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Vol. 38 (1): 33-39, January - February, 2012
Evaluation of Tadalafil effect on lower urinary tract
symptoms of benign prostatic hyperplasia in patients
treated with standard medication
Ali Hamidi Madani, Amin Afsharimoghaddam, Ali Roushani, Alireza Farzan, Ahmad Asadollahzade,
Urology Research Center, Guilan University of Medical Sciences, Iran
To evaluate safety and efficacy of tadalafil on lower urinary tract symp-
toms (LUTS) suggestive of benign prostatic hyperplasia (BPH) in patients treated Tadalafil; benign prostatic
Materials and Methods:
In this case-controlled randomized clinical trial, from no-
vember 2008 to August 2009, 132 patients with obstructive and irritative urinary
tract symptoms due to BPH, IPSS ≥ 8, no indication for surgical intervention and Int Braz J urol. 2012; 38: 33-39
that reached plateau levels of response to treatment were selected. These patients ________________
were randomly allocated in two groups (each containing 66 patients). The treatment group received standard treatment of BPH and tadalafil (10 mg nightly); the placebo
group received only standard treatment of BPH. IPSS, maximum urinary flow rate November 03, 2010(Q ) and quality of life were assessed before and after a 3-month period of study.
Before treatment, mean IPSS, Q and quality of life values in the treat-
ment and placebo groups were 13.06 ± 4.37 and 13.66 ± 4.25, 8.92 ± 2.96 mL/s Accepted after revision:
and 9.09 ± 2.91 mL/s, 2.93 ± 0.86 and 2.66 ± 0.78, respectively. After treatment, October 24, 2011
mean IPSS, Q , and quality of life values in treatment group were 7.66 ± 3.99,
9.99 ± 4.76 mL/s and 1.80 ± 0.98, respectively. These findings were compared to corresponding values of the placebo group (11.37 ± 3.64, 8.73 ± 2.22 mL/s and 2.19 ± 0.53, respectively): IPSS and quality of life were significantly different but Qmax
didn’t show a significant change.Conclusions:
Tadalafil improves quality of life and urinary symptoms in patients with LUTS suggestive of BPH, but doesn’t have any significant effect on Qmax. Therefore, this drug may be effectively used in combination with standard medical therapies for BPH.
The incidence of BPH increases with age.
It is observed in about 50% of men over 50 year
Benign Prostatic Hyperplasia (BPH) is a with prevalence increasing up to 90% in those
pathological process responsible for the majority
older than 80 year. Moreover, 25% to 50% of men
of lower urinary tract symptoms (LUTS) in elderly
with histological confirmed BPH have LUTS (3).
men (1). In addition, erectile dysfunction (ED),
The α-blockers and/or 5-α reductase in-
which has negative effect on quality of life (QoL),
hibitors are used for the treatment of BPH fre-
is another major problem of this age group (2).
quently. The phosphodiesterase inhibitors are
IBJu | TadalaFil ON lOwEr uriNary TraCT
used in the treatment of ED (4,5) and there are
tion (UTI), renal insufficiency, bilateral hydrone-
increasing data of effects of these drugs on blad-
phrosis and bladder stones all secondary to BPH,
der and urethral relaxation as well as of prostatic
spinal cord injury, prostatitis, bladder or prostate
smooth muscles that may relief the symptoms of
malignancy, bladder neck or urethral stricture,
BPH (6,7). Preliminary data have suggested that
post voided residual urine volume greater than
treatment with PDE-5 inhibitors such as silde-
120 CC, pelvic trauma or surgery, recent cardiac
nafil improves LUTS in men with ED possibly
infarction (within the last 6 months), unstable
as the result of smooth muscle relaxation of the
angina, concomitant use of nitrates or nO do-
nors, and androgens or anti-androgens, antico-
This study was conducted to evaluate the
agulants, cytochrome p-450 3A4 inhibitors. Also,
role of Tadalafil (a PDE-5 inhibitor) in combination
if any complication occurred during the study
with standard therapy for the treatment of BPH.
