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It has been hypothesized that in patients with benign prostatic hyperplasia, selective antagonism of the alpha1A-adrenoceptor-mediated contraction of lower urinary tract tissues may, via a selective relief of outlet obstruction, lead to an improvement in symptoms. The present study describes the alpha1-adrenoceptor (alpha1-AR) subtype selectivities of two novel alpha1-AR antagonists, Ro 70-0004 (aka RS-100975) and a structurally-related compound RS-100329, and compares them with those of prazosin and tamsulosin. Radioligand binding and second-messenger studies in intact CHO-K1 cells expressing human cloned alpha1A-, alpha1B- and alpha1D-AR showed nanomolar affinity and significant alpha1A-AR subtype selectivity for both Ro 70-0004 (pKi 8.9: 60 and 50 fold selectivity) and RS-100329 (pKi 9.6: 126 and 50 fold selectivity) over the alpha1B- and alpha1D-AR subtypes respectively. In contrast, prazosin and tamsulosin showed little subtype selectivity. Noradrenaline-induced contractions of human lower urinary tract (LUT) tissues or rabbit bladder neck were competitively antagonized by Ro 70-0004 (pA2 8.8 and 8.9), RS-100329 (pA2 9.2 and 9.2), tamsulosin (pA2 10.4 and 9.8) and prazosin (pA2 8.7 and 8.3 respectively). Affinity estimates for tamsulosin and prazosin in antagonizing alpha1-AR-mediated contractions of human renal artery (HRA) and rat aorta (RA) were similar to those observed in LUT tissues, whereas Ro 70-0004 and RS-100329 were approximately 100 fold less potent (pA2 values of 6.8/6.8 and 7.3/7.9 in HRA/RA respectively). The alpha1A-AR subtype selectivity of Ro 70-0004 and RS-100329, demonstrated in both cloned and native systems, should allow for an evaluation of the clinical utility of a 'uroselective' agent for the treatment of symptoms associated with benign prostatic hyperplasia.

Objective: To compare detrusor function and outlet behaviour on ambulatory urodynamic monitoring (AUM) with conventional cystometrography in symptomatic men with borderline evidence of bladder outlet obstruction (BOO), as determined by conventional cystometrography, and to assess the usefulness of AUM in reclassifying this population of patients into obstructed and unobstructed groups., Patients and Methods: Sixty-nine consecutive men (mean age 59.6 years) with lower urinary tract symptoms (mean International Prostate Symptom Score 19.1) and borderline BOO on a medium-fill conventional urodynamic study (CUS) were examined prospectively with AUM. Detrusor contractility, obstruction grade, maximal voiding detrusor pressure (pdet(max)), detrusor pressure at peak flow (pdet Qmax) and peak flow rate (Qmax) determined by both methods were compared. The incidence of detrusor instability (DI) detected by both modalities was also evaluated., Results: There was considerable disagreement between the investigations during the voiding phase. Detrusor contractility was higher on AUM than on CUS (P= 0.003) and obstruction grade was significantly lower on AUM (P=0.018). There was no difference in pdet(max) nor pdet Qmax. The mean (95% confidence interval) Qmax was higher on AUM, at 12.9 (1.3) mL/s, than on CUS, at 8.9 (0.8) mL/s. On the Abrams-Griffiths nomogram the most significant changes were six men (10%) from equivocal to obstructed, seven (11%) from equivocal to unobstructed and two (3%) from obstructed to unobstructed on CUS and on AUM, respectively. Thus, in 24% of patients there was a potentially clinically significant change resulting from the information generated by AUM. DI was identified on CUS in 26 (41%) men and on AUM in 25 (40%); 35 men (56%) had evidence of DI on either AUM or CUS., Conclusion: The significant disagreement between the findings on CUS and AUM suggests that the conditions under which pressure-flow investigations are carried out significantly affect findings in borderline cases. The reclassification of patients by AUM into obstructed and unobstructed groups occurs in 24% and may be clinically relevant. AUM appears to be complementary to CUS in the assessment of men who are borderline for obstruction on conventional testing, but the clinical implications of this have yet to be determined.

Objective: To assess the numbers of men in outpatients and subsequently undergoing transurethral resection of the prostate (TURP) who were referred during 1993-94 and 1996-97, thereby assessing the feasibility of a subsequent study of treatment efficacy in men with bladder outlet obstruction secondary to benign prostatic hyperplasia, prospectively randomized to the surgical treatment options, i.e. TURP, laser ablation of the prostate, transurethral needle ablation and T3 thermotherapy, to investigate treatment outcome, cost-efficacy and cost-benefit., Patients and Methods: All patients considered and consenting for prostate surgery were reviewed prospectively with a view to inclusion in the proposed trial. The diagnosis was based on two estimates of flow rate from voids of >150 mL and from symptoms assessed using the International Prostate Symptom Score. All patients had TURP explained by a urological surgeon and nursing staff, and subsequently had further consultation with research staff., Results: Patients seen in clinic as new referrals increased by 11% between the periods assessed, although the numbers undergoing TURP decreased by 19%. Of the 383 patients screened, who were on the waiting list for TURP, only 13 elected to enter the trial. Of the 383 men, 267 (67%) ultimately had prostate surgery, with 39 (10%) electing to continue with watchful waiting and 34 (9%) continuing with pharmacotherapy., Conclusion: Although more men with benign prostatic disease and lower urinary tract symptoms are being seen in clinics, the reduced proportion of patients continuing to surgical intervention will lead to increasing difficulty in carrying out randomized controlled clinical trials assessing surgical options. With ever more therapeutic options available, patients find it difficult to make decisions in both the clinical situation and when asked to enter a trial. Fully informed decisions by both the surgeon and the patient will only be possible when objective data are available from trials that investigate outcome, cost-efficacy and cost-benefit. This study suggests that when presented with more information and counselling, fewer men decide to undergo prostate surgery for symptomatic BPH.

Radiofrequency thermal therapy of the prostate is a new minimally invasive treatment for symptomatic benign prostatic hyperplasia (BPH). The procedure is called transurethral needle ablation (TUNA). With TUNA, the inner region of the prostate is selectively ablated with temperatures approaching 90-100 degrees C while the prostatic urothelium is preserved. The objective of this article is to discuss the basics of radiofrequency energy, instrumentation, surgical techniques, and to present an update of the clinical results as it applies to the treatment of BPH.

The complexity of the signal transduction pathways linked to alpha1A-adrenoceptors are becoming clearer. At one time it was thought that the alpha1A-subtype was linked to the influx of extracellular Ca2+ while the alpha1B-subtype was linked via inositol phosphate formation to the release of intracellular Ca2. However the coupling of the alpha1-adrenoceptors to G-proteins leads to the activation of a number of different effector enzymes which produce intracellular second messengers and alterations in biological activity. One area of diversity is in the many forms of the Galpha, beta, gamma heterotrimeric G-proteins which confer specificity towards certain effectors. All alpha1-adrenoceptor subtypes have been shown to couple to phospholipase C in many cells and tissues leading to the breakdown of PiP2 to give IP3, which releases intracellular Ca2+, and diacylglycerol, which stimulates protein kinase C. Additional effectors which can couple to alpha1-adrenoceptors include phospholipase D, adenylate cyclase and the mitogen-activated protein kinase pathway. The latter involves a longer term response and causes increased cell growth and may be important in, for example, the prostate as well as in vascular smooth muscle and the heart. In human prostate alpha1-adrenoceptor activation leads to the release of intracellular Ca2+ from ryanodine-sensitive store followed by an influx of extracellular Ca2+, a mechanism different from that linked to the same receptor subtype in several other smooth muscles. Therefore a given alpha1-subtype may be coupled to a variety of different signal transduction mechanisms in different systems. Further, there may be different effector mechanisms linked to alpha1-subtypes in a given cell or tissue e.g. phospholipase C and mitogen-activated protein kinase. An increased understanding of the complexity of signal transduction mechanisms and the elucidation of the details in a particular tissue will open up new possibilities for therapeutic interventions.

