Damiano Turini

Cystometric Evidence that Capsaicin-Sensitive Nerves Modulate the Afferent Branch of Micturition Reflex in Humans

Intravesical instillation of capsaicin (0.1 to 10 microM) in six patients (five with hypersensitive disorders of the lower urinary tract, one with benign prostatic hyperplasia) produced a concentration-related reduction of the first desire to void, bladder capacity and pressure threshold for micturition. At a threshold concentration of one microM, capsaicin also produced a warm to burning sensation referred to the suprapubic area during the collecting phase and to the urethra during micturition. All the patients with hypersensitive disorders of the lower urinary tract reported disappearance or marked attenuation of their symptoms for a few days after capsaicin application. In three other patients with hypersensitive disorders of the lower urinary tract, intravesical instillation of capsaicins vehicle (0.1% ethanol in saline) did not produce significant cystometric changes nor modify the symptomatology. These observations provide the first indication that capsaicin-sensitive structures (nerves?) may be present in the human urinary bladder as they have been shown to occur in various other species.

INTRAVESICAL RESINIFERATOXIN FOR THE TREATMENT OF HYPERSENSITIVE DISORDER: A RANDOMIZED PLACEBO CONTROLLED STUDY

PURPOSE Present therapeutic approaches to control hypersensitive disorder of the lower urinary tract and bladder pain are clinically and scientifically unsatisfactory. We performed a randomized placebo controlled study with followup after 1 and 3 months using intravesical resiniferatoxin to treat hypersensitive disorder and bladder pain. MATERIALS AND METHODS We prospectively randomized 18 patients into 2 groups to receive a single dose of 10 nM. resiniferatoxin intravesically (group 1) or a placebo saline solution only (group 2). All patients had at least a 6-month history of frequency, nocturia, urgency and symptoms of pelvic pain as well as no urinary tract infection within the last 3 months, functional disorders of the lower urinary tract, or other vesical or urethral pathology. Pretreatment voiding pattern and pain score were recorded. Patients were evaluated after 30 days (primary end point) and 3 months (secondary end point). RESULTS The 2 groups were adequately homogeneous in regard to patient age, sex ratio, disease duration, voiding pattern and pain score. At the primary end point mean frequency plus or minus standard error of mean was decreased from 12. 444 +/- 0.70 voids to 7.111 +/- 0.67 and nocturia from 3.777 +/- 0. 27 to 1.666 +/- 0.16 (p <0.01). We observed a lesser significant improvement in mean frequency in group 1 at the secondary end point to 10.444 +/- 0.94 voids (p <0.05). No significant modification was noted in patients assigned to placebo. Mean pain score significantly decreased in group 1 at the primary end point from 5.555 +/- 0.29 to 2.666 +/- 0.23 (p <0.01) but not at the secondary end point (4.777 +/- 0.66, p >0.05). No statistically significant improvement in mean pain score was observed in placebo group 2. During resiniferatoxin infusion 4 group 1 patients noticed a light warm or burning sensation at the suprapubic and/or urethral level. CONCLUSIONS Intravesical resiniferatoxin may significantly improve the voiding pattern and pain score in patients with hypersensitive disorder and bladder pain. Because resiniferatoxin did not cause a significant warm or burning sensation at the suprapubic and/or urethral level, it may be considered a new strategy for treating hypersensitive disorder and bladder pain. However, further studies are necessary to confirm our results and define the resiniferatoxin mechanism of action, dose and necessary treatment schedule.

URODYNAMIC EFFECTS OF INTRAVESICAL RESINIFERATOXIN IN HUMANS: PRELIMINARY RESULTS IN STABLE AND UNSTABLE DETRUSOR

PURPOSE Resiniferatoxin, a substance isolated from some species of euphorbia, a cactus-like plant, presents pharmacological effects similar to those of capsaicin. We studied the urodynamic effects of intravesical resiniferatoxin* in normal subjects and patients with unstable detrusor contraction to provide insight into the action mechanism of the molecule on sensory neurons and possible future pharmacological and clinical use. MATERIALS AND METHODS A total of 15 subjects with normal (8 patients) or unstable detrusor muscle (1 with detrusor instability and 6 with detrusor hyperreflexia) underwent urodynamic assessment during and after intravesical instillation of resiniferatoxin. Volume required to elicit the first desire to void, maximum bladder capacity and maximum bladder pressure were recorded during instillation of resiniferatoxin at a flow rate of 20 ml. per minute (normal subjects) or 15 minutes after instillation of 30 cc of a saline solution containing 10(-8) M. of resiniferatoxin and kept for 30 minutes in patients with unstable detrusor. The experiment was examined by the analysis of variance for repeated measures and post hoc comparisons were performed by Tukey-Kramer procedure. A p value <0.05 was accepted as significant. RESULTS Resiniferatoxin did not decrease the volume required to elicit the first desire to void and did not produce warm or burning sensations at the suprapubic/urethral level during infusion in subjects with normal detrusor function. In patients with bladder hyperactivity mean bladder capacity increased from 175.28 ml. plus or minus standard deviation 36.05 to 280.85 ml. plus or minus standard deviation 93.33 (p <0.01) immediately after treatment, and no significant modification of bladder pressure was recorded. Four weeks after treatment, bladder capacity remained increased in 2 patients but mean capacity did not increase significantly from 175.28 ml. plus or minus standard deviation 36.053 to 216.71 plus or minus standard deviation 86.91. The 2 patients with stable increase of bladder capacity reported significant clinical improvement of frequency, nocturia and incontinence 4 weeks later. CONCLUSIONS Our results suggest that in humans there may be substantial differences in urodynamic effects between resiniferatoxin and capsaicin when the drugs are instilled into the bladder. Further studies, in vitro and in vivo, are necessary to define the pharmacological and clinical effects of resiniferatoxin. Because resiniferatoxin did not produce warm or burning sensations at the suprapubic/urethral level during infusion and seems to have rapid desensitization, it could be an interesting alternative to intravesical capsaicin in the treatment of select cases of bladder hyperactivity.

