Professional Documents
Culture Documents
DOI 10.1007/s40266-014-0177-1
REVIEW ARTICLE
1 Introduction
L. Vignozzi M. Maggi
Department of Clinical Physiopathology, University of Florence,
Florence, Italy
G. Corona
Endocrinology Unit, Medical Department, Azienda Usl,
Maggiore-Bellaria Hospital, Bologna, Italy
K. T. McVary
Department of Urology, Northwestern University, Feinberg
School of Medicine, Chicago, IL, USA
S. A. Kaplan
Department of Urology, Weill Cornell Medical College, Cornell
University, New York, USA
M. Oelke
Department of Urology, Hannover Medical School, Hannover,
Germany
426
been attributed to the physical presence of BOO. Longstanding BOO and bladder over-distension have been
proposed as causal in the fibrotic changes of the bladder
wall leading to changes in detrusor function (i.e. detrusor
instability). Detrusor instability is thought to be a contributor to the storage symptoms seen in LUTS. The interindividual differences in the static and dynamic components of prostatic enlargement were assumed to be critical
in determining which men are affected by LUTS and the
degree of their symptom bother.
LUTS include storage and/or voiding disturbances
common in aging men. LUTS may be due to structural
or functional abnormalities in one or more parts of the
lower urinary tract, which comprises the bladder, bladder
neck, prostate, distal sphincter mechanism, and urethra.
Of note, LUTS may result from abnormalities of the
peripheral and/or central nervous systems that provide
neural control to the lower urinary tract. LUTS may also
be secondary to cardiovascular, respiratory, or renal
dysfunction or disease. Thus, this disease entity is particularly complex to evaluate, survey, and treat. In men,
enlargement of the prostate gland from hyperplasia can
cause BOO and be a major cause of LUTS or mimicked
by other issues, such as infection, malignancy, centralperipheral neurologic disease, or overactivity/hypoactivity
of detrusor muscles.
It is becoming widely accepted that the symptoms we
relate in many older males may not have an etiology in
prostate enlargement. For that reason, the term LUTS
independent of BPH has been introduced and is gaining
worldwide acceptance.
1.1 The Impact of Benign Prostatic Hyperplasia/Lower
Urinary Tract Symptoms (BPH/LUTS) on Quality
of Life
Although LUTS secondary to BPH is not often a lifethreatening condition, the impact of LUTS/BPH on quality
of life (QoL) can be significant and should not be underestimated. Patients report loss of sleep; anxiety/worry
about the condition; effects on mobility, leisure activities,
and activities of daily life; and an effect on sexual activities
as among their most important concerns (International
Prostate Symptom Score [IPSS] [7). Those surveyed
experienced decrements in both QoL and health status as
LUTS severity increased, with most men reporting problems with mobility, self-care, activities of daily living, pain
or discomfort, and anxiety or depression. For many, the
most important parameter motivating them to seek treatment of LUTS/BPH is the symptom severity and the degree
of bother associated with LUTS; these are also important
considerations when assessing BPH and deciding when
treatment is indicated [2].
M. Gacci et al.
427
428
M. Gacci et al.
Although the efficacy of all currently available treatments for LUTS/BPH are well defined, the negative impact
on sexual function has led to the evaluation and identification of new treatment options, such as the PDE5-Is,
which are safe and valuable options for treating comorbid
ED and LUTS.
Several PDE5-Is are in clinical use worldwide (Table 1)
and six of these selective PDE5-Is are currently licensed
for the oral treatment of ED; of those, only avanafil, sildenafil, tadalafil, and vardenafil are registered in the EU.
Additionally, sildenafil and tadalafil are also indicated for
the treatment of pulmonary arterial hypertension and, since
October 2012, tadalafil for the treatment of signs and
symptoms of BPH (LUTS/BPH).
