Pharmacodynamics

Mechanism of Action

By blocking the sympathetic nervous system, which mediates the α1A-adrenoceptor subtype which is distributed in lower urinary tract tissue (prostate, urethra, and trigone of the urinary bladder), silodosin reduces smooth muscle tone of lower urinary tract tissue and inhibits increases in urethral pressure, thereby improving lower urinary tract symptoms associated with benign prostatic hyperplasia.

Effects in human tissue

  1. Affinity to α-adrenergic receptors in the sympathetic nervous system

In a receptor-binding assay on human a α1-adrenergic receptors, silodosin showed a high affinity to the a α1A-adrenergic receptor subtype.

2. Effect on prostate gland

In a receptor-binding assay using human prostate membrane specimens, silodosin showed a high affinity to the α1-adrenergic receptor subtype. Silodosin inhibited noradrenalin-induced contractions of human prostate smooth muscle.

 

Effects in animals

1) Effect on lower urinary tract tissue (prostate, urethra, and trigone of the urinary bladder)

Silodosin exhibited a potent antagonistic action against noradrenalin induced contractions in isolated rabbit prostate, urethra, and trigone of the urinary bladder.

2) Effect on urethral pressure

In anesthetized male rats, phenylephrine-induced increases in urethral pressure in the region of the prostate were selectively inhibited by silodosin. The inhibitory dose was lower than hypotensive dose.

In anesthetized male dogs, increased urethral pressure in the region of the prostate due to electrical stimulation of the hypogastric nerve was also selectively inhibited by silodosin. The inhibitory dose was lower than the hypotensive dose.

3) Effect in prostatic hypertrophy model

In a male rat prostatic hypertrophy model prepared by administration of sex hormone, bladder irritation symptoms associated with urinary retention were inhibited.


 

Clinical Studies

  1. Phase II Double-Blind Comparative Study

When silodosin at a dose of 2 or 4 mg, or placebo was administered orally twice daily for 4 weeks to patients with lower urinary tract symptoms associated with benign prostatic hyperplasia, subjective symptoms (total I-PSS) were significantly improved in the 4-mg group compared to the placebo group (Table 6).

Group Score at baseline Change in week 4 compared to baseline Compared to placebo
Dunnett’s multiple comparison test
Placebo 18.1 ± 5.6 (88) -3.0 ± 5.8 (88)
2mg x 2/day 18.3 ± 6.5 (84) -5.7 ± 6.1 (84) P=0.013
4 mg x 2/day 18.7 ± 6.0 (87) -6.6 ± 5.5 (86) P=0.000

Unit: Point           Mean±SD ( ): No. of subjects       a) I-PSS: International Prostate Symptom Score (Mild: 0-7, Moderate: 8-19, Severe: 20-35)

 

  1. Phase III Double-blind Comparative Study

When silodosin at a dose of 4 mg or placebo was administered orally twice daily for 12 weeks to patients with lower urinary tract symptoms associated with benign prostatic hyperplasia, the total I-PSS in the silodosin and placebo groups on completion of the study showed a decrease of 8.3 and 5.3 points, respectively, compared to baseline (Fig. 3, Table 7). The percentage (%) of patients in the silodosin and placebo groups whose total I-PSS improved by at least 25%  compared to baseline was 76.4% (133/174 patients) and 50.6% (45/89 patients), respectively. The percentage (%) of patients in the silodosin and placebo groups whose symptoms improved to mild (total I-PSS:< 8) was 47.7% (83/174 patients) and 31.5% (28/89 patients), respectively.

In the silodosin group, an improvement in subjective symptoms was seen from as early as wk 1 and an improvement effect was also observed in patients whose symptoms were severe.

Figure 3 Time course of change in total I-PSS

 

Group n Score at baselinea) Score on completion of treatmenta) Change compared to baselinea) Group difference in change 2-sided 95% Confidence interval
Silodosin 174 17.1 ± 5.7 8.8 ± 5.9 -8.3 ± 6.4 -3.0 -4.6, -1.3
Placebo 89 17.1 ± 6.1 11.8 ± 7.1 -5.3 ± 6.7

(a) Mean±SD

 

  1. Long-term Administration Study

In a long-term administration study, silodosin was administered at a dose of 4 mg twice daily for 52 weeks to 364 patients with lower urinary tract symptoms associated with benign prostatic hypertrophy. A continuous improvement effect and drug safety were reported and stable subjective symptoms (total I-PSS) and improvement in maximum urine flow rate were observed.