Uroselectivity in male dogs of silodosin (KMD-3213), a novel drug for the obstructive component of benign prostatic hyperplasia

Aims: Our main aim was to compare the prostatic selectivity of silodosin with that of other alpha(1)-adrenoceptor (AR) antagonists. Methods: We examined uroselectivities in two sets of experiments namely, in vitro and in vivo functional studies using male dogs. In the in vitro study, after evaluating the inhibitory effects of silodosin on noradrenaline (NA)-induced contractions in the isolated prostate and isolated carotid artery using the Magnus method, we calculated prostatic selectivity. In the in vivo study, we examined the effects of drugs on the hypogastric nerve stimulation (HNS)-induced increase in intraurethral pressure (IUP) and on blood pressure. The uroselectivity of silodosin was compared with those of tamsulosin and naftopidil. Results: In vitro, all drugs antagonized NA-induced contraction in both prostate and carotid artery. The prostatic selectivity of siloclosin (79.4) was much higher than those of tamsulosin (1.78), naftopidil (0.55), BMY 7378 (0.115), and prazosin (0.01). In vivo, intravenously (i.v.) administered silodosin dose-dependently inhibited the HNS-induced increase in IUP with much less hypotensive effect than either tamsulosin or naftopidil, the uroselectivity (ED15/ID50) of silodosin (237) being significantly higher than those of tamsulosin (1.21) and naftopidil (2.65). Conclusions: Our results clearly demonstrate that siloclosin is a potent and highly selective alpha(1A)-AR antagonist. A selective alpha(1A)-AR antagonist such as silodosin may have good potential as a less-hypotensive drug for the treatment of urinary dysfunction in benign prostatic hyperplasia patients. (c) 2006 Wiley-Liss, Inc.