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european urology 52 (2007) 990–1005
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Review – Sexual Medicine
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
b
Department of Surgery, Division of Urology, University of Ottawa, Ottawa, Canada
Department of Surgery, Division of Urology, St Joseph’s HealthCare London, University of Western Ontario, London, Canada
Article info
Abstract
Article history:
Accepted June 29, 2007
Published online ahead of
print on July 23, 2007
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.
Keywords:
Sildenafil
Vardenafil
Tadalafil
Phosphodiesterase (type) 5
inhibitors
Erectile dysfunction
Dosing
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# 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: [email protected] (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
european urology 52 (2007) 990–1005
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
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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
Fig. 1 – Primary clinical indications for daily PDE5-I regimens.
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european urology 52 (2007) 990–1005
Table 1 – Summary of potential benefits and limitations to urological and nonurological clinical use of daily PDE5-Is
Indication
Erectile dysfunction
Potential benefits
Salvage of on-demand nonresponders
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
Limitations
Selected references
Extended term follow-up limited—
safety and efficacy profiles require
further elucidation
Clinical: [6–8,10,11,
13–15,30,36,47,48,51,
56,71,73,147,149,150]
Mechanisms of treatment effects
incompletely understood
Basic science:
[21–24,27,37–40,42,
43,53–55,77,78]
Disease modification—attractive
concept but evidence-based data
limited
No evidence of tachyphylaxis to
date but longer follow-up needed
Patient cost
Benign prostatic
hyperplasia/LUTS
Meaningful symptomatic improvements
noted in well-designed trials
Mechanism of action for BPH/LUTS
unknown
Clinical: [80–90,
144–146,148]
Decrease in IPSS
Trials limited with regards to
duration of treatment and follow-up
Basic science: [91]
Primarily animal study evidence
Clinical: [59–61,95]
Limited, although promising
clinical reports
Basic science: [60,61,96]
Flow remains similar to pretreatment
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
Premature ejaculation
Improvement of overall sexual function
Further investigation (controlled
trials) needed to validate and fully
characterise PDE5-I therapeutic effect
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
Basic science: [104]
Pulmonary hypertension
PDE5-Is approved for clinical use
Long-term efficacy and safety
data continue to be accrued
Clinical: [19,74–76,
79,105–112,115–118]
Early COPD and secondary PH
data only
Basic science:
[33,113–114]
Well-designed, large-scale clinical trials
demonstrating treatment effect
Improvements in functional pulmonary
arterial hypertension parameters,
haemodynamics, and exercise capacity
Evolving data suggests PDE5-I role for
COPD and secondary pulmonary
hypertension
Systemic hypertension
Known vasodilators
Single-agent or combination therapy
Agent-specific characteristics
required each PDE5-I to be
evaluated separately
Limited randomized, placebocontrolled, double-blind data
available
Clinical: [119,64,
120,121,122,143,144]
Limited primarily to animal
evidence and early human
study
Clinical: [28,31,32,
58,62,115,125,132–134]
Role may also be defined for renal
injury-induced hypertension
Cardioprotection and
endothelial function
Potential reduction of morbidity and
mortality of ischaemia-reperfusion injury
Basic science:
[123–124]
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european urology 52 (2007) 990–1005
Table 1 (Continued )
Indication
Potential benefits
Limitations
Several potential target pathways for
treatment effects identified
Selected references
Basic science:
[67,68,126–131,135–137]
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
Decreased type-2 diabetic morbidity
Raynaud’s phenomenon
Modulate temperature-sensitive digital
vasospasm
Basic science: [138]
Limited clinical data
Clinical: [139]
Mechanism of PDE5-I
incompletely understood
Small, well-designed clinical trial supports
decreased frequency and shorter duration
of effects
Altitude sickness
Significance and mechanism of
decreased microalbuminuria
yet to be determined
Treatment and prevention of high-altitude
pulmonary oedema
Limited clinical data
Clinical: [140–142]
Extended daily-use trials not
performed to date
Prevent rapid progression to death
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.
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
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.
3.
Results—erectile dysfunction
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
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european urology 52 (2007) 990–1005
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), 25 mg (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
european urology 52 (2007) 990–1005
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
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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
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european urology 52 (2007) 990–1005
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].
european urology 52 (2007) 990–1005
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
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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
european urology 52 (2007) 990–1005
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].
(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.
4.2.3.
Systemic hypertension
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
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.
european urology 52 (2007) 990–1005
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 KATP 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-
999
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.
european urology 52 (2007) 990–1005
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.
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