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Endothelial Antioxidant Administration Ameliorates the Erectile Response to PDE5 Regardless of the Extension of the Atherosclerotic Process
jsm_1420 1247..1253

Enzo Vicari, MD, Sandro La Vignera, MD, Rosita Condorelli, MD, and Aldo Eugenio Calogero, MD
Section of Endocrinology, Andrology and Internal Medicine, and Master in Andrological and Human Reproduction Sciences, Department of Biomedical Sciences, University of Catania, Catania, Italy DOI: 10.1111/j.1743-6109.2009.01420.x

ABSTRACT

Introduction. The lack of phosphodiesterase type 5 inhibitor effects in patients with erectile dysfunction (ED) of arterial origin may be caused by an endothelial dysfunction that causes a series of biochemical alterations leading to a reduced nitric oxide (NO) bioavailability and increased oxidative stress. Aim. The aim of this study was to evaluate the effects of the treatment with endothelial antioxidant compounds (EAC) on the erectile response to sildenal in patients with arterial ED already treated with sildenal (100 mg twice a week for 8 weeks). Mean Outcome Measures. A patient was considered responsive when the 5-item International Index of Erectile Function questionnaire score increased by >5 points. Methods. Fifty-three patients with arterial ED, hypertension, and diabetes mellitus were randomly given, for 8 weeks, EAC (1 dose/day) and, after a wash out of 8 weeks, sildenal (100 mg) plus EAC. The patients were divided into the following four groups: A (N = 12): patients with ED alone; B (N = 14): patients with ED plus atheromasic plaques and/or increased intima-media thickness of common carotid arteries; C (N = 14): patients with ED plus lower limb artery abnormalities; and D (N = 13): patients with ED plus carotid and lower limb artery abnormalities. Results. The administration of EAC plus sildenal resulted in a signicantly higher number of responsive patients (N = 36, 68%) compared with sildenal alone (N = 24, 45%) or EAC alone (N = 17, 32%). The percentage of patients who successfully responded to the combined treatment increased in the various groups. It was 83%, 64%, 71%, and 54%, respectively, for groups A, B, C, and D. Furthermore, patients treated with EAC and sildenal reached a successful response in a shorter length of time (3 weeks) compared with patients responsive to sildenal (5.2 weeks) or EAC (5.7 weeks) alone. Conclusion. EAC administration to patients with arterial ED improved the success rate to sildenal. These data suggest that, in such patients, a combined treatment may be considered to increase bioavailable NO and to neutralize radical oxygen species, which in turn inactive NO. Vicari E, La Vignera S, Condorelli R, and Calogero AE. Endothelial antioxidant administration ameliorates the erectile response to PDE5 regardless of the extension of the atherosclerotic process. J Sex Med 2010;7:12471253. Key Words. Erectile Dysfunction; Sildenal; Antioxidant; IIEF; Endothelium

Introduction

rectile dysfunction (ED) of organic origin mainly appears after the age of 50 years, in presence of arterial treatable abnormalities [1]. This type of ED has been interpreted as an initial sign of local penile atherosclerosis without the

presence of a signicant hemodynamic vascular stenosis. However, it is likely to progress toward a more generalized arterial involvement in the future [2,3]. Therefore, arterial ED may appear before an ischemic cardiopathy in ~70% of the cases [4] or atherosclerotic involvement of other organs with denitive arterial stenosis [5]. We have
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2009 International Society for Sexual Medicine