Intravesical Capsaicin for Treatment of Severe Bladder Pain: A Randomized Placebo Controlled Study

PURPOSE Present therapeutic approaches to control bladder pain are clinically and scientifically unsatisfactory, and pain in the lower urinary tract remains a challenge even to the skilled urologist. A randomized placebo controlled study was done to evaluate intravesical capsaicin for severe bladder pain. Followup was 6 months. MATERIALS AND METHODS A total of 36 patients was prospectively randomized into those receiving 10 microM. intravesical capsaicin twice weekly for 1 month (group 1) or placebo (group 2). All patients had pelvic pain for at least 6 months, and had no urinary tract infection within the last 3 months, functional disorders of the lower urinary tract, or other vesical or urethral pathology. Pretreatment voiding pattern and pain score were recorded. Patients were evaluated immediately at the end of treatment (primary end point) and 6 months later (secondary end point). RESULTS Both groups were adequately homogeneous with regard to age, sex ratio, duration of disease, voiding pattern and pain score. At both end points group 1 had significant improvement in frequency and nocturia but no improvement in urgency. No change was noted in group 2. A significant decrease in pain score was found in group 1 at the primary (mean plus or minus standard deviation 3.22 +/- 0.42, p < 0.01) and secondary (3.83 +/- 0.47, p < 0.01) end points compared to before treatment (5.61 +/- 0.40, chi-square with 2 degrees of freedom 29.25, p < 0.0001). A significant improvement was also observed in the placebo group, in which the pretreatment pain score (5.47 +/- 0.37) was decreased at the primary (4.47 +/- 0.36, p < 0.01) and secondary (4.48 +/- 0.34, p < 0.01, chi-square with 2 degrees of freedom 12.71, p < 0.002) end points. There were no statistically significant differences between the 2 groups. CONCLUSIONS We confirmed the beneficial effect of intravesical instillation of capsaicin on voiding pattern in patients with hypersensitive disorders (frequency and nocturia). We could not confirm improvement in pain score after capsaicin treatment compared to placebo. Possibly a larger dose of capsaicin would be more effective in controlling pain and neurological disease of the bladder.

LONG-TERM OUTCOME OF URETHROPLASTY AFTER FAILED URETHROTOMY VERSUS PRIMARY REPAIR

PURPOSE A urethral stricture recurring after repeat urethrotomy challenges even a skilled urologist. To address the question of whether to repeat urethrotomy or perform open reconstructive surgery, we retrospectively review a series of 93 patients comparing those who underwent primary repair versus those who had undergone urethrotomy and underwent secondary treatment. MATERIALS AND METHODS From 1975 to 1998, 93 males between age 13 and 78 years (mean 39) underwent surgical treatment for bulbar urethral stricture. In 46 (49%) of the patients urethroplasty was performed as primary repair, and in 47 (51%) after previously failed urethrotomy. The strictures were localized in the bulbous urethra without involvement of penile or membranous tracts. The etiology was ischemic in 37 patients, traumatic in 23, unknown in 17 and inflammatory in 16. To simplify evaluation of the results, the clinical outcome was considered either a success or a failure at the time any postoperative procedure was needed, including dilation. RESULTS In our 93 patients primary urethroplasty had a final success rate of 85%, and after failed urethrotomy 87%. Previously failed urethrotomy did not influence the long-term outcome of urethroplasty. The long-term results of different urethroplasty techniques had a final success rate ranging from 77% to 96%. CONCLUSIONS We conclude that failed urethrotomy does not condition the long-term result of surgical repair. With extended followup, the success rate of urethroplasty decreases with time but it is in fact still higher than that of urethrotomy.

