Daily intravesical instillation of 1 mg nociceptin/orphanin FQ for the control of neurogenic detrusor overactivity: a multicenter, placebo controlled, randomized exploratory study.

PURPOSE: We studied the feasibility, safety and efficacy of daily intravesical instillation of 1 mg of the endogenous peptide nociceptin/orphanin FQ in a selected group of patients who perform clean intermittent self-catheterization for neurogenic detrusor overactivity incontinence. MATERIALS AND METHODS: A total of 18 patients with neurogenic detrusor overactivity incontinence and on clean intermittent self-catheterization were prospectively randomized to receive 1 mg nociceptin/orphanin FQ in 10 cc saline (9) or placebo (saline) solution (9) at the first morning catheterization for 10 days. All patients completed a voiding diary using a frequency/volume chart according to International Continence Society guidelines, and reported daily incontinence frequency. Mean changes in incontinence episode frequency and voiding diary mean bladder capacity from baseline throughout treatment were the primary outcome variables. Urodynamic parameters (cystomanometric bladder capacity, maximum bladder pressure) were also recorded at baseline and during the study. RESULTS: The 2 groups were well balanced and all patients completed the study. The urodynamic parameters recorded during the study showed an increase in cystomanometric bladder capacity and a decrease in maximum bladder pressure compared to baseline only in patients assigned to the nociceptin/orphanin FQ group. Mean daily urine leakage episodes during nociceptin/orphanin FQ treatment were 0.94 vs a pretreatment baseline of 2.18 (p < 0.05), while no significant changes were reported in the placebo group (2.06 vs 2.43 baseline). The total mean voiding diary bladder capacity increased from 171 +/- 70 to 294 +/- 107 ml in patients receiving nociceptin/orphanin FQ, while voiding diary mean bladder capacity remained unchanged in patients receiving placebo (from 182 +/- 55 to 178 +/- 23 ml). No significant problems related to feasibility of the procedure as well as significant side effects were reported by patients. CONCLUSIONS: This study showed that intravesical nociceptin/orphanin FQ but not placebo inhibited the micturition reflex in patients with neurogenic detrusor overactivity incontinence, and demonstrated the clinical efficacy of nociceptin/orphanin FQ during 10 days of treatment. These findings support the use of nociceptin/orphanin FQ peptide receptor agonists as an innovative therapeutic approach for controlling detrusor overactivity incontinence.

Bulbar urethroplasty using buccal mucosa grafts placed on the ventral, dorsal or lateral surface of the urethra: are results affected by the surgical technique?

PURPOSE: The use of buccal mucosa graft onlay urethroplasty represents the most widespread method of bulbar urethral stricture repair. The graft may be placed on the ventral or dorsal urethral surface according to surgeon experience and preference. We investigated whether the results are affected by the surgical technique by comparing the outcome of 3 types of bulbar urethroplasty using buccal mucosa graft. MATERIAL AND METHODS: We repaired 50 bulbar urethral strictures with buccal mucosa grafts from 1997 to 2002. Mean patient age was 42 years. The etiology of stricture was ischemia in 12 cases, trauma in 6, instrumentation in 4 and unknown in 28. Patients with lichen sclerosus, failed hypospadias or urethroplasty and stricture extending into the penile urethra were not included. A total of 47 patients (94%) had undergone previous urethrotomy or dilation. The buccal mucosa graft was always harvested from the cheek using a 2 team approach. Mean graft length was 4.2 cm. The graft was placed on the ventral, dorsal and lateral bulbar urethral surface in 17, 27 and 6 cases, respectively. Clinical outcome was considered a success or failure at the time that any postoperative procedure was needed, including dilation. Mean followup was 42 months (range 12 to 76). RESULTS: Of 50 cases 42 (84%) were successful and 8 (16%) failed. The 17 ventral grafts provided success in 14 cases (83%) and failure in 3 (17%). The 27 dorsal grafts provided success in 23 cases (85%) and failure in 4 (15%). The 6 lateral grafts provided success in 5 cases (83%) and failure in 1 (17%). No surgical complications were observed. Failures involved the anastomotic site (distal in 2 and proximal in 3) and the whole grafted area in 3 cases. They were treated with urethrotomy in 5 cases and 2-stage urethroplasty in 3. CONCLUSIONS: In our experience the placement of buccal mucosa grafts into the ventral, dorsal or lateral surface of the bulbar urethra showed the same success rates (83% to 85%) and the outcome was not affected by the surgical technique. Moreover, stricture recurrence was uniformly distributed in all patients.