1248 previously reported that, at the moment of the diagnosis, ED of arterial origin is associated with poly-district atherosclerosis in the vast majority of the cases. Indeed, ED, as a clinical sign of isolated penile artery abnormality, was found in 25% of the patients, whereas penile artery atherosclerosis was found in association with carotid (intima-media thickening and/or plaque) and/or lower limb artery atherosclerosis in the remaining 75% of the cases [6]. In a subsequent study, we reported that patients with arterial ED and generalized atherosclerosis had a lower peak-systolic velocity (PSV) compared with patients with isolated arterial ED or with ED and carotids or lower limb atherosclerosis [7]. Although the advent of phosphodiesterase type 5 inhibitors (PDE5) has revolutionized the treatment of men with ED, the highest efcacy, both in terms of number of responsive patients and quality of erection, has been observed in patients with ED and a normal vascular component and/or presumably psychogenic ED (80%). In contrast, the success rate is much lower in patients with altered arterial and/or venous components [810]. Thus, it is difcult to envisage the patients with ED who will be poor responders to PDE5 treatment [11,12]. To reduce the number of false poor responders, some pre-treatment key points should be considered during the andrological counseling [13]. As the effect of PDE5 relates to nitric oxide (NO) production and to cavernous nerve integrity, a low responsiveness may be justied by the presence of clinical conditions or comorbidities [5], which cause a severe endothelial disorder by reducing NO bioavailability and increasing oxidative stress [1416]. In this regard, de Tejada stated that the limitation in the efcacy of PDE5i is that a minimum or critical amount of NO is necessary for these drugs to work. Thus, the Author suggests that therapeutic strategies for optimizing PDE5 treatment success rate or in resistant patients should be oriented in the following three directions: (i) facilitate NO release by a2-antagonist administration; (ii) enhance NO synthesis by administering more substrate (L-arginine; hydroxyarginine) for the reaction; and (iii) reduce radical oxygen species-mediated NO inactivation by antioxidant administration [15]. Propionyl-L-carnitine was initially available as the only active compound having an endothelial antioxidant activity. Recently, at the dose of 250 mg, it has become available on the market as an integrating drug, in association with vitamin
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Vicari et al. B3 (20 mg) and L-arginine (2,500 mg), hence with an amino acid physiological precursor of NO (Ezerex, Sigma Tau, Pomezia, Rome, Italy). The efcacy of the treatment with propionyl-Lcarnitine plus sildenal (salvage therapy) in diabetic patients with ED, who are poor responders to the administration of sildenal alone [17], has recently found preliminary support [18]. This study showed that propionyl-L-carnitine plus sildenal improves penile arterial hemodynamics and the clinical response (increased 5-item International Index of Erectile Function questionnaire [IIEF5] score) in patients with ED, suggesting that such a therapeutic strategy more efcaciously improves the endothelial metabolism (decreased monocyte oxidative response) in these patients. Therefore, the purpose of this study was to evaluate the effects of the administration of endothelial antioxidant compounds (EAC) plus sildenal in patients with ED of arterial origin associated with atherosclerotic signs in other arterial districts (generalized atherosclerosis) who were low responders to PDE5 [19]. A group of patients with arterial ED alone (a clinical model of atherosclerosis still in its initial phase, limited to the penile district) who had the best erectile response to sildenal served as a control group.
Subjects and Methods

Patient Selection We evaluated the erectile response in 53 consecutively selected patients (average age 56.0 years, range 5277 years) with both controlled hypertension (pharmacologically treated but without b-blockers and thiazide diuretics that may cause ED and/or with values < 160/95 mm Hg) and diabetes mellitus (fasting plasma glucose < 115 mg/dL and/or hemoglobin A1c < 7.5%). All patients also fullled the following criteria:
1. Arterial ED diagnosed by dynamic duplex Doppler ultrasound of the penile arteries with pulsed Doppler analysis following intracavernous administration of 20 mg of alprostadil (Caverject, Pzer, New York, NY, USA). After injection, PSV was measured every 10 minutes for 2030 minutes. A PSV <30 cm/sec and a non-temporal peak-systolic progression suggested the presence of an arterial disease [20]. 2. Penile arterial dysfunction observed alone or in combination with peripheral atherosclerosis diagnosed by duplex ussimetry of the carotid and lower limb arteries. In particular, carotid