period that needed surgical intervention, the pa-
MATERIALs AND METHODs
tion, urine analysis, serum creatinine measure-
ment, as well as ultrasonography of kidney, blad-
blind placebo controlled clinical trial which has
der and prostate with post voided residual urine
been approved by the ethical review board of
volume measurement; uroflowmetry with mea-
Guilan Medical University. All patients signed an
surement of the maximum flow rate (Q ) and the
assessment of quality of life (QoL) (Table-1) were
performed. Then, the selected patients were ran-
tients with definitive diagnosis of BPH whose re-
domized in two groups (66 patients in each group)
sponse to medical therapy with standard medica-
by using random block method generated by Ex-
tion had reached plateau levels (the symptoms of
cell program. One group received placebo once
patients didn’t change in the last three months)
nightly and another group received Tadalafil 10
were selected. In the placebo group, 23 patients
mg nightly, in combination with previous treat-
received an α-blocker and 43 patients received
ment of BPH for 3 months. After 3 months, IPSS,
an α-blocker plus Finasteride, as well as placebo.
Q , post voided residual urine volume and qual-
In the treatment group, besides Tadalafil, 16 pa-
ity of life score were determined again.
tients received an α-blocker and 50 patients re-
Furthermore, during the study period, the
ceived an α-blocker plus Finasteride.
adverse effects including orthostatic hypotension,
Inclusion criteria were a total IPSS ≥ 8,
headache, flushing, lumbar pain and gastrointes-
Q from 5 mL/s to 15 mL/s and the plateau re-
tinal complaints were recorded. All patients were
sponse to the routine medical treatment of BPH.
evaluated 6 weeks after the beginning of the study
Exclusion criteria included patients with
and the side effects were assessed as well.
history of refractory urinary retention, persistent
Statistical analysis was performed using
gross hematuria, recurrent urinary tract infec-
SPSS version16 with paired T-Test, independent
Table 1 - Assessment of quality of life in order to quantify urinary problems.
IBJu | TadalaFil ON lOwEr uriNary TraCT
T-Test, Wilcoxon signed ranks test, and Mann-
creased and the difference was statistically signifi-
Whitney test. P < 0.05 was considered significant.
At the end of study, in relation to the be-
review committee of Guilan University of Medi-
ginning of the study, the mean IPSS was 7.66 ±
cal Science and the trial registered at IRCT.IR 3.99 and 11.37 ± 3.64 in the treatment and pla-
cebo groups, respectively. The mean Q was 9.99
± 4.76 mL/s and 8.73 ± 2.22 mL/s in the treatment
and placebo groups, respectively. The mean qual-
ity of life score was 1.8 ± 0.98, and 2.19 ± 0.53
Based on inclusion and exclusion criteria,
in the treatment and placebo group, respectively.
132 patients were selected randomly in two groups
The mean post voided residual volume was 22.13
(66 patients in each group). Mean ages of patients
± 21.65 mL and 26.91 ± 23.17 mL in the treatment
were 64.4 ± 10.33 years in the treatment group and placebo group, respectively (Table-4).
and 64.87 ± 9.20 years in the placebo group. Mean
The side effects of Tadalafil included or-
prostate volume was 40.29 CC ± 11.18 CC in the
thostatic hypotension, headache or flushing, lum-
treatment group and 42.22 CC ± 12.38 CC in the
bar pain and the side effects of placebo included
placebo group. There was no significant difference
gastrointestinal complaints. 9.1% of patients from
in the IPSS, post voided residual urine volume, Q
the treatment group and 6.1% of patients from the
and quality of life score (baseline characteristics)
placebo group dropped out of study due to drug
before treatment between the two groups.
