Findings from basic research studies
Clinical data on the safety and efficacy of the orally active PDE5 inhibitors sildenafil (ViagraTM), vardenafil (LevitraTM) and tadalafil (CialisTM) for the treatment of male erectile dysfunction (ED) have boosted research activities on intracellular signal transduction pathways controlling the function of the lower urinary tract, including the prostate, urinary bladder (detrusor) and urethra [6, 7].
The expression of the cAMP and cGMP phosphodiesterase isoenzymes PDE1, PDE2, PDE4, PDE5, PDE7, PDE8, PDE9 and PDE10 in the human prostate was shown by means of molecular biology methods (reverse transcriptase polymerase chain reaction). The activities of PDE4 and PDE5 were isolated using anion exchange chromatography from cytosolic supernatants prepared from tissue specimens taken from the transition zone of the prostate. PDE4 was also detected in the microsomal fraction of prostate tissue . Later, immunohistochemistry revealed the distribution of PDE4 and PDE5 in stromal and glandular areas of the transition zone .
In organ bath studies, the tension of prostate strip preparations mediated via the activation of α1-adrenergic receptors was dose-dependently reversed by the PDE4 inhibitors rolipram, Ro 20-1724 and RP 73401, as well as the PDE5 inhibitors sildenafil, tadalafil and vardenafil. The reversion of tension was accompanied by an enhancement in tissue cAMP or cGMP [8–10]. Interestingly, the contraction of isolated prostate tissue brought about by the vasoconstrictor peptide endothelin 1 (ET-1) was also counteracted by rolipram, tadalafil, sildenafil and vardenafil, with rolipram and tadalafil being most effective . In experiments using a model of cultured human prostate smooth muscle cells, the number of cells showing constriction in response to ET-1 was significantly reduced by the non-specific PDE inhibitor theophylline, PDE5 inhibitor sildenafil and the adenylyl cyclase activator forskolin . These results provided evidence for a significance of both the cGMP and cAMP signalling in controlling the function of prostate smooth muscle and are considered important for the identification of new drug options to treat BPH/LUTS. Another hypothesis postulates that the abnormal growth pattern of smooth muscle, connective and glandular tissue in prostatic stromal and glandular compartments, respectively, seen in conjunction with BPH might be induced by hypoxia resulting from an age-related impairment in local blood flow. Consequently, a key role of urogenital ageing and subsequent alterations in the blood supply to the prostate has been suggested in the development of BPH. This issue is addressed in more detail at the end of the following section.
PDE5 inhibitors in the treatment of BPH/LUTS
The basic research efforts outlined above have provided the basis for the development and introduction of new therapeutic modalities into the management of lower urinary tract dysfunction (LUTD), some of which might soon be offered to patients. BPH represents a major health care problem in westernized countries. Symptoms and signs of BPH comprise storage and voiding dysfunction, as well as benign prostatic enlargement (BPE) with variable degrees of benign prostatic obstruction (BPO) . Major symptoms include urinary frequency, nocturia and slow stream. It is estimated that approximately 50% of men older than 50 years have moderate to severe LUTS, as measured by means of the International Prostate Symptom Score (IPSS, 8–19 = moderate symptoms, 20–35 = severe symptoms) . The current pharmacological management of LUTS and BPE involves α1-adrenoceptor antagonists, such as alfuzosin, doxazosin, silodosin, tamsulosin and terazosin, or intervention into the hormonal control of prostate growth by using the enzyme 5α-reductase inhibitors (5-ARI) finasteride or dutasteride [15–17].
The role of PDE5 inhibitors sildenafil, vardenafil and tadalafil in the treatment of BPH/LUTS was initially addressed by preliminary open-label studies [18, 19]. Later, larger randomized, double-blind trials, of which some were placebo-controlled, were conducted enrolling patients presenting with LUTS with or without erectile dysfunction (ED) (Table 2). Main study endpoints were changes in the IPSS, BPH Impact Index (BPH II), Quality of Life Questionnaire (QoL), LUTS Global Assessment Questionnaire (GAQ) and parameters from uroflowmetry measurements, such as peak urinary flow (Qmax), average urinary flow (Qave) and postvoid residual urine (PVR). The duration of the trials was 8–12 weeks. Administration of the PDE5 inhibitors significantly reduced IPSS and led to an improvement in the BPH II and QoL. In some protocols, patients presenting with severe LUTS experienced greater improvement in IPSS than those with moderate symptoms. A significant reduction of bladder storage and voiding symptoms during treatment was also noted while PVR and Qmax did not change significantly. From this finding, it was concluded that extraprostatic pathophysiological mechanisms related to an impairment in the activity of the nitric oxide (NO) system might also be involved in the onset of LUTS. Although some studies showed an increase in Qmax with an increased dose of a PDE5 inhibitor, this observation was not significantly different from the placebo group [20–24]. This might be due to the fact that baseline values measured were already close to normal at the time patients were enrolled into the studies .