Administration of EAC with Sildenal and lower limb artery assessment was performed by B-mode ultrasonography, using a 7.5 MHz high resolution transducer (Esaote, Genoa, Italy), as recently reported [7], according to specic general ultrasound principles [21], involving both the grading of any stenosis present and an attempt to characterize the plaque or the intima-media thickness. 3. Previous treatment with sildenal (100 mg twice a week for 8 weeks). Sildenal was prescribed at the highest recommended dosage and for a time long enough to allow a proper evaluation of its efcacy [22]. 4. Having sildenal prescription criteria even in the presence of comorbidities, at low cardiovascular risk, to avoid adverse cardiovascular events during sexual activity, according to published guidelines [23]. Patients with arterial ED were excluded if they also had: (i) hypogonadism, dened as a low serum total testosterone in two blood samples 1 week apart and/or reduced testicular volume (<12 mL at the Praders orchidometer); (ii) Peyronies disease; (iii) radical pelvic surgery; (iv) venogenic ED (also known as corporo-venocclusive dysfunction or venous leak, suspected by the presence of an end-diastolic velocity > 5 cm/sec); and (5) severe hyperlipidemia (total serum cholesterol concentration exceeding 280 mg/dL and/or serum triglyceride concentration exceeding 350 mg/dL). On the basis of this methodological approach, the patients enrolled were divided into the following four groups: group A (N = 12), when they had ED alone; group B (N = 14), when their arterial ED was associated with ultrasound ndings of atheromasic plaques and/or increased intimamedia thickness of common carotid arteries; group C (N = 14), when their arterial ED was associated with lower limb artery abnormalities; and group D (N = 13), when their arterial ED was associated with both carotid and lower limb artery abnormalities. The protocol was approved by the Institutional Review Board, and an informed written consent was obtained by each patient.

1249 All patients were treated to achieve a better erectile performance after having given their informed consent to a therapeutic planning that included their random distribution into two groups (a1 and a2) of treatment. Randomization was performed by a computer-generated list. The rst random set of numbers constituted group a1, whereas the second random set of numbers made up group a2. The patients of group a1 were prescribed EAC, containing L-arginine, propionyl-Lcarnitine, and nicotinic acid (Ezerex, Sigma Tau: 1 small envelope/daily for 8 weeks), alone, followed by EAC plus sildenal (100 mg twice weekly, on demand, for 8 weeks), whereas the patients of group a2 were given EAC plus sildenal followed by EAC alone, both at the same dosages. Propionyl-carnitine and arginine were chosen because these compounds cover two of the therapeutic strategies suggested for optimizing PDE5 treatment success rate in patients resistant to PDE5 administration alone [15]. Nicotinic acid, a molecular form of niacin (vitamin B3), was chosen because its plays an important role in the cellular energy production. Thus, favoring the cellular energetic process compromised in the endothelial dysfunction present in ED patients. In addition, it is also a vasodilator and, lastly, there is increasing evidence that nicotinic acid alone or in addition to low-density lipoprotein cholesterol-lowering drugs can reduce the progression of atherosclerosis and reduce the risk of cardiovascular events [25]. The amount of the substances in the EAC and the posology (1 small envelope/daily) were suggested by the manufacturer. No placebo group was included in this study because the presence of three active compounds in the EAC would have required a large number of patients and a complex experimental design. In addition, the main purpose of the study was to compare the effects of EAC + sildenal with EAC alone or sildenal alone. For each phase, all patients were instructed about efcacy, safety, side effects, correct use to minimize the false negative response, and follow-up plan.

Study Procedures and Main Outcome Measures All patients underwent a comprehensive medical history and a physical examination. All patients also answered the IIEF5 version; IIEF [24] was recorded at weeks 0 and 8. The primary outcome consisted in the number of patients achieving more than a 5-point gain from baseline in the erectile function domain of the IIEF5.

Statistical Analysis Results are shown as median and range throughout the study. The data were analyzed by one-way analysis of variance followed by the Duncans multiple range test. A comparison between the frequency of responder patients for each group was made by chi-square test. SPSS 9.0 software for
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Vicari et al.

