Faculty Bibliography

BACKGROUND: Men with benign prostatic hyperplasia can be treated with alpha 1-adrenergic-antagonist drugs that relax prostatic smooth muscle or with drugs that inhibit 5 alpha-reductase and therefore reduce tissue androgen concentrations. However, the effects of the two types of drugs have not been compared. METHODS: We compared the safety and efficacy of placebo, terazosin (10 mg daily), finasteride (5 mg daily), and the combination of both drugs in 1229 men with benign prostatic hyperplasia. American Urological Association symptom scores and peak urinary-flow rates were determined at base line and periodically for one year. RESULTS: The mean changes from base line in the symptom scores in the placebo, finasteride, terazosin, and combination-therapy groups at one year were decreases of 2.6, 3.2, 6.1, and 6.2 points, respectively (P<0.001 for the comparisons of both terazosin and combination therapy with finasteride and with placebo). The mean changes at one year in the peak urinary-flow rates were increases of 1.4, 1.6, 2.7, and 3.2 ml per second, respectively (P<0.001 for the comparisons of both terazosin and combination therapy with finasteride and with placebo). Finasteride had no more effect on either measure than placebo. In the placebo group, 1.6 percent of the men discontinued the study because of adverse effects, as did 4.8 to 7.8 percent of the men in the other three groups. CONCLUSIONS: In men with benign prostatic hyperplasia, terazosin was effective therapy, whereas finasteride was not, and the combination of terazosin and finasteride was no more effective than terazosin alone

The alpha-adrenoceptor antagonist properties of doxazosin and its enantiomers were characterized using human prostate tissue and cell membranes isolated from rat-1 fibroblast expressing each of the cloned human alpha 1-adrenoceptor subtypes. In the alpha 1-adrenoceptor-binding studies on the human prostate with [3H]doxazosin and 2-[beta-(3-[125I],4-hydroxyphenyl)ethyl]aminomethyl-l-tetralone ([125I]HEAT), no significant differences were observed between racemic doxazosin, R-doxazosin and S-doxazosin (mean -log Ki (pKi) values were 8.60-8.63, 8.47-8.55 and 8.61-8.65, respectively), whereas the alpha 2-adrenoceptor-binding studies with [3H]rauwolscine and [3H]clonidine revealed that the alpha 2-adrenoceptor-binding affinity of S-doxazosin (pKi = 5.91-5.94) was slightly (3- or 4-fold), but significantly lower than that of R-doxazosin (pKi = 6.47-6.54). Studies in phenylephrine-contracted prostatic tissue showed no significant difference in alpha 1-adrenoceptor antagonist potency between racemic doxazosin, R-doxazosin and S-doxazosin (pA2 values were 8.43 +/- 0.28, 8.64 +/- 0.56 and 8.75 +/- 0.38, respectively). In the binding studies with cloned alpha 1-adrenoceptor subtypes using [3H]prazosin and [125I]HEAT, racemic doxazosin, R-doxazosin and S-doxazosin showed no selectivity for the alpha 1-adrenoceptor subtypes. The present study demonstrated that doxazosin and its enantiomers are highly selective alpha 1-adrenoceptor antagonists and that there is no evidence suggesting differential alpha 1-adrenoceptor antagonist effects of doxazosin and its enantiomers in the human prostate. Doxazosin, therefore, could be described as displaying balanced activity across all three alpha 1-adrenoceptor subtypes

