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.

Heat/burning sensation induced by topical application of capsaicin on perineal cutaneous area: new approach in diagnosis and treatment of chronic prostatitis/chronic pelvic pain syndrome?

OBJECTIVES: To investigate the feasibility, safety, and efficacy of perineal cutaneous application of capsaicin as a test for the diagnosis, as well as a potential therapeutic tool, in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). METHODS: We recruited 22 patients (mean age 34.5 years, range 19 to 56), who had been diagnosed with CP/CPPS according to the National Institutes of Health criteria, and 6 healthy control subjects. Both groups received a topical application of 5 mL capsaicin at a concentration of 10(-5) M to the perineal body skin. The patients were asked to mark on a visual analogue scale the intensity of any heat or burning sensation. All the patients had completed a National Institutes of Health Chronic Prostatitis Symptom Index before and 1 week after the test. The scores of the two groups were compared using the Mann-Whitney U test. RESULTS: The patients with CP/CPPS reported a heat/burning sensation intensity that was statistically greater than that of the healthy controls (7.5 versus 4.3, P <0.001) and a shorter time to heat sensation onset and maximal intensity (1.5 versus 3.4 minutes, P <0.001, and 2.5 versus 7 minutes, P <0.001, respectively). Of the 22 patients, 16 reported an improvement of symptoms after 7 days and the mean National Institutes of Health Chronic Prostatitis Symptom Index score decreased from 27 to 16 (P <0.01). CONCLUSIONS: We found a statistically significant difference in the pain visual analogue scale and interval between topical application and the onset of the heat/burning sensation between patients with CP/CPPS and healthy controls. The small sample size strongly suggests the need for additional larger and more controlled studies.

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).

Urodynamic effects of intravesical nociceptin/orphanin FQ in neurogenic detrusor overactivity: a randomized, placebo-controlled, double-blind study.

OBJECTIVES: To evaluate the acute urodynamic effects of the neuropeptide nociceptin/orphanin FQ (N/OFQ) in a selected group of patients with neurogenic detrusor overactivity incontinence in a randomized, placebo-controlled, double-blind study. METHODS: The study involved 14 patients who presented with neurogenic detrusor overactivity due to spinal cord injury. They were randomized to receive intravesical infusion of 1 microM N/OFQ or the same dose of [desPhe(1)]N/OFQ (the placebo). The urodynamic parameters were the bladder capacity, volume threshold for the appearance of detrusor overactivity, and the maximal bladder pressure. The study was performed on a double-blind basis: neither the patients nor the doctors who performed the instillation could distinguish the solution containing N/OFQ from that containing [desPhe(1)]N/OFQ. Data are expressed as the mean +/- SD of seven determinations. Data were statistically analyzed using the Student t test for paired or unpaired data and P <0.05 was set as the criterion for a statistically significant difference. RESULTS: The two groups were well balanced with respect to mean age, male/female ratio, etiology of spinal cord disease, and years from the lesion. Also, the baseline mean values of bladder capacity, volume threshold for the appearance of detrusor overactivity, and maximal bladder pressure were similar. The intravesical infusion of the solution containing 1 microM N/OFQ produced the following changes: bladder capacity and volume threshold for the appearance of detrusor overactivity significantly increased from 139 +/- 48 mL to 240 +/- 61 mL, and from 84 +/- 32 mL to 201 +/- 68 mL, respectively. Maximal bladder pressure decreased from 81 +/- 25 cm H(2)O to 66 +/- 12 cm H(2)O; however, this difference was not statistically significant. The intravesical infusion of the solution containing 1 microM [desPhe(1)]N/OFQ did not produce any statistically significant modification of the urodynamic parameters. CONCLUSIONS: The results of this study confirm and extend previous results showing that N/OFQ, but not the placebo, elicits a robust acute inhibitory effect on the micturition reflex in patients with a neurogenic bladder. These findings apply nociceptin orphan peptide receptor agonists as potential novel drugs for the treatment of neurogenic urinary incontinence.