Table 1 Percentage of patients responsive (IIEF score > 5 points) to treatment with sildenal alone (100 mg twice a week for 8 weeks), endothelial antioxidant compounds (EAC) alone (1 dose/day for 8 weeks), or sildenal plus EAC, divided according to the extension of the atherosclerotic process
Group A (N = 12) B (N = 14) C (N = 14) D (N = 13) Age (years) 57 60 62 63 (5268) (5270) (5375) (5577) PSV (cm/sec) 24.0 21.0 19.5 14.0 (1730) (1027) (1026) (720)* Sildenal alone (%) 58.3 42.8 42.8 38.5* EAC alone (%) 50.0 28.6*,** 28.6*,** 23.0*,** Sildenal plus EAC (%) 83.0*** 64.0*** 71.4*** 53.8*,***

EAC = L-arginine, propionyl-L-carnitine, and nicotinic acid. Group A: patients with arterial erectile dysfunction (ED) alone; Group B: ED plus carotid abnormalities; Group C: ED plus lower limb artery abnormalities; Group D: ED plus carotid and lower limb artery abnormalities. *P < 0.01 vs. Group A (analysis of variance followed by Duncan test); **P < 0.05 vs. sildenal alone; ***P < 0.05 vs. EAC alone. Median and range in parentheses. IIEF = International Index of Erectile Function; PSV = peak-systolic velocity.

Windows (SPSS Inc., Chicago, IL) was used for statistical evaluation. A statistically signicant difference was accepted when the P value was lower than 0.05.
Results

The patients enrolled had an ED average duration of about 3 years (range 1.66 years). The median age and the PVS for each of the four groups of ED patients are reported in Table 1. The treatment with EAC alone resulted in a success rate similar to that recorded with the treatment with sildenal alone in the control group (Table 1). However, it produced a signicantly lower success rate in the other three groups of patients, characterized by a more generalized atherosclerotic process (Table 1). Overall, the patients who were responsive to EAC administration were 17 (32%) compared with 24 (45%) responsive to the administration of sildenal alone (P < 0.05). The percentage of patients responsive to the combined administration of EAC plus sildenal increased in each group of patients (Table 1). The success rate was negatively related to the extension

of atherosclerosis, as it was signicantly higher (P < 0.05) in the control group who only had penile atherosclerosis and lower in the patients of group D who had the more generalized picture of atherosclerosis (Table 1). Overall, 36 patients (68%) had a successful response to the combined treatment. Thus, the addition of EAC to sildenal administration resulted in an additional 12 responder patients out of the 29 (41.4%) initially unresponsive to sildenal alone (P < 0.05). The mean pre- and posttreatment IIEF scores for each group of patients are reported in Table 2. Furthermore, the patients responsive to EAC alone reached the maximal effect after 5.7 weeks of treatment, a length of time similar to that observed following treatment with sildenal alone (5.2 weeks). The combined administration of EAC and sildenal reduced signicantly (P < 0.05) the interval of time needed to reach a successful response to 3 weeks (Table 3). Patients with a greater atherosclerosis extension (groups B, C, and D) required a longer time to become responsive to the administration of sildenal or EAC alone compared with the control group (A) (Table 3). EAC plus sildenal reduced the time needed to reach the efcacy in

Table 2 IIEF scores before treatment and following administration of sildenal alone (100 mg twice a week for 8 weeks), endothelial antioxidant compounds (EAC) alone (1 dose/day for 8 weeks), or sildenal plus EAC in patients with arterial erectile dysfunction (ED), divided according to the extension of the atherosclerotic process
Posttreatment Group A (N = 12) B (N = 14) C (N = 14) D (N = 13) Pre-treatment 14.5 12.5 9.5 7 (218) (219) (217) (017)* Sildenal alone 19 15.0 13.0 11.0 (524) (622) (423) (322) EAC alone 16 13.5 12.5 11.0 (524) (424) (522) (222) Sildenal plus EAC 21 16.5 17.0 14.0 (524)*,** (624)* (624)*,** (423)*,**

