, CHD,post MI included Percentage of Successful Intercourse Attempts SEP 3: successful intercourse with completion 75% 61% 42% 36% 32% Placebo 2.5 mg 5 mg 10 mg 20 mg Tadalafil Treatment Group Fig. 2. Results of integrated phase III analyses with tadalafil (Cialis). Source: Brock et al. [32] Adverse events in clinical studies The most frequently (>5%) treatment emergent adverse events were: headache (15.3%), dyspepsia (11.0%), infection (10%), back pain (7.3%) rhinitis (6.5%), flu syndrome (6.2%) pain (6.1%) and surgical procedures (6.0%). Overall 5.4% discontinued prematurely due to adverse events. 3. Final conclusions on the three PDE5 inhibitors sildenafil, tadalafil and vardenafil All three PDE5 inhibitors have shown a comparable efficacy profile with success rates of 70 75% (successful intercourse with maintenance of erection) in broad-spectrum ED populations. The efficacy profile declines in special subpopulations, such as diabetic patients and those after pelvic surgical procedures to a level of between 40 and 50%, depending on the severity of the underlying etiology and the procedure (radical or BNSP RRP) being performed, respectively [12,14,33]. According to the personal experiences of the author with more than 8000 patients on sildenafil and meanwhile more than 1400 both on tadalafil and vardenafil the likelihood that one individual patient is non-responsive (definition: unsuccessful vaginal penetration in at least four attempts with the maximum dose) to one PDE5 inhibitor but responsive to another one is clearly less than 5%. Clinical trials claiming that they were able to convert nonresponders to responders in 40 50% by switching them from one to another PDE5 inhibitor will be never confirmed by the market from the clinical point of view because these findings are exclusively due to a scientifically speaking incorrect (arbitrary definition of non-responders) study design [36]. As a rule of thumb real non-responders (vaginal penetration impossible) remain real non-responders in about 95%. Of course there are patients who are more satisfied with the efficacy (hardness of erection) of one drug which may be one motivating point to opt for a certain PDE5 inhibitor. Principally the same statement applies in terms of the drug-related adverse events. Considering the pooled date of the phase III clinical trials of all three drugs the frequency of these side-effects were comparable except color visual disturbances, which are more often observed with sildenafil and myalgia/back pain more frequently reported by patients while on tadalafil (Table 4). But in this regard it has to be considered that both the occurrence and intensity of the a certain adverse event,especially of headache and dyspepsia, may vary considerably in the same individuum among the three PDE5 inhibitors. From both perspectives individual variability of efficacy (hardness of erection) and side-effect profile it seems reasonable and is therefore recommended by the author to offer the patients the option to go through all three PDE5 inhibitors sequentially in order to provide the patients/couples from their individual perspective with the optimum choice. Table 4 Drug-related adverse events of the 3 PDE5 inhibitors Sildenafil a (n ¼ 5.918) Vardenafil b (n ¼ 2.203) Tadalafil c (n ¼ 804) Headache 14.6% 14.5% 14% Flush 14.1% 11.1% 4% Dyspepsia 6.2% 3.7% 10% Rhinitis 2.6% 9.2% 5% Back pain 0% 0% 6% Color visual disturbances 5.2% 0% 0% Results of the pooled phase III trials. a Padma-Nathan [34]. b Kloner [35]. c Brock [32].

