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Review – Sexual Medicine 

european urology 52 (2007) 990–1005 

Daily Administration of Phosphodiesterase Type 5 

Inhibitors for Urological and Nonurological Indications 

Anthony J. Bella a , Ling X. DeYoung b , Mussa al-Numi b , Gerald B. Brock b, * 

a Department of Surgery, Division of Urology, University of Ottawa, Ottawa, Canada 

b Department of Surgery, Division of Urology, St Joseph’s HealthCare London, University of Western Ontario, London, Canada 

Article info 

Article history: 

Accepted June 29, 2007 

Published online ahead of 

print on July 23, 2007 

Keywords: 

Sildenafil 

Vardenafil 

Tadalafil 

Phosphodiesterase (type) 5 

inhibitors 

Erectile dysfunction 

Dosing 

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Abstract 

Objectives: Although the discovery of phosphodiesterases (PDEs) was 

made soon after the identification of cyclic adenosine monophosphate 

nearly half a century ago, their true importance in medicine has taken 

many decades to be realised. The recognition of the important role PDE 

enzymes play and the impact of altering intracellular cyclic nucleotide 

levels became significant for most urologists and clinicians in the early 

1990s with the discovery of sildenafil, a PDE5 inhibitor (PDE5-I). Once 

approved around the world, on-demand use of PDE5-Is became the gold 

standard. Recently, the potential beneficial effects of PDE5-Is on the 

pulmonary, vascular, and other systems has led to examination of 

alternative dosing regimens. In this review, we have synthesised the 

available published peer-reviewed literature to provide a critical contemporary 

view of evolving indications for PDE5-Is and how alternative 

dosing regimens may impact on sexual and other functions. 

Methods: MEDLINE search of all peer-reviewed English literature for the 

period 1990–2007. 

Results: The plethora of articles detailing potential uses of PDE5-I in 

multiple fields of medicine was uncovered. Use of alternative dosing 

regimens shows great promise across a number of clinical indications, 

including post–radical retropubic prostatectomy, pulmonary hypertension, 

endothelial dysfunction, and salvage of on-demand PDE5-I nonresponders. 

Conclusions: Use of PDE5-I on a daily basis may evolve into a major form 

of drug administration both for men with erectile dysfunction and for 

those with a myriad of other conditions shown to benefit from this 

approach. 

# 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. 

* Corresponding author. Department of Surgery, Division of Urology, St Joseph’s Heathcare 

London, 268 Grosvenor Street, London, Ontario, Canada N6A 4V2. Tel. +1 519 646 6042; 

Fax: +1 519 646 6037. 

E-mail address: gebrock@sympatico.ca (G.B. Brock). 

0302-2838/$ – see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2007.06.048

1. Introduction 

A wealth of clinical experience supports oral PDE5-I 

as safe and efficacious agents of choice for treatment 

of erectile dysfunction (ED) in most men [1–4]. 

Reported efficacy rates of 60–70% are reported; 

however, therapeutic success is often lower in 

european urology 52 (2007) 990–1005 991 

Fig. 1 – Primary clinical indications for daily PDE5-I regimens. 

subpopulations identified as more difficult to treat, 

including diabetics, severe vasculogenic ED, and 

post–radical retropubic prostatectomy (RRP) patients 

[5,6]. Real or perceived lack of spontaneity 

or treatment flexibility, adverse effects, or improper 

administration/use may also limit patient satisfaction. 

Patient-identified criteria for success—namely

992 

Table 1 – Summary of potential benefits and limitations to urological and nonurological clinical use of daily PDE5-Is 

Indication Potential benefits Limitations Selected references 

Erectile dysfunction Salvage of on-demand nonresponders Extended term follow-up limited— 

Benign prostatic 

hyperplasia/LUTS 

Improved treatment response in 

difficult-to-treat groups 

Disease modification 

May approximate more natural 

sexual function 

Randomized, placebo-controlled trials 

demonstrate efficacy and safety for 

erectile dysfunction of various etiologies 

Meaningful symptomatic improvements 

noted in well-designed trials 

safety and efficacy profiles require 

further elucidation 

Mechanisms of treatment effects 

incompletely understood 

Disease modification—attractive 

concept but evidence-based data 

limited 

No evidence of tachyphylaxis to 

date but longer follow-up needed 

Patient cost 

Mechanism of action for BPH/LUTS 

unknown 

Decrease in IPSS Trials limited with regards to 

Flow remains similar to pretreatment 

duration of treatment and follow-up 

May use in conjunction with alphablockers 

to modulate several proposed 

pathophysiological targets 

Priapism Alleviate recurrent priapism without 

interfering with normal erectile function 

Scientific basis for PDE5-I mechanism 

of action 

Clinical: [6–8,10,11, 

13–15,30,36,47,48,51, 

56,71,73,147,149,150] 

Basic science: 

[21–24,27,37–40,42, 

43,53–55,77,78] 

Clinical: [80–90, 

144–146,148] 

Basic science: [91] 

Primarily animal study evidence Clinical: [59–61,95] 

Limited, although promising 

clinical reports 

Further investigation (controlled 

trials) needed to validate and fully 

characterise PDE5-I therapeutic effect 

Basic science: [60,61,96] 

Premature ejaculation Improvement of overall sexual function Role of PDE5-Is unclear Clinical: [97–101,103] 

Prolong intravaginal ejaculation latency time Conflicting data Basic science: [102] 

May be more efficacious in combination 

with SSRI (example paroxetine) and 

psychological-behavioural counselling 

Little to support on-demand or 

daily PDE5-Is for lifelong PE and 

normal erectile function 

Peyronie’s disease Reversal of plaque or fibrosis Data limited to animal study of 

Peyronie’s disease-like plaques 

Pulmonary hypertension PDE5-Is approved for clinical use Long-term efficacy and safety 

Well-designed, large-scale clinical trials 

data continue to be accrued 

demonstrating treatment effect Early COPD and secondary PH 

Improvements in functional pulmonary 

data only 

arterial hypertension parameters, 

Agent-specific characteristics 

haemodynamics, and exercise capacity required each PDE5-I to be 

Evolving data suggests PDE5-I role for 

COPD and secondary pulmonary 

hypertension 

evaluated separately 

Systemic hypertension Known vasodilators Limited randomized, placebocontrolled, 

double-blind data 

Single-agent or combination therapy 

available 

Cardioprotection and 

endothelial function 

Role may also be defined for renal 

injury-induced hypertension 


Potential reduction of morbidity and 

mortality of ischaemia-reperfusion injury 

Limited primarily to animal 

evidence and early human 

study 


Clinical: [19,74–76, 

79,105–112,115–118] 


[33,113–114] 

Clinical: [119,64, 

120,121,122,143,144] 


[123–124] 

Clinical: [28,31,32, 

58,62,115,125,132–134]

Table 1 (Continued ) 

Indication Potential benefits Limitations Selected references 

cure, pleasure, partner satisfaction, naturalness, 

and reliability—may not be fulfilled by on-demand 

dosing because sexual activity is linked to drug 

administration [7,8]. 

The concept of daily dosing or chronic administration 

was introduced in an effort to provide a 

treatment alternative for nonresponders to ondemand 

PDE5-Is and to more closely approximate 

‘‘natural’’ erectile function [7,9–12]. These PDE5-I 

schedules have also been investigated for other 

urological and nonurological indications including 

pulmonary and systemic hypertension, cardioprotection, 

and endothelial dysfunction (Fig. 1). In this 

review, we synthesised the available literature to 

provide a critical contemporary view of evolving 

indications for PDE5-Is and how alternative dosing 

regimens may impact on sexual and other functions 

(Table 1). 

2. Methods 

Several potential target pathways for 

treatment effects identified 

Endothelium: protection, improved 

function if at risk or damaged, and 

increased endothelial progenitor cells 

(thought to contribute to repair and 

lower risk of cardiac death) 

Diabetes Decreased microalbuminuria Significance and mechanism of 

Decreased type-2 diabetic morbidity 

decreased microalbuminuria 

yet to be determined 

Raynaud’s phenomenon Modulate temperature-sensitive digital 

vasospasm 

Small, well-designed clinical trial supports 

decreased frequency and shorter duration 

of effects 

Altitude sickness Treatment and prevention of high-altitude 

pulmonary oedema 

MEDLINE search of all peer-reviewed English literature for 

1990–2007 was performed for search terms phosphodiesterase 

inhibitors, sildenafil, vardenafil, and tadalafil. Critical analysis 

of the existing literature on PDE5-Is with alternative dosing 

and uses was performed; all reports were included in the 

review with emphasis on methodologically sound articles 

determined to be most clinically meaningful. 


Prevent rapid progression to death 

3. Results—erectile dysfunction 


[67,68,126–131,135–137] 


Limited clinical data Clinical: [139] 

Mechanism of PDE5-I 

incompletely understood 

Limited clinical data Clinical: [140–142] 

Extended daily-use trials not 

performed to date 

PDE5-I, phosphodiesterase type 5 inhibitor; LUTS, lower urinary tract symptoms; BPH, benign prostatic hyperplasia; IPSS, International 

Prostate Symptom Score; SSRI, selective serotonin reuptake inhibitor; PE, premature ejaculation; COPD, chronic obstructive pulmonary 

disease; PH, pulmonary hypertension. 

3.1. Daily dosing of PDE5 inhibitors for erectile dysfunction 

Mirone et al [13] reported the first comparative trial 

of alternative dosing, investigating treatment efficacy 

and patient preference for 20-mg tadalafil 

taken on-demand versus 3 times per week, over a 

6-wk study period. This study demonstrated that 

42.2% of men preferred scheduled dosing versus 

57.8% for on-demand; both treatment regimens 

were well tolerated and efficacious. 