OBJECTIVES. To compare the cellular composition of benign prostatic hyperplasia (BPH) in Chinese and Caucasian-American men. METHODS. Surgical specimens of the prostate were obtained from 9 Chinese and 8 Caucasian-American men undergoing cystoprostatectomy for invasive transitional cell carcinoma. The mean ages of the Chinese and Caucasian-American men were 66.8 years and 66.4 years, respectively (P = 0.94). The mean prostate weight of the Chinese and Caucasian-American men was 53.4 g and 32.1 g, respectively (P = 0.01). Double immunoenzymatic staining with antibodies against actin and prostatic acid phosphatase and computer-assisted color image analysis were performed on whole-mount tissue sections. The percent area density of smooth muscle (SM), connective tissue (CT), epithelium (E), and epithelial lumen (L) were obtained by analyzing 30 fields from each specimen. RESULTS. The mean percent area density of SM, CT, E, and L in the prostate of Chinese men was 32%, 9.1%, 10.8%, and 48.5%, respectively. The mean percent area density of SM, CT, E, and L in the prostate of Caucasian-American men was 52.5%, 27.9%, 12.8%, and 7%, respectively. Overall, the prostates of Chinese men contained significantly more glandular lumen and significantly less SM and CT. CONCLUSIONS. The present study demonstrates that the cellular composition of BPH in the prostates of Caucasian-American and Chinese men is different. These cellular differences may account for previously observed differences in the incidence of clinical BPH

alpha-Adrenoceptor antagonists increase urinary flow and improve urinary symptoms in patients with benign prostatic hyperplasia (BPH). The rationale for the use of these agents in this indication is based on evidence that the contraction of prostatic smooth muscle is mediated via alpha(1)-adrenoceptors. The alpha(1)-adrenoceptor can be subdivided into at least three distinct subtypes - 1A, 1B, and 1D. Current opinion that the alpha-1A subtype mediates contraction of the prostatic smooth muscle has led to increased speculation that alpha-blockers selective for the alpha-1A subtype may offer the advantage of prostate selectivity in the clinic. This paper outlines the rationale for alpha-blockade in the treatment of BPH, focusing on the evidence for antagonist subtype selectivity and its potential clinical relevance

PURPOSE/OBJECTIVE:We assessed the relationship between changes in scores for the American Urological Association (AUA) symptom index and benign prostatic hyperplasia (BPH) impact index with patient global ratings of improvement in a large Veterans Affairs trial comparing different pharmacological therapies for BPH. MATERIALS AND METHODS/METHODS:The primary analyses compared absolute score changes from baseline with global ratings of improvement at 13 weeks for 1,218 men. RESULTS:Subjects who rated themselves as being slightly improved had a mean decrease in AUA symptom index and BPH impact index scores of 3.1 and 0.4 points, respectively. However, the baseline scores strongly influenced this relationship. CONCLUSIONS:These data provide guidance for investigators using the AUA symptom index and BPH impact index as outcome measures.

1. To examine the presence of nitric oxide synthase (NOS) activity in female dog urethra, pharmacological experiments were performed using electrical field stimulation (EFS), guanethidine, atropine, NG-nitro-L-arginine methyl ester and L-arginine, NOS immunohistochemistry using specific anti-NOS antibody, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase staining were also performed. 2. EFS caused frequency-dependent contractions in all urethral preparations, but in the presence of guanethidine and atropine, EFS caused significant relaxation in the proximal urethra and was without effect on the distal urethra. 3. In the presence of guanethidine, atropine, and NG-nitro-L-arginine methyl ester, small contractions to EFS were re-established in the proximal urethra, but not in the distal urethra. NG-nitro-D-arginine methyl ester had no such effect. 4. In the presence of guanethidine, atropine, and NG-nitro-L-arginine methyl ester, the addition of L-arginine, restored the EFS-elicited relaxant responses previously seen with guanethidine and atropine alone in the proximal urethra (at 30 Hz; 12.89 +/- 5.27% to -2.44 +/- 4.43%, mean +/- s.e., P < 0.05). D-Arginine had no such effect. 5. In the distal urethra, the addition of NG-nitro-L-arginine methyl ester and then L-arginine had no effect on responses to EFS in preparations treated with guanethidine and atropine. 6. Sodium nitroprusside caused relaxation in both the proximal and distal urethra. The relaxant responses per cm2 cross sectional area in the proximal and distal urethra were 1.23 +/- 0.29, and 2.02 +/- 0.54 g cm-2 cross sectional area (mean +/- s.e.), respectively: there was no significant difference between them. 7. Both NOS and NADPH diaphorase-positive neurones were present in dog urethra, the densities of both being higher in the proximal urethra than in the distal urethra. 8. These results show that female dog urethra possesses NOS nerves and that endogenous NO may play a role in relaxation in the proximal but not the distal urethra.