The aim of the study was to establish a methodology whereby ambulatory urodynamic monitoring (AUM) may be used in the assessment of the effects of darifenacin on urodynamic measures of detrusor function and symptoms associated with detrusor instability. Six patients (one man and five women) with detrusor instability (DI) on conventional urodynamic monitoring were recruited into this placebo-controlled crossover study. The study was divided into two periods of 7 days of treatment with either darifenacin 5 mg t.d.s. or placebo with the patient crossing over to the alternative treatment after a washout period of 7 days. On the 7th day of each treatment, AUM was carried out. Parameters used to quantify detrusor activity on AUM were the number, amplitude, and duration of detrusor contractions and the total area under the detrusor pressure/time curve. "Events" recorded were urge, leakage episodes, voids, and pain. Six comparable hours of AUM for each treatment period could be analyzed in four patients and 4 hr in one. In three of the five patients, reduction in activity on AUM while on darifenacin was apparent. Symptom data closely matched the changes in detrusor activity measured on AUM. This is the first study reporting the use of AUM in the development of a drug with an effect on detrusor activity. AUM has clear advantages over conventional cystometry, which can only measure surrogate urodynamic parameters at a single time point. The optimal duration of monitoring in this context appears to be 6 hr with prolongation of monitoring time beyond this being unlikely to yield additional useful information. Correlation between symptoms and findings on AUM is good with changes in parameters recorded on AUM relating closely to the improvement in symptoms.

Objectives: To examine the use of prostate-specific antigen (PSA) density (PSAD) and free to total PSA ratio (f/tPSA) in enhancing the specificity of PSA in the diagnosis of prostate cancer in patients with a total PSA (tPSA) of 4-10 ng/mL and with a normal digital rectal examination (DRE)., Patients and Methods: The study comprised 77 consecutive men in whom the fPSA and tPSA levels were obtained before DRE and transrectal ultrasonography-guided sextant prostate biopsy. Prostate cancer was found in 39 patients and the histology was benign in 38. Receiver operator characteristic curves, obtained from all 77 patients, were used to determine the optimal thresholds for PSAD and f/tPSA in detecting cancer. A subset of 28 patients, including seven with prostate cancer, was identified who had a normal DRE and a tPSA of 4-10 ng/mL; PSAD and f/tPSA values were applied at the optimal thresholds to assess their use in identifying those patients with cancer., Results: When applied to the selected group of 28 patients, the PSAD (threshold 0.15) failed to identify any with prostate cancer. The f/tPSA (threshold 0.12) yielded a sensitivity of 65% and a specificity of 38%, identifying only three of seven patients with cancer. By increasing the threshold to 0.25, six patients were correctly identified, giving a sensitivity of 86%, with a lower specificity of 14%., Conclusions: These findings suggest that the neither PSAD nor f/tPSA either significantly reduce the negative biopsy rate or identify patients at greater risk of prostate cancer, particularly when the tPSA is equivocal at 4-10 ng/mL.

1 The present study has investigated the alpha1-adrenoceptor subtype mediating contraction of the rat isolated prostatic vas deferens and the possible effector mechanisms involved in this response by use of functional experiments. 2 Contractions to noradrenaline in the rat isolated prostatic vas deferens were antagonized by prazosin (9.4, 1.04+/-0.19, pA2 and Schild plot slope), 5-methyl urapidil (8.9, 1.10+/-0.13), BMY 7378 (6.4, 1.53+/-0.07) and RS 17053 (8.3, 1.13+/-0.18). These affinities are consistent with the response being mediated by the alpha1A-adrenoceptor subtype. 3 The contraction to noradrenaline at 37 degrees C consisted of an initial phasic response, composed of many rhythmic contractile spikes and a more slowly developing tonic contraction. When the temperature was lowered to 25 degrees C the phasic contraction became a smooth single response which was increased in magnitude. 4 In Ca2+-free Krebs solution the tonic contraction to noradrenaline (10(-4) M) was abolished, suggesting that this response was dependent on influx of extracellular Ca2+. After 2 min in Ca2+-free Krebs solution at 37 degrees C and 25 degrees C the phasic response to noradrenaline (10(-4) M) was 38+/-2% and 91+/-4%, respectively, compared with the phasic contraction to noradrenaline (10(-4) M in normal Krebs solution) and after 30 min it was abolished at 37 degrees C and was 7+/-1% at 25 degrees C. Ryanodine abolished the noradrenaline response in Ca2+-free Krebs solution for 2 min at 25 degrees C, while cyclopiazonic acid reduced it to 36+/-2%. 5 In normal Krebs solution at 25 degrees C the protein kinase C inhibitor calphostin C reduced the tonic contraction to noradrenaline (10(-5) M) from 36+/-8% to 14+/-3% compared with the phasic contraction to noradrenaline (10(-4) M). The DAG kinase inhibitor R 59022 increased the contraction following the initial phasic response to a maximum of 107+/-17% after 35 s, before dropping down to a well maintained contraction which was still greater in magnitude compared with the control. Nifedipine (3x10(-7) M) reduced the tonic contraction from 49+/-6% to 7+/-1% but did not reduce the phasic response. Ryanodine (10(-4) M) reduced the phasic contraction from 50+/-2% to 7+/-1% and the tonic response from 47+/-5% to 27+/-5%. 6 The phorbol ester phorbol-12,13-dibutyrate at 25 degrees C produced a transient contraction of the rat prostatic vas deferens, maximum response (10(-5) M) 48+/-4%, compared with the maximum tonic response to noradrenaline. The contraction to PDBu (10(-5) M) was reduced to 23+/-2% by calphostin C (10(-6) M) and to 15+/-1% by nifedipine (3x10(-7) M) and was abolished after 2 min in Ca2+-free Krebs solution. 7 In conclusion, the alpha1A-adrenoceptor mediated contraction to noradrenaline of the rat prostatic vas deferens appears to consist of an initial phasic component due to the release of intracellular Ca2+ from ryanodine-sensitive stores. These stores are depleted in the absence of extracellular Ca2+ and this depletion is slower at 25 degrees C than at 37 degrees C. The phasic contraction is followed by a tonic contraction involving activation of protein kinase C by diacylglycerol and influx of Ca2+ through nifedipine-sensitive channels.

Intractable detrusor overactivity can result in considerable morbidity and, in the case of neurogenic bladder dysfunction, can put the upper tracts at risk. Once conservative treatments have been exhausted the aim of surgery is to increase functional bladder capacity and decrease the maximal detrusor pressure at this capacity. The mainstay of contemporary therapy has been augmentation cystoplasty; the different techniques and recent literature are reviewed herein. Bladder autoaugmentation is compared and contrasted with augmentation cystoplasty and its role is discussed, as is the less invasive technique of sacral neuromodulation with reference to their role within the range of surgical treatments for detrusor activity.

