Endothelial Antioxidant Administration Ameliorates the ErectileResponse to PDE5 Regardless of the Extension of theAtherosclerotic Processjsm_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 ReproductionSciences, Department of Biomedical Sciences, University of Catania, Catania, Italy

DOI: 10.1111/j.1743-6109.2009.01420.x

A B S T R A C T

Introduction. The lack of phosphodiesterase type 5 inhibitor effects in patients with erectile dysfunction (ED) ofarterial origin may be caused by an endothelial dysfunction that causes a series of biochemical alterations leading toa 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 sildenafil in patients with arterial ED already treated with sildenafil (100 mg twicea week for 8 weeks).Mean Outcome Measures. A patient was considered responsive when the 5-item International Index of ErectileFunction questionnaire score increased by >5 points.Methods. Fifty-three patients with arterial ED, hypertension, and diabetes mellitus were randomly given, for 8weeks, EAC (1 dose/day) and, after a wash out of 8 weeks, sildenafil (100 mg) plus EAC. The patients were dividedinto the following four groups: A (N = 12): patients with ED alone; B (N = 14): patients with ED plus atheromasicplaques and/or increased intima-media thickness of common carotid arteries; C (N = 14): patients with ED pluslower limb artery abnormalities; and D (N = 13): patients with ED plus carotid and lower limb artery abnormalities.Results. The administration of EAC plus sildenafil resulted in a significantly higher number of responsive patients(N = 36, 68%) compared with sildenafil alone (N = 24, 45%) or EAC alone (N = 17, 32%). The percentage ofpatients 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 sildenafilreached a successful response in a shorter length of time (3 weeks) compared with patients responsive to sildenafil(5.2 weeks) or EAC (5.7 weeks) alone.Conclusion. EAC administration to patients with arterial ED improved the success rate to sildenafil. These datasuggest that, in such patients, a combined treatment may be considered to increase bioavailable NO and to neutralizeradical 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 exten-sion of the atherosclerotic process. J Sex Med 2010;7:1247–1253.

Key Words. Erectile Dysfunction; Sildenafil; Antioxidant; IIEF; Endothelium

Introduction

E rectile dysfunction (ED) of organic originmainly appears after the age of 50 years, in

presence of arterial treatable abnormalities [1].This type of ED has been interpreted as an initialsign of local penile atherosclerosis without the

presence of a significant hemodynamic vascularstenosis. However, it is likely to progress toward amore generalized arterial involvement in thefuture [2,3]. Therefore, arterial ED may appearbefore an ischemic cardiopathy in ~70% of thecases [4] or atherosclerotic involvement of otherorgans with definitive arterial stenosis [5]. We have

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previously reported that, at the moment of thediagnosis, ED of arterial origin is associated withpoly-district atherosclerosis in the vast majority ofthe cases. Indeed, ED, as a clinical sign of isolatedpenile artery abnormality, was found in 25% of thepatients, whereas penile artery atherosclerosis wasfound in association with carotid (intima-mediathickening and/or plaque) and/or lower limbartery atherosclerosis in the remaining 75% of thecases [6]. In a subsequent study, we reported thatpatients with arterial ED and generalized athero-sclerosis had a lower peak-systolic velocity (PSV)compared with patients with isolated arterial EDor with ED and carotids or lower limb atheroscle-rosis [7].

Although the advent of phosphodiesterase type5 inhibitors (PDE5) has revolutionized the treat-ment of men with ED, the highest efficacy, both interms of number of responsive patients and qualityof erection, has been observed in patients withED and a normal vascular component and/or pre-sumably psychogenic ED (80%). In contrast, thesuccess rate is much lower in patients with alteredarterial and/or venous components [8–10]. Thus,it is difficult to envisage the patients with ED whowill be poor responders to PDE5 treatment[11,12]. To reduce the number of “false” poorresponders, some pre-treatment key points shouldbe 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 justified by thepresence of clinical conditions or comorbidities[5], which cause a severe endothelial disorder byreducing NO bioavailability and increasing oxida-tive stress [14–16]. In this regard, de Tejada statedthat “the limitation in the efficacy of PDE5i is thata minimum or ‘critical amount’ of NO is necessaryfor these drugs to work.” Thus, the Author sug-gests that therapeutic strategies for optimizingPDE5 treatment success rate or in resistantpatients should be oriented in the followingthree directions: (i) facilitate NO release bya2-antagonist administration; (ii) enhance NOsynthesis by administering more substrate(L-arginine; hydroxyarginine) for the reaction;and (iii) reduce radical oxygen species-mediatedNO inactivation by antioxidant administration[15].