Transient receptor potential vanilloid type 1 (TRPV1) expression changes from normal urothelium to transitional cell carcinoma of human bladder.

OBJECTIVE: To investigate possible changes in the expression of the transient receptor potential vanilloid type 1 (TRPV1) from normal urothelium to transitional cell carcinoma (TCC) of human bladder. METHODS: Specimens from normal bladder (n=13, mean age 62 yrs), superficial TCC (n=16, mean age 62,4 yrs) and muscle invasive bladder cancer (n=12, mean age 67 yrs), were obtained by multiple cold cup and full-thickness biopsy during open surgery. All the specimens were processed for H&E staining, immunohistochemistry and Western Blot analysis. RESULTS: In controls, the urothelium showed a labelling whose intensity was higher in the superficial cells than in the basal and club-shaped ones. In the superficial TCC, the urothelium showed a reduced labelling intensity. In the muscle invasive TCC, a very light labelling was occasionally detected in scattered superficial cells and no labelling was present in the basal cells and in those that had invaded the muscle. In controls, Western Blot analysis recognized two thick, intensely stained bands, with a molecular weight of approximately 100 and 95 kDa. In all superficial TCC there were two bands similar to control ones and in the muscle invasive two very thin, lightly stained bands. No band was detected in the patients staged as pT4. CONCLUSION: These data demonstrated a progressive loss of TRPV1 expression in the urothelium as TCC stage increased and cell differentiation was lower. Future studies will establish the importance of this loss for TCC differentiation and progression.

Immunohistochemical evidence of vanilloid receptor 1 in normal human urinary bladder.

PURPOSE: Experimental and clinical evidences have shown the importance of the vanilloid receptor 1 (TRPV1) in the lower urinary tract. In humans, this receptor has been detected in nerve endings of primary sensory neurons, smooth muscle and connective tissue cells and in the rat also in the urothelium. The aim of this study is to identify, by immunohistochemistry, the cell types expressing TRPV1 in the human urinary bladder. MATERIAL AND METHODS: Specimens, obtained from normal urinary bladder by multiple biopsy and from ureter at the time of radical nefrectomy for renal cell carcinoma, were fixed and frozen. Full-thickness sections were processed for light and fluorescence microscopes. To label the TRPV1, three polyclonal antibodies were used: the anti-capsaicin receptor, the anti-VR1 (N-15) and the anti-VR1 (C-15). RESULTS: Urothelium, smooth muscle cells, mast cells and endothelium were labelled and the labelling was intracytoplasmatic. In the urothelial cells, the labelling was slightly granular. In the bladder urothelium, the superficial cells were more intensely stained than the basal and club-shaped cells. VR1-positive nerve fibers were seen running single and/or in groups in the sub-urothelium and as single varicose fibers in the muscle coat, and VR1-positive nerve endings in the urothelium. CONCLUSION: The present findings provide the evidence of the presence of TRPV1 on normal human urothelium where it could have important implications in the mechanism of action of intravesical vanilloids (capsaicin and resiniferatoxin).

New 2-stage buccal mucosal graft urethroplasty.

PURPOSE: Previously buccal mucosal grafts used for repairing adult bulbourethral stricture with the 1-stage dorsal technique has provided a satisfactory outcome in our experience. We present the wider use of buccal mucosal grafts for 2-stage urethroplasty. MATERIALS AND METHODS: A total of 24 men 25 to 60 years old (median age 45) with a complex bulbar stricture underwent 2-stage urethroplasty using a buccal mucosal graft to repair the perineostomy. The primary etiology of stricture was traumatic in 4 cases, inflammatory in 16 and unknown in 4. The 2 x 6 cm. graft was harvested from the inner cheek and sutured to the left margin of the urethral mucosal plate with running 6-zero polyglactin suture. Patients were discharged from the hospital within 3 days with a 14Fr silicone urethral catheter in place. Radiological studies and urethroscopy were done 1 year after closure. RESULTS: A final successful outcome with no recurrent stricture was achieved in 23 of 24 men (92.8%) at a median followup of 18 months (range 13 to 32). In 1 case a urethrocutaneous fistula at the initial radiological assessment closed spontaneously after 14 days of catheterization. No urethral diverticula developed. The mean postoperative peak flow rate is 22 ml. per second (range 18 to 25). CONCLUSIONS: Our new 2-stage buccal mucosal graft urethroplasty may be an excellent technique for complex bulbar urethral stricture disease. Our suggestions may increase usefulness of the 2-stage technique for repairing complex strictures due to the avoidance of classic complications.