The risk of mortality and long-term morbidity, including loss of sexual function, associated with surgical procedures for symptomatic benign prostatic hyperplasia (BPH) has prompted research into alternative medical therapies. Phytotherapy involves the use of herbal formulations, where the mechanisms of action are usually obscure and although studies have confirmed their effectiveness in symptom relief and improving quality of life (QOL), few placebo-controlled trials exist. Both the 5 alpha-reductase inhibitor finasteride and alpha 1-adrenoceptor antagonists (e.g. alfuzosin, doxazosin, prazosin, tamsulosin and terazosin) have been recommended as appropriate treatment options for patients with lower urinary tract symptoms (LUTS) associated with benign prostatic obstruction (BPO), and their efficacy has been proven in several placebo-controlled trials. Finasteride reduces the static component of BPO--by reducing the size of the prostate--and, as a result, symptom relief is slow (6-12 months) and is predominantly restricted to patients with large prostates (> 40 g). The alpha 1-adrenoceptor antagonists, on the other hand, reduce the dynamic component of obstruction--relaxation of smooth muscle in the prostate, urethra and bladder neck--and provide rapid symptom relief after only a few doses, relieving LUTS more effectively than finasteride and irrespective of prostate size. All of the various alpha 1-adrenoceptor antagonists provide effective and comparable relief of LUTS, and an improvement in bothersomeness and symptom-related QOL. However, it is also important that the therapy is fast acting and acceptable to the patient, in that it does not interfere with other medication or produce unpleasant side effects. These documented properties of the alpha 1A-adrenoceptor antagonists make them an ideal choice for the medical treatment of symptomatic BPH.

We report a complex case in which the left kidney had undergone giant hydronephrotic change after chronic obstruction at the vesicoureteric junction. Minor blunt abdominal trauma caused rupture of the parenchyma of this expanded and dilated kidney, with bleeding into its collecting system. The mixture of blood and urine remained contained within the kidney's structural layers, so producing a tense, cystic, fluid-filled mass arising from the left hypochondrium. Pathogenesis, differential diagnosis and investigation of giant hydronephrosis and its rupture are discussed. The observation is made that gross distortion of the renal parenchyma by rupture or hydronephrosis impairs arterial inflow to the kidney.

Objectives: To examine, in an observational study, the safety and efficacy of transurethral needle ablation (TUNA) of the prostate as a treatment for symptomatic benign prostatic enlargement., Patients and Methods: This prospective study included 71 symptomatic men with unequivocal obstruction on pressure-flow urodynamics. The variables measured at baseline and up to 12 months after treatment included the American Urological Association (AUA)-7 symptom index and an added quality-of-life question, the AUA BPH-Impact Index, a sexual function score, transrectal ultrasonography of the prostate, a frequency-volume chart, free-flow uroflowmetry, post-void residual urine volume (PVR) and pressure-flow urodynamics. Transurethral resection of the prostate (TURP) was offered if the symptoms failed to resolve at any time during the follow-up period. TUNA was performed under local anaesthetic and sedation in 63 (89%) men and as a day-case procedure in 10 (14%). Five patients were on warfarin which was not discontinued., Results: There were no serious treatment-related adverse events. Eight of the initial nine patients who were not routinely catheterized after treatment with TUNA developed acute urinary retention. Although some haematuria occurred in all patients, only one (1.4%) developed catheter blockage by clot. There were no problems with bleeding in those patients on warfarin at the time of treatment. The mean (95% confidence interval, CI) AUA-7 index fell from 23 (1.7) to 10.6 (1.8) (P < 0.001, Mann-Whitney U-test) at 12 months, 29 men (41%) had an AUA-7 index of < or = 7. The maximum (95% CI) urinary flow rate increased from 9.0 (0.8) to 11.3 (1.1) mL/s (P < 0.001) and this was accompanied by a small but significant reduction in PVR of 70 (14) mL to 35 (8) mL (P < 0.001 Mann-Whitney U-test). There was a significant reduction in both maximal voiding pressure and detrusor pressure at peak flow at 3 months (Mann-Whitney U-test, both P < 0.001) and at 12 months (P < 0.001, Wilcoxon matched-pairs signed-ranks test). However, 78% of the 45 men undergoing repeat pressure-flow studies at 12 months were unequivocally obstructed according to the Abrams-Griffiths nomogram. The mean (95% CI) prostatic volume fell from 49.0 (4.8) mL at baseline to 40.8 (4.9) mL at 3 months, but this change was not statistically significant (P = 0.011, Mann-Whitney U-test). Two men reported erectile dysfunction, one experienced ejaculatory problems and seven reported an improvement in erectile function after TUNA. During the study, 22 men (31%) underwent TURP., Conclusions: TUNA is a safe treatment which can be performed as an out-patient procedure under local anaesthesia and sedation in the vast majority of patients. There was no evidence of serious adverse events and no significant adverse effect on sexual function. The symptomatic improvement was sustained at 12 months in most (54%) patients, with modest improvements in peak flow rate, PVR and voiding pressures, indicating that TUNA may result in prolonged symptomatic improvement in a proportion of patients suffering from bladder outlet obstruction. A randomized controlled study against established therapies is now essential to clearly delineate its place in the management of such patients.

Purpose: All urethral reconstruction that involves substitution has an inherent ongoing incidence of restenosis with time. Anastomotic restoration of urethral continuity naturally obviates these complications but to achieve its potential of a long-term stricture-free success rate that approaches 100% circumstances must be ideal and the reconstructive surgical technique must be meticulous. If the critical indications for anastomotic reconstruction are overextended, complications inevitably increase. Considerable additional urethral length is required to overcome the terminal atretic deficiency associated with hypospadias and create a tension-free anastomotic neomeatoplasty. Mobilization and advancement of the penile urethra alone are rarely sufficient to achieve this without causing penile chordee. We describe the details of bulbar elongation anastomotic meatoplasty (BEAM) that we have been using for approximately the last 8 years., Materials and Methods: The only part of the urethra that can be mobilized to provide extra length for anastomotic urethroplasty without creating penile curvature chordee is the bulbar urethra. Full length mobilization of the whole length of the bulbar urethra through a perineal incision provides 2 to 2.5 cm. of tension-free lengthening in children and 4 to 5 cm. in adults. Thus, many subterminal urethral deficiencies can be resolved by bulbar elongation anastomotic meatoplasty when the total extent of the urethral deficiency is not disproportionally long. We performed bulbar elongation anastomotic meatoplasty in 12 patients 2 to 25 years old., Results: At a followup of 2 to 7 years the neomeatus is functionally and cosmetically satisfactory in all cases with no long-term complications or chordee., Conclusions: When circumstances are appropriate, bulbar elongation anastomotic meatoplasty is a preferable alternative to some of the current substitution procedures. Once established, anastomotic reconstructions are generally stable in the long term.

Objective: To compare the effects of the potassium-channel openers, levcromakalim and YM934, in isolated human detrusor muscle from normal and hyper-reflexic bladders., Materials and Methods: Strips of human detrusor muscle from normal and hyper-reflexic bladder were pre-contracted with carbachol and the potassium-channel openers (0.1-0.3 mumol/L) were added cumulatively to the organ baths. Other strips were field-stimulated at frequencies producing 25% and 75% of the maximum response to field stimulation. Contractions could be abolished by atropine (10 mumol/L) and tetrodotoxin (1 mumol/L)., Results: The hyper-reflexic bladder was significantly more sensitive to carbachol than the normal bladder but the maximum response was significantly lower in the hyper-reflexic tissue. There was no significant difference between the potency of the potassium-channel openers in normal and hyper-reflexic detrusor muscle. Hyper-reflexic bladder was significantly more sensitive to electrical field stimulation than was normal bladder: maximum responses to field stimulation were not significantly different. Concentration-response curves for the potassium-channel openers were displaced to the left in hyper-reflexic bladder at both 25% and 75% maximum frequencies: however, only with levcromakalim at 75% of the maximum frequency was the shift significant., Conclusion: The greater sensitivity of hyper-reflexic bladder to carbachol and field stimulation supports existing evidence for post-junctional supersensitivity in detrusor instability. The results of this study also suggest that there are no appreciable changes in KATP channel function in the unstable bladder.