More recent studies have demonstrated that 

chronic dosing may be advantageous versus ondemand 

regimens, offering a valuable treatment 

option for ED. McMahon [10] reported upon the 

efficacy, safety, and tolerability of on-demand 20-mg 

versus daily dosed 10-mg tadalafil in 145 men with 

mild to severe ED of various etiologies. Primary 

outcome measures included changes from baseline 

in the erectile function domain of the International 

Index of Erectile Function (IIEF) and the proportion of 

‘‘yes’’ responses to questions 2 (successful penetration) 

and 3 (successful completion of intercourse) of 

the Sexual Encounter Profile (SEP), in addition to a 

Global Assessment Question (GAQ) administered at 

completion of this 26-wk study. Patients receiving ondemand 

and daily tadalafil experienced a significant

994 

mean improvement of 8.3 and 11.9 points in the IIEF, 

respectively ( p < 0.001), with daily-dose mean 

changes significantly higher versus on-demand 

tadalafil ( p < 0.05). SEP3 was answered ‘‘yes’’ in 

69% and 84% of patients in on-demand and daily 

tadalafil groups, respectively, compared with 30% at 

baseline ( p < 0.001). Successful completion of sexual 

intercourse was also statistically higher for daily 

tadalafil than for on-demand tadalafil ( p < 0.05), with 

both treatments well tolerated. On the basis of these 

results, McMahon concluded that treatment with 

daily tadalafil was associated with a significantly 

higher IIEF erectile function domain score and 

completion of successful intercourse compared with 

on-demand tadalafil. 

Porst et al [7] reported a randomised, doubleblind, 

placebo-controlled, parallel-group, 12-wk 

daily-dose study consisting of 268 men. Groups 

were divided 1:2:2 to placebo, tadalafil 5mg, and 

tadalafil 10 mg taken once daily in this study with 

primary outcome measures of changes in the IIEF 

erectile function domain (IIEF-EF), Sexual Encounter 

Profile diary questions 2 (SEP2, successful penetration) 

and 3 (SEP3, successful completion of intercourse), 

and treatment tolerability. Patients in 

placebo and tadalafil 5 mg or 10 mg groups reported 

score changes of 0.9, 9.7%, and 9.4 for the IIEF-EF, 

successful penetration for 11.2%, 36.5%, and 39.4% of 

intercourse attempts, and completion rates of and 

13.2%, 45.5%, and 50.1%, respectively. At the conclusion 

of the study, 28.3%, 84.5%, and 84.6%, 

respectively, reported improved erections, whereas 

8.3%, 51.5%, and 50.5% demonstrated ‘‘no ED’’ 

(defined as IIEF 26–30), respectively. All comparisons 

between tadalafil and placebo were significant 

( p < 0.001). Adverse events included dyspepsia, 

headache, back pain, upper abdominal pain, and 

myalgia; however, only 8 treated patients discontinued 

because of adverse events. 

Recently, Buvat et al [14] presented data from a 

randomised, double-blind, placebo-controlled, 12-wk 

study of 268 men assigned to once-a-day placebo, or 

5 mg or 10 mg tadalafil; those treated with once-daily 

tadalafil were more satisfied with the hardness of 

their erections (SEP 4) and overall sexual experience 

(SEP 5) versus men receiving placebo. 

These studies support previously published data 

by Olsson et al [11] assessing the efficacy and 

tolerability of sildenafil for treating ED of psychogenic 

and mixed psychogenic/organic etiology. Patients 

were randomised in a double-blind, fixed-dose 

manner to placebo (n = 95) or sildenafil 10 mg 

(n =90), 25mg (n = 85), or 50 mg (n = 81) once daily 

for 28 d. Patients receiving sildenafil had significantly 

more grade 3 (rigidity sufficient for penetration) or 


grade 4 (fully rigid) erections per week than patients 

receiving placebo ( p < 0.001). Patients treated with 

sildenafil noted significant improvements compared 

with placebo for frequency, hardness, and duration of 

erections ( p < 0.01), satisfaction ( p < 0.05), and significant 

improvement in the partners’ own sex lives 

( p < 0.001). Adverse events were mostly mild to 

moderate in nature. The most common adverse 

events were headache, dyspepsia, flushing, myalgia, 

arthralgia, and flu syndrome. Discontinuations due 

to treatment-related adverse events, most commonly 

headache, dyspepsia, flushing, and myalgia, 

ranged from 1.1% to 6.2% for sildenafil and 4.2% for 

placebo. 

3.2. Salvaging nonresponders to on-demand PDE5-I 

therapy 

Currently, 30–35% of patients fail to respond or are 

dissatisfied with treatment; as a consequence of 

inadequate patient education, incorrect PDE5-I 

usage, unrecognised hypogonadism, severity of ED 

at presentation, and psychosocial factors [15,16]. 

PDE5-I salvage strategies include patient education, 

lifestyle changes, correction of modifiable risk 

factors, dose adjustment or switch of PDE5-I agents, 

androgen replacement, psychosexual or relationship 

counseling, and progression to second- or 

third-line treatment options [17]. 

McMahon [9] has reported results for efficacy and 

safety of daily tadalafil in 112 men with moderate to 

severe ED previously unresponsive to on-demand 

tadalafil. Compared with pretreatment and ondemand 

scores, 10-mg daily dosing resulted in a 

mean improvement of 12.8 and 8.2 from respective 

IIEF baseline scores ( p < 0.001), and 58% of intercourse 

attempts (SEP 3) were successfully completed 

( p < 0.001). Improved erections were reported by 

69% of men compared with 42% of men using ondemand 

tadalafil. Daily tadalafil proved an effective 

salvage strategy for previous nonresponders. 

Haztimouratidis et al [18] investigated the efficacy 

of 20-mg vardenafil daily, as well as tadalafil 

20 mg every other day, over a 2-wk period, in a group 

of PDE5-I nonresponders [18]; 18.2% and 11.1%, 

respectively, converted to responders. No side-effect 

or safety issues were identified for this, or the 

previously discussed McMahon [10] and Porst et al 

[7] studies. Continuous dosing of PDE5-Is has been 

shown to significantly improve treatment outcome 

measures; although data on the systemic effects of 

prolonged continuous administration for the three 

PDE5-Is is limited primarily to clinical trials of 

sildenafil for pulmonary hypertension [19], chronic 

therapy is well tolerated and thought to improve

various aspects of endothelial and haemodynamic 

function [20]. 

3.3. Mechanisms for treatment effects of once-daily PDE5-I 

dosing 

On the basis of currently available evidence, it is 

possible that endothelial dysfunction and systemic 

cardiovascular pathology are modulated by chronic 

PDE5-I use, resulting in improved erectile function 

owing to effects upon both local and systemic 

targets [6]. Endothelium-dependent cavernosal 

responses were potentiated by an 8-wk course of 

subcutaneous sildenafil (60 mg/kg) given daily [21]. 

In this study, Behr-Roussel et al concluded that 

chronic sildenafil may regulate the transduction 

pathway, leading to the activation of endothelial 

nitric oxide synthase (eNOS), but has no effect on 

nitric oxide (NO) bioavailability or on the cyclic 

guanosine monophosphate (cGMP) pathway; therefore, 

they eliminated tachyphylaxis as an unwanted 

byproduct of prolonged PDE5-I exposure. Long-term 

continuous sildenafil (20 mg/kg for 45 d) in aged rats, 

as reported by Ferrini et al [22], facilitated reversal of 

aging-related cavernosal fibrosis, prevented loss of 

corporal smooth muscle, and stimulated nitric oxide 

synthase-2A. Chronic sildenafil treatment (20 mg/ 

kg) for 3 wk showed greater improvement for rats 

with impaired baseline erectile function (aged) 

versus young healthy rats [23]. This phenomenon 

was further investigated by Musicki et al [24], who 

concluded that, under preconditions of erectile 

impairment, long-term PDE-I augments erectile 

function through Akt-dependent eNOS phosphorylation. 

Furthermore, it was observed that the lack 

of erectile enhancement in young rats by long-term 

PED5 inhibition might relate to restrained NO 

signalling by PDE5 upregulation, lack of incremental 

Akt and eNOS phosphorylation, and heightened 

Rho-kinase signalling in the penis. 

PDE5-Is have also been shown to confer favourable 

effects upon systemic endothelial dysfunction, 

which is clearly associated with ED [25–27]. Cardiovascular 

risk factors such as hypertension, diabetes, 

smoking, dyslipidaemia, and the metabolic syndrome 

can cause endothelial damage, leading to 

impaired NO release or increased endothelial ‘‘stickiness,’’ 

which often leads to progressive atherosclerosis. 

Rosano et al [28] demonstrated improved 

endothelial function in men with increased cardiovascular 

risk using chronic tadalafil treatment. In this 

study of 32 men, flow-mediated dilation (FMD) of 

the brachial artery, nitrite/nitrate ratios, and 

endothelin-1 (vasoconstrictor) responded positively 

to PDE5-I treatment. Halcox et al [29] reported 


sildenafil use improved epicardial coronary artery 

dilation, lessened endothelial dysfunction, and 

inhibited platelet activation in men with various 

vascular risk factors, whereas Vlachopoulos et al [30] 

demonstrated abrogation of smoking-induced acute 

decreases in FMD of the brachial artery. These 

studies provide the experimental support for the 

chronic administration of PDE5-I [31–33]. Mechanistic 

studies also suggest that PDE5-Is may exert 

endothelial and cardioprotective effects via activation 

of protein kinase C/ERK signalling, opening of 

mitochondrial adenosine triphosphate–sensitive 

potassium channels, or modulation of the hormonal 

milieu [34–36]. 