Randomized, placebo-controlled clinical trials that investigated the efficacy of the phosphodiesterase type 5 (PDE5) inhibitors sildenafil, tadalafil or vardenafil in patients with lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH)
|McVary et al. (2007)*,†||Sildenafil||3 months||369||‡||ns||ns|
|McVary et al. (2007)*||Tadalafil||3 months||281||‡||ns||ns|
|Stief et al. (2008)*||Vardenafil||2 months||222||‡||ns||ns|
|Roehrborn et al. (2008)*||Tadalafil||3 months||1058||‡||ns||ns|
|Porst et al. (2009)*†||Tadalafil||3 months||581||‡||ns||+8.6 ml‡|
|Guven et al. (2009)†||Sildenafil||> 2 h (acute study)||68||NA||‡||na|
The combination of the PDE5 inhibitors sildenafil (25 mg once daily) or tadalafil (10 mg once daily) and the α1-adrenoceptor antagonist alfuzosin (10 mg once daily) for the treatment of LUTS has also been evaluated. Men with untreated LUTS (and concomitant ED) were randomized to either alfuzosin, sildenafil or tadalafil, or the combination of the α-adrenoceptor blocker and a PDE5 inhibitor. Study endpoints were changes from baseline in IPSS, Qmax, Qave and PVR volume. Improvement in IPSS was significant in all treatment arms but most pronounced with the drug combinations. PVR, Qmax, frequency and nocturia were significantly improved with alfuzosin only and the combination regimen [25, 26]. The efficacy of tadalafil (20 mg day−1) and tamsulosin (0.4 mg day−1) (administered for 45 days) vs. tamsulosin only (0.4 mg day−1) was also assessed in a randomized, double-blind, crossover study design. Improvements in the IPSS and IPSS-QoL were greater with the drug combination. Both drug regimens improved Qmax and decreased PVR. However, no significant differences between tamsulosin only vs. tamsulosin in combination with tadalafil were noted . Similar findings emerged from a protocol evaluating the efficacy of administering the PDE5 inhibitor udenafil in patients with BPH and concomitant ED. One hundred and twenty patients who had been treated with α-adrenoceptor blockers for BPH were given udenafil (100 mg day−1) for 8 weeks. At study end point, IPSS scores had improved significantly when compared with baseline values . It was concluded that combined therapy was more effective than monotherapy with either agents to improve voiding dysfunction in men with BPH/LUTS. A very recent study conducted by Tuncel et al.  evaluated the efficacy of sildenafil citrate (25 mg, four times per week for 8 weeks), tamsulosin (0.4 mg, once daily for 8 weeks) and the combination of both regimens in 60 men presenting with BPH/LUTS. The authors found that the improvements in IPSS, Qmax and PRV were significantly more pronounced in those patients who had received the combination therapy than in those who were on sildenafil citrate only. However, treatment with the drug combination did not enhance the improvements in IPSS and voiding symptoms seen in the tamsulosin group . Additional large-scale, randomized, placebo-controlled studies are needed in order to assess further the clinical effectiveness of combining PDE5 inhibitors and α-adrenoceptor blockers to treat BPH/LUTS.
Some studies focused in particular on the urodynamic effects of PDE5 inhibitors on voiding function, including Qmax and detrusor pressure at maximum urinary flow, in men with BPO. Dose-dependent changes in Qmax or detrusor pressure at maximum urinary flow rate were registered in comparison with placebo in men with BPH/LUTS who had been given tadalafil on a once daily basis. However, these improvements were not significant [30, 31]. In contrast, it was shown that the acute administration of sildenafil can improve Qmax and Qave in men with BPH/LUTS. A single dose of the PDE5 inhibitor (50 mg or 100 mg) resulted in an improvement in Qmax in the patients. Qave and the mean voided volumes of the patients also increased while no significant differences were registered in Qmax, Qave and voided volumes of the control group before and after placebo administration [32, 33]. It should be taken into consideration that the study design, and especially the small number of patients, made it rather difficult to draw firm conclusions from these observations.
A few clinical studies have provided evidence that an impairment in the blood supply of the prostate might account for the development of BPH/LUTS. It was shown by means of transrectal contrast-enhanced colour Doppler ultrasonography that perfusion of the transition zone of the prostate was significantly lower and mean flow resistance index significantly higher in men with BPH than in healthy controls. Similar observations were made in men with diabetes mellitus and/or peripheral arterial occlusive disease but not coronary arterial disease. These findings are in support of the hypothesis that an age-related limitation in blood supply to the lower urinary tract might be an important aspect of the pathophysiology underlying BPH/LUTS. Thus, it seems likely that the regular administration of a PDE5 inhibitor may, to a certain degree, overcome ischaemia due to vascular damage and normalize local blood flow patterns [34–36].