1. The actions of the alpha 1-adrenoceptor antagonist tamsulosin have been examined at functional alpha 1-adrenoceptor subtypes and compared with those at the human prostate receptor. 2. At the alpha 1D-adrenoceptors of the rat aorta, tamsulosin acted as a competitive antagonist with a high affinity (pKB = 10.1). 3. At the alpha 1B-adrenoceptor of the rat spleen and rabbit corpus cavernosum penis, tamsulosin again acted as a competitive antagonist but with a significantly lower affinity (pKB = 8.9-9.2). 4. Tamsulosin acted as an unsurmountable antagonist of the alpha 1A-adrenoceptor-mediated responses of the rat and human vas deferens, reducing maximal responses to phenylephrine by 20% and 50%, respectively, at an antagonist concentration of 1 nM. Responses of depolarized (100 mM KCl) rat vas deferens preparations were unaffected by 10 nM tamsulosin but this concentration reduced maximal responses to 5-hydroxytryptamine (5-HT) in this tissue. 5. When longer antagonist incubation periods (> or = 60 min) were used, tamsulosin behaved as a competitive antagonist on the human prostate with a significantly higher affinity (pKB = 10.0) than obtained at the alpha 1B-adrenoceptor. 6. The data demonstrate that tamsulosin is a high affinity antagonist at functional alpha 1-adrenoceptors with a selectivity alpha 1D > or = alpha 1A > alpha 1B. In some tissues the compound exhibits an additional unsurmountable antagonist action, the clinical significance of which is unknown.

Objectives: To compare the safety and tolerability of tamsulosin 0.4 mg once daily in younger (< 65 years) and older (> or = 65 years) patients with lower urinary tract symptoms (LUTS) suggestive of benign prostatic obstruction (BPO)., Methods: In a retrospective analysis of two European double-blind, randomized, placebo-controlled trials, safety was assessed in 574 younger or older patients treated with tamsulosin or placebo for 12 weeks., Results: The incidence of adverse events, drug-related adverse events, serious adverse events and discontinuations due to adverse events was similar in older and younger tamsulosin-treated patients and was not significantly different from placebo. Although abnormal ejaculation was slightly more common in younger than older men receiving tamsulosin, the difference was not statistically significant from the placebo groups in both age groups. The incidence of adverse events possibly associated with vasodilation in tamsulosin-treated younger and older patients was 8.4 and 4.2%, respectively; these were comparable with the values for placebo-treated patients: 7.5 and 6%, respectively. Baseline systolic blood pressure was higher in older than younger patients, but there were minimal changes in blood pressure or pulse rate in tamsulosin- or placebo-treated patients in either age group., Conclusions: Tamsulosin is well tolerated and suitable for use in older and younger patients with LUTS suggestive of BPO (symptomatic BPH).

Objective: To assess the efficiency of a prostate clinic and to determine the treatment outcomes and the proportion of patients who could potentially be managed by their General Practitioners (GPs)., Patients and Methods: Referral letters from GPs were screened by the consultant urologists and appropriate patients seen in the next available prostate clinic. The initial assessment consisted of an International Prostate Symptom Score and a medical history, uroflowmetry, ultrasonographically determined post-void urine volumes, renal function tests and measurement of prostate specific antigen, in addition to a physical examination and a digital rectal examination. Further investigations were requested as required., Results: Over a period of 18 months, 403 patients were seen, 90% of them within 12 weeks from the time of referral. Uroflowmetry was performed in 96% of patients and further urodynamics in 22%. Bladder outlet obstruction was diagnosed in 246 (61%) patients and primary detrusor instability was detected in 20 (5%) patients. Fourteen per cent of patients were returned to the care of the GP following their first visit. The audit identified a potential group of patients (52%) who could be managed by their GP. Seven per cent underwent prostate surgery for the relief of bladder outlet obstruction., Conclusion: The prostate clinic significantly reduced the delay for patients to be seen at the hospital and facilitated rapid assessment and investigation, much of which was carried out by a nurse practitioner during the first visit (in most cases). Several patients were identified who could be managed in the community.

1. The affinity of the alpha 1-adrenoceptor antagonist SB 216469 (also known as REC 15/2739) has been determined at native and cloned alpha 1-adrenoceptor subtypes by radioligand binding and at functional alpha 1-adrenoceptor subtypes in isolated tissues. 2. In radioligand binding studies with [3H]-prazosin, SB 216469 had a high affinity at the alpha 1A-adrenoceptors of the rat cerebral cortex and kidney (9.5-9.8) but a lower affinity at the alpha 1B-adrenoceptors of the rat spleen and liver (7.7-8.2). 3. At cloned rat alpha 1-adrenoceptor subtypes transiently expressed in COS-1 cells and also at cloned human alpha 1-adrenoceptor subtypes stably transfected in Rat-1 cells, SB 216469 exhibited a high affinity at the alpha 1a-adrenoceptors (9.6-10.4) with a significantly lower affinity at the alpha 1b-adrenoceptor (8.0-8.4) and an intermediate affinity at the alpha 1d-adrenoceptor (8.7-9.2). 4. At functional alpha 1-adrenoceptors, SB 216469 had a similar pharmacological profile, with a high affinity at the alpha 1A-adrenoceptors of the rat vas deferens and anococcygeus muscle (pA2 = 9.5-10.0), a low affinity at the alpha 1B-adrenoceptors of the rat spleen (6.7) and guinea-pig aorta (8.0), and an intermediate affinity at the alpha 1D-adrenoceptors of the rat aorta (8.8). 5. Several recent studies have concluded that the alpha 1-adrenoceptor present in the human prostate has the pharmacological characteristics of the alpha 1A-adrenoceptor subtype. However, the affinity of SB 216469 at human prostatic alpha 1-adrenoceptors (pA2 = 8.1) determined in isolated tissue strips, was significantly lower than the values obtained at either the cloned alpha 1a-adrenoceptors (human, rat, bovine) or the native alpha 1A-adrenoceptors in radioligand binding and functional studies in the rat. 6. Our results with SB 216469, therefore, suggest that the alpha 1-adrenoceptor mediating contractile responses of the human prostate has properties which distinguish it from the cloned alpha 1a-adrenoceptor or native alpha 1A-adrenoceptor. Since it has previously been shown that the receptor is not the alpha 1B- or alpha 1D-adrenoceptor, the functional alpha 1-adrenoceptor of the human prostate may represent a novel receptor with properties which differ from any of the alpha 1-adrenoceptors currently defined by pharmacological means.

