Effect of KMD‐3213, an α_1A‐adrenoceptor antagonist, on the prostatic urethral pressure and blood pressure in male decerebrate dogs

Abstract

Background: KMD-3213 is an a 1A -adrenoceptor-selective antagonist currently being developed for the treatment of urinary outlet obstruction in patients with benign prostatic hyperplasia. In the present study, the uroselectivity of KMD-3213 was evaluated and compared with that of prazosin and tamsulosin in a decerebrate dog model. Methods: Intercollicular decerebration was carried out in male mongrel dogs under anesthesia. The inhibitory effects of intravenously and intraduodenally administered compounds on the increase in intraurethral pressure (IUP) induced by electrical stimulation of the hypogastric nerve were estimated. Systemic blood pressure was measured simultaneously. Results:The a 1 -antagonists tested produced a dose-dependent inhibition of the induced IUP response and decreased mean blood pressure (MBP). The ID 50 of KMD-3213, tamsulosin and prazosin for IUP (dose required to inhibit the increase in IUP by 50%) was 3.15, 1.73 and 11.8 mg/kg i.v., respectively, and the ED 20 for the hypotensive effect (dose required to reduce MBP by 20%) was 8.03, 0.59 and 2.46 mg/kg i.v., respectively. The data indicate that uroselectivity (ED 20 /ID 50 ) of KMD-3213 is 12-and 7.5-fold higher than that of prazosin and tamsulosin, respectively. When the drugs were administered intraduodenally, KMD-3213 was sufficiently absorbed from the digestive tract and continued to demonstrate at least 3.8-fold higher uroselectivity than tamsulosin. Conclusion: Based on these findings, KMD-3213 appears to be an effective orally active compound for decreasing urethral resistance during micturition that does not induce any negative cardiovascular effects in patients with benign prostatic hyperplasia.

Effects of KMD-3213, a Uroselective α1A-Adrenoceptor Antagonist, on the Tilt-Induced Blood Pressure Response in Normotensive Rats

“…Moreover, KMD-3213 had the highest uroselectivity index (Table 3). These results agree very well with the several data that we reported (14,26). On the other hand, significant reductions in the basal MBP were observed at 1 and 3 mg/kg, i.v.…”

Influence of hypertension on lower urinary tract symptoms in benign prostatic hyperplasia

“…Alpha-1 adrenergic receptor antagonists (alpha-1 antagonists) decrease the prostatic urethral closing pressure. [2][3][4][5][6] These antagonists have been used for the treatment of BPH, and can not only improve voiding disorders but also assist in the treatment of collecting disorders. 2,5,7 Among non-selective alpha-1 antagonists used for the treatment of BPH, terazosin hydrochloride (terazosin), prazosin hydrochloride, and urapidil have also been employed for the treatment of hypertension.…”

1098 Efficacy and safety of silodosin and dutasteride combination therapy in acute urinary retention due to benign prostatic hyperplasia: A single-arm prospective study

“…One reason for this may be that silodosin's -1A : -1B binding ratio is extremely high (162 : 1), leading to its selective action in the lower urinary tract with minimal side effects on blood pressure regulation [8]. Therefore, silodosin has a good uroselectivity compared with other ABs and may have better efficacy than tamsulosin [16,17].…”