7 62 H. Porst / EAU Update Series 2 (2004) With regard to the contraindications these are the same for all PDE5 inhibitors: Concomitant medications of nitrates and other NO-donors (molsidomine) represent an absolute contraindication for any PDE5 inhibitor. A relatively new safety issue came up with the concomitant medication of non-selective alphablockers such as prazosin, doxazosin and terazosin, prescribed in the indications of BPH and hypertension. With all three PDE5 inhibitors there were individually clinically meaningful blood pressure drops when these non-selective alpha-blockers were applied simultaneously with a PDE5 inhibitor which caused the regulatory authorities to insist on a warning in the European label and to not recommend the simultaneous use of both medications. In terms of the uroselective alpha-blocker tamsulosin no interferences were observed in the interaction studies, with the uroselective alpha-blocker alfuzosin at present no data are published so far. Regarding the frequency of serious cardiovascular events with all three PDE5 inhibitors these were more often in clinical trials with placebo than with active medication although these differences did not reach the level of statistical significance. To conclude, all three PDE5 inhibitors can be considered as highly effective and safe in the treatment of ED. Finally the development in the open drug-market will show us in the future, which one of the three PDE5 inhibitors will be preferred and whether the new two PDE5 inhibitors may contribute to a higher consultation-and treatment rate of ED patients and to a lower drop-out rate in long-term follow-up. References [1] Beavo JA. Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol Rev 1995;75(4): [2] Corbin JD, Francis SH, Webb D. Phosphodiesterase type 5 as a pharmacologic target in erectile dysfunction. Urology 2002;60,Suppl.: SB,4 11. [3] Corbin JD, Francis SH. Pharmacology of phosphodiesterase 5 inhibitors. IJCP 2002;56(6): [4] Maurice DH. Phosphodiesterases and sexual function and dysfunction. Presented at the ISSIR Symposium Molecular Mechanisms of Erectile Function at the 4th Biennal Congress of ESSIR, 29 September 2001, Rome. [5] Rybalkin SD, Beavo JA. Multiplicity within cyclic nucleotide phosphodiesterases. Biochemical Society Transactions 1997;24: [6] Küthe A, Wiedenroth A, Mägert HJ, et al. Expression of different phosphodiesterase genes in human cavernosum smooth muscle. J Urol 2001;165: [7] 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: [8] Angulo, Gadau M, Fernandez A, et al. IC351 enhences NO-mediated relaxation of human arterial and trabecular penile smooth muscle. Eur Urol 2001; 39 Suppl. 5: 106: 415. [9] Bischoff E, Niewohner U, Haning H, et al. Vardenafil, a new PDE5 inhibitor, increases cgmp in rabbit corpus cavernosum. Int J Impotence Res 2000;12 Suppl. 3:S 67, A 24. [10] Bischoff E. Personal communication [11] Baxendale RW, Wayman CP, Turner L, et al. Cellular localisation of phosphodiesterase type 11 (PDE 11) in human corpus cavernosum and the contribution of PDE 11 inhibition on nerve-stimulated relaxation. J Urol 2001; 165 No. 5 Suppl: 223, Abstr. 922 [12] Blonde L, Korenman SG, Siegel RL, et al. Sildenafil citrate for treatment of erectile dysfunction is similarily effective in men with type 1 and type 2 diabetes mellitus. Diabetes 2000;49(Suppl 1):A88. [13] Kloner RA, Brown M, Prisant LM, et al. Effect of Sildenafil in patients with erectile dysfunction taking antihypertensive therapy. Am J Hypertens 2001;14:70 3. [14] Rendell MS, Rajfer J, Wicker PA, et al. Sildenafil for treatment of erectile dysfunction in men with diabetes. JAMA 1999;281(5): [15] Olsson AM, Persson CA. Efficacy and safety of Viagra 1 (sildenafil citrate) in men with cardiovascular disease and erectile dysfunction. Urologe A 2000;39(Suppl 1):S118. [16] Conti CR, Pepine CR, Sweeney M. Efficacy and safety of sildenafil citrate in treatment of erectile dysfunction in patients with ischemic heart disease. Am J Cardiol 1999;83(Suppl 5A):29C 34C. [17] Rosen R, Seidman S, Menza M, et al. The efficacy and safety of Viagra 1 (sildenafil citrate) for the treatment of erectile dysfunction in men with comorbid depression. Poster, First international consultation on erectile dysfunction. Paris, July 1 3, [18] Giuliano F, Hultling C, El Masry WS, et