Propionyl-L-carnitine was initially available asthe only active compound having an endothelialantioxidant activity. Recently, at the dose of250 mg, it has become available on the market asan “integrating” drug, in association with vitamin

B3 (20 mg) and L-arginine (2,500 mg), hence withan amino acid physiological precursor of NO(Ezerex®, Sigma Tau, Pomezia, Rome, Italy).The efficacy of the treatment with propionyl-L-carnitine plus sildenafil (“salvage therapy”) in dia-betic patients with ED, who are poor respondersto the administration of sildenafil alone [17], hasrecently found preliminary support [18]. Thisstudy showed that propionyl-L-carnitine plussildenafil improves penile arterial hemodynamicsand the clinical response (increased 5-item Inter-national Index of Erectile Function questionnaire[IIEF5] score) in patients with ED, suggesting thatsuch a therapeutic strategy more efficaciouslyimproves the “endothelial metabolism” (decreasedmonocyte oxidative response) in these patients.Therefore, the purpose of this study was to evalu-ate the effects of the administration of endothelialantioxidant compounds (EAC) plus sildenafil inpatients with ED of arterial origin associatedwith atherosclerotic signs in other arterial dis-tricts (generalized atherosclerosis) who were lowresponders to PDE5 [19]. A group of patients witharterial ED alone (a clinical model of atheroscle-rosis still in its initial phase, limited to the peniledistrict) who had the best erectile response tosildenafil served as a control group.

Subjects and Methods

Patient SelectionWe evaluated the erectile response in 53 consecu-tively selected patients (average age 56.0 years,range 52–77 years) with both controlled hyper-tension (pharmacologically treated but withoutb-blockers and thiazide diuretics that may causeED and/or with values < 160/95 mm Hg) anddiabetes mellitus (fasting plasma glucose <115 mg/dL and/or hemoglobin A1c < 7.5%). Allpatients also fulfilled the following criteria:

1. Arterial ED diagnosed by dynamic duplexDoppler ultrasound of the penile arteries withpulsed Doppler analysis following intracavern-ous administration of 20 mg of alprostadil(Caverject, Pfizer, New York, NY, USA). Afterinjection, PSV was measured every 10 minutesfor 20–30 minutes. A PSV <30 cm/sec and anon-temporal peak-systolic progression sug-gested the presence of an arterial disease [20].

2. Penile arterial dysfunction observed alone orin combination with peripheral atherosclerosisdiagnosed by duplex flussimetry of the carotidand lower limb arteries. In particular, carotid

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and lower limb artery assessment was per-formed by B-mode ultrasonography, using a7.5 MHz high resolution transducer (Esaote,Genoa, Italy), as recently reported [7], accord-ing to specific general ultrasound principles[21], involving both the grading of any stenosispresent and an attempt to characterize theplaque or the intima-media thickness.

3. Previous treatment with sildenafil (100 mgtwice a week for 8 weeks). Sildenafil was pre-scribed at the highest recommended dosageand for a time long enough to allow a properevaluation of its efficacy [22].

4. Having sildenafil prescription criteria even inthe presence of comorbidities, at low cardio-vascular risk, to avoid adverse cardiovascularevents during sexual activity, according to pub-lished guidelines [23].

Patients with arterial ED were excluded if theyalso had: (i) hypogonadism, defined as a low serumtotal testosterone in two blood samples 1 weekapart and/or reduced testicular volume (<12 mL atthe Prader’s orchidometer); (ii) Peyronie’s disease;(iii) radical pelvic surgery; (iv) venogenic ED (alsoknown as corporo-venocclusive dysfunction orvenous leak, suspected by the presence of anend-diastolic velocity > 5 cm/sec); and (5) severehyperlipidemia (total serum cholesterol concen-tration exceeding 280 mg/dL and/or serum trig-lyceride concentration exceeding 350 mg/dL).

On the basis of this methodological approach,the patients enrolled were divided into the follow-ing four groups: group A (N = 12), when they hadED alone; group B (N = 14), when their arterialED was associated with ultrasound findings ofatheromasic plaques and/or increased intima-media thickness of common carotid arteries;group C (N = 14), when their arterial ED wasassociated with lower limb artery abnormalities;and group D (N = 13), when their arterial ED wasassociated with both carotid and lower limb arteryabnormalities.