1. The alpha 1-adrenoceptor subtype mediating contraction of the rat hepatic portal vein to phenylephrine was characterized by use of competitive antagonists previously shown to have selectivity between the expressed alpha 1-subtype clones. Prazosin competitively antagonized the phenylephrine contractions with a pA2 value of 9.2, as did WB 4101 (pA2 9.4), 5-methyl urapidil (pA2 8.6), indoramin (pA2 8.4) and BMY 7378 (pA2 6.5). 2. The pA2 values on the rat portal vein correlated highly with their previously published pA2 values for the alpha 1A-adrenoceptors mediating contraction of the rat epididymal vas deferens and human prostate and poorly with those for the alpha 1B- and alpha 1D-adrenoceptors mediating contraction of the rat spleen and aorta, respectively. The antagonist pA2 values on the rat portal vein correlated highly with their previously published pK1 values for the expressed alpha 1a-clone and poorly with those for the expressed alpha 1b- and alpha 1d-clones. Therefore the results show that contraction of the rat portal vein to phenylephrine is mediated by alpha 1A-adrenoceptors. 3. The novel alpha 1-adrenoceptor antagonist RS 17053 had a relatively high affinity for the alpha 1A-adrenoceptors mediating contraction of the rat epididymal vas deferens (pA2 9.5) compared with the alpha 1B-adrenoceptors in the rat spleen (pA2 7.2) or the alpha 1D-adrenoceptors in the rat aorta (pKB 7.1), in agreement with its selectivity for the expressed alpha 1a-clone. However, RS 17053 had over 100 fold lower affinity for the alpha 1A-adrenoceptors mediating contraction of the rat portal vein (pKB 7.1) and human prostate (pKB 7.1) compared with its affinity for the alpha 1A-adrenoceptors in the rat epididymal vas deferens or the expressed alpha 1a-clone. 4. The difference in affinity of RS 17053 between the rat epididymal vas deferens and rat portal vein cannot be explained by a species difference in the receptor. Therefore RS 17053 may distinguish between subtypes of the alpha 1A-adrenoceptor in the rat portal vein and human prostate compared with those in the rat epididymal vas deferens or the expressed alpha 1a-clone.

Objective: This meta-analysis of two European studies evaluated the efficacy and safety of modified-release tamsulosin 0.4 mg once daily compared with placebo in patients with benign prostatic enlargement, lower urinary tract symptoms and prostatic obstruction (symptomatic BPH)., Methods: Patients entered a 2-week placebo run-in period, followed by randomization to treatment with tamsulosin (382 patients) or placebo (193 patients) once daily for 12 weeks., Results: Maximum urinary flow rate improved to a greater extent in the tamsulosin group (1.6 ml/s, 16%) than the placebo group (0.6 ml/s, 6%) (p = 0.002). Total Boyarsky symptom score also improved to a greater extent in the tamsulosin group (3.3 points, 35.1% reduction) than the placebo group (2.4 points, 25.5% reduction) (p = 0.002). Significantly more tamsulosin patients (66%) than placebo patients (49%) had a > or = 25% decrease in total symptom score at endpoint (p < 0.001). Twelve weeks of treatment with tamsulosin also produced significant improvements in average urinary flow rate (p = 0.005) and voiding or "obstructive" (p = 0.008) and storage or "irritative' (p = 0.017) symptom scores. The incidence of drug-related adverse events was comparable for the tamsulosin and placebo groups (13 and 12% respectively, p = 0.802). The same applies to the incidence of adverse events commonly attributed to alpha 1-adrenoceptor antagonists, such as dizziness, headache, postural hypotension, syncope, asthenia, somnolence and rhinitis. There were no clinically significant changes in blood pressure or pulse rate in tamsulosin patients compared with placebo patients both in hypertensive and normotensive BPH patients., Conclusion: Tamsulosin 0.4 mg once daily is safe, well-tolerated and improves both the symptoms and urinary flow rate in patients with benign prostatic obstruction (symptomatic BPH).

Symptomatic benign prostatic hyperplasia (BPH) is a common condition in older men and has a significant impact on their daily lives. Transurethral resection of the prostate is currently the most effective remedy for BPH but is not suitable for all patients. There is now clear evidence for the efficacy of alpha-adrenoceptor antagonists, particularly selective alpha 1-adrenoceptor antagonists, in the treatment of BPH. Inhibition of alpha-adrenoceptors significantly increases urinary flow and improves symptoms in BPH. alpha 1-Adrenoceptor antagonists have a place in the management of BPH patients with mild to moderate disease, who are bothered by their symptoms, or for those awaiting or wishing to delay surgery. Treatment with selective alpha 1-adrenoceptor antagonists is generally better tolerated than nonselective-alpha-blockers. alpha 1-Selective adrenoceptor antagonists with a long half-life such as terazosin, doxazosin and tamsulosin, as a modified release formulation, permit once-daily dosing. Tamsulosin is the first subtype-specific (cloned alpha 1c/functional alpha 1A) adrenoceptor antagonist in clinical practice. Initial reports suggest that it gives no clinically relevant lowering of blood pressure and that its (vasodilatory) side effect profile is minimal. The scientific rationale behind the therapeutic use of alpha-adrenergic blockade as treatment for BPH and the trials data relating to the various agents which are available for clinical use are reviewed in the context of the contemporary literature.

Objectives: To review the options available for the surgical management of vesicovaginal fistulae (VVF)., Methods: A comprehensive review of the literature related to the surgical management of VVF., Results: Numerous methods for the treatment of VVF have been described. The success of surgical treatment is excellent, even for complex fistulae. There is an increasing move towards early rather than delayed repair. Paramount to the success of surgical treatment is adherence to the principles of fistula closure. Use of an interposition flap will greatly improve the chances of a good outcome. When using a transabdominal approach, the omentum should be the tissue of first choice for an interposition flap., Conclusion: There are few VVF that are not amenable to successful surgical intervention.

1. The mechanism of contraction to noradrenaline (pEC50 5.6 +/- 0.1) in the rat epididymal vas deferens (mediated via alpha 1A-adrenoceptors) has been studied in functional experiments. 2. Contractions to noradrenaline at 10(-6) M were potentiated by the diacylglycerol (DAG) kinase inhibitor R 59022 (3 x 10(-7) M) from 49 +/- 4% to 63 +/- 3% maximum response and the time taken from initiation of contraction to the maximum response was reduced from 16 +/- 2 s to 9 +/- 1 s. The same contractions were not significantly potentiated by the DAG lipase inhibitor, U-57,908, 10(-5) M (51 +/- 2% control and 53 +/- 4% in the presence of U-57,908) nor was the time taken from initiation of contraction to the maximum response significantly altered (17 +/- 1 s control and 16 +/- 1 s in the presence of U-57,908). 3. Concentration-dependent contractions to noradrenaline (NA) were reduced by staurosporine (10(-7) M) and the selective protein kinase C inhibitor, calphostin C (10(-6) M) from 68 +/- 2% (NA, 3 x 10(-6) M) to 28 +/- 2% and 20 +/- 2% respectively and from 94 +/- 2% (NA, 3 x 10(-5) M) to 50 +/- 2% and 44 +/- 2% respectively. Contractions to K+ (40 +/- 2% maximum response to NA) were also significantly reduced by staurosporine (10(-7) M) (35 +/- 2%) but not by calphostin C (43 +/- 3%). 4. The phorbol ester, phorbol-12,13-dibutyrate (PDBu), produced a phasic, concentration-dependent contraction (10(-7) M - 10(-4) M) which was 41 +/- 2% of the maximum response to NA at 10(-4) M PDBu. The contraction to PDBu (10(-5) M) was reduced by calphostin C (10(-6) M) from 33 +/- 5% to 4 +/- 1% maximum response to NA. 5. Non-cumulative contractions to NA (10(-8) M - 10(-4) M) were abolished in Ca(2+)-free Krebs solution containing EGTA (1 mM) and were reduced in the presence of nifedipine (10(-6)M) in normal Krebs solution by 91 +/- 2% at 10(-4)M NA. The contraction to PDBu (10(-5)M, 33 +/- 5% maximum response to NA) was also abolished in Ca(2+)-free Krebs solution containing EGTA (1 mM) or by the presence of nifedipine (10(-6)M) in normal Krebs solution. 6. When NA (10(-4)M) was added to vasa deferentia in Ca(2+)-free Krebs solution containing EGTA (1 mM), following its wash out (and with EGTA later removed from the Krebs solution), readdition of Ca2+ (2.5 mM) to the Krebs solution produced no response. Cyclopiazonic acid (10(-5)M), which can deplete Ca2+ from intracellular stores, also produced no contraction. Therefore influx of extracellular Ca2+ is not a consequence of depletion of intracellular Ca2+ stores (capacitative Ca2+ influx). 7. Pre-incubation of tissues for 30 min with either cyclopiazonic acid (10(-5)M) or ryanodine (10(-4)M), which can both deplete intracellular Ca2+ stores, did not reduce the contractions to NA (3 x 10(-6)M). Pre-incubation of vasa deferentia with cyclopiazonic acid (1 or 3 min, when any rise in [Ca2+]i produced by cyclopiazonic acid might still exist) did not potentiate the contraction to PDBu (10(-5)M). Thus mobilization of intracellular Ca2+ may not be required for the activation of protein kinase C involved in these contractions. 8. In conclusion, the contraction of the rat epididymal vas deferens to NA mediated by alpha 1A-adrenoceptors appears to depend upon activation of protein kinase C by diacylglycerol, resulting in the influx of extracellular Ca2+ through voltage-gated Ca2+ channels. There was no evidence for a role of inositol trisphosphate in the contraction to noradrenaline in this tissue.

