Electromotive delivery of mitomycin C into human bladder wall.

The aim of this investigation was to establish an appropriate tissue pharmacokinetic model to compare concentrations of mitomycin C (MMC) in the human bladder wall after either passive delivery or electromotive administration (EMDA) and to evaluate the effects of EMDA on tissue morphology and MMC structure. Tissue sections of human bladder were inserted into two chamber cells with urothelium exposed to donor compartments containing MMC (10 mg in 100 ml of 0.24% NaCl solution) and an anode and with serosa exposed to receptor compartments containing 100 ml of 0.9% NaCl solution and a cathode. Fourteen paired experiments ("current 5 mA/no current") were conducted over 15 min; MMC tissue content was assessed by high-pressure liquid chromatography. Tissue viability and morphology and MMC stability were assessed by trypan blue exclusion test, tissue pH, histological analysis, and mass spectrometry analysis. MMC concentrations were increased, and variability in drug delivery rate was reduced in all tissue in samples exposed to electric current. Tissues were viable and undamaged histologically, and no MMC structural modification was observed. In conclusion, EMDA enhances administration of MMC into viable bladder wall tissue and reduces the variability in drug delivery rates.

Electromotive versus passive diffusion of mitomycin C into human bladder wall: concentration-depth profiles studies.

The objectives of these investigations were: (a) to make a preliminary study to assess concentration-depth profiles of mitomycin C (MMC) in the bladder wall at specified time intervals after passive diffusion (PD); and (b) to conduct a major study to compare concentration-depth profiles after PD and electromotive drug administration (EMDA) of MMC. Full thickness sections of viable human bladder wall were placed in two-chamber cells with urothelium exposed to donor compartments containing 40 mg of MMC in 100 ml of 0.96% NaCl solutions and with serosa-facing receptor compartments containing 0.9% NaCl solutions. In the preliminary study during each of nine experimental sessions, five sections of bladder wall were individually exposed to MMC for either 5, 15, 30, 45, or 60 min. In the major study, an anode and a cathode were sited in the donor and receptor compartments, and 14 paired experiments--current (20 mA)/no current--were conducted over a 30-min period. Bladder wall sections were cut serially into 40-microm slices parallel to the urothelium and analyzed by high-performance liquid chromatography for MMC concentration (microg/g wet tissue weight). Tissue viability and morphology and MMC stability were assessed by trypan-blue exclusion test, histological examination, and mass spectrometry analysis. In the preliminary study (PD only), mean MMC concentrations (microg) at 5, 15, 30, 45, and 60 min were: (a) for urothelium, 15.3, 60.0, 58.2, 60.1, and 57.8, respectively; (b) for lamina propria, 2.2, 18.9, 19.3, 16.1, and 17.3, respectively; and (c) for muscularis, 0.4, 2.0, 1.8, 1.3, and 2.4, respectively. In the comparative study, MMC concentrations and coefficients of variation (CV) were as follows: (a) for urothelium after PD, 46.6 with CV = 69%, and after EMDA, 170.0 with CV = 43% (P < 0.0001); (b) for lamina propria after PD, 16.1, with CV = 60%, and after EMDA, 65.6 with CV = 29% (P < 0.0001); and (c) for muscularis after PD, 1.9 with CV = 82%, and after EMDA, 15.9 with CV = 82% (P < 0.0005). All of the bladder sections remained viable, and the chemical structure of MMC was unchanged. It was concluded that EMDA significantly enhances MMC transport into all of the layers of the bladder wall, and sections of viable human bladder are a reliable tool for assessing different modes of drug delivery.

New therapeutic options for refractory neurogenic detrusor overactivity.

AIM: Current pharmacologic treatment of detrusor overactivity relies on anticholinergic drugs. However, they often have untolerable side effects so that they are administered in doses insufficient to restore urinary continence. Recently, intravesical instillations and injections into the detrusor muscle of new pharmacological agents have been developed. The present study report our own experience in the treatment of detrusor overactivity with intravesical administrations of vanilloid agents and with botulinum-A toxin injections into the detrusor muscle in a group of spinal cord injured patients. In particular, we compared the clinical and urodynamic effects of the 2 drugs in an attempt to find a new and valid therapeutic option in those cases unresponsive to conventional treatment. METHODS: Seventy-five patients with spinal cord injury and refractory detrusor overactivity were included in the study: 35 patients received repeated intravesical instillations of resiniferatoxin (RTX) dissolved in normal saline; 40 patients received repeated injections of 300 units botulinum A-toxin diluted in 30 ml normal saline. Clinical assessment and urodynamics were performed at baseline and 6, 12 and 24 months after treatment. RESULTS: With both treatments there was a significant reduction in mean catheterization and episodes of incontinence and a significant increase in mean first involuntary detrusor contraction and in mean maximum bladder capacity at 6, 12 and 24 months after therapy. We did not detect any local side effects with either treatment. Botulinum-A toxin significantly reduced also the maximum pressure of uninhibited detrusor contractions more than RTX at all follow-up time points. CONCLUSION: In patients with spinal cord injury and refractory detrusor overactivity intravesical RTX and botulinum-A toxin injections into the detrusor muscle provided beneficial clinical and urodynamic results with reduction of detrusor overactivity and restoration of urinary continence in most patients. Botulinum-A toxin injection provided better clinical and urodynamic benefits than intravesical RTX.

