Faculty Bibliography

Randomized double-blind placebo controlled studies have consistently demonstrated the safety and effectiveness of selective alpha 1 blockers for the treatment of clinical BPH. Selective alpha 1 blockers relieve the symptoms of prostatism and decrease bladder outlet obstruction. The advantages of this class of drugs for the medical treatment of BPH include the extremely rapid onset of action, statistically and clinically significant effects on relevant outcome measures, adverse experiences that are generally infrequent, mild, and reversible, serum PSA levels are not affected, and hypertension is also effectively treated. The long-term effectiveness of selective alpha 1 blockers has recently been reported. Prostate smooth muscle tension is mediated by the alpha 1a (previously defined as alpha 1c) AR. The pharmaceutical industry is aggressively pursuing development of alpha 1a 'prostate' selective AR antagonists

The treatment of BPH has changed dramatically over the last decade. Industry has recognized the potential market for BPH therapies. Urologists have accepted and embrace the development of alternative treatment strategies. The combined resources and talents of industry and academic urology will lead to exciting future advances in this field. The optimal treatment of BPH requires not only new technology but a better understanding of the pathophysiology and natural history of this disease. Urologists are presently engaged in studies to better define these fundamental aspects of the disease process. The end result of these investigative efforts will be to the advantage of patients afflicted with BPH

The pathophysiology of clinical BPH has been attributed to bladder outlet obstruction resulting from the enlarged prostate. A direct relationship does not exist between prostate size, symptom severity, or bladder outlet obstruction. The pathophysiology of prostatism is most likely multifactorial. Elucidating the factors contributing to symptoms will likely provide the foundation for the development of new pharmacological alternatives for the medical treatment of BPH

Preliminary clinical observations suggest that the efficacy of combination therapy (alpha 1 blockade + androgen suppression) is superior to the individual monotherapies. Several randomized double-blind multicenter placebo controlled studies are being done to define the efficacy and safety of combination therapy relative to the monotherapies. The ultimate role of combination therapy in clinical practice depends on a critical assessment of relative efficacy, safety, and cost

OBJECTIVES. To characterize nitric oxide synthase (NOS), which catalyzes nitric oxide (NO) production, in the human prostate using biochemical and immunohistochemical techniques. METHODS. NOS catalytic assay and NOS immunohistochemistry were performed on histologically verified nonmalignant prostate tissue obtained from the peripheral and transition zones of seven radical prostatectomy specimens. RESULTS. Biochemical analysis revealed NOS activity in the human prostate, with a greater amount in the peripheral zone than in the transition zone (P < 0.01). In both prostate zones, NOS was immunohistochemically localized to nerve fibers and ganglia coursing throughout the smooth musculature of the stroma and to subepithelial nerve plexuses. NOS immunoreactivity was also localized to glandular epithelium. CONCLUSIONS. The presence, activity, and distribution of NOS were described in two regions of the human prostate. The present evidence implicates NO in the automatic innervation and physiology of the human prostate. It is proposed that NO may modulate smooth muscle tone and secretory functions in the human prostate, although functional studies are needed to support these hypotheses

OBJECTIVES. To determine whether nitric oxide (NO) is a mediator of prostatic smooth muscle activity. METHODS. Pharmacologic experiments using electrical field stimulation (EFS) were performed on strips of human and canine prostate. RESULTS. EFS alone elicited frequency-dependent contractions in preparations of human and canine prostates. The greatest contractile activity was achieved at 30 Hz. In the presence of 10(-5) M guanethidine (GUA) and 2 x 10(-6) M atropine (ATR), EFS elicited relaxation of canine prostate strips relative to baseline tension. A weak biphasic response consisting of initial relaxation and subsequent contraction relative to baseline tension was observed in the human prostate strips exposed to similar conditions. The smooth muscle activity observed in the presence of GUA plus ATR was attributed to nonadrenergic, noncholinergic (NANC) nerve transmission. 10(-4) M L-NG-nitroarginine methylester (NAME) significantly increased EFS-elicited NANC smooth muscle activity both in human and canine prostates. L-arginine, 10(-2) M, reversed the effect of L-NAME in human and canine prostates. Sodium nitroprusside, 10(-4) M, a donor of NO, caused relaxation of both human and canine prostates. The mean magnitude of the relaxant response/cross-sectional area in human prostate (2.64 +/- 0.4 g/cm2) was significantly greater than in the canine prostate (1.09 +/- 0.17 g/cm2) (P < 0.005). CONCLUSIONS. These results provide compelling evidence that NO plays a role in mediating contractile function of human and canine prostates

OBJECTIVES. To evaluate long-term efficacy and safety of terazosin, a selective alpha 1 blocker, in the treatment of benign prostatic hyperplasia (BPH). METHODS. This was a long-term (42 months), open-label, multicenter study with patients evaluated at 1- to 6-month intervals. Twenty-three outpatient clinics throughout the United States and Canada participated in the study. A total of 494 men with symptomatic BPH, lacking absolute indications for surgery, were enrolled in this study; 298 were transferred into the study from randomized, placebo-controlled studies of terazosin and 196 had no prior terazosin therapy. Terazosin was given starting at 1 mg/d and titrated upward until symptoms were relieved or a maximum dose of 20 mg/d was achieved, whichever came first. RESULTS. Peak urinary flow rates at all visits were significantly higher than baseline values, with mean improvements ranging from 1.0 to 4.0 mL/s. At 3 months, 40% of patients exhibited a 30% or greater improvement in peak flow rate; this improvement was maintained through 42 months. Boyarsky symptom scores improved significantly at all visits; mean total score improved by at least 4.0 points (40%) at all visits beyond 3 months. The most common adverse events resulting in premature termination from the study were dizziness (6.7%), asthenia (3.8%), and somnolence (2.0%). CONCLUSIONS. This study suggests that terazosin is well tolerated and effective in longterm treatment of patients with BPH