EAC = L-arginine, propionyl-L-carnitine, and nicotinic acid. Median and range in parentheses. Group A: patients with arterial ED alone; Group B: ED plus carotid abnormalities; Group C: ED plus lower limb artery abnormalities; Group D: ED plus carotid and lower limb artery abnormalities. *P < 0.01 vs. Group A (analysis of variance followed by Duncan test); **P < 0.05 vs. EAC alone. IIEF = International Index of Erectile Function questionnaire.

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Table 3 Number of patients responsive (IIEF score > 5 points) to the treatment with sildenal alone (100 mg twice a week for 8 weeks), endothelial antioxidant compounds (EAC) alone (1 dose/day for 8 weeks), or sildenal plus EAC, and minimal length of time needed to reach a successful response
Sildenal alone Group A (N = 12) B (N = 14) C (N = 14) D (N = 13) Total (N = 53) Number of responders 7 6 6 5 24 (45.3%) Time (weeks) 2 5 7 7 (04) (27) (28) (58) EAC alone Number of responders 6 4 4 3 17 (32.1%)* Time (weeks) 3 6 7 7 (15) (37) (68) (68) Sildenal plus EAC Number of responders 10 9 10 7 36 (67.9%)*,** Time (weeks) 1 1 4 6 (02) (04) (26) (48)

5.2 (08)

5.7 (18)

3.0 (08)***

EAC = L-arginine, propionyl-L-carnitine, and nicotinic acid. Patients were divided according to the extension of the atherosclerotic process. Group A: patients with arterial erectile dysfunction (ED) alone; Group B: ED plus carotid abnormalities; Group C: ED plus lower limb artery abnormalities; Group D: ED plus carotid and lower limb artery abnormalities. *P < 0.05 vs. total number of responders to sildenal alone; **P < 0.05 vs. total number of responders to EAC alone; ***P < 0.05 vs. sildenal alone or EAC alone. IIEF = International Index of Erectile Function.

all groups and, particularly, in controls and group B patients (Table 3). The main side effects recorded after treatment with sildenal and/or EAC are reported in Table 4. The frequency of those observed after sildenal alone was markedly reduced during the simultaneous administration of this PDE5 and EAC (Table 4).
Discussion

In most recent literature, the interest for the role played by the hyperproduction and the activity of oxygen (O2 kind) and nitrogen (ONOO-) free radicals in the erectile function is continuously increasing because of their negative inuence on vascular homeostasis, with deleterious effects both at cellular and molecular levels. This interaction, known as oxidative/nitrosative, suggests new pharmacotherapeutic approaches that can promote a

recovery of the endothelial function and, consequently, of the erectile function and the prophylaxis of the erectile tissues health [26]. An efcient erectile response, in theory, depends upon the recovery of the endothelial metabolism, based on the realignment of the oxidative balance that regulates both NO bioavailability and eNOS activity [27,28]. Indeed, this study showed that the addition of EAC to sildenal treatment resulted in an increased success rate and a reduced length of time to become efcacious in patients with arterial ED, low PSV, and in presence of two risk factors (hypertension and diabetes) compared with treatment with sildenal alone. Although we do not have any quantitative data on NO or eNOS, these ndings suggest that the only increase of NO, mediated by the administration of sildenal, is unable to restore the erectile function in patients with severe endothelial dysfunction. The NO increase may induce a further pro-oxidative effect,