3.4. Difficult to treat populations: diabetes 

As early as 1998, Price et al [12] described daily use of 

sildenafil for ED in diabetic men. Twenty-one men 

were enrolled in a double-blind, placebo-controlled, 

three-way crossover study; daily diary records of 

erectile activity and a global efficacy question were 

used to evaluate once-daily dosing versus placebo 

for 10 d. Sildenafil increased the number of erections 

considered sufficiently rigid for vaginal penetration 

compared with placebo ( p = 0.0005); 50% and 52% of 

patients treated with 25 and 50 mg of sildenafil 

reported improved erection quality compared with 

10% of those receiving placebo ( p < 0.05). 

Several lines of basic research support the use of 

chronic PDE5-Is in diabetics. PDE5-I administration 

attenuated the development of ED in diabetic rats, in 

association with improved endothelial function as 

measured by thoracic aorta relaxation in vitro and 

measurement of plasma endothelin-1 levels [37]. 

Oral sildenafil (5 mg/kg) given daily for 3 wk to 

streptozotocin-induced diabetic rats preserved both 

penile expression of neuronal NOS and erections 

compared with controls [38]. Other proposed 

mechanisms of action include antioxidant activities, 

upregulation of diminished central NO effects, 

enhanced vasodilation response, and prevention 

of diabetes-induced tissue damage [39–42]. 

In humans, Desouza et al [43] reported the acute 

and prolonged effects of sildenafil on brachial artery 

FMD, an index of NO-dependent endothelial function 

that is impaired in patients with type 2 diabetes. 

In this double-blind, placebo-controlled crossover 

trial in 16 patients, treatment with sildenafil 25 mg 

daily for 2 wk and testing 24 h after the final dose 

resulted in a mean FMD increase of 14% ( p = 0.01). 

Subsequently, improvements in FMD were also 

demonstrated for tadalafil 20 mg taken every other 

day [29]. Although endothelium-dependent FMD 

improved in both studies, further investigations

996 

are required to determine the clinical implications of 

this measure for patients with type 2 diabetes. 

3.5. Difficult to treat populations: post-RRP 

Despite advances in operative technique, erectile 

function is frequently compromised in men undergoing 

RRP for prostate cancer [6]. Injury to the 

neurovascular bundle initiates progressive corporal 

smooth muscle apoptosis and increased fibrosis, 

inducing veno-occlusive dysfunction. The landmark 

report by Montorsi et al [44] demonstrated that early 

ED treatment helps preserve erectile function 

following RRP. Several studies have been performed 

in an effort to define the role of PDE5-Is as a part of a 

penile rehabilitation program [45–49]; as evidenced 

by the number of ongoing trials, clinical data about 

potential mechanisms and patient outcomes for 

chronic use in this patient group remain incomplete 

[50]. Further data are also required to define which 

role, if any, daily PDE5-Is may have in men undergoing 

non–nerve-sparing procedures. 

Despite the limitations of available data, evidence 

suggests that daily use of a PDE5-I merits careful 

consideration. Schwartz et al [51] reported on 40 

volunteers who had undergone RRP and were treated 

with every-other-day sildenafil for 6 mo; after the 

treatment period, cavernosal biopsy demonstrated 

smooth muscle preservation at 50 mg, and decreased 

levels of fibrosis and substantially increased smooth 

muscle content at 100 mg doses [51]. Up to 6-fold 

increases in the return of spontaneous erections for 

men treated with nightly sildenafil versus placebo 

have also been reported [52]. 

Animal studies provide further support for daily 

PDE5-I therapy in this group of patients. Vignozzi et al 

[53] recently reported their findings of protection 

against cavernous tissue protein and messenger RNA 

(mRNA) changes, and preservation of PDE5 expression 

and tadalafil efficacy after a 3-mo treatment 

course of daily tadalafil (2 mg/kg) following bilateral 

cavernous neurotomy in the rat. Using a similar rat 

model, Ferrini et al [54] demonstrated that long-term 

vardenafil may prevent veno-occlusive dysfunction 

after RRP by preserving smooth muscle content and 

inhibiting corporal fibrosis, possibly by an effect on 

inducible NOS (iNOS), as evidenced by increased iNOS 

and proliferating cell nuclear antigen expression 

(smooth muscle cell replication), with functional 

normalisation of the dynamic infusion cavernosometry 

drop rate and smooth muscle-to-collagen 

ratio. Daily-use sildenafil has also demonstrated 

the ability to protect against structural changes 

secondary to cavernous nerve injury and to preserve 

erectile function in the rat [55]. 


3.6. Disease modification 

The unique mechanisms of action for PDE5-Is and 

their varied pharmacological properties have 

encouraged investigation for potential ‘‘disease 

modification’’ or ‘‘cure’’ via chronic therapy [56]. 

Sighinolfi et al [57] observed an extended 

response to chronic PDE5-I treatment using sildenafil 

for up to 20 mo; peak systolic velocity before 

and after treatment were compared, demonstrating 

a 10.5% improvement ( p < 0.001). Modulation of the 

NO signalling pathways is proposed as the primary 

mechanism for these effects. Carreta et al [58] 

demonstrated that chronic and non–on-demand 

treatment with tadalafil induced spontaneous 

resumption of erections, likely through improvement 

of endothelial function. Although promising, 

evidence-based data are limited and direct evidence 

to confirm these hypotheses is required. 

Potential nonurological targets for disease modification 

with chronic PDE5-I therapy include endothelial 

dysfunction, pulmonary and essential 

hypertension, and cardioprotection against ischaemia-reperfusion 

injury or drug-induced toxicity 

[19,28,62–64]. 

3.7. Tachyphylaxis 

PDE5 gene expression in the penis may be modulated 

by influences including PDE5-regulated NO/ 

cGMP molecular signalling and the androgen milieu 

[61,65–68]. Although it has been suggested that 

tachyphylaxis may occur with extended use, this 

hypothesis remains unproven on the basis of 

existing clinical trial data [50,68]. 

Daily dose PDE5-I therapy and excessive cGMP 

accumulation may upregulate PDE5 expression 

[69,70]. The clinical sequelae of tachyphylaxis 

secondary to these mechanisms should include 

increased dosage requirements for efficacy. However, 

a review of more than 1000 men using 

sildenafil for ED demonstrated low tachyphylaxis 

potential and dropout rates; subsequent studies 

have corroborated these findings [9,71]. Nonurological 

applications for daily PDE5-I use have also 

reported longer-term (up to 20 mo) satisfactory 

safety, efficacy, and tolerability data [27,57,72–75]. 

Several animal studies have shown no evidence of 

tachyphylaxis [21,67,76–78]. 

3.8. Potential barriers to the treatment of ED with daily 

dosing 

Patient cost represents the primary barrier to 

treatment using an every-day dosing schedule [50].

Unlike pulmonary hypertension, for which sildenafil 

may provide a net cost savings compared with 

inhaled or intravenous medications [79], daily 

PDE5-I use may be limited by high costs, given the 

average intercourse frequency of five to six times 

per month [6]. Should lower-dose daily administration 

provide attractive efficacy and safety profiles 

compared with on-demand use, and equivalent net 

monthly cost approach, chronic PDE5-I use may 

become an important treatment option [50]. 

4. Results—other urological conditions 

4.1. Lower urinary tract symptoms 

The proposed links between lower urinary tract 

symptoms (LUTS) and ED include changes in the 

NOS and cGMP pathways in the prostate and penis, 

Rho-kinase activation, endothelin pathway modulation, 

autonomic hyperactivity and changes secondary 

to pelvic atherosclerosis [80–84]. Further, the 

rationale for further study of potential PDE5-I 

treatment for BPH and LUTS is underpinned by 

the presence of PDE5 isoenzymes in the transition 

zone of the human prostate, along with PDE4 and 

PDE11, and the roles of cGMP and cAMP as controls 

of prostate physiology as reported by Sairam et al, 

demonstrating improved International Prostate 

Symptom Score (IPSS) and sexual function scores 

after treatment with sildenafil [85,86]. 

Data demonstrating efficacy of PDE5-I use in men 

with LUTS with and without accompanying ED 

shows promise. In a study of 48 men with ondemand 

sildenafil, Mulhall et al [87] reported 60% 

improved their IPSS score, with 35% demonstrating 

at least a 4-point improvement. Subsequently, 

McVary et al [88] assessed the safety and efficacy 

of tadalafil dosed once daily (5 mg initially, dose 

escalation to 20 mg) in 281 men for the treatment of 

LUTS; in this double-blind, placebo-controlled 

study, IPSS decreased 7.1 for tadalafil versus 4.5 

for placebo. In a double-blind, randomised, placebocontrolled 

study [89] of 369 men, once-daily dosing 

of 50 and 100 mg sildenafil was shown to improve 

IPSS scores by 6.32 (vs. 1.93 placebo; p < 0.0001) and 

resulted in a 71.2% treatment satisfaction rate 

compared with 41.7% for placebo ( p < 0.0001). 

No change in flow rate was measured in these 

studies, potentially indicating a new, as yet unidentified, 

pathophysiological mechanism not involving 

prostatic smooth muscle relaxation [87–89]. 