429
Table 1 Doses and pharmacokinetic properties of phosphodiesterase-5 inhibitors (in alphabetical order)
Drug (brand
names)
Indication(s)
Daily dose
tmax (h)
t (h)
50200 mg on
demand
0.50.75
[5
Registered in the EU
Avanafil
ED
(StendraTM,
SpedraTM)
AUC/Cmax dose-proportional
Food intakea: tmax : (1 h), Cmax ; (39 %)
Age C65 years: AUC :, Cmax ;, no dose
adjustment necessary
Renal function ; or ;;: without influence,
no dose adjustment
Renal function ;;;: not investigated
(do not use in these pts)
Liver function ;: without influence,
no dose adjustment necessary
Liver function ;;: AUC :/Cmax ;,
no dose adjustment necessary
Liver function ;;;: not investigated
(do not use in these pts)
Sildenafil
ED, PAH
(ViagraTM [ED],
RevatioTM
[PAH])
ED: 25100 mg
on demand
[ 1 (0.52)
35
AUC/Cmax dose-proportional
Food intakea: tmax : (approx. 1 h),
Cmax ; (29 %)
PAH: 3 9 20 mg/
day orally or
3 9 10 mg/day
IV
Tadalafil
(CialisTM [ED,
LUTS/BPH],
AdcircaTM
[PAH])
ED, LUTS/BPH,
PAH
ED: 520 mg on
demand or
2.55 mg od
[ 2 (0.512)
[ 17.5
LUTS/BPH: 5 mg
od
PAH: 40 mg od
2 9 20 mg
Vardenafil
(LevitraTM)
ED
520 mg on
demand
[ 1 (0.52)
45
AUC/Cmax dose-proportional
Food intakea: tmax : (approx. 1 h), Cmax ; (20 %)
Age C65 y: AUC/Cmax :, no dose adjustment
necessary but caution with 20 mg
Renal function ; or ;;: no dose adjustment
necessary
Renal function ;;;: AUC:, Cmax; (starting dose
5 mg)
Liver function ; or ;;: AUC/Cmax: (dose 5: max.
10 mg)
Liver function ;;;: not investigated
430
M. Gacci et al.
Table 1 continued
Drug (brand
names)
Indication(s)
Daily dose
tmax (h)
t (h)
1.0 0.54
2.6 0.43c
(UK-369003)
Investigated in pts
with ED, LUTS/
BPH and OAB
Mirodenafil
EDd
50150 mg on
demand
[ 1.4 (0.82.0)
[ 2.5
EDe
100200 mg on
demand
13
[ 1011
Gisadenafil
(SK3530)
(MvixTM)
Udenafil
(DA-8164)
TM
(Zydena
AUC area under the plasma concentrationtime curve, Cmax maximum plasma concentration, ED erectile dysfunction, IV intravenously, LUTS/
BPH lower urinary tract symptoms suggestive of benign prostatic hyperplasia, OAB overactive bladder, od once daily, PAH pulmonary arterial
hypertension, pts patients, tmax time to maximum plasma concentration, t elimination half life, [ average
Renal function: ; indicates mild, ;; moderate, ;;; severe renal insufficiency
Liver function: ; indicates mild, ;; moderate, ;;; severe liver insufficiency
a
No information concerning od dosing or doses [10 mg; recommended maximum dose 10 mg/day but careful consideration of riskbenefit
necessary
431
432
was 16.7 % with alfuzosin (p = 0.11), 49.7 % with sildenafil (p = 0.01), and 58.6 % with the combination therapy
(p = 0.002). IPSS score improvement was significant in all
arms of the study but was higher in the combination therapy group: alfuzosin -15.6 %, sildenafil -16.9 %, and
combination therapy -24.1 %. Maximum flow rate (Qmax)
and postvoiding residual (PVR) significantly improved in
the alfuzosin and combination therapy arms but not in the
sildenafil monotherapy group. There were seven adverse
event-related discontinuations (11 %). The most frequent
AEs were dizziness (n = 2) in the alfuzosin group; flushing
(n = 1) and dyspepsia (n = 1) in the sildenafil group, and
dizziness (n = 1) and gastric upset (n = 2) in the combination group.