[Echography in prostatitis]. / Ecografia nelle flogosi prostatiche.

In many infertile patients abnormalities in sperm are due to prostatic inflammatory disease. In the male reproductive system temporary episodes of inflammation, caused by newly discovered micro-organisms such as Chlamydia Trachomatis and Ureaplasma Urealyticum, may occur frequently and cause sub-clinical inflammation. This rapidly became chronic and induce the development of anti-spermatozoon antibodies. This latent clinical pattern and lack of symptoms often means diagnosis is late and medical treatment inadequate. In recent years attention has been focused on transrectal ultrasonography as a possible gold standard for diagnosing prostatic inflammatory disease. Widespread use of technologically advanced instruments has significantly improved the quality and definition of prostatic images. This paper discusses the current role of transrectal ultrasonography in the diagnosis of prostatic inflammatory disease. Abnormalities in the ultrasound pattern, caused by infection, are analyzed in detail and discussed critically in order to assess their role as markers of prostatic inflammation.

[Color Doppler echography in the diagnosis of nonspecific granulomatous prostatis: personal experience]. / L'ecocolor Doppler nella diagnosi di prostatite granulomatosa aspecifica: esperienza personale.

Non-specific granulomatous prostatitis (NSGP) is a rare but important pathology of the prostate because it often is confused with prostatic cancer. In fact, NSGP, presents at digital rectal examination as an area of increased consistency and painful, and at endorectal ultrasonography as an hypoechoic area with inhomogeneous echo structure. The frequent elevation of Prostatic-Specific Antigen (PSA) serum level vanish, moreover, its role of a differential factor. Since 1994 we used Echo-color doppler (ECD) in the evaluation of prostate cancer with satisfying results. The aim of our work is to value the route of ECD in the diagnosis of NSGP, and in the differential diagnosis with prostate cancer, actually only bioptic . Since January 1994 we observed 9 cases of NSGP; 7 patients with prostatic symptomatology and 2 with PSA serum level between 4 and 10 ng/ml. In all patients we performed endorectal US who showed, in 7 cases, nodular hypoechoic areas in the peripheral or central zone of the prostate, and in 2 cases the presence of evident BPH. In 5/7 cases with hypoechoic areas, ECD-US showed an increase of color intensity intra-perinodular. In 2 patients with BPH no marked color enhancement was observed. The diagnosis of NSGP has been done after needle biopsy in the 7 patients with suspect nodular areas, and in the 2 patients with BPH, after histological examination secondary to open prostatectomy. Our experience shows that ECD-US scanning picture in NSGP is superimposable with the prostatic cancer one. In fact the anatomical presupposition on the grounds of the "positivity" in ECD-US, focal hypervascularization, is present in ECD scanning pictures of both pathologies. In conclusion, ECD doesn't give an advantage in the differential diagnosis between NSGP and prostate cancer that actually remains only bioptic .

[Intravesical Electromotive Drug Administration®(EMDA)with Mitomycin-C for non-muscle invasive bladder cancer].

Electromotive Drug Administration® (EMDA) offers a means of controlling and enhancing the tissue transport of certain drugs, when applied to a surface epithelium, where they have a local therapeutic effect, in order to increase their efficacy. One application option is the treatment of non-muscle invasive bladder cancer with intravesical mitomycin-C (MMC). Laboratory studies demonstrated that EMDA/MMC can reduce the variability and enhance the drug administration rate into all layers of the bladder wall, and that the applied electric current causes no histological damage to tissue and no chemical modification of MMC. A prospective randomized study, performed in patients with in situ carcinoma, validated the prediction that electromotive enhancement of MMC delivery would provide results superior to those achieved using passive MMC transport. A further randomized study in patients with pT1 bladder cancer demonstrated that a regimen combining intravesical BCG and EMDA/MMC increased the disease-free interval and reduced the recurrence rate, as well as the disease progression and mortality rate if compared with BCG alone. The possibility that BCG may enhance the efficacy of MMC against high-grade pT1 transitional cell carcinoma and in situ carcinoma represents an important new therapeutic perspective in the high-risk non-muscle invasive bladder cancer.

Psychosocial issues of ART in aging male.

The role of androgens in human sexuality as regards the mechanism of erection and the pathogenesis of impotence is under debate. In addition, it is difficult to define the psychosocial impact of both hypogonadism and androgen replacement. However, sexual hormones largely influence mood, well-being, and quality of life. For this reason, despite the methodological difficulties of assessment, testosterone replacement has a deep impact on the social, psychological and sexual life of the treated patient. Considering the obvious characteristic of testosterone as an hormone, it appears evident that the endocrinologist is the unique experienced specialist able to diagnose and treat the hypogonadal men, monitoring potential side effects and following the psychosocial issues of androgen therapy.

Electromotive administration of oxybutynin into the human bladder wall.

PURPOSE: To compare concentrations of oxybutynin in the human bladder wall after either passive delivery (PD) or electromotive administration (EMDA). MATERIALS AND METHODS: Tissue sections of human bladder were inserted into a diffusion cell with urothelium exposed to the donor compartment containing oxybutynin