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 ABsTRACT
_______________________________________________________________ _____________________
Objectives: To evaluate safety and efficacy of tadalafil on lower urinary tract symp- Key words:
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.
Results: 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- DIsCussION
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
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