In 2010, Tuncel et al. [63] evaluated the efficacy of
combination therapy of tamsulosin plus sildenafil for the
treatment of LUTS/BPH in an 8-week, randomized threearm study in 60 men: 4 days/week sildenafil 25 mg citrate
(n = 20), daily tamsulosin 0.4 mg (n = 20), and 4 days/
week combination of both (n = 20). In terms of erectile
function, in the sildenafil and the combination treatment
groups, for the third question in the IIEF (achieving penetration), the improvement was, respectively, 83.3 and
75.0 % (p = 0.438), and for the fourth IIEF question
(sustaining penetration), 73.3 and 89.1 % (p = 0.083). At
the end of the treatment, these values in the tamsulosin
group were 25.0 and 21.6 %. Improvement in IPSS score
was more remarkable in the combination (-40.1 %) and
tamsulosin (-36.2 %) groups compared with the sildenafil
group (-28.2 %; p \ 0.001). The Qmax improvement for
the sildenafil and tamsulosin groups were 26.9 and 26.2 %
(p = 0.870). The Qmax improvement rate of the combination group was 42.0 %, which was significantly higher than
those of the other groups (p \ 0.001); PRV reduction was
78.8 % in the combination group and 62.7 % in the tamsulosin group, which was significantly higher than in the
sildenafil group (?29.3 %; p \ 0.001). Tuncel et al. [63]
concluded that treatment with the combination of tamsulosin and sildenafil was not superior to tamsulosin alone to
enhance voiding symptoms.
The efficacy of alfuzosin plus sildenafil versus alfuzosin
alone in the treatment of LUTS/BPH was investigated by
zturk et al. [64] in 2011, evaluating 100 men with a mean
O
age of 60 years randomized in two groups receiving daily
alfuzosin 10 mg versus combination therapy (alfuzosin
10 mg plus sildenafil 50 mg) for 3 months. After
3 months, IIEF improvement was ?12.7 versus ?51.4 %
for alfuzosin alone and combination therapy, respectively.
IPSS improvement was -5.1 (-26.8 %) in the alfuzosin
group versus -5.8 (-28.2 %) in the combination therapy
group. Qmax improvement was ?3.2 (?29.6 %) versus
?3.4 (?33 %), while PVR reduction was -23 versus
-26.2 % for alfuzosin and combination treatment,
M. Gacci et al.
(p [ 0.05). IIEF improvement was significant with tamsulosin plus tadalafil (p \ 0.001) but not with tamsulosin
alone (p [ 0.05) [67].
In 2009, Liguori et al. [68] considered the combination
of tadalafil 20 mg with alfuzosin 10 mg for the treatment
of LUTS/BPH and ED. They enrolled 66 men who were
randomized to alfuzosin 10 mg once daily (22 patients),
tadalafil 20 mg on alternative days (21 patients), or a
combination of both (23 patients). No significant IPSS
improvement was found for tadalafil alone (change of
-8.4 %; p = not significant), but a significant IPSS
reduction was demonstrated for alfuzosin monotherapy
(-27.2 %; p \ 0.003) and combination therapy (-41.6 %;
p \ 0.001). The authors found an increased efficacy in
improving erectile function and uroflowmetry parameters
when using the combination therapy. All treatment
modalities significantly (p B 0.044) improved IIEF scores
(change of ?37.6, ?15.0, and ?36.3 % with combination
therapy, a-blocker monotherapy, and tadalafil monotherapy, respectively) and Qmax (change of ?29.6, ?21.7,
and ?9.5 %, respectively) from baseline, but the difference
was greatest with combination therapy. Regarding safety,
15 AEs (55.5 %) occurred in the combination therapy arm
and five (18.5 %) in the alfuzosin monotherapy arm; two
AE-related discontinuations were found, and headache was
the most reported AE [68].
Porst et al. [69] evaluated 581 LUTS/BPH and ED men
with a mean age of 62 years and a mean BMI of 28.3 kg/
m2. After a 4-week washout period and a 4-week placebo
run-in period, patients were assigned to once-daily placebo
or once-daily tadalafil 2.5, 5, 10, or 20 mg for 12 weeks.