Filippi et al [90] have reported on PDE5 expression 

and activity in the human bladder and PDE5-I effects 

both in vitro and in vivo. Sildenafil, tadalafil, and 


vardenafil blocked 70% of the total cGMP catabolising 

activity in the bladder. Results demonstrated 

that PDE5-Is regulate bladder smooth muscle tone 

and strongly limit NO/cGMP signalling, providing a 

possible therapeutic option for bladder dysfunction 

targeting irritative LUTS. Tinel et al [91] also tested 

PDE5-Is in this capacity using organ-bath experiments 

and a partial bladder outlet obstruction rat 

model in vivo. They identified PDE5 mRNA expression 

in the bladder, followed by the urethra and 

prostate, confirming expression in tissues generally 

held responsible for LUTS. PDE5-Is also induced 

significant relaxation of these tissues, inhibited the 

proliferation of human prostate stromal cells, and 

reduced the irritative symptoms of BPH/LUTS in 

vivo. 

Combination therapy consisting of daily 25-mg 

sildenafil and 10-mg alfuzosin has been reported by 

Kaplan et al [80]. Patients were randomised to either 

agent alone, or combined, in this 12-wk, open-label, 

randomised, single-centre study; PDE5-I alone 

resulted in a 16.9% decrease in IPSS score (compared 

with 15.6% and 24.1% for alfuzosin and combination 

treatments, respectively). 

4.2. Priapism, premature ejaculation, and Peyronie’s 

disease 

4.2.1. Priapism 

An increased understanding of the pathological 

mechanisms responsible for ischemic priapism 

has identified PDE5-Is as possible modulatory 

agents for underlying penile smooth muscle PDE 

dysregulation [59–61]. Current guidelines emphasise 

the use of established clinical interventions for 

presentations of high-risk episodes (greater than 

4 h); reactive management is usually successful in 

the acute setting, but does not prevent further 

episodes [4,92]. However, the opportunity for 

chronic PDE5-I therapy exists for men who are 

known to have prodromal symptoms in the form of 

short-lived attacks, also known as stuttering priapism, 

which often heralds subsequent major and 

possibly permanently debilitating episodes [93,94]. 

Applied daily in a manner not associated with 

stimulatory conditions, PDE5-Is have been shown to 

alleviate recurrent priapism without interfering 

with normal erectile function [95]. Burnett et al 

[61] have further reported their experience for seven 

patients with repeated episodes of prolonged erections 

not associated with sexual stimulation, and 

noted that daily doses of 25 to 50 mg, as well as 

tadalafil 10 mg every other day, resulted in safe, 

efficacious, and tolerable control of priapism 

(patients followed up to 24 mo). PDE5-Is used in a

998 

long-term, continuous fashion cause a heightened 

basal amount of cGMP in the penis, which progressively 

re-establishes normal PDE5 expression and 

activity, and counters the altered NO signalling 

responsible for priapism [96]. Further investigation 

in the form of controlled trials is needed to validate 

and fully characterise PDE5-I therapeutic profiles in 

this context. 

4.2.2. Premature ejaculation 

Available studies provide conflicting data regarding 

the role of PDE5-Is for the treatment of premature 

ejaculation (PE). Sildenafil, in combination with 

paroxetine prolongs intravaginal ejaculation latency 

time (IELT) and, when combined with paroxetine 

and psychological-behavioural counseling, has 

shown some effectiveness in nonresponders to 

other treatments [97,98]. However, others have 

demonstrated an absence of superiority compared 

with placebo or combination treatment with topical 

anesthetics [99]. 

The proposed mechanism for PDE5-I modulation 

of PE pathophysiology focuses on both central and 

peripheral inhibition of vas deferens, seminal 

vesicle, prostate, and urethral contractions [50, 

100–102]. However, there is no convincing evidence 

at this time to support on-demand or daily PDE5-Is 

in the treatment of men with lifelong PE and normal 

erectile function. Further well-designed controlled 

studies are required, especially with daily or ondemand 

selective serotonin reuptake inhibitors, 

which have previously shown promise in this group 

of patients [103]. 

4.2.3. Peyronie’s disease 

Vardenafil has been shown to slow and reverse the 

early stages of a Peyronie’s disease (PD)–like plaque 

in the rat, with some amelioration of more advanced 

plaques [104]. In this study reported by Ferrini et al, 

45 cumulative days of once-daily (1 and 3 mg/kg) 

treatment resulted in reduced collagen/smooth 

muscle and collagen III/I ratios, and myofibroblasts 

and tumour growth factor-beta1–positive cells, and 

selectively increased the apoptotic index in the PDlike 

plaque. However, no clinical data for this 

application are available at this time. 

5. Results—nonurological indications 

5.1. Pulmonary hypertension 

The use of extended, daily-dose PDE5-Is for the 

treatment of various forms of pulmonary hypertension 

(PH), including primary arterial hypertension 


(PAH), chronic thromboembolic PH, and portalpulmonary 

hypertension, has gained rapid acceptance 

in clinical practice owing to safety, therapeutic 

efficacy, and cost-effectiveness [79,105–112]. 

The major source of NO production in lung is 

eNOS, which is located in the vascular endothelium 

and the airway epithelium [113,114]. Rossi et al [115] 

reported sildenafil effects on pulmonary and 

endothelial function, demonstrating significant 

reductions of mean pulmonary artery pressure 

and arteriolar resistances, as well as improved 

endothelial-dependent vasodilation and reduced 

plasma concentrations of endothelin-1. 

Sildenafil is currently licensed for the treatment 

of pulmonary arterial hypertension, having demonstrated 

improvements in World Health Organization 

functional PAH parameters, haemodynamics, and 

exercise capacity in landmark studies [105]; vardenafil 

and tadalafil have also shown sustained 

pulmonary vasodilation and satisfactory safety 

profiles in early trials [106,116]. PDE5-I agentspecific 

characteristics have also been shown. For 

example, although vardenafil demonstrated most 

rapid onset of effect, selectivity for pulmonary 

circulation was not seen as for sildenafil and 

tadalafil, whereas improved arterial oxygenation 

has been observed only for sildenafil to date [116]. 

Encouraging initial data have also been reported for 

PDE5-I treatment of chronic obstructive pulmonary 

disease and secondary pulmonary hypertenstion 

due to chronic heart failure in patients undergoing 

cardiac transplantation [117,118]. 

5.2. Systemic hypertension 

PDE5-Is are known vasodilators and may offer 

therapeutic potential as a treatment of essential 

hypertension and blood pressure (BP) [119,64]. Oliver 

et al reported the first randomised, double-blind, 

study of a PDE5-I for this purpose, showing a 

reduction in BP similar to that of other antihypertensives 

[120,121]. These results correspond to 

previously reported class effects of PDE5-Is on BP, 

namely that decreases in arterial pressure average 

9/8 mm Hg (systolic and diastolic, respectively) at 

rest [122]. Early animal evidence also provides 

insight into chronic hypertension induced by renal 

injury, as deficient NO production and activity were 

evidenced by downregulation of endothelial, neuronal, 

and inducible NOS, and soluble guanylate 

cyclase in the injured kidney of the rat [122]. Given 

that PDE5 is the dominant isoform in the kidney, Bai 

et al [123] concluded that PDE5-Is might serve as a 

potential modulator of secondary renal sympathetic 

activation.

5.3. Cardioprotection and endothelial function 

Myocardial ischaemia-reperfusion injury contributes 

significantly to morbidity and mortality 

[124]. PDE5-Is have shown great promise in animal 

studies as a possible cardioprotective pharmacological 

agent via several potential pathways; cardioprotection 

may occur through NO generated from 

eNOS/iNOS, activation of protein kinase C/ERK or 

protein kinase G signalling, opening of mitochondrial 

ATP-sensitive potassium channels, attenuation 

of cell death resulting from necrosis and 

apoptosis, and increased Bcl2/Bax ratios through 

NO signalling in adult cardiomyocytes [34,62,125– 

126]. Sildenafil, vardenafil, and tadalafil have all 

demonstrated decreased infarct size after ischaemia-reperfusion 

in animal models, providing overwhelming 

evidence for cardioprotective effects 

[32,126–135]. Gori et al [131] have also reported 

human in vivo results for 10 healthy male volunteers, 

confirming the ability of oral sildenafil to 

induce potent protection against ischaemia- and 

reperfusion-induced endothelial dysfunction via 

opening of K ATP channels [131]. Chronic PDE5-Is 

have been shown to increase endothelium-dependent 

flow-mediated vasodilation in chronic heart 

failure and to improve endothelium function in atrisk 

cardiac patients and among those with altered 

endothelial function [27,28,132–134]. Foresta et al 

[135] demonstrated that chronic tadalafil and 

vardenafil improve endothelial function and 

increase the number of circulating endothelial 

progenitor cells (EPCs). EPCs are thought to contribute 

to endothelial repair and neovascular repair, 

and increased levels are associated with lowered 

risk for cardiac death [136,137]. Altogether, daily use 

of PDE5-Is for cardioprotection and modulation of 

endothelial dysfunction is supported by animal and 

early clinical data; eventual clinical use of these 

agents may represent a significant advance in 

cardiovascular medicine should pivotal trials establish 

an expanded PDE5-I role in cardiac health. 

5.4. Other indications 

5.4.1. Diabetes 

There is currently little data available on the effects 

of long-term PDE5-I use in patients with type-2 

diabetes. However, Grover-Paez et al [138] reported 

that sildenafil taken daily (50 mg) for 30 d diminished 

microalbuminuria. 

5.4.2. Raynaud’s phenomenon 

The effects of PDE5-Is on temperature-sensitive 

digital vasospasms, known as Raynaud’s phenom- 


enon, was recently reported by Fries et al [139] who 

demonstrated decreased frequency and shorter 

duration of attacks coupled with a 4-fold increase 

in mean capillary flow velocity in this double-blind, 

placebo-controlled, fixed-dose (sildenafil 50 mg 

twice daily) crossover study over 4 wk. 