Penile Carcinoma in Patients With Genital Lichen Sclerosus: A Multicenter Survey

PURPOSE In this observational descriptive study we reviewed the histology and the clinical records of 130 patients with LS involving the male genitalia to determine the presence of premalignant or malignant lesions. MATERIALS AND METHODS A total of 130 male patients (from 1991 to 2001) with genital LS were treated at our centers. Mean patient age at diagnosis was 42.5 years. In all patients with a clinical diagnosis of LS, the histology was reexamined to look for evidence of LS, applying strict histological criteria. All cases of histologically proven epithelial malignancy, namely SCC, VC and EQ, were reviewed to confirm the presence of neoplastic changes and ascertain the degree of SCC differentiation. RESULTS Of 130 men 11 (8.4%) with genital LS showed premalignant or malignant histopathological features including 7 (64%) with SCC, 2 (18%) with VC, 1 (9%) with EQ and 1 (9%) with SCC associated with VC. In 6 of 11 patients (55%) the histological study showed the presence of epithelial dysplasia. CONCLUSIONS Survival of patients with penile carcinoma depends on early diagnosis and treatment, and all patients with genital LS should be observed closely to detect the development of neoplastic or preneoplastic lesions as early as possible.

Tachykinin antagonists inhibit nerve-mediated contractions in the circular muscle of the human ileum: Involvement of neurokinin-2 receptors

The effects of some newly developed tachykinin antagonists that are selective for the neurokinin (NK)-1 (L 668,169) or the NK-2 (MEN 10,207, L 659,877 and R 396) tachykinin receptor on the cholinergic and noncholinergic contraction and on the nonadrenergic noncholinergic relaxation produced by electrical field stimulation (50 Hz) were investigated in mucosa-free circular strips of the human ileum. The strips were contracted by substance P and neurokinin A as well as by selective NK-2-receptor ligands, [beta Ala8]neurokinin A(4-10), and MDL 28,564, the latter peptide being capable of discriminating between NK-2-receptor subtypes. The selectivity of the antagonists for NK-1 or NK-2 receptors was confirmed in pharmacological experiments using substance P, neurokinin A, and [beta Ala8]neurokinin A(4-10) as stimulants. Among the NK-2-selective antagonists, MEN 10,207 displayed the highest affinity, followed by L 659,877 and R 396. The antagonists MEN 10,207 and L 659,877 inhibited the noncholinergic contraction to electrical stimulation in a concentration-dependent manner; L 668,169 and R 396 were poorly effective. Thus the potency of antagonists toward the noncholinergic response closely paralleled their rank order of potency at NK-2 receptors. The cholinergic contraction and nonadrenergic noncholinergic relaxation were not inhibited by the antagonists. Both substance P- and neurokinin A-like immunoreactivities were detected in extracts of the human ileum, and the identity of the corresponding peptides was confirmed by reverse-phase high-performance liquid chromatography. It was concluded that in addition to NK-1 receptors, the circular muscle of the human ileum also contains NK-2 receptors. Activation of the latter is chiefly responsible for the noncholinergic contraction to nerve stimulation.

Conservative Surgical Treatment of Renal Cell Carcinoma: Clinical Experience and Reappraisal of Indications

During a 14-year period 36 patients who presented with renal cell carcinoma underwent conservative surgical treatment. The patients were divided into 3 groups according to treatment indications and condition of the contralateral kidney: group 1 included patients with a solitary kidney or bilateral tumors, group 2 patients had a damaged contralateral kidney and group 3 patients were without abnormalities of the contralateral kidney. Cumulative 6-year survival rates were 58 per cent for group 1, and 90 per cent for groups 2 and 3 combined. The over-all cumulative 6-year survival rate was 74 per cent. Based on these data extension of the indication for conservative surgical treatment seems to be justified in patients who present with low stage tumors and partial or potential damage to the contralateral organ.

NK2 tachykinin receptors and contraction of circular muscle of the human colon: characterization of the NK2 receptor subtype

The contractile effect of substance P, neurokinin A, receptor selective agonists for tachykinin receptors and NK2 tachykinin receptor antagonists was investigated in mucosa-free circular strips of the human isolated colon. Neurokinin A and substance P produced concentration-dependent contractions which approached 80-90% of the maximal response to carbachol. Neurokinin A was about 370 times more potent than substance P. The action of neurokinin A and substance P was not modified by peptidase inhibitors (bestatin, captopril and thiorphan, 1 microM each). The NK2 receptor selective agonist, [beta-Ala8]neurokinin A-(4-10) closely mimicked the response to neurokinin A while NK1 and NK3 receptor selective agonists were active only at microM concentrations. The pseudopeptide, MDL 28,564, which is one of the most selective NK2 ligands available, behaved as a full agonist. Responses to [beta-Ala8]neurokinin A were antagonized by NK2 receptor selective antagonists, with the rank order of potency MEN 10,376 greater than L 659,877 much greater than R 396. These data indicate that NK2 tachykinin receptors play a dominant role in determining the contraction of the circular muscle of the human colon to peptides of this family. The NK2 receptor subtype responsible for this effect belongs to the same subtype (NK2A) previously identified in the rabbit pulmonary artery and guinea-pig bronchi.

Potent contractile activity of endothelin on the human isolated urinary bladder

Endothelin (1 nm‐0.3μm) produced a concentration‐related contraction of mucosa‐free muscle strips excised from the dome of the human urinary bladder. The response to endothelin was unaffected by either atropine (1 μm) or nifedipine (1 μm) at concentrations that abolished the response to carbachol and KCl, respectively. These findings indicate that mechanisms other than activation of dihydropyridine‐ and voltage‐sensitive calcium channels may be involved in the action of endothelin on smooth muscles.