1. The mechanism of contraction to phenylephrine in the rat spleen (mediated via alpha 1B-adrenoceptors) has been studied in functional experiments. 2. The concentration-dependent contraction of the rat spleen to cumulative additions of phenylephrine (pD2 4.8 +/- 0.1) was not significantly reduced by the selective protein kinase C (PKC) inhibitor, calphostin C (10(-6)M) or potentiated by the DAG kinase inhibitor, R59022 (10(-6) M). 3. Contraction of the rat spleen in normal Krebs solution containing Ca2+ (2.5 mM) to a single concentration of phenylephrine (3 x 10(-4) M) produced a maximal response consisting of an initial phasic component and a more slowly developing tonic component. However in Ca(2+)-free Krebs solution (containing EGTA), phenylephrine (3 x 10(-4)M) produced only a phasic contraction which was reduced to 46 +/- 3% maximum response to phenylephrine in normal Krebs solution. 4. In some tissues after the contraction to phenylephrine (3 x 10(-4) M) in Ca(2+)-free Krebs solution (containing EGTA), the phenylephrine was washed out and the tissue was allowed to recover. After 2 h, upon addition of Ca2+ (2.5 mM) to the Krebs solution (EGTA now removed) a tonic contraction developed in the tissue (97 +/- 4% maximum response to phenylephrine). 5. Cyclopiazonic acid produced a tonic contraction of the rat spleen with a maximum effect at 10(-5) M (202 +/- 8% maximum response compared with that to phenylephrine). The contraction to CPA (10(-5) M) was reduced in Ca(2+)-free Krebs solution containing EGTA (30 +/- 4% of the maximum response to phenylephrine). One hour after the end of the contraction in Ca(2+)-free Krebs solution (EGTA now removed), upon addition of Ca2+ (2.5 mM) to the Krebs solution a tonic contraction developed in the tissue (263 +/- 12% maximum response to phenylephrine). 6 In Ca2+-free Krebs solution, after the spleen had been incubated with cyclopiazonic acid for 30 min,the subsequent contraction to phenylephrine (3 x 10-4 M) was reduced from 46+/-3% to 9+/-2%maximum response to phenylephrine.7 Cumulative contractions to phenylephrine and the contraction to cyclopiazonic acid (10-5 M) in the spleen were not significantly affected by nifedipine (10-6 M). The non-selective Ca2+channel blocker,SK&F 96365 (3 x 10-5 M) reduced the maximum response for the cumulative additions of phenylephrine to 35+/-1% and the contraction to CPA (10-5 M) from 202+/-8% to 108+/-8% maximum response to phenylephrine.8 The tyrosine kinase inhibitors genistein (3 x 10-5 M and tyrphostin 23 (10-4 M), reduced the maximum response to phenylephrine in the spleen to 51+/-4% and 44+/-5% respectively and the maximum contraction to cyclopiazonic acid (3 x 10-6 M) in the spleen from 132 +/- 6% to 82 +/-5% and 80 +/- 7% maximum response to phenylephrine respectively without affecting contractions to K+.9 In conclusion, these results are consistent with the contraction of the rat spleen to phenylephrine consisting of an initial phasic contraction due to release of intracellular Ca2+ and a larger tonic contraction due to capacitative Ca2+ influx through non-voltage-gated Ca2+ channels and which may involve a tyrosine kinase. This suggests that inositol triphosphate but not diacylglycerol is involved in the contraction.

1. The predominant alpha 1-adrenoceptor mediating contractions of the human vas deferens has been characterised in vitro by use of subtype selective antagonists. 2. Responses of human epididymal vas deferens were obtained to phenylephrine in the presence of amine uptake inhibitors and propranolol. The effects of the alpha 1-adrenoceptor antagonists, 5-methylurapidil, oxymetazoline, WB4101, prazosin and chloroethylclonidine were examined and also the L-type calcium channel blocker, nifedipine. 3. 5-Methylurapidil, WB4101, oxymetazoline and prazosin acted as competitive antagonists of the responses to phenylephrine, yielding pA2 values of 8.8, 9.2, 7.7 and 8.8 respectively. All four antagonists produced Schild plots with slopes similar to unity and maximum responses to phenylephrine were not altered in the presence of any of the antagonists. 4. Tamsulosin (1 nM) caused rightward shifts of phenylephrine concentration-response curves yielding an apparent pKB value of 10.0. However, maximum responses were also reduced by 51% with this concentration of antagonist. 5. Incubation of tissues with chloroethylclonidine (100 microM for 40 min) failed to alter responses significantly but the presence of nifedipine (1 microM) reduced maximum responses to phenylephrine by 32%. 6. The high affinity of 5-methylurapidil, oxymetazoline and WB4101, together with the failure of chloroethylclonidine to antagonize responses, indicate that the predominant alpha 1-adrenoceptor mediating contraction of the human vas deferens has the characteristics previously described for the pharmacologically-defined alpha 1A-adrenoceptor. The data are also consistent with those described for the cloned alpha 1c-adrenoceptor subtype thereby supporting the hypothesis that the two receptors are identical. The human vas deferens therefore represents a readily accessible preparation for functional studies of the human alpha 1A-adrenoceptor.