5.4.3. Altitude sickness 

Early data suggests that PDE5-Is may have a role in 

the treatment and prevention of high altitude 

pulmonary edema, a devastating illness at high 

altitudes that is characterised by a rapid progression 

to death [140–142]. Extended, daily-use PDE5-Is trials 

in this cohort have not been performed to date. 

6. Safety of daily PDE-5 inhibitor use 

Although the safety of this class of agents has 

been indisputably established for the treatment 

of ED on an on-demand basis, there remains a 

paucity of data on the long-term effects of chronic 

PDE5-I use. Studies that are available for extended 

use indicate maintained treatment benefit (no 

tachyphylaxis) with minimal, well-tolerated sideeffects 

as described previously in this review 

[79,105–110]. 

Randomised, placebo-controlled assessment of 

daily tadalafil for 26 wk did not demonstrate 

meaningful differences in systolic and diastolic BP 

between groups, suggesting no significant deterioration 

after chronic use [143]. Co-administration 

with selective a1-adrenergic blockers is safe, as long 

as directions for the use of both medications are 

followed [144–148]. The influence of daily administration 

of PDE5-Is on the occurrence of rare adverse 

events, such as nonarteritic ischaemic optic neuropathy, 

remains to be elucidated [149]. The patient 

should be informed of commonly anticipated sideeffects, 

such as flushing, headache, congestion, and 

so forth, as well as the current gap in a complete 

understanding of the potential ramifications of 

extended-term daily PDE5-I use. 

Cardiac safety for PDE5-Is has been clearly 

established [150]. Although all three approved 

PDE5-Is are contraindicated in men using or 

requiring nitrates for cardiovascular disease, the 

concern about daily PDE5-I use always raises 

concern about co-administration in cases of cardiac 

emergency. Based on nearly 10 yr of clinical 

experience among thousands of men with ED and 

cardiovascular risk factors, a cardiac event should 

be managed at all times in an appropriate environment 

with little concern related to long- or shortacting 

PDE5-Is.

1000 

7. Conclusions 

The use of daily dosing of PDE5-I may prove to be 

highly significant, given the emerging data on 

endothelial function, LUTS, smooth preservation, 

general vascular health, and its potential to salvage 

erectile function in populations of men not responding 

to on-demand PDE5-I. Cost and tolerability may 

limit its widespread early application among large 

groups of individuals until and unless these added 

values can be conclusively demonstrated. 

Among the cohorts of men most likely to benefit 

from this approach are those who have both ED and 

LUTS. In this large subset of men aged 40 years or 

older, the ability to relieve two dysfunctions that 

significantly impact their quality of life may prove to 

be too attractive to ignore. At present, despite a 

rapidly growing cache of reports indicating the 

potential of PDE5-Is, well-designed large prospective 

studies producing robust data are needed prior to 

this approach becoming a standard of care. 

Conflicts of interest 

Gerald B. Brock: Consultant/advisor, meeting participant/lecturer, 

and owns stock in Pfizer, Lilly, 

Bayer, GlaxoSmithKline, and Schering. 

Anthony J. Bella: Consultant/advisor and meeting 

participant/lecturer; Pfizer Inc, Eli Lilly Inc, and 

American Medical Systems. 

References 

[1] Conti M, Beavo J. Biochemistry and physiology of cyclic 

nucleotide phosphodiesterases: essential components in 

cyclic nucleotide signaling. Annu Rev Biochem 2007;76: 

481–511. 

[2] Wespes E, Amar E, Hatzichristou D, et al. EAU guidelines 

on erectile dysfunction: an update. Eur Urol 2006;49: 

806–15. 

[3] Montague DK, Jarow JP, Brodercik GA, et al. Chapter 1: The 

management of erectile dysfunction: an AUA update. 

J Urol 2005;174:230–9. 

[4] Lue TF, Giuliano F, Montorsi F, et al. Summary of the 

recommendations on sexual dysfunction in men. J Sex 

Med 2004;1:6–23. 

[5] Goldstein I, Kim E, Steers WD, et al. Efficacy and safety of 

tadalafil in men with erectile dysfunction with a high 

prevalence of comorbid conditions: results from the 

MOMENTUS: multiple observations in men with erectile 

dysfunction in National Tadalafil Study in the U.S. J Sex 

Med 2007;4:166–75. 

[6] McMahon CG. Treatment of erectile dysfunction with 

chronic dosing of tadalafil. Eur Urol 2006;50:215–7. 


[7] Porst H, Giuliano F, Glina S, et al. Evaluation of the 

efficacy and safety of once-a-day dosing of tadalafil 

5 mg and 10 mg in the treatment of erectile dysfunction: 

results of a multicenter, randomized, double-blind, placebo 

controlled trial. Eur Urol 2006;50:351–9. 

[8] Hanson-Divers C, Jackson SE, Lue TF, Crawford SY, 

Rosen RC. Health outcomes important to patients in 

the treatment of erectile dysfunction. J Urol 1998;159: 

1541–7. 

[9] McMahon CG. Efficacy and safety of daily tadalafil in men 

with erectile dysfunction previously unresponsive to ondemand 

tadalafil. J Sex Med 2004;1:292–300. 

[10] McMahon CG. Comparison, efficacy, and tolerability of 

on-demand tadalafil and daily dosed tadalafil for the 

treatment of erectile dysfunction. J Sex Med 2005;2: 

415–25. 

[11] Olsson AM, Speakman MJ, Dinsmore WW, et al. Sildenafil 

citrate (Viagra) is effective and well tolerated for 

treating erectile dysfunction of psychogenic or mixed 

aetiology. Int J Clin Pract 2000;54:561–6. 

[12] Price DE, Gingell JC, Gepi-Attee S, Wareham K, Yates P, 

Boolell M. Sildenafil: study of a novel oral treatment for 

erectile dysfunction in diabetic men. Diabet Med 1998; 

15:821–5. 

[13] Mirone V, Costa P, Damber JE, et al. An evaluation of an 

alternative dosing regimen with tadalafil, 3 times/week, 

for men with erectile dysfunction: SURE study in 14 

European countries. Eur Urol 2005;47:846–54. 

[14] Buvat J, Faria G, Wetterauer U, et al. Tadalafil 5 mg and 

10 mg taken once a day for the treatment of erectile 

dysfunction improves patient sexual satisfaction. J Sex 

Med 2007;4(Suppl 1):91 (abstract no. 84). 

[15] Hatzichristou D, Rosen RC, Broderick G, et al. Clinical 

evaluation and management strategy for sexual dysfunction 

in men and women. J Sex Med 2004;1:49–57. 

[16] McMahon CN, Smith CJ, Shabsigh R. Treating erectile 

dysfunction when PDE5 inhibitors fail. BMJ 2006;332: 

589–92. 

[17] Bella AJ, Brock GB. Strategies for PDE-5 Failures. Geriatr 

Aging 2006;9(Suppl 9):9–15. 

[18] Hatzimouratidis K, Moysidis K, Bekos A, Tsimtsiou Z, 

Ioannidis E, Hatzichristou D. Treatment strategy for 

‘‘non-responders’’ to tadalafil and vardenafil: a real-life 

study. Eur Urol 2006;50:126–33. 

[19] Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate 

therapy for pulmonary arterial hypertension. N Engl J 

Med 2005;353:2148–57. 

[20] Carson CC, Lue TF. Phosphodiesterase type 5 inhibitors 

for erectile dysfunction. BJU Int 2005;96:257–80. 

[21] Behr-Roussel D, Gorny D, Mevel K, et al. Chronic sildenafil 

improves erectile function and endotheliumdependent 

cavernosal relaxations of normal rats: lack 

of tachyphylaxis. Eur Urol 2005;47:87–91. 

[22] Ferrini MG, Kovanecz I, Sanchez S, et al. Long-term 

continuous treatment with sildenafil ameliorates 

aging-related erectile dysfunction and the underlying 

corporal fibrosis in the rat. Biol Reprod 2007;76:915–23. 

[23] Musicki B, Champion HC, Becker RE, et al. In vivo analysis 

of chronic phosphodiesterase-5 inhibition with sil

denafil in penile erectile tissues: no tachyphylaxis effect. 

J Urol 2005;174:1493–6. 

[24] Musicki B, Champion HC, Becker RE, Liu T, Kramer MF, 

Burnett AL. Erection capability is potentiated by longterm 

sildenafil treatment: role of blood flow-induced 

endothelial nitric-oxide synthase phosphorylation. Mol 

Pharmacol 2005;68:226–32. 

[25] Chester AH, O’Neil GS, Moncada S, Tadjkarimi S, Yacoub 

MH. Low basal and stimulated release of nitric oxide in 

atherosclerotic epicardial coronary arteries. Lancet 

1990;336:897–900. 

[26] Ludmer P, Slewyn A, Shook TL, et al. Paradoxical vasoconstriction 

induced by acetylcholine in atherosclerotic 

coronary arteries. N Engl J Med 1986;315:1046–51. 

[27] Schwarz ER, Kapur V, Rodriguez J, Rastogi S, Rosiano. The 

effects of chronic phosphodiesterase-5 inhibitor use on 

different organ systems. Int J Impot Res 2007;19:139–48. 

[28] Rosano GM, Aversa A, Vitale C, Fabbri A, Fini M, Spera G. 

Chronic treatment with tadalafil improves endothelial 

function in men with increased cardiovascular risk. Eur 

Urol 2005;47:214–22. 