IPSS improvement was significantly greater for all tadalafil
doses versus placebo: change in score was -2.1 for placebo, -3.6 for tadalafil 2.5 mg (p = 0.043), -4.2 for
tadalafil 5 mg (p = 0.004), -4.7 for tadalafil 10 mg
(p \ 0.001), and -4.7 for tadalafil 20 mg (p \ 0.001).
Qmax did not improve significantly in any tadalafil groups
versus placebo. In men with IIEF \26 at baseline, normal
erectile function (IIEF C26) was dose-dependently
obtained for tadalafil-treated subjects. AEs occurring in
C2 % of tadalafil-treated patients were headache, dyspepsia, back pain, and myalgia. For 2.5, 5, 10, and 20 mg
tadalafil, the discontinuation due to AEs was 2.7, 5.1, 5,
and 5.2 %, respectively [69].
Roehrborn et al. [66] enrolled 1,058 LUTS/BPH patients
and randomly allocated these men to receive once-daily
treatment with placebo or tadalafil (2.5, 5, 10, or 20 mg)
for 12 weeks. They found that tadalafil induces a dosedependent increase of Qmax, although not significantly
different from placebo: change of 1.4 ml/s (?15 %) for
tadalafil 2.5 mg, 2.0 ml/s (?22 %) for tadalafil 20 mg and
1.2 ml/s (?12 %) for placebo. Regarding safety, tadalafil
2.5, 5, 10, or 20 mg once daily led to AE-related study
433
434
M. Gacci et al.
7.4 Avanafil
435
Avanafil is a recently developed drug, the chemical structure of which is different from that of previous molecules
of PDE5-Is: avanafil can bind to the catalytic site of PDE5
independently of the spatial orientation of the molecule.
This unique property may significantly increase the affinity
towards the target enzyme PDE5. Avanafil is associated
with low rates of hemodynamic side effects and a shorter
duration of interaction in combination with NO-releasing
drugs, such as glyceryl trinitrate [79].
Despite these promising pharmacodynamic and -kinetic
properties, no actual clinical trial data are available on the
efficacy of avanafil in treatment of LUTS/BPH.
7.7 Mirodenafil
Tamimi et al. [80], in 2010, evaluated the efficacy of gisadenafil (UK-369,003) in treatment of LUTS/BPH with a
multicenter, double-blind, placebo-controlled study in 418
men aged C40 years with IPSS C13 and Qmax 515 ml/s
randomly allocated for 12 weeks to gisadenafil 10, 25, 50,
100 mg modified release (MR) or gisadenafil 40 mg immediate release (IR) or tamsulosin 0.4 mg, or placebo. Mean
treatment differences for the change in IIEF for gisadenafil
100 mg MR and gisadenafil 40 mg IR versus placebo were,
respectively, ?4.70 and ?4.68. The mean improvement
from baseline in IPSS for gisadenafil 100 mg MR and 40 mg
IR were, respectively, -2.91 and -2.50 points better than
placebo, while the mean improvement in IPSS for gisadenafil
25, 50, and 100 mg MR were -0.59, -1.18, and -1.12
points better than for tamsulosin 0.4 mg. Qmax changes from
baseline for gisadenafil 100 mg MR and placebo were ?2.10
and ?0.84 ml/s, respectively. The Bayesian statistical analysis gave high posterior probabilities for true differences
between gisadenafil 100 mg MR and placebo in treating
LUTS/BPH with regard to IPSS score and Qmax [80].
In 2011, Lee et al. [83] conducted an open-label, multicenter, prospective, non-comparative study on the efficacy
and safety of combination therapy with mirodenafil
100 mg on demand and a-blocker on 121 men (mean age
58.17 6.35 years) with comorbid LUTS/BPH and ED.