Table 4 Frequency of the main side effects during treatment with sildenal alone (100 mg twice a week for 8 weeks), endothelial antioxidant compounds (EAC) alone (1 dose/day for 8 weeks), or sildenal plus EAC, divided according to the extension of the atherosclerotic process
Group A (N = 12) Sildenal alone (%) Headache = 16.6 Hot ash = 8.3 Nasal congestion = 8.3 Headache = 28.6 Hot ash = 28.6 Nasal congestion = 8.3 Headache = 28.6 Hot ash = 28.6 Nasal congestion = 8.3 Headache = 30.7 Hot ash = 23 Dyspepsia = 23 EAC alone (%) Dyspepsia = 8.3 Sildenal plus EAC (%) None

B (N = 14)

Headache = 7.1

Headache = 7.1

C (N = 14)

None

Headache = 14.3

D (N = 13)

Headache = 7.1 Hot ash = 7.1

Headache = 7.1 Dyspepsia = 7.1

Group A: patient with arterial erectile dysfunction (ED) alone; Group B: ED plus carotid abnormalities; Group C: ED plus lower limb artery abnormalities; Group D: ED plus carotid and lower limb artery abnormalities.

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1252 because of the formation of peroxynitrite radical, and may cause the side effects that depend upon the pharmacological properties of sildenal. Following administration of EAC plus sildenal, the sexual response signicantly improved in all groups, reaching the highest rate (83%) in group A constituted by patients with penile artery atherosclerosis. A substantial improvement of the success rate was also observed in patients with a more extended atherosclerotic process. In all, 12 patients unresponsive to the administration of sildenal alone responded to the combined treatment with an IIEF5 score greater than 5 points; this accounts for about the 40% of the total number of patients who did not benet from the treatment with sildenal alone. A greater success rate and a better erectile response have been observed in ED patients with a normal vascular function and/or psychogenic ED (80%), whereas the success rate varies widely (50.7 74.5%) in ED patients with an altered vascular (arterial and/or venous) component, being higher in patients with pure arterial ED [8,9]. The lack of PDE5 effects in about 2530% of the ED patients treated may be explained by the presence of comorbids [10], and it is the nal end point of a severe endothelial dysfunction that causes a series of biochemical alterations leading to a reduced NO bioavailability and increased oxidative stress [1416]. The oral formulation of L-arginine and antioxidant compounds used in this study should be preferred in the treatment of arterial ED patients. Indeed, in conditions characterized by an increased oxidative stress, although NO is produced in proper quantities, it is rapidly converted into biologically inactive products or even in toxic ones (peroxynitrite) [26]. Although L-arginine has an antiradical action on its own [29], the presence of co-formulated antioxidant (propionyl-carnitine) is potentially able to increase the bioavailability of NO in a more efcient manner by supplying the physiological precursor (L-arginine) and by neutralizing the reactive chemical species that would tend to inactivate it. Furthermore, L-arginine and PDE5 may complementarily enhance vascular endothelial growth factor synthesis in corpus cavernosal smooth muscle cells and may consequently restore impaired endothelial function [30].
Conclusion

Vicari et al. with arterial ED treated with sildenal. In addition, the responder patients achieved an efcacious response in a shorter length of time. These effects were spread to all patients regardless of the extension of the atherosclerotic process. We suggest that this therapeutic strategy could be adopted for patients with ED of arterial origin.
Corresponding Author: Enzo Vicari, MD, Section of Endocrinology, Andrology and Internal Medicine, and Master in Andrological and Human Reproduction Sciences, Department of Biomedical Sciences, University of Catania, Catania, Italy. E-mail: enzodante@email.it Conict of Interest: None.
Statement of Authorship

Category 1
(a) Conception and Design Enzo Vicari (b) Acquisition of Data Sandro La Vignera; Rosita Condorelli (c) Analysis and Interpretation of Data Enzo Vicari; Aldo Eugenio Calogero

Category 2
(a) Drafting the Article Enzo Vicari; Aldo Eugenio Calogero (b) Revising It for Intellectual Content Enzo Vicari; Aldo Eugenio Calogero

Category 3
(a) Final Approval of the Completed Article Enzo Vicari; Aldo Eugenio Calogero
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