[29] Halcox JP, Nour KR, Zalos G, et al. The effect of sildenafil 

on human vascular function, platelet activation, and 

myocardial ischemia. J Am Coll Cardiol 2002;40:1232–40. 

[30] Montorsi F, Briganti A, Salonia A, Rigatti P, Burnett AL. 

Can phosphodiesterase type 5 inhibitors cure erectile 

dysfunction? Eur Urol 2006;49:979–86. 

[31] Vlachopoulos C, Tsekoura D, Alexopolous N, Panagiotakos 

D, Aznaouridis K, Stefanadis C. Type 5 phosphodiesterase 

inhibition by sildenafil abrogates acute smoking 

induced endothelial dysfunction. Am J Hypertension 

2004;17:1040–4. 

[32] Sommer F, Schulze W. Treating erectile dysfunction by 

endothelial rehabilitation with phosphodiesterase 5 

inhibitors. World J Urol 2005;23:385–92. 

[33] Rossoni G, Manfredi B, De Gennaro Colonna V, Berti M, 

Guazzi M, Berti F. Sildenafil reduces L-NAME-induced 

severe hypertension and worsening of myocardial 

ischaemia-reperfusion damage in the rat. Br J Pharmacol 

2007;150:567–76. 

[34] Kukreja RC, Salloum F, Das A, et al. Pharmacological 

preconditioning with sildenafil: basic mechanisms and 

clinical implications. Vascul Pharmacol 2005;42:219– 

232.35. 

[35] Kukreja RC, Ockaili R, Salloum F, et al. Cardioprotection 

with phosphodiesterase-5 inhibition—a novel preconditioning 

strategy. J Mol Cell Cardiol 2004;36:165–73. 

[36] Greco EA, Pili M, Bruzziches R, Corona G, Spera A, Aversa 

A. Testosterone:estradiol ratio changes associated with 

long-term tadalafil administration: a pilot study. J Sex 

Med 2006;3:716–22. 

[37] Ahn GJ, Yu JY, Choi SM, et al. Chronic administration of 

phosphodiesterase 5i improves erectile and endothelial 

function in a rat model of diabetes. Int J Androl 2005; 

28:260–6. 

[38] DeYoung L, Yu D, Freeman D, Brock GB. Effect of PDE5 

inhibition combined with free oxygen radical scavenger 

therapy on erectile function in a diabetic animal model. 

Int J Impot Res 2003;15:347–54. 


[39] Milani E, Nikfar S, Khorasani R, Zamani MJ, Abdollahi M. 

Reduction of diabetes-induced oxidative stress by phosphodiesterase 

inhibitors in rats. Comp Biochem Physiol 

C Toxicol Pharmacol 2005;140:251–5. 

[40] Thompson CS, Mumtaz FH, Khan MA, et al. The effect of 

sildenafil on corpus cavernosal smooth muscle relaxation 

and cyclic GMP formation in the diabetic rabbit. Eur J 

Pharmacol 2001;425:57–64. 

[41] Zheng H, Bidasee KR, Mayhan WG, Patel KP. Lack of central 

nitric oxide triggers erectile dysfunction in diabetes. Am J 

Physiol Integr Comp Physiol 2007;292:R1158–64. 

[42] Ayala JE, Bracy DP, Julien BM, Rottman JN, Fueger PT, 

Wasserman DH. Chronic treatment with sildenafil 

improves energy balance and insulin action in high 

fat-fed conscious mice. Diabetes 2007;56:1025–33. 

[43] Desouza C, Parulkar A, Lumpkin D, Akers D, Fonseca VA. 

Acute and prolonged effects of sildenafil on brachial 

artery flow-mediated dilatation in type 2 diabetes. Diabetes 

Care 2002;25:1336–9. 

[44] Montorsi F, Guazzoni G, Strambi LF, et al. Recovery 

of spontaneous erectile function after nerve-sparing 

radical retropubic prostatectomy with and without early 

intracavernous injections of alprostadil: results of a prospective, 

randomized trial. J Urol 1997;158:1408–10. 

[45] Goldstein I, Lue TF, Padam-Nathan H, Rosen RC, Steers 

WD, Wicker PA. Oral sildenafil in the treatment of erectile 

dysfunction. N Engl J Med 1998;338:1332–6. 

[46] Brock G, Nehra A, Lipshultz LI, et al. Safety and efficacy of 

vardenafil for the treatment of erectile dysfunction after 

radical retropubic prostatectomy. J Urol 2003;170:1278– 

83. 

[47] Montorsi F, Nathan HP, McCullough A, et al. Tadalafil in 

the treatmenf of erectile dysfunction following bilateral 

nerve sparing radical retropubic prostatectomy: a randomized, 

double-blind, placebo controlled trial. J Urol 

2004;172:1036–41. 

[48] Montorsi F, McCullough A. Efficacy of sildenafil citrate in 

men with erectile dysfunction following radical prostatectomy: 

a systematic review of clinical data. J Sex Med 

2005;2:658–67. 

[49] Mulhall JP, Land S, Parker M, Waters WB, Flanigan RC. 

The use of an erectogenic pharmacotherapy regimen 

following radical prostatectomy improves recovery of 

spontaneous erectile function. J Sex Med 2005;2:532–40. 

[50] Hatzimouratidis K, Hatzichristou D. Phosphodiesterase 

type 5 inhibitors: the day after. Eur Urol 2007;51:75–81. 

[51] Schwartz EJ, Wong P, Graydon RJ. Sildenafil preserves 

intracorporeal smooth muscle after radical prostatectomy. 

J Urol 2004;171:771–4. 

[52] Casperson JM, Steidle CP, Pollifrone DL. Penile rehabilitation 

in a community setting. J Sex Med 2007;4(Suppl 

1):85–6. 

[53] Vignozzi L, Filippi S, Morelli A, et al. Effect of chronic 

tadalafil administration on penile hypoxia induced 

by cavernous neurotomy in the rat. J Sex Med 2006;3: 

419–31. 

[54] Ferrini MG, Davila HH, Kovanecz I, Sanchez SP, Gonzalex-Cadavid 

NF, Rajfer J. Vardenafil prevents fibrosis and 

loss of corporal smooth muscle that occurs after bilateral

1002 

cavernosal nerve resection in the rat. Urology 2006; 

68:429–35. 

[55] Donohue JF, Tal T, Akin-Olugbade Y, et al. Sildenafil and 

cavernous nerve injury in the rat: defining the optimal 

dosing and timing regimen. J Urol 2006;4(Suppl):327–8 

(abstract no. 1017). 

[56] Hellstrom WJ, Kendirci M. Type 5 phosphodiesterase 

inhibitors: curing erectile dysfunction. Eur Urol 2006; 

49:942–5. 

[57] Sighinolfi MC, Mofferdin A, De Stefani S, et al. Changes in 

peak systolic velocity induced by chronic therapy with 

phosphodiesterase type-5 inhibitor. Andrologia 2006;38: 

84–6. 

[58] Caretta N, Palego P, Ferlin A, et al. Resumption of spontaneous 

erections in selected patients affected by erectile 

dysfunction and various degrees of carotid wall 

alteration: role of tadalafil. Eur Urol 2005;48:326–32. 

[59] Champion HC, Bivalacqua TJ, Takimoto E, et al. Phosphodiesterase-5A 

dysregulation in penile erectile tissue 

as a mechanism of priapism. Proc Natl Acad Sci U S A 

2005;102:661–6. 

[60] Bivalacqua TJ, Burnett AL. Priapism: new concepts in the 

pathophysiology and new treatment strategies. Curr 

Urol Rep 2006;7:497–502. 

[61] Burnett AL, Bivalacqua TJ, Champion HC, et al. Feasibility 

of the use of phosphodiesterase type 5 inhibitors in a 

pharmacologic prevention program for recurrent priapism. 

J Sex Med 2006;3:1077–84. 

[62] Raja SG. Cardioprotection with sildenafil: implications 

for clinical practice. Curr Med Chem 2006;13:3155–64. 

[63] Fisher PW, Salloum F, Das A, Hyder H, Kukreja RC. Phosphodiesterase-5 

inhibition with sildenafil attenuates cardiomyocyte 

apoptosis and left ventricular dysfunction in 

a chronic model of doxorubicin cardiotoxicity. Circulation 

2005;111:1601–10. 

[64] Taddei S, Ghiadoni L. Phosphodiesterase 5 inhibition to 

treat essential hypertension. Hypertension 2006;48: 

546–8. 

[65] Traish AM, Park K, Dhir V, Kim NN, Moreland RB, Goldstein 

I. Effects of castration and androgen replacement 

on erectile function in a rabbit model. Endocrinology 

1999;104:1861–8. 

[66] Morelli A, Fillip S, Mancina T, et al. Androgens regulate 

phosphodiesterase type 5 expression and functional 

activity in corpora cavernosa. Endocrinology 2004; 

145:2253–63. 

[67] Lin CS, Chow S, Lau A, Tu R, Lue TF. Human PDE5A gene 

encodes three PDE5 isoforms from two alternate promoters. 

Int J Impot Res 2002;14:15–24. 

[68] Musicki B, Champion HC, Becker RE, Liu T, Kramer MF, 

Burnett AF. Erection capability is potentiated by longterm 

sildenafil treatment: role of blood flow-induced 

endothelial nitric-oxide synthase phosphorylation. Mol 

Pharmacol 2005;68:226–32. 

[69] Steers WD. Tachyphylaxis and phosphodiesterase type 5 

inhibitors. J Urol 2002;168:207. 

[70] Moreland RB, Goldstein I, Kin NN, Traish A. Sildenafil 

citrate, a selective phosphodiesterase type 5 inhibitor. 