1. The subtype of alpha 1-adrenoceptor mediating contractions of human prostate to noradrenaline was characterized by use of a range of competitive and non-competitive antagonists. 2. Contractions of the prostate to either noradrenaline (pD2 5.5), phenylephrine (pD2 5.1) or methoxamine (pD2 4.4) were unaltered by the presence of neuronal and extraneuronal uptake blockers. Noradrenaline was about 3 and 10 times more potent than phenylephrine and methoxamine respectively. Phenylephrine and methoxamine were partial agonists. 3. Pretreatment with the alkylating agent, chlorethylclonidine (10(-4M) shifted the noradrenaline concentration-contraction curve about 3 fold to the right and depressed the maximum response by 31%. This shift is 100 fold less than that previously shown to be produced by chlorethylclonidine under the same conditions on alpha 1B-adrenoceptor-mediated contractions. 4. Cumulative concentration-contraction curves for noradrenaline were competitively antagonized by WB 4101 (pA2 9.0), 5-methyl-urapidil (pA2 8.6), phentolamine (pA2 7.6), benoxathian (pA2 8.5), spiperone (pA2 7.3), indoramin (pA2 8.2) and BMY 7378 (pA2 6.6). These values correlated best with published pKi values for their displacement of [3H]-prazosin binding on membranes expressing cloned alpha 1c-adrenoceptors and poorly with values from cloned alpha 1b- and alpha 1d-adrenoceptors. 5. The good correlation between the functional data on the prostate and the binding data on the expressed alpha 1c-subtype clone for the affinities of the competitive antagonists suggests that they are the same subtype. As the expressed alpha 1c-adrenoceptor clone corresponds to the alpha 1A-adrenoceptor expressed in tissues, contraction of the human prostate to noradrenaline is therefore mediated by an alpha 1A-adrenoceptor.

1. The alpha 1-adrenoceptor subtype mediating contraction of the rat epididymal vas deferens and rat spleen has been investigated by use of alpha 1-adrenoceptor antagonists that have shown selectivity between the different cloned receptor subtypes. 2. In the rat epididymal vas deferens the potency of noradrenaline and phenylephrine was increased in the presence of neuronal and extra-neuronal uptake blockers, cocaine and beta-oestradiol, but these did not alter that of methoxamine. The order of potency of the agonists in the presence or absence of uptake blockade was noradrenaline > phenylephrine > methoxamine. In the rat spleen the potency of these agonists was not altered in the presence of cocaine and beta-oestradiol, and their order of potency was the same as in the vas deferens. 3. The non subtype selective alpha 1-adrenoceptor antagonist prazosin (up to 1 x 10(-7) M) was found to antagonize contractions to noradrenaline in the vas deferens competitively (pA2 9.2), but only in a non competitive manner in the spleen. Contractions to phenylephrine in the spleen however were competitively antagonized by prazosin (up to 1 x 10(-7) M) with a pA2 of 9.2. This suggests that there is an alpha 1- and a non alpha 1-adrenoceptor response to noradrenaline in the rat spleen. 4. Pretreatment with chlorethylclonidine (10(-4) M for 30 min) did not alter the noradrenaline contractions in the vas deferens, but contractions to noradrenaline and phenylephrine in the spleen were shifted 30 and 300 fold to the right of the control curve, respectively. This suggests that only the contractions in the spleen were mediated by alpha 1B-adrenoceptors. 5. The noradrenaline contractions in the vas deferens were competitively antagonized by WB 4101 (pA29.6), 5-methyl-urapidil (pA2 8.7), phentolamine (pA2 8.3), benoxathian (pA2 9.4), spiperone (pA2 7.5),indoramin (pA2 8.4) and BMY 7378 (pA2 6.7), consistent with the affinities of these antagonists in binding studies on tissue alpha 1A-adrenoceptors. These values correlated best with their published affinities on the expressed alpha 1c-adrenoceptor clone and poorly with those at either the expressed alpha lb- or alpha 1d adrenoceptor clones. Therefore the classical alpha 1A-adrenoceptor appears to be the same as the expressed alpha lc-adrenoceptor clone.6. The phenylephrine contractions in the spleen were competitively antagonized by WB 4101 (pA2 8.1),5-methyl-urapidil (pA2 7.1), phentolamine (pA2 7.3), benoxathian (pA2 7.4), spiperone (pA2 7.9),indoramin (pA2 7.5) and BMY 7378 (pA2 7.4), consistent with the affinities of these antagonists in binding studies on tissue alB-adrenoceptors. The pA2 values correlated best with the published affinities of these compounds on the expressed alb-adrenoceptor clone and poorly with those at either the expressed alpha ld- or alpha lc-adrenoceptor clones. Therefore the alpha lB-adrenoceptor appears to be the same as the expressed alpha lb-adrenoceptor clone.7. The results provide pharmacological evidence that the alpha1-adrenoceptor mediating noradrenaline contractions in the epididymal portion of the rat vas deferens is the alpha 1A-(alpha lC) subtype and that contractions to phenylephrine in the rat spleen are mediated by the alpha 1B-subtype.

Objective: To review the pre-operative assessment of bladder neck competence and assess the success of non-operative management of the bladder neck in patients with pelvic fracture membranous urethral distraction defects., Patients and Methods: A series of four patients with long-standing post-pelvic fracture urethral distraction defects and open bladder necks demonstrated on pre-operative investigation are presented., Results: All four patients were managed by perineal urethroplasty without surgery to the bladder neck. All patients were continent post-operatively despite the injury having ablated the distal sphincter mechanism., Conclusion: We believe that the majority of patients can be managed successfully by a non-operative approach to the bladder neck, sparing them the unnecessary operative morbidity of an abdomino-perineal repair, which should be reserved for those with obviously scarred or distorted bladder necks.

Objective: The aim of this work was to investigate the effects of intravenously administered thyrotropin-releasing hormone (TRH) on the urethral closure pressure in a double-blind, placebo-controlled study., Patients and Methods: Sixteen female subjects with either bladder outlet obstruction (BOO) or detrusor underactivity were included in the study. Following randomization, 8 subjects (3 BOO, 5 detrusor underactivity) received 200 micrograms of TRH intravenously, and 8 (4 BOO, 4 detrusor underactivity) received saline (placebo). Standard fluid fill urethral pressure profilometry was performed at baseline and 2, 3, 5, 10, 15, and 20 min following TRH injection, measuring functional profile length (FPL), maximum urethral closure pressure (UCP), and closure pressures at the proximal quarter of the FPL (1/4 UCP) and at the distal quarter of the FPL (3/4 UCP)., Results: Significant reductions were found in both FPL (p = 0.022) and 3/4 UCP (p = 0.014) in the 'active' group as compared with the 'placebo' group., Conclusions: TRH administration significantly reduces the distal urethral closure pressure. Clarification of the mechanism of action of TRH on the urethra may point the way towards new developments in the management of female voiding dysfunction.

Objective: To determine the subset of alpha 1-adrenoceptors mediating the functional abstraction of the prostate to noradrenaline., Materials and Methods: Radioligand experiments were performed with membranes prepared from rat 1 fibroblasts transfected with rat alpha 1a, hamster alpha 1b or bovine alpha 1c adrenoceptor cDNA. Human prostatic tissue obtained from transurethral resection of the prostate with full informed consent was submitted to functional in vitro muscle strip experiments., Results: The binding experiments defined the potential subtype selectivity of various antagonists. Using this information, it was possible to define the functionally important alpha 1-adrenoceptor subtype in the human prostate., Conclusion: This work reports the results of the first functional characterization of the alpha 1c-adrenoceptor subtype. The most functionally important alpha 1-adrenoceptor type in the human prostate appears to be the alpha 1c subtype. This finding may aid the development of prostate-selective adrenoceptor pharmacotherapy.