al. Randomized trial of sildenafil for the treatment of erectile dysfunction in spinal cord injury. Ann Neurol 1999;46: [19] Schmid DM, Schurch B, Hauri D. Sildenafil in the treatment of sexual dysfunction in spinal cord-injured male patients. Eur Urol 2000;38: [20] Maytom MC, Derry FA, Dinsmore WW, et al. A two-part pilot study of sildenafil (Viagra 1 ) in men with erectile dysfunction caused by spinal cord injury. Spinal Cord 1999;37: [21] Wagner G, Maytom M, Smith MD, et al. Analysis of the efficacy of sildenafil (Viagra 1 ) in the treatment of male erectile dysfunction in elderly patients. Poster, First international consultation on erectile dysfunction. Paris July 1 3, [22] Fowler C, Miller J, Sharief M and the Sildenafil Study Group. Viagra (Sildenafil Citrate) for the treatment of erectile dysfunction in men with multiple sclerosis. Ann Neurol 1999;46(3):497. [23] Chen J, Mabjeesh N, Greenstein A, et al. Clinical efficacy of sildenafil in patients on chronic dialysis. J Urol 2001;165: [24] Bischoff E, Niewoehner U, Hanig U, et al. The inhibitory selectivity of vardenafil on bovine and human recombinant phosphodiesterase enzymes. Int J Impotence Res 2001;13(Suppl 4):S41. Abstr [25] Saenz de Tejada I, Angulo J, Cuevas P, et al. The phosphodiesterase inhibitory selectivity and the in vitro and in vivo potency of the new PDE5 inhibitor vardenafil. Int J Impotence Res 2001;13: [26] Gbekor E, Bethell S, Fawcett L, et al. Phosphodiesterase 5 inhibitor profiles against all human phosphodiesterase families: Implications for use as pharmacological tools. J Urol 2002; 167: No.4 Suppl.: p246 Abstr [27] Bischoff E, Mondritzki T, Niewoehner U, et al. Vardenafil improved erections in rabbits longer than expected from half-life. Int J Impotence Res 2002; 14 Suppl 4: S42, P-009. [28] Porst H, Rosen R, Padma-Nathan H, et al. The efficacy and tolerability of vardenafil, a new, oral selective phosphodiesterase type

8 H. Porst / EAU Update Series 2 (2004) inhibitor, in patients with erectile dysfunction: the first at-home clinical trial. Int J Impotence Res 2001;13: [29] Hellstrom WJG, Gittelman M, Karling G, et al. Vardenafil for treatment of men with erectile dysfunction: Efficacy and safety in a randomized, double-blind, placebo-controlled trial. J Andrology 2002;23: [30] Goldstein I, Young JM, Fischer J, et al. Vardenafil, a new phosphodiesterase type 5 inhibitor, in the treatment of erectile dysfunction in men with diabetes. Diabetes Care 2003;26:1 7. [31] Porst H, Padma-Nathan H, Giuliano F, et al. Efficacy of Tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: A randomized controlled trial. Urology 2003;62: [32] Brock GB, McMahon CG, Chen KK, et al. Efficacy and safety of tadalafil for the treatment of erectile dysfunction: Results of integrated analyses. J Urol 2002;168: CME questions Please visit to answer these CME questions on-line. The CME credits will then be attributed automatically. 1. Which of the following is not a PDE5 inhibitor? A. sildenafil, B. apomorphine, C. tadalafil, D. vardenafil. 2. What is the second messenger of PDE5 inhibition? A. cyclic GMP, B. cyclic AMP, C. PKG, [33] Saenz de Tejada I, Anglin G, Knight JR, et al. Effects of tadalafil on erectile dysfunction in men with diabetes. Diabetes Care 2002;25: [34] Padma-Nathan H, Eardley I, Kloner RA, Laties AM, Montorsi F. 4 year update on the safety of sildenafil citrate (Viagra 1 ). Urology 2002;60(Suppl 2B): [35] Kloner R, Porst H, Mohan P, Norenberg C, Pomerantz K, Segerson T, et al. Cardiovascular safety of the selective PDE5 inihibitor vardenafil in patients with erectile dysfunction; an analysis of five placebocontrolled clinical trials. Int J Impotence Res 2002;14(Suppl 4):S22. [36] Hatzichristou D, Carrier S, Carson C, et al. Vardenafil is efficacious in men with erectile dysfunction unresponsive to prior sildenafil therapy: results of a phase III clinical trial patient response with vardenafil in sildenafil nonresponders (PROVEN). Int J Impot Res 2003;15(Suppl 6):S5. D. nitric oxide. 3. Which PDE5 inhibitor has the longest half-life? A. sildenafil, B. tadalafil, C. vardenafil, D. no difference. 4. The efficacy of PDE5 inhibitor declines in particular subsets of patients including: A. patiens with psychogenic ED, B. patients with diabetic ED, C. patients younger than 50 years, D. none of the above.