Faculty Bibliography

OBJECTIVES: To evaluate the long-term efficacy and safety of once-daily tamsulosin (0.4 and 0.8 mg), a unique selective alpha1A-adrenoceptor antagonist in patients with benign prostatic hyperplasia (BPH). METHODS: This trial extended a 13-week, Phase III multicenter placebo-controlled, double-blind outpatient trial for an additional 40 weeks. Of 618 patients, 418 (68%) continued into the extension phase on the same double-blind medication and dose. The primary efficacy parameters were total American Urological Association (AUA) symptom score and maximum urinary flow (Qmax). RESULTS: The mean changes in AUA symptom score from baseline to end point were statistically significant in all groups (P <0.001). Significant improvements were observed in Qmax for both tamsulosin groups but not for the placebo group. The statistically significant improvements from baseline in efficacy parameters observed for each tamsulosin group at the end of the 13-week Phase III trial were maintained during the long-term extension phase. Tamsulosin at both dosages was well tolerated as maintenance therapy. Clinically significant orthostatic hypotension was not observed. Vital sign changes in either hypertensive or normotensive patients were not clinically significantly different across the three groups. CONCLUSIONS: Tamsulosin once-daily at 0.4 or 0.8 mg was shown to be effective, safe, and well tolerated in the target BPH population during long-term use

OBJECTIVES: To evaluate the efficacy and safety of two once-daily doses of tamsulosin, the first selective alpha1A-antagonist studied in clinical trials. METHODS: Patients with benign prostatic hyperplasia (BPH) were randomized to receive either tamsulosin (0.4 and 0.8 mg/day) or placebo (n = 756). Primary efficacy parameters were improvement in the total American Urological Association (AUA) symptom score and peak urinary flow (Qmax). Secondary efficacy parameters were improvement in measurements at individual double-blind visits corresponding to the primary efficacy parameters; percentage of patients with a 3-mL/s increase in Qmax; total AUA irritative, obstructive, and bother scores; individual AUA symptom scores; total, irritative, obstructive, and individual Boyarsky symptom scores; average urinary flow rate and other uroflowmetric parameters; and investigator's global assessment. RESULTS: Statistically significant improvements in all efficacy parameters were observed in tamsulosin-treated compared with placebo-treated patients. Additionally, the 0.4-mg/day dose demonstrated a rapid onset of action (4 to 8 hours) based on Qmax after the first dose of double-blind medication. A review of the safety parameters demonstrated excellent tolerance at 1 week after the initial 0.4-mg/day dose and continued tolerance during the additional 12 weeks of 0.4- and 0.8-mg/day dosing. The incidence of positive orthostatic test results in the tamsulosin groups was comparable to that observed in the placebo group. Adverse events were comparable in the 0.4-mg/day tamsulosin and placebo groups and were somewhat higher in the 0.8-mg/day tamsulosin group. CONCLUSIONS: Tamsulosin was effective, safe, and well tolerated in the target BPH population at both the 0.4- and 0.8-mg/day dose levels, without the blood pressure-lowering effects typical of nonselective alpha-adrenergic antagonists

BACKGROUND: Endothelin-1 (ET-1) interacts with specific G-protein-coupled receptors to initiate short-term (contraction) and long-term (mitogenesis) events in target cells. ET-1 is an abundant prostate secretory protein that, in its biologically active form, elicits prostatic smooth muscle contraction. The present study was designed to determine the effects of ET-1 on prostate cell growth and to examine the regulation of endogenous ET-1 activity and bioavailability. METHODS: Primary cultures of prostate secretory epithelial (PE) and prostate fibromuscular stromal (PS) cells were established from benign human prostate tissue. RESULTS: In culture, PE cells secrete immunoreactive ET-1 (38.5 +/- 1.6 pg/ml/10(6) cells/24 hr) into the conditioned medium. Levels of immunoreactive ET-1 produced by PS cells were more than 10-fold lower. Endothelin-converting enzyme-1 (ECE-1) mRNA was detected in PE cells and not in PS cells; however, big ET-1 was the predominant immunoreactive ET-1 secretory product of PE cells. The ET(B) endothelin receptor was the predominant subtype in both PE and PS cells. In PS cells, but not PE cells, ET-1 induced significant inositol phosphate accumulation and [3H]-thymidine uptake. Agonist activity was inhibited by the ET(B) receptor selective antagonist, BQ 788. Intact PE cell monolayers secrete ET-1 through the apical surface, consistent with secretion of ET-1 into the glandular lumen in vivo. CONCLUSIONS: On the basis of these findings, regulation of ET-1 activity and bioavailability appears to be tightly regulated. Such findings have important implications in the pathophysiology of prostate disease