The protocol was approved by the InstitutionalReview Board, and an informed written consentwas obtained by each patient.

Study Procedures and Main Outcome MeasuresAll patients underwent a comprehensive medicalhistory and a physical examination. All patientsalso answered the IIEF5 version; IIEF [24] wasrecorded at weeks 0 and 8. The primary outcomeconsisted in the number of patients achievingmore than a 5-point gain from baseline in theerectile function domain of the IIEF5.

All patients were treated to achieve a bettererectile performance after having given theirinformed consent to a therapeutic planning thatincluded their random distribution into twogroups (a1 and a2) of treatment. Randomizationwas performed by a computer-generated list. Thefirst random set of numbers constituted group a1,whereas the second random set of numbers madeup group a2. The patients of group a1 were pre-scribed EAC, containing L-arginine, propionyl-L-carnitine, and nicotinic acid (Ezerex®, Sigma Tau:1 small envelope/daily for 8 weeks), alone, fol-lowed by EAC plus sildenafil (100 mg twiceweekly, on demand, for 8 weeks), whereas thepatients of group a2 were given EAC plus sildena-fil followed by EAC alone, both at the samedosages.

Propionyl-carnitine and arginine were chosenbecause these compounds cover two of the thera-peutic strategies suggested for optimizing PDE5treatment success rate in patients resistant toPDE5 administration alone [15]. Nicotinic acid, amolecular form of niacin (vitamin B3), was chosenbecause its plays an important role in the cellularenergy production. Thus, favoring the cellularenergetic process compromised in the endothelialdysfunction present in ED patients. In addition, itis also a vasodilator and, lastly, there is increasingevidence that nicotinic acid alone or in additionto low-density lipoprotein cholesterol-loweringdrugs can reduce the progression of atherosclero-sis and reduce the risk of cardiovascular events[25]. The amount of the substances in the EACand the posology (1 small envelope/daily) weresuggested by the manufacturer.

No placebo group was included in this studybecause the presence of three active compounds inthe EAC would have required a large number ofpatients and a complex experimental design. Inaddition, the main purpose of the study was tocompare the effects of EAC + sildenafil with EACalone or sildenafil alone.

For each phase, all patients were instructedabout efficacy, safety, side effects, correct useto minimize the false negative response, andfollow-up plan.

Statistical AnalysisResults are shown as median and range throughoutthe study. The data were analyzed by one-wayanalysis of variance followed by the Duncan’s mul-tiple range test. A comparison between the fre-quency of responder patients for each group wasmade by chi-square test. SPSS 9.0 software for

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Windows (SPSS Inc., Chicago, IL) was used forstatistical evaluation. A statistically significant dif-ference was accepted when the P value was lowerthan 0.05.

Results

The patients enrolled had an ED average durationof about 3 years (range 1.6–6 years). The medianage and the PVS for each of the four groups of EDpatients are reported in Table 1. The treatmentwith EAC alone resulted in a success rate similar tothat recorded with the treatment with sildenafilalone in the control group (Table 1). However, itproduced a significantly lower success rate in theother three groups of patients, characterized by amore generalized atherosclerotic process (Table 1).Overall, the patients who were responsive to EACadministration were 17 (32%) compared with 24(45%) responsive to the administration of sildenafilalone (P < 0.05).

The percentage of patients responsive to thecombined administration of EAC plus sildenafilincreased in each group of patients (Table 1). Thesuccess rate was negatively related to the extension

of atherosclerosis, as it was significantly higher(P < 0.05) in the control group who only hadpenile atherosclerosis and lower in the patients ofgroup D who had the more generalized pictureof atherosclerosis (Table 1). Overall, 36 patients(68%) had a successful response to the combinedtreatment. Thus, the addition of EAC to sildenafiladministration resulted in an additional 12responder patients out of the 29 (41.4%) initiallyunresponsive to sildenafil alone (P < 0.05). Themean pre- and posttreatment IIEF scores for eachgroup of patients are reported in Table 2.