On average, 2.14 mirodenafil doses were taken per week
(range 05), and 73 men completed the 8-week clinical
trial. At end point, there was no significant change in blood
pressure and heart rate. A significant average improvement
for combination therapy with mirodenafil and a-blocker of
-6.59 IPSS points (from 15.6 to 9.01; p \ 0.001) and of
-0.8 IPSS/QoL points (p = 0.001) was reported. Significant improvements in Qmax or PVR were not observed. In
addition, IIEF-5 raised from baseline (7.78 4.30) by
95.2 % to 15.22 4.00 (p \ 0.001) [83].
In 2013, Chung et al. [84] compared the safety and
efficacy of once-daily 50 mg mirodenafil versus placebo in
180 patients with ED. No abrupt changes in pulse rate or
blood pressure, and no significant changes in mean sitting
or standing heart rate, or systolic and diastolic blood
pressure were observed. At 12 weeks, mirodenafil
improved IPSS (-3.17 [-4.35 to -2.04]; p \ 0.001) and
IIEF scores (4.39 [3.645.06]; p \ 0.001), and Qmax (2.26
[1.762.77]; p \ 0.001) from baseline [84].
In the same year, Bang et al. [85] evaluated the efficacy
and safety of the simultaneous administration of mirodenafil 50 mg once daily in LUTS/BPH patients already
receiving stable a-blocker therapy for 8 weeks. The additional administration of mirodenafil 50 mg significantly
improved LUTS from baseline, with an average decrease of
-4.98 IPSS points (from 18.70 to 13.72; p \ 0.001) and an
improvement in IIEF-5 score from 10.94 to 16.16
(p \ 0.001). Also, Qmax improved at 8 weeks
(14.5116.80 ml/s; p = 0.026). The combination of mirodenafil with an a-blocker did not significantly improve
PVR [85]. No significant changes in diastolic blood
7.6 Udenafil
Zhao et al. [81] evaluated the impact and distribution of a
single dose of udenafil 200 mg or tadalafil 20 mg in
prostate tissue and plasma, administered to 30 comorbid
LUTS/BPH and ED patients 1 h before transurethral
resection of the prostate (TURP). The concentration of
udenafil in prostate tissue and plasma was
2,028.6 360.8 ng/g and 463.7 39.1 ng/ml, respectively, and the resulting prostate tissue-to-plasma (T/P)
ratio was 4.4. The tadalafil concentration in prostate tissue
and plasma was 385.7 83.8 ng/g and 305.8 41.1 ng/
ml, respectively, and the T/P ratio was 1.3. In addition,
they found significantly increased cAMP and cGMP levels
in plasma and prostate tissues 1 h after TURP [81].
436
9 Conclusions
In men with LUTS/BPH, PDE5-Is are effective and well
tolerated, either alone or in combination with a-blockers.
The combination of PDE5-Is with a-blockers induces a
small improvement in flow urinary rate and PVR, whereas
PDE5-Is alone fail to do so. The most frequently reported
AEs after PDE5-Is in men with LUTS/BPH are headache,
dyspepsia, and back pain. Long-term safety and efficacy
outcomes and the overall cost-effectiveness of this treatment are not yet evaluated, so further studies are needed.
Finally, since the prevalence of co-morbid LUTS and ED in
BPH men is significant in the elderly, the option of a single
therapy to treat both conditions can be of clinical interest.
Acknowledgments No sources of funding were used to assist in the
preparation of this article. Dr. Gacci has received support for travel to
meetings for the study, manuscript preparation, or other purposes and
payment for lectures from GSK, Eli Lilly, Menarini, Pfizer, and Bayer. Dr. McVary has received consulting fees from Allergan (consultant or advisor; honorarium), Lilly/ICOS (consultant or advisor;
honorarium), NxThera (consultant or advisor; honorarium), Watson
Pharmaceuticals (consultant or advisor; honorarium), GSK (honorarium), and payment for lectures from GSK (meeting participant or
lecturer). Dr. Oelke has worked on the advisory board for Eli-Lilly
and Company, and has received payment for lectures from Eli-Lilly
and Company, Pfizer, and Bayer. Drs. Serni, Salvi, Sebastianelli,
Vignozzi, Corona, Maggi, Kaplan, and Carini have no conflicts of
interest to declare.
M. Gacci et al.
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