PURPOSE: We investigated the role of performing 2 consecutive sets of transrectal ultrasound guided sextant biopsies of the prostate in a single office visit as the protocol for detecting prostate cancer in men presenting for the first time with an abnormal digital rectal examination and/or elevated serum prostate specific antigen (PSA). MATERIALS AND METHODS: A total of 137 consecutive men presenting for the first time with a clinically localized prostate nodule on digital rectal examination and/or elevated serum PSA based upon age specific reference ranges underwent 2 consecutive sets of sextant prostate biopsies under transrectal ultrasound guidance in a single office visit. The 2 sets of biopsies were processed and analyzed separately by pathologists. RESULTS: Adenocarcinoma of the prostate was diagnosed in 43 of the patients (31%) undergoing biopsy. Adenocarcinoma of the prostate was diagnosed in only the second set of biopsies in 13 cases (10%). High grade prostatic intraepithelial neoplasia without adenocarcinoma of the prostate was observed in 18 of the first set of biopsies (15%). High grade intraepithelial neoplasia without adenocarcinoma of the prostate was the only pathological diagnosis in the second set of biopsies in 3 cases. The second set of biopsies provided important new clinical information related to prostate cancer in 20 cases (28%) and increased the number of cancers detected by 30%. In addition, 14 patients with high grade intraepithelial neoplasia who would have required a second set of biopsies were found not to have adenocarcinoma of the prostate. Prostate cancer was detected in 43, 27 and 24% of men with prostate volumes less than 30, 30 to 50 and greater than 50 cc, respectively. The percentage of prostate cancers detected only in the second set of biopsies was not significantly related to prostate size. CONCLUSIONS: Two consecutive sets of transrectal ultrasound guided sextant biopsies of the prostate performed in a single office visit represent a cost-effective biopsy strategy for men presenting with an abnormal digital rectal examination and/or elevated serum PSA. The benefits include increasing the detection of adenocarcinoma of the prostate and providing the recommended second set of biopsies for high grade intraepithelial neoplasia without increased morbidity or cost

BACKGROUND: Although quantitative morphometry of benign prostatic hyperplasia (BPH) has been described, there is a paucity of information on the morphometry of the nonhyperplastic prostate. This study determines the histologic composition of prostates obtained from males, ages 2 days to 40 years, in order to provide insights into the morphometry of the 'normal' gland. METHODS: The histologic composition of 45 prostates was obtained from autopsies of males with age groups stratified to reflect the neonatal, childhood, peripubertal, adolescent, and young adult periods. Double immunoenzymatic staining and computer image analysis were used to determine the mean area densities of the smooth muscle (SM), connective tissue (CT), glandular epithelium (E), and lumen (L). RESULTS: A progressive decrease in SM area density throughout childhood, prepuberty, and puberty was seen. The density of SM significantly increased following puberty and throughout adolescence and early adulthood. There was a concomitant increase in CT from the neonatal period throughout childhood, prepuberty, and puberty, and a decrease after puberty and throughout adolescence and early adulthood. Since the changes in SM and CT were inversely related, the percent contribution of the stromal compartment to the total gland remained constant. CONCLUSIONS: The stromal to epithelial ratio remains constant from birth to age 40 in nonhyperplastic glands and is similar to the ratios in asymptomatic and symptomatic BPH tissues