Furthermore, the patients responsive to EACalone reached the maximal effect after 5.7 weeks oftreatment, a length of time similar to that observedfollowing treatment with sildenafil alone (5.2weeks). The combined administration of EAC andsildenafil reduced significantly (P < 0.05) the inter-val of time needed to reach a successful response to3 weeks (Table 3). Patients with a greater athero-sclerosis extension (groups B, C, and D) required alonger time to become responsive to the adminis-tration of sildenafil or EAC alone compared withthe control group (A) (Table 3). EAC plus sildena-fil reduced the time needed to reach the efficacy in

Table 1 Percentage of patients responsive (IIEF score > 5 points) to treatment with sildenafil alone (100 mg twice aweek for 8 weeks), endothelial antioxidant compounds (EAC) alone (1 dose/day for 8 weeks), or sildenafil plus EAC,divided according to the extension of the atherosclerotic process

Group Age (years)† PSV (cm/sec)†Sildenafilalone (%)

EACalone (%)

Sildenafil plusEAC (%)

A (N = 12) 57 (52–68) 24.0 (17–30) 58.3 50.0 83.0***B (N = 14) 60 (52–70) 21.0 (10–27) 42.8 28.6*,** 64.0***C (N = 14) 62 (53–75) 19.5 (10–26) 42.8 28.6*,** 71.4***D (N = 13) 63 (55–77) 14.0 (7–20)* 38.5* 23.0*,** 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; GroupD: 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. sildenafil alone; ***P < 0.05 vs. EAC alone.†Median and range in parentheses.IIEF = International Index of Erectile Function; PSV = peak-systolic velocity.

Table 2 IIEF scores before treatment and following administration of sildenafil alone (100 mg twice a week for 8weeks), endothelial antioxidant compounds (EAC) alone (1 dose/day for 8 weeks), or sildenafil plus EAC in patients witharterial erectile dysfunction (ED), divided according to the extension of the atherosclerotic process

Group Pre-treatment

Posttreatment

Sildenafil alone EAC alone Sildenafil plus EAC

A (N = 12) 14.5 (2–18) 19 (5–24) 16 (5–24) 21 (5–24)*,**B (N = 14) 12.5 (2–19) 15.0 (6–22) 13.5 (4–24) 16.5 (6–24)*C (N = 14) 9.5 (2–17) 13.0 (4–23) 12.5 (5–22) 17.0 (6–24)*,**D (N = 13) 7 (0–17)* 11.0 (3–22) 11.0 (2–22) 14.0 (4–23)*,**

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 andlower 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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all groups and, particularly, in controls and groupB patients (Table 3).

The main side effects recorded after treatmentwith sildenafil and/or EAC are reported inTable 4. The frequency of those observed aftersildenafil alone was markedly reduced during thesimultaneous administration of this PDE5 andEAC (Table 4).

Discussion

In most recent literature, the interest for the roleplayed by the hyperproduction and the activity ofoxygen (O2 kind) and nitrogen (ONOO-) freeradicals in the erectile function is continuouslyincreasing because of their negative influence onvascular homeostasis, with deleterious effects bothat cellular and molecular levels. This interaction,known as oxidative/nitrosative, suggests new phar-macotherapeutic approaches that can promote a

recovery of the endothelial function and, conse-quently, of the erectile function and the prophy-laxis of the erectile tissue’s health [26]. An efficienterectile response, in theory, depends upon therecovery of the endothelial metabolism, based onthe realignment of the oxidative balance that regu-lates both NO bioavailability and eNOS activity[27,28]. Indeed, this study showed that the addi-tion of EAC to sildenafil treatment resulted in anincreased success rate and a reduced length of timeto become efficacious in patients with arterial ED,low PSV, and in presence of two risk factors(hypertension and diabetes) compared with treat-ment with sildenafil alone. Although we do nothave any quantitative data on NO or eNOS, thesefindings suggest that the only increase of NO,mediated by the administration of sildenafil, isunable to restore the erectile function in patientswith severe endothelial dysfunction. The NOincrease may induce a further pro-oxidative effect,

Table 3 Number of patients responsive (IIEF score > 5 points) to the treatment with sildenafil alone (100 mg twice aweek for 8 weeks), endothelial antioxidant compounds (EAC) alone (1 dose/day for 8 weeks), or sildenafil plus EAC, andminimal length of time needed to reach a successful response

Group

Sildenafil alone EAC alone Sildenafil plus EAC

Number ofresponders

Time(weeks)

Number ofresponders

Time(weeks)

Number ofresponders

Time(weeks)