Trends Endocrin Metab 1999;10:97–104. 


[71] El-Galley R, Rutland H, Talic R, Keane T, Clark H. Longterm 

efficacy of sildenafil and tachyphylaxis effect. J Urol 

2001;166:927–31. 

[72] Steers W, Guay AT, Leriche A, et al. Assessment of the 

efficacy and safety of Viagra (sildenafil citrate) in men 

with erectile dysfunction during long-term treatment. 

Int J Impot Res 2001;13:261–7. 

[73] Steibelleher L, Petkov V, Vonbank K, et al. Long-term 

treatment with oral sildenafil in addition to continuous 

IV epoprostenol in patients with pulmonary arterial 

hypertension. Chest 2003;123:1293–5. 

[74] Berreto AC, Franchi SM, Castro S, Lopes AA. One-year 

follow-up of the effects of sildenafil therapy for pulmonary 

hypertension and veno-occlusive disease. Braz J Med 

Biol Res 2005;38:185–95. 

[75] Knodere CA, Ebenroth ES, Brown JW. Chronic outpatient 

sildenafil therapy for pulmonary hypertension in a 

child after cardiac surgery. Pediatr Cardiol 2005;26:859– 

61. 

[76] Gonzalez CM, Bervig T, Podlasek C, Huang CF, McKenna 

KE, McVary KT. Sildenafil causes a dose-dependent 

downregulation of phosphodieasterase type 6 expression 

in the rat retina. Int J Impot Res 1999;11(Suppl 1): 

S9–14. 

[77] Lin C, Xin ZC, Lue TF, Lin CS. Up and down-downregulation 

of phosphodiesterase-5 as related to tachyphylaxis 

and priapism. J Urol 2003;170:S15–8. 

[78] Ferrini MF, Valente EG, Rajfer J, Gonzalez-Cadavid NF. 

Long-term treatment with high levels of sildenafil does 

not up-regulate the levels of phosphodiesterase 5 (PDE5) 

in the rat penis. J Urol 2004;171:424. 

[79] Vida VL, Gaitan G, Quezada E, Barnoya J, Castaneda AR. 

Low-dose oral sildenafil for patients with pulmonary 

hypertension: a cost-effective solution in countries with 

limited resources. Cardiol Young 2007;17:72–7. 

[80] Kaplan SA, Gonzalez RR, Te AE. Combination of alfuzosin 

and sildenafil is superior to monotherapy in treating 

lower urinary tract symptoms and erectile dysfunction. 

Eur Urol 2007;51:1717–23. 

[81] Rosen RC, Giuliano F, Carson CC. Sexual dysfunction and 

lower urinary tract symptoms (LUTS) associated with 

benign prostatic hyperplasia (BPH) Eur Urol 2005;47: 

824–37. 

[82] McVary KT, Rademaker A, Lloyd GL, et al. Autonomic 

nervous system overactivity in men with LUTS secondary 

to benign prostatic hyperplasia. J Urol 2005;174:1327–33. 

[83] McVary K. Lower urinary tract symptoms and sexual 

dysfunction: epidemiology and pathophysiology. BJU 

Int 2006;97(Suppl 2):23–8. 

[84] Uckert S, Oelke M, Stief CG, Andersson KE, Jonas U, 

Hedlund P. Immunohistochemical distribution of cAMPand 

cGMP-phosphodiesterase (PDE) isoenzymes in the 

human prostate. Eur Urol 2006;49:740–5. 

[85] Sairam K, Kulinskaya E, McNicholas TA, Boustead GB, 

Hanbury DC. Sildenafil influences lower urinary tract 

symptoms. BJU Int 2002;90:836–9. 

[86] McVary KT. Unexpected insights into pelvic function 

following phosphodiesterase manipulation—what’s next 

for urology? Eur Urol 2006;50:1153–6.

[87] Mulhall JP, Guhring P, Parker M, Hopps C. Assessment of 

the impact of sildenafil citrate on lower urinary tract 

symptoms in men with erectile dysfunction. J Sex Med 

2006;3:662–7. 

[88] McVary KT, Roehrborn CG, Kaminetsky JC, et al. Tadalafil 

relieves lower urinary tract symptoms secondary to 

benign prostatic hyperplasia. J Urol 2007;177:1401–7. 

[89] McVary KT, Monnig W, Camps Jr JL, Young JM, Tseng L-J, 

van den Ende G. Sildenafil citrate improves erectile function 

and urinary symptoms in men with erectile dysfunction 

and lower urinary tract symptoms associated 

with benign prostatic hyperplasia: a randomized, double-blind 

trial. J Urol 2007;177:1071–7. 

[90] Filippi S, Morelli A, Sandner P, et al. Characterization and 

functional role androgen-dependent PDE5 activity in the 

bladder. Endocrinology 2006;148:1019–29. 

[91] Tinel H, Stelte-Ludwig B, Hutter J, Sandner P. Pre-clinical 

evidence for the use of phosphodiesterase-5 inhibitors 

for treating benign prostatic hyperplasia and lower urinary 

tract symptoms. BJU Int 2006;98:1259–63. 

[92] Montague DK, Jarow J, Broderick GA, et al. American 

Urological Association guidelines on the management 

of priapism. J Urol 2003;170:1318–24. 

[93] Emond AM, Holman R, Haes RJ, Serjeant GR. Priapism 

and impotence in homozygous sickle cell disease. Arch 

Intern Med 1980;140:1434–7. 

[94] Fowler Jr JE, Koshy M, Strub M, Chinn SK. Priapism 

associated with sickle cell hemoglobinopathies: Prevalance, 

natural history, and sequelae. J Urol 1991;145: 

65–8. 

[95] Burnett AL, Bivalacqua TJ, Champion HC, Musicki B. 

Long-term phosphodiesterase 5 inhibitor therapy alleviates 

recurrent priapism. Urology 2006;67:104–8. 

[96] Bivalacqua TJ, Champion HC, Mason W, Burnett AL. 

Long-term phosphodiesterase type 5 inhibitor therapy 

reduces priapic activity in transgenic sickle cell mice. 

J Urol 2006;175:387. 

[97] Salonia A, Maga T, Colombo R, et al. A prospective study 

comparing paroxetine alone versus paroxetine plus sildenafil 

in patients with premature ejaculation. J Urol 

2002;168:2486–9. 

[98] Chen J, Mabjeesh NJ, Matzkin H, Greenstein A. Efficacy of 

sildenafil as adjuvant therapy to selective serotonin 

reuptake inhibitor in alleviating premature ejaculation. 

Urology 2003;61:197–200. 

[99] Atan A, Basar MM, Tuncel A, Ferhat M, Agras K, Tekdogan 

U. Comparison of efficacy of sildenafil-only, sildenafil 

plus topical EMLA cream, and topical EMLA-creamonly 

in treatment of premature ejaculation. Urology 

2006;67:388–91. 

[100] Abdel-Hamid IA. Phosphodiesterase 5 inhibitors in rapid 

ejaculation: potential use and possible mechanisms of 

action. Drugs 2004;64:13–26. 

[101] Uckert S, Hedlund P, Andersson KE, Truss MC, Jonas U, 

Stief CG. Update on phosphodiesterase (PDE) isoenzymes 

as pharmacologic targets in urology: present 

and future. Eur Urol 2006;50:1194–207. 

[102] Uckert S, Stief CG, Mayer M, Jonas U, Hedlund P. Distribution 

and functional significance of phosphodiester- 


ase isoenzymes in the human lower urinary tract. World 

J Urol 2005;23:368–73. 

[103] McMahon CG, McMahon CN, Leow LJ, Winestock CG. 

Efficacy of type-5 phosphodiesterase inhibitors in the 

drug treatment of premature ejaculation: a systematic 

review. BJU Int 2006;98:259–72. 

[104] Ferrini MG, Kovanecz I, Nolazco G, Rajfer J, Gnzalez- 

Cadavid NF. Effects of long-term vardenafil treatment 

on the development of fibrotic plaques in a rat model of 

Peyronie’s disease. Br J Urol 2006;97:625–33. 

[105] Ghofrani HA, Osterloh IH, Grimminger F. Sildenafil: from 

angina to erectile dysfunction to pulmonary hypertension 

and beyond. Nat Rev Drug Discov 2006;5:689–702. 

[106] Aizawa K, Hanaoka T, Kasai H, et al. Long-term vardenafil 

therapy improves hemodynamics in patients 

with pulmonary hypertension. Hypertens Res 2006;29: 

123–8. 

[107] Madden BP, Allenby M, Loke T_K, Sheth A. A potential 

role for sildenafil in the management of pulmonary 

hypertension in patients with parenchymal lung disease. 

Vascul Pharmacol 2006;44:373–6. 

[108] Reichenberger F, Voswinckel R, Steveling E, et al. Sildenafil 

treatment for portopulmonary hypertension. Eur 

Respir J 2006;28:563–7. 

[109] Deobert P, Schumacher O, Ruecker G, et al. Effect of 

vardenafil, an inhibitor of phosphodiesterase-5, on portal 

haemodynamics in normal and cirrhotic liver— 

results of a pilot study. Aliment Pharmacol Ther 2006; 

23:121–8. 

[110] Bresser P, Pepke-Zaba J, Jais X, Humbert M, Hoeper MM. 

Medical therapies for chronic thromboembolic pulmonary 

hypertension. Proc Am Thorac Soc 2006;3:594– 

600. 

[111] Suntharalingam J, Hughes RJ, Goldsmith K, et al. Acute 

haemodynamic responses to inhaled nitric oxide and 

intravenous sildenafil in distal chronic thromboembolic 

pulmonary hypertension (CTEPH) Vascul Pharmacol 

2007;46:449–55. 