OBJECTIVES: In an effort to avoid allogeneic transfusions, many patients scheduled for radical retropubic prostatectomy (RRP) participate in preoperative autologous donation (PAD) programs. Yet, PAD programs are costly, time-consuming, and not without risks. Perioperative administration of recombinant human erythropoietin (Epoetin alfa) also has been shown to reduce patients exposure to allogeneic transfusion. This study sought to compare the costs and transfusion rates associated with either PAD or perioperative Epoetin alfa in patients undergoing RRP. METHODS: The study population consisted of 120 men randomized to one of two treatment groups. Patients in group 1 donated up to 3 U of autologous blood preoperatively, provided that their hematocrit (HCT) was 33% or higher. Patients in group 2 received 600 IU/kg of Epoetin alfa on days -14 and -7 preoperatively, provided that their HCT was 46% or lower. RESULTS: Overall, 107 (89%) of 120 patients underwent RRP. In group 1, 5 (9.6%) of 52 patients received a total of 12 U of allogeneic blood (0.23 U/patient). In group 2, 5 (9.6%) of 52 patients received a total of 10 U of allogeneic blood (0.19 U/patient). Three patients in group 1 but no patients in group 2 experienced an adverse event. The average costs related to PAD and pharmacologic administration per patient were $540 in group 1 and $657 in group 2. Participation in PAD required an average of 5 hours more per patient compared with Epoetin alfa administration. CONCLUSIONS: Preoperative Epoetin alfa therapy is safe, well tolerated, and equally effective as PAD in reducing allogeneic blood transfusion requirements. Epoetin alfa therapy also is comparable in cost to PAD and offers patients greater convenience and less of a time commitment

PURPOSE: To evaluate the contractile effect of endothelin-1 (ET-1) on prostatic urethral pressure and to characterize the effect of the selective ETA receptor antagonist PD155080 on ET-1 mediated prostatic urethral pressure. MATERIALS AND METHODS: The effect of intravenous ET-1 administration on canine urethral pressure was determined in the presence and absence of PD155080. The affinity of PD155080 for endothelin-mediated contraction was determined using antagonist dissociation studies. Saturation and competition binding studies were performed using [125I] ET-1 in both human and canine prostate. RESULTS: ET-1 bolus injection elicited shallow and prolonged increases the prostatic urethral pressure. Pretreatment with PD155080 totally abolished the urethral contractile response to ET-1. Specific [125I] ET-1 binding was saturable and of high affinity. Two ET receptor subtypes (ETA receptor, ETB receptor) have been identified in human prostate. The ratio of ETA to ETB receptors was approximately 1.5:1 in both human and canine prostates. Isometric tension studies revealed that PD155080 shifted the ET-1 dose-response curves to the right and exhibited no effect on the ETB receptor selective agonist sarafotoxin dose-response curves. CONCLUSION: ET-1 mediates prostate smooth muscle tone and may play a role in the pathophysiology and treatment of benign prostatic hyperplasia (BPH)

PURPOSE: We determined if total prostate volume, transition zone volume or transition zone index is correlated with the severity of clinical benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: A total of 93 men 52 to 85 years old, who were referred to a urology outpatient facility for treatment of clinical BPH, elevated serum prostate specific antigen or abnormal digital rectal examination, underwent measurement of total prostate and transition zone volume at transrectal ultrasonography. All men were requested to undergo uroflowmetry and complete the American Urological Association (AUA) symptom score. RESULTS: The pairwise correlations between AUA symptom score, versus total prostate and transition zone volumes and transition zone index were not statistically or clinically significant. A weak pairwise relationship was observed between peak flow rate versus total prostate volume (r2 = 0.160), transition zone volume (r2 = 0.156) and transition zone index (r2 = 0.147). The pairwise relationships between AUA symptom scores versus all prostate volumes were not statistically significant for subjects with mild (score 8 or less) or moderate to severe (score more than 8) symptoms. CONCLUSIONS: Total prostate and transition zone volumes, and transition zone index are not directly related to AUA symptom score and only weakly related to peak flow rate. These findings provide further evidence that the total prostate, total BPH and relative BPH volumes are not useful determinants of the severity of clinical BPH