Tadalafil exerts an additive effect on alfuzosin-induced relaxation
in pre-contracted human isolated prostatic adenoma
Stefano Palea1, Moèz Rekik1, Pascal Rischmann2, Henri Botto3 and Philippe Lluel1
(1) UROsphere, Toulouse, France; (2) CHU Rangueil, Toulouse, France; (3) Foch hospital, Suresnes, France This work was supported by sanofi-aventis INTRODUCTION
● Lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) are highly prevalent in aging men with benign prostatic hyperplasia (BPH) and are strongly linked, independently of age and cardiovascular Figure 1A: relaxant effect of tadalafil and DMSO
Figure 2A: relaxant effect of tadalafil and the combination
in human isolated prostatic adenoma
of alfuzosin and tadalafil in human isolated prostatic adenoma
● Alpha1-blockers (alfuzosin, doxazosin, tamsulosin, terazosin) are considered the most effective monotherapy for LUTS associated with BPH3. They act by relaxing smooth muscle tone in the prostate which is predominantly ● Phosphodiesterase (PDE) 5 inhibitors (sildenafil, tadalafil, vardenafil) are the standard treatment for ED4.
Placebo-controlled trials have shown that they improve LUTS associated with BPH5-7 and this effect is biologically plausible. Nitric oxyde (NO) levels are reduced in transition zone of human adenoma compared to normal prostate2. NO has a direct relaxant effect on human isolated prostate8. A fall in NO levels could thus contribute to increase prostatic smooth muscle tone in BPH patients. Moreover, PDE5 isoenzymes have been identified in transitional zone of human prostate, along with PDE4 and PDE112. ● Together, these findings suggest that the co-administration of an ␣1-blocker and a PDE-5 inhibitor in men with LUTS associated with BPH may be of benefit by combining the effect of each drug alone. Indeed, the combination of alfuzosin and tadalafil shows an additive relaxant effect on human non adenomatous prostate tissue9 and corpus cavernosum in vitro10. A recent pilot study also suggested that daily intake of alfuzosin 10 mg and sildenafil 25 mg for 12 weeks was safe and more effective than monotherapy to improve LUTS and sexual Figure 1B: relaxant effect of alfuzosin and DMSO
Figure 2B: relaxant effect of alfuzosin and the combination
in human isolated prostatic adenoma
of alfuzosin and tadalafil in human isolated prostatic adenoma
This study was aimed at determining whether the combination of alfuzosin and tadalafil is more effective
than each drug alone in relaxing prostatic muscle strips obtained from the transitional zone of men
requiring surgery for BPH.
● Human prostate specimens (transitional zone) were obtained from 11 men (mean age 68.8±3.2 years) undergoing transvesical prostatectomy or transurethral resection of the prostate for BPH in 2 French Urology departments.
Institutional approvals for use and shipment of human tissues were obtained, and all patients gave written informed consent. Tissues were placed in a cold storage solution and transported to the laboratory, immediately after surgery, in a container at 4°C. Upon receipt, tissues were stored at 4°C until the start of the experiment.
● Strips were connected to tension transducers in organ baths containing Krebs solution. Prostatic strips were allowed to equilibrate for 1 hour at a preload tension of 1.5 g, during which tissues were washed with KrebsHenseleit solution every 15 min. At the end of the equilibration time, strips were exposed to 30 µM norepinephrine(NE) to measure their viability. Strips with contractile response below 0.3 g were discarded.