A (N = 12) 7 2 (0–4) 6 3 (1–5) 10 1 (0–2)B (N = 14) 6 5 (2–7) 4 6 (3–7) 9 1 (0–4)C (N = 14) 6 7 (2–8) 4 7 (6–8) 10 4 (2–6)D (N = 13) 5 7 (5–8) 3 7 (6–8) 7 6 (4–8)

Total (N = 53) 24 (45.3%) 5.2 (0–8) 17 (32.1%)* 5.7 (1–8) 36 (67.9%)*,** 3.0 (0–8)***

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; GroupD: ED plus carotid and lower limb artery abnormalities.*P < 0.05 vs. total number of responders to sildenafil alone; **P < 0.05 vs. total number of responders to EAC alone; ***P < 0.05 vs. sildenafil alone or EAC alone.IIEF = International Index of Erectile Function.

Table 4 Frequency of the main side effects during treatment with sildenafil alone (100 mg twice a week for 8 weeks),endothelial antioxidant compounds (EAC) alone (1 dose/day for 8 weeks), or sildenafil plus EAC, divided according to theextension of the atherosclerotic process

Group Sildenafil alone (%) EAC alone (%) Sildenafil plus EAC (%)

A (N = 12) Headache = 16.6Hot flash = 8.3Nasal congestion = 8.3

Dyspepsia = 8.3 None

B (N = 14) Headache = 28.6Hot flash = 28.6Nasal congestion = 8.3

Headache = 7.1 Headache = 7.1

C (N = 14) Headache = 28.6Hot flash = 28.6Nasal congestion = 8.3

None Headache = 14.3

D (N = 13) Headache = 30.7Hot flash = 23Dyspepsia = 23

Headache = 7.1Hot flash = 7.1

Headache = 7.1Dyspepsia = 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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because of the formation of peroxynitrite radical,and may cause the side effects that depend uponthe pharmacological properties of sildenafil.

Following administration of EAC plus sildena-fil, the sexual response significantly improved in allgroups, reaching the highest rate (83%) in group Aconstituted by patients with penile artery athero-sclerosis. A substantial improvement of the successrate was also observed in patients with a moreextended atherosclerotic process. In all, 12patients unresponsive to the administration ofsildenafil alone responded to the combined treat-ment with an IIEF5 score greater than 5 points;this accounts for about the 40% of the totalnumber of patients who did not benefit from thetreatment with sildenafil alone.

A greater success rate and a better erectileresponse have been observed in ED patients with anormal 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 higherin patients with pure arterial ED [8,9]. The lack ofPDE5 effects in about 25–30% of the ED patientstreated may be explained by the presence of comor-bids [10], and it is the final end point of a severeendothelial dysfunction that causes a series of bio-chemical alterations leading to a reduced NO bio-availability and increased oxidative stress [14–16].

The oral formulation of L-arginine and antio-xidant compounds used in this study should bepreferred in the treatment of arterial ED patients.Indeed, in conditions characterized by anincreased oxidative stress, although NO is pro-duced in proper quantities, it is rapidly convertedinto biologically inactive products or even in toxicones (peroxynitrite) [26]. Although L-arginine hasan antiradical action on its own [29], the presenceof co-formulated antioxidant (propionyl-carnitine)is potentially able to increase the “bioavailability”of NO in a more efficient manner by supplying thephysiological precursor (L-arginine) and by neu-tralizing the reactive chemical species that wouldtend to inactivate it. Furthermore, L-arginine andPDE5 may complementarily enhance vascularendothelial growth factor synthesis in corpus cav-ernosal smooth muscle cells and may consequentlyrestore impaired endothelial function [30].

Conclusion

This study showed that a combined treatment withprecursors of NO and antioxidants improves theerectile response in a larger number of patients

with arterial ED treated with sildenafil. In addi-tion, the responder patients achieved an efficaciousresponse in a shorter length of time. These effectswere spread to all patients regardless of the exten-sion of the atherosclerotic process. We suggestthat this therapeutic strategy could be adopted forpatients with ED of arterial origin.

Corresponding Author: Enzo Vicari, MD, Section ofEndocrinology, Andrology and Internal Medicine, andMaster in Andrological and Human Reproduction Sci-ences, Department of Biomedical Sciences, Universityof Catania, Catania, Italy. E-mail: enzodante@email.it

Conflict 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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