After treatment, in relation to the begin-
ning of the study, the placebo group showed re-
duction of mean IPSS statistically significant. The
mean post voided residual urine volume increased
but was not statistically significant. The mean QoL
compass all urinary symptoms such as storage,
score decreased and was statistically significant. voiding and postmicturation symptoms. LUTS in
The mean Q decreased but it was not statistically
men may be related to bladder outlet obstruction
(BOO) which is often associated with benign pros-
Table 2 - Mean values of variables before and after treatment of the placebo group.
tatic hyperplasia (BPH) in about 50% of men over
ginning of the study, in the treatment group the
50 year with increasing prevalence up to 90% in
mean IPSS and QoL score decreased, a difference
those older than 80 year. Moreover, 25 to 50% of
that was statistically significant. The mean Q
men with histologically confirmed BPH have LUTS
increased but it was not statistically significant.
(3). Likewise, male LUTS may result from bladder
The mean post voided residual urine volume de-
dysfunction or overactive bladder (OAB) (9). Epi-
IBJu | TadalaFil ON lOwEr uriNary TraCT
Table 3 - Mean values of variables before and after treatment of the drug group.
Table 4 - Mean values after treatment of the two groups.
demiological evidence provides a clear and clini-
bladder and highlighted the need to investigate
cally meaningful association between LUTS and other possible underlying mechanisms. Increase
various types of sexual dysfunction in aging men
smooth muscle tone in the prostate with BPH is
worldwide. The result of a longitudinal population
related to the stimulation of α1-adrenergic recep-
based study of 428 Brazilian men without ED at
baseline indicates that the adjusted relative risk of
Other receptors which have been identified
developing ED is 3.67 for those with self-reported
in human prostate tissue may play a role in LUTS
BPH after a mean follow up of 2 years (10).
associated with BPH, including dopaminergic, mus-
carinic, serotoninergic and histaminergic receptors
function, particularly ED and EjD, has suggested
(13). nitric oxide (nO) which is present in the hu-
some common components that may be involved.
man prostate (14) and modulates prostatic smooth
The prostate gland contains both epithelial and muscle tone (15) may also play a role in the patho-
stromal components; excessive growth of either physiology of LUTS associated with BPH. Although
or both components, increase smooth muscle tone
the precise mechanism of action by which PDE-5
in the prostate capsule and the bladder neck can
inhibitors may alleviate LUTS is not completely
also contribute to the LUTS associated with BPH.
understood, several putative mechanisms are cur-
Although the pathophysiology of LUTS associated
with BPH was historically attributed to prostate
gland enlargement and bladder outlet obstruction,
tion of intracellular prostatic and bladder smooth
the weak correlation between LUTS and prostate
muscle cyclic guanosine monophosphate follow-
size (10,11) has resulted in a greater focus on the
ing PDE-5 inhibition which may decrease tension
role of increase muscle tone in the prostate and of the smooth muscle of the prostatic stroma and
IBJu | TadalaFil ON lOwEr uriNary TraCT
capsule. This muscle relaxation results in bladder placebo twice daily. After 8 weeks of treatment,
neck opening and improved voiding function (16).
there was a significant improvement in the IPSS
Another possible mechanism involves pel-
total score in the Vardenafil group compared to
vic arterial insufficiency and ischemia, which may
placebo (-5.9 and -3.6, respectively; p = 0.0013).
compromises normal bladder detrusor function nominally significant improvements in irritative
that causes a change in prostatic structure (17,18).
and obstructive IPSS subscores (p = 0.0017 and p
Increased vascular perfusion of the lower urinary = 0.0081, respectively), EF (Erectile function) (p =
tract especially the prostate or bladder neck can re-
0.0001), and Urolife QoL-9 (p < 0.0001) were also
sult in a beneficial therapeutic effect and decrease
associated with Vardenafil treatment. Q and PVR
urine volume did not change significantly with
Additional theories about PDE-5 inhibition
treatment, although baseline values were already
of the lower urinary tract suggest that LUTS de-
considered close to normal. Vardenafil was general-
crease via modification of afferent nerve signaling
ly well tolerated, with most adverse events consid-
ered mild or moderate in severity. They concluded
In the study (21) by McVary et al., follow-
that Vardenafil treatment significantly improved
ing a 4-week period, single-blind, placebo run-in LUTS, EF, and QoL in men with BPH/LUTS and Var-
281 men were randomly assigned (1:1) to 5 mg denafil may be considered a promising treatment
Tadalafil for 6 weeks, followed by dose titration to
option for men with symptoms secondary to BPH.