Objective: To evaluate the efficacy and tolerability of doxazosin in the treatment of bladder outflow obstruction resulting from benign prostatic hyperplasia (BPH)., Patients and Methods: One-hundred and thirty-five patients with symptomatic urodynamically confirmed obstructive BPH were treated for 12 weeks with either doxazosin (67 patients) or placebo (68 patients) after an initial 2 week baseline evaluation. The main outcome measures were urodynamic and symptomatic evaluation for efficacy. Blood pressure and adverse events were monitored., Results: Data were obtained in 122 patients (60 doxazosin, 62 placebo). Doxazosin produced increases in both mean and maximum urinary flow rates of 1.01 ml/s and 3.2 ml/s respectively, compared with 0.21 ml/s and 2.2 ml/s on placebo. The increase in mean flow rate was statistically significant (P = 0.04), while that for maximum flow rate approached significance (P = 0.09). The maximum subtracted voiding pressure was substantially reduced (P = 0.007) and 19 of 53 (36%) patients had an increase in maximum flow rate of 50% or more compared with 9 of 54 (17%) on placebo (P = 0.024). Twelve weeks' therapy with doxazosin resulted in significant improvements (compared with placebo) in: hesitancy (doxazosin 26 of 46, placebo 11 of 43; P = 0.003), impaired urinary stream (doxazosin 31 of 55, placebo 16 of 48; P = 0.019) nocturia (doxazosin 22 of 56, placebo 10 of 54; P = 0.017) and urgency (doxazosin 27 of 45, placebo 16 of 42; P = 0.041). Frequency improved with doxazosin therapy (doxazosin 26 of 59, placebo 15 of 55; P = 0.062). Adverse events, most frequently dizziness and headache, were usually mild and transient and led to a discontinuation of doxazosin therapy in one patient. No clinically significant changes in sexual function or blood pressure were seen., Conclusion: Doxazosin was well-tolerated and produced both urodynamic and symptomatic improvement in men with BPH, thereby providing a satisfactory alternative to existing drugs with the additional benefit of once daily dosage.

Paget's disease of the male external genitalia is rare. We describe a case involving the glans penis, 2 years following total cysto-urethrectomy for invasive transitional cell carcinoma of the bladder and review the literature on this unusual malignancy.

Renal adenocarcinoma is rare in young people. The prognosis of the condition would appear to be better in young people justifying a radical treatment rationale even in cases of advanced disease. This report describes a series of patients under the age of 30 with renal adenocarcinoma and a review of the literature. The possible mechanisms for the apparent improved survival of patients in this age group is discussed.

Alternative treatments for benign prostatic hyperplasia (BPH) are the source of much discussion at present. Pharmacotherapy has been demonstrated to have an increasing role in the management of BPH. This study contrasts the efficacy of the selective alpha antagonist prazosin as compared with placebo and the subsequent improvements seen following surgical treatment. Whilst selective alpha blockade has undoubted therapeutic efficacy the improvement in symptom scores and the objective urodynamic measure of the flow rate are not as marked as those seen following surgery.

There were 54 patients entered into this study of the UroLume permanent prostatic stent, most of whom were unfit for conventional prostatic surgery. The stents were inserted with the patient under local or regional anesthesia. Of the patients 34 presented in acute retention, 12 had chronic retention, 4 had severe and worsening symptoms, and 4 had symptoms and urodynamic evidence of obstruction occurring in the presence of Parkinson's disease. Following stent insertion 50 patients were able to void satisfactorily, while the remaining 4 presented with chronic retention and detrusor failure. The 40 patients who had no or minimal remaining symptoms were satisfied with the stent. Most patients experienced frequency and urgency of micturition for 1 to 3 months, which resolved in all but 9 patients with persistent severe detrusor instability. Symptom scores decreased to 6.5 (total) at 1 year for nonretention patients and 6.0 for retention patients. Stents were covered with epithelium within 6 to 9 months. However, when the stent was positioned with any part of the proximal end within the bladder or when the stent could not be epithelialized incrustation occurred (14 cases, all of which were asymptomatic). No serious urosepsis was noted in any patient in this study. Six stents were removed endoscopically without difficulty or damage to the urethra at up to 18 months. The implications of these findings to the potential role of the UroLume stent in the management of a wider range of patients with prostatic obstruction are discussed.

Controlled clinical studies have demonstrated that blockade of alpha 1-adrenergic receptors relaxes prostatic muscle tone and decreases the symptoms of benign prostatic hyperplasia (BPH). Doxazosin, a once-daily quinazoline derivative and postsynaptic alpha 1-adrenoceptor antagonist, proven as treatment for hypertension, was evaluated in the treatment of BPH in dosages of 1-16 mg. 456 BPH patients (287 doxazosin-treated and 169 placebo-treated) were evaluated for efficacy and safety in five double-blind, placebo-controlled clinical studies. Doxazosin treatment resulted in improvements in both urodynamic and symptomatic parameters associated with BPH. Efficacy was only assessed in 1, 2 and 4 mg. Adverse experiences were reported in 127 (44.3%) of the patients treated with doxazosin and in 49 (29%) of the patients treated with placebo. Fifteen (5.2%) doxazosin patients and 4 (2.4%) placebo patients withdrew from the studies due to adverse effects. Results from these five clinical trials demonstrate doxazosin is effective and safe and well tolerated in both normotensive and hypertensive patients with BPH.

The principal aim of this study was to provide an objective assessment of the potential role of urethral pressure profilometry as a technique for assessing prostatic size by direct comparison with endoscopic assessment of prostatic length and computed tomographic measurement of prostatic volume and length. There was a poor correlation between pre-operative prostatic length and amount resected in the operating theatre. The results obtained with urethral pressure profilometry correlated poorly with those obtained using the other techniques, and cannot therefore be relied upon in routine clinical practice. Although there was good correlation between the length of the prostate and prostatic size, assessed by pre-operative computed tomography, this correlated poorly with the amount of tissue resected at operation. Further studies need to be conducted to compare objectively the completeness of prostatic resection with the outcome following prostatectomy.

Different regions of the prostate gland, namely prostatic capsule, peripheral prostate and central prostate (subdivided into proximal (near the bladder neck), distal (near the verumontanum) and midway between these areas) were obtained from 32 obstructed (stable obstructed, n = 8; unstable obstructed, n = 13; acute retention, n = 11) and five control patients. The innervation of these tissues was studied both histochemically to localise acetylcholinesterase activity and immunohistochemically for dopamine-beta-hydroxylase, 5-hydroxytryptamine, vasoactive intestinal polypeptide, neuropeptide Y, leu- and met-enkephalin, calcitonin gene-related peptide, substance P and somatostatin. In control patients the greatest density of nerves was found in the proximal central prostate, followed by the anterior capsule and distal central prostate, with the least density in the peripheral prostate. The greatest density of nerves were acetylcholinesterase positive and immunoreactive to neuropeptide Y followed (in decreasing order) by nerves immunoreactive to: vasoactive intestinal polypeptide and dopamine beta-hydroxylase; leu-enkephalin and 5-hydroxytryptamine; calcitonin gene-related peptide; met-enkephalin; substance P; somatostatin. In addition a group of periacinar 5-hydroxytryptamine-immunoreactive cells and ganglia containing acetylcholinesterase, dopamine beta-hydroxylase and all of the peptides studied except somatostatin were identified. In the prostate gland from obstructed patients there was a significant reduction in the density of acetylcholinesterase-positive nerves (p less than 0.001) when compared with the controls. A similar trend was found for dopamine beta-hydroxylase, 5-hydroxytryptamine and all of the putative neuropeptides in most areas of the prostate, the most notable exceptions being in the peripheral prostate, with an increase in dopamine beta-hydroxylase- and leu-enkephalin-immunoreactive nerves in all three groups of obstructed patients an an increase in vasoactive intestinal polypeptide- and calcitonin gene-related peptide-immunoreactive nerves in those presenting in urinary retention. The functional significance of these findings is discussed.