[112] German Z, Chambliss KL, Pace MC, Arnet UA, Lowenstein 

CJ, Shaul PW. Molecular basis of cell-specific 

endothelial nitric-oxide synthase expression in airway 

epithelium. J Biol Chem 2000;275:8183–9. 

[113] Giordano D, De Stefano ME, Citro G, Modica A, Giorgi M. 

Expression of cGMP-binding cGMP-specific phosphodiesterase 

(PDE5) in mouse tissues and cell lines using 

an antibody against the enzyme amino-terminal 

domain. Biochem Biophys Acta 2001;1539:16–27. 

[114] Corbin JD, Beasley A, Blount MA, Francis SH. High lung 

PDE5: a strong basis for treating pulmonary hypertension 

with PDE5 inhibitors. Biochem Biophys Res Commun 

2005;334:930–8. 

[115] Rossi R, Nuzzo A, Lattanzi A, Coppi F, Modena MG. 

Sildenafil improves endothelial function in patients with 

pulmonary hypertension. Pulm Pharmacol Ther 2007, 

Epub ahead of print. 

[116] Ghofrani HA, Pepke-Zaba J, Barbera JA, et al. Nitric 

oxide pathway and phosphodiesterase inhibitors in pulmonary 

arterial hypertension. J Am Coll Cardiol 2004; 

43:68S–72S.

1004 

[117] Alp S, Skrygan M, Schmidt WE, Bastian A. Sildenafil 

improves hemodynamic parameters in COPD—an investigation 

of six patients. Pulm Pharmacol Ther 2006; 

19:386–90. 

[118] Jabbour A, Keogh A, Hayward C, Macdonald P. Chronic 

sildenafil lowers transpulmonary gradient and improves 

cardiac output allowing successful heart transplantation. 

Eur J Heart Fail 2007;9:674–7. 

[119] Jackson G, Benjamin N, Jackson N, Allen MJ. Effects of 

sildenafil citrate on human hemodynamics. Am J Cardiol 

1999;83:13C–20C. 

[120] Oliver JJ, Melville VP, Webb DJ. Effect of regular phosphodiesterase 

type 5 inhibition in hypertension. Hypertension 

2006;48:622–7. 

[121] Materson BJ, Reda DJ, Cushman WC, et al. Single-drug 

therapy for hypertension in men. A comparison of six 

antihypertensive agents with placebo. N Engl J Med 

1993;328:914–21. 

[122] Jackson G. Hemodynamic and exercise effects of phosphodiesterase-5 

inhibitors. Am J Cardiol 2005;96(Suppl 

2):32–6. 

[123] Bai Y, Ye S, Mortazavi R, Campese V, Vaziri ND. Effect of 

renal injury-induced neurogenic hypertension on NO 

synthase, caveolin-1, AKt, calmodulin and soluble guanylate 

cyclase expressions in the kidney. Am J Physiol 

Renal Physiol 2007;292:974–80. 

[124] Mattson DL, Lu S, Nakanishi K, Papnek PE, Cowley Jr AW. 

Effect of chronic renal medullary nitric oxide inhibition 

on blood pressure. Am J Physiol Heart Circ Physiol 

1994;266:H1918–26. 

[125] Kukreja RC. Cardiovascular protection with sildenafil 

following chronic inhibition of nitric oxide synthase. 

Br J Pharmacol 2007;150:538–40. 

[126] Das A, Smolenski A, Lohmann SM, Kukreja RC. Cyclic 

GMP-dependent protein kinase Ia attenuates necrosis 

and apoptosis following ischemia/reoxygenation in cardiomyocytes. 

J Biol Chem 2006;281:38644–52. 

[127] Das A, Xi L, Kukreja RC. Phosphodiesterase-5 inhibitor, 

sildenafil preconditions adult cardiac myocytes against 

necrosis and apoptosis: essential role of NO signaling. 

J Biol Chem 2005;280:12944–55. 

[128] Salloum F, Ockaili R, Michael Wittkamp M, Marwaha VR, 

Kukreja RC. Vardenafil: a novel type 5 phosphodiesterase 

inhibitor reduces myocardial infarct size following 

ischemia/reperfusion injury via opening of mitochondrial 

K ATP channels in rabbits. J Mol Cell Cardiol 

2006;40:405–11. 

[129] Salloum F, Takenoshita Y, Ockaili R, et al. Sildenafil 

and vardenafil but not nitroglycerin limit myocardial 

infarction through opening of mitochondrial K APT 

channels when administered at reperfusion following 

ischemia in rabbits. J Mol Cell Cardiol 2007;42: 

453–8. 

[130] Sesti C, Florio V, Johnson EG, Kloner RA. The phosphodiesterase-5 

inhibitor tadalafil reduces myocardial 

infarct size. Int J Impot Res 2007;19:55–61. 

[131] Gori T, Sicuro S, Dragoni S, Donati G, Forconi S, Parker JD. 

Sildenafil prevents endothelial dysfunction induced by 

ischemia and reperfusion via opening of adenosine 


triphosphate-sensitive potassium channels: a human 

in vivo study. Circulation 2005;111:721–3. 

[132] Solomon H, Man JW, Anderson TJ. Erectile dysfunction 

and the cardiovascular patients: endothelial dysfunction 

is the common denominator. Heart 2003;89:251–3. 

[133] Kirby M, Jackson G, Simonsen U. Endothelial dysfunction 

links erectile dysfunction to heart disease. Int J Clin Pract 

2005;59:225–9. 

[134] Yavuzgil O, Altay B, Zoghi M, Gurgun C, Kayikcioglu M, 

Kultursay H. Endothelial function in patients with vasculogenic 

erectile dysfunction. Int J Cardiol 2005;103:19– 

26. 

[135] Foresta C, Felin A, De Toni L, et al. Circulating endothelial 

progenitor cells and endothelial function after chronic 

tadalafil treatment in subjects with erectile dysfunction. 

Int J Impot Res 2006;18:484–8. 

[136] Foresta C, Lana A, Cabrelle A, et al. PDE-5 inhibitor 

vardenafil increases circulating progenitor cells in 

humans. Int J Impot Res 2005;17:377–80. 

[137] Werner N, Kosiol S, Schiegl T, et al. Circulating endothelial 

progenitor cells and cardiovascular outcomes. N Engl 

J Med 2005;353:999–1007. 

[138] Grover-Paez F, Villegas Rivera G, Guillen Ortiz R. 

Sildenafil citrate diminishes microalbuminuria and 

the percentage of A1c in male patients with type 2 

diabetes. Diabetes Res Clin Pract 2007, Epub ahead of 

print. 

[139] Fries R, Shariat K, von Wilmowsky H, Bohm M. Sildenafil 

in the treatment of Raynaud’s phenomenon resistant to 

vasodilatory therapy. Circulation 2005;112:2980–2985. 

[140] Bates MG, Thompson AA, Baillie JK. Phosphodiesterase 

type 5 inhibitors and prevention of high altitude 

pulmonary edema. Curr Opin Investig Drugs 2007;8: 

226–31. 

[141] Das BB, Wolfe RR, Chan KC, Larsen GL, Reeves JT, Ivy D. 

High-altitude pulmonary edema in children with underlying 

cardiopulmonary disorders and pulmonary hypertension 

living at altitude. Arch Pediatr Adolesc Med 

2004;158:1170–6. 

[142] Maggiorini M, Brunner-La Rocca HP, Peth S, et al. Both 

tadalafil and dexamethosone may reduce the incidence 

of high-altitude pulmonary edema: a randomized trial. 

Ann Intern Med 2006;145:497–506. 

[143] Kloner RA, Mitchell M, Emmick JT. Cardiovascular effects 

of tadalafil. Am J Cardiol 2003;92:37M–46M. 

[144] Auerbach SM, Gittelman M, Mazzu A, Cihon F, Sundaresan 

P, White WB. Simultaneous administration of vardenafil 

and tamsulosin does not induce clinically 

significant hypotension in patients with benign prostatic 

hyperplasia. Urology 2004;64:998–1003. 

[145] Giuliano F, Kaplan SA, Cabanis MJ, et al. Hemodynamic 

interaction study between alpha1-blocker alfuzosin 

and the phosphodiesterase-5 inhibitor tadalafil in middle-aged 

healthy male subjects. Urology 2006;67: 

1199–204. 

[146] Kloner RA, Jackson G, Emmick JT, et al. Interaction 

between the phosphodiesterase 5 inhibitor, tadalafil 

and 2 alpha-blockers, doxasocin and tamsulosin in 

healthy normotensive men. J Urol 2004;1935–40.

[147] Kloner RA. Pharmacology and drug interaction effects of 

the phosphodiesterase 5 inhibitors. Am J Cardiol 

2005;96(Suppl):42M–6M. 

[148] Carson CC. Combination of phosphodiesterase-5 inhibitors 

and alpha-blockers in patients with benign prostatic 

hyperplasia: treatments of lower urinary tract symptoms, 

erectile dysfunction, or both? BJU Int 2006; 

97(Suppl 2):39–43. 


[149] Bella AJ, Brant WO, Lue TF, Brock GB. Non-arteritic 

anterior ischemic optic neuropathy (NAION) and 

phosphodiesterase type-5 inhibitors. Can J Urol 2006; 

13:3233–8. 

[150] Kostis JB, Jackson G, Rosen R, et al. Sexual dysfunction 

and cardiac risk (the Second Princeton Consensus Conference) 

Am J Cardiol 2005;96:313–21.

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