20 mg for 6 weeks, or 12 weeks of placebo. In their
In the study by Broderick et al. (24), men
study, Tadalafil significantly improved the IPSS at
with moderate-to-severe BPH-LUTS who received
6 weeks and 12 weeks of the Tadalafil group. no placebo for 4 weeks, were randomized to placebo
change in post voided residual volume was report-
or Tadalafil 2.5, 5, 10, or 20 mg once daily for 12
ed. They concluded that Tadalafil once daily was weeks. At the end of treatment, changes in IPSS in
well tolerated and demonstrated clinically mean-
men with ED and without ED were evaluated and
ingful and statistically significant symptomatic im-
were not significantly different. Changes in IPSS,
provement of lower urinary tract symptoms/benign
quality of life and BPH Impact Index were similar
prostatic hyperplasia. Tadalafil also improved erec-
in 2 groups. Tadalafil was generally well tolerated
tile function in men with lower urinary tract symp-
in men with or without ED. They concluded that
toms and erectile dysfunction. Of the doses stud-
changes in BPH-LUTS in placebo and Tadalafil
ied, 5 mg Tadalafil appeared to provide a positive groups were similar in men with or without co-
risk-benefit profile. Treatment adverse side effects morbid ED.
included dyspepsia, back pain, headache, naso-
In another study by Kim et al. (25), men
pharyngitis and upper respiratory tract infection. In
with an International Index of Erectile Function-5
the current study, 6 patients experienced adverse (IIEF-5) score of less than 11 and with an IPSS of
side effects such as orthostatic hypotension, head-
more than 8 were included for treatment with 20
ache or lumbar pain in the treatment group and 2
mg Tadalafil (once every 3 days) for 12 weeks.
patients experienced the gastrointestinal upsets in Changes in IPSS and IIEF-5 scores were significant
different between baseline and end of treatment.
In another study (22), during a 12 week Furthermore, the differences of these scores were
study period, 369 men with ED and LUTS (IPSS >
significant between baseline and week 20 after
12, mean age of 50 years) received Sildenafil 50 mg
treatment. However, except for IIEF-5 scores, there
daily or placebo. Results showed that Sildenafil sig-
were no significant differences between week 12
nificantly improved IPSS and quality of life scores.
and week 20. They concluded that treatment with
Interestingly, there was no change in maximum tadalafil were effective on LUTS and ED in patients
with moderate-to-severe ED and LUTS.
In the study by Stief et al. (23), men aged
Mirone et al. (26) reported the first com-
45-64 years with BPH/LUTS and an IPSS > 12 were
parative trial of alternative dosing, investigating
randomized to receive either 10 mg Vardenafil or treatment efficacy and patient preference for 20
IBJu | TadalaFil ON lOwEr uriNary TraCT
mg Tadalafil taken on-demand versus 3 times per
age group, this drug may be used in combination
week, over a 6-weeks study period for the treat-
with standard medical therapies of BPH. However,
ment of ED. This study demonstrated that 42.2% further studies with larger samples are needed to
of men preferred scheduled dosing versus 57.8% document these findings.
for on-demand; both treatment regimens were well
CONFLICT OF INTEREsT
that constant doses may be advantageous versus
on-demand regimens, offering a valuable treatment
McMahon (27) reported upon the efficacy,
safety, and tolerability of on-demand 20 mg versus
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ment of 8.3 and 11.9 points in the IIEF, respectively
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RENEWAL MINISTRIES REPORT ON HAITI 2009 Renewal Ministries was invited by Haiti Missions to add a “spiritual dimension” to their humanitarian work in Haiti—a kind of melting together of proclamation and demonstration of the Gospel. We flew from Texas to Miami and met the team who were mainly from Louisiana. We were here with a pharmacist, Deacon Lloyd Duplantis and his wife Faie who are