● A-61603 (0.1 µM) induced a stable and sustained contraction of prostatic strips. Mean plateau of ● Alfuzosin+tadalafil (n=14) induced a concentration-dependent relaxation of the plateau of contraction contractions value for strips exposed to alfuzosin+tadalafil (1.00±0.15 g, n=14) did not significantly differ which was significantly greater than alfuzosin alone (p<0.05 to <0.01) and tadalafil alone (p<0.01 to ● After washout and 1-hour re-equilibration, solvent (dimethylsulfoxide, DMSO) or cumulative concentrations from those exposed to tadalafil alone (1.11±0.24 g, n=14), alfuzosin alone (1.45±0.28 g, n=13), DMSO p<0.001) for concentrations between 0.1 and 10 µM (Figure 2A and 2B). The pIC (0.01 to 10 µM) of alfuzosin, tadalafil or alfuzosin+tadalafil were tested on the plateau of contractions induced at 250 µl (1.16±0.22 g, n=14) and DMSO at 500 µl (0.97±0.21 g, n=10). Maximal relaxant effects alone was 5.92±0.23 compared to 6.47±0.24 for the combination of alfuzosin+tadalafil (p< 0.0001).
␣1-adrenoceptor agonist. For a given patient, alfuzosin, tadalafil or alfuzosin + induced by DMSO 250 µl (48.1±8.9 %, n=14) and DMSO 500 µl (66.5±17.1 %, n=10) were not tadalafil were tested in separate strips. Each concentration was added after having obtained a clear plateau of significantly different, allowing to pool both groups. relaxation. DMSO concentration in organ bath ranged from 0.001% to 1% when testing alfuzosin or tadalafil Comparison with therapeutic concentrations used in humans
alone (250 µl solvent for each compound) and from 0.002% to 2% when testing alfuzosin+tadalafil (250 µl for ● Tadalafil alone (n=14) induced a mild relaxation of the plateau of contraction which was not significantly ● Concentrations used in this experimental model are in agreement with therapeutic concentrations used in humans. In patients, alfuzosin at 10 mg once daily (recommended dose for treating LUTS), produces ● Relaxant effects were expressed as the percentage inhibition of the plateau of contractions to A-61603, measured a maximal plasma concentration (Cmax) corresponding to a concentration of 0.094 µM in the prostatic just before testing the relaxant compounds. ● Alfuzosin alone (n=13) totally abolished, in a concentration-dependent manner, the plateau of contraction tissue12. This is closed to the concentration (0.1 µM) showing a significant interaction with tadalafil in induced by A-61603 (Figure 1B). The difference versus DMSO was significant (p<0.01 to <0.0001) for ● Between group comparisons were done on measures obtained in the same patient. Comparisons were performed our experiment. On the other hand, tadalafil at 20 mg once daily (highest recommended dose for treating alfuzosin concentrations between 0.3 and 10 µM.
by a Winer analysis followed by Student-Newman-Keuls test.
ED) produces a Cmax corresponding to a concentration of 1 µM13. This is in the range of concentrationstested in our model where potentiation of alfuzosin (0.1 µM) by tadalafil occurred for concentrations aslow as 0.1 µM. CONCLUSIONS
(1) Rosen R et al. Eur Urol 44: 637-49, 2003; (2) McVary KT et al. BJU Int 97 (suppl 2): 23-28, 2006; (3) AUA Practice Guidelines CommitteeIn human isolated prostatic adenoma, the combination of alfuzosin and tadalafil shows a greater relaxant effect than alfuzosin alone.
J Urol 170: 530-547, 2003; (4) Lue TF et al. J. Sex. Med. 1: 6-23, 2004; (5) McVary KT et al. J Urol 177: 1401-1407, 2007; (6) McVaryKT et al. J Urol 177: 1071-1077, 2007; (7) Stief C et al. J Urol 177 [4 suppl]., pp517 (abstract 1565), 2007; (8) Takeda M et al. UrologyThe clinical relevance of this finding for treating LUTS associated with BPH needs to be confirmed in placebo-controlled clinical studies.
45: 440-6, 1995; (9) Oger S et al. EAU 2008 (abstract 98); (10) Oger S et al. SIU 2007 (abstract MP-12.08); (11) Kaplan S et al. Eur. Urol.
51: 1717-23, 2007. (12) McKeage K et al. Drugs 62: 1-21, 2002; (13) Forgue ST et al. Br J Clin Pharmacol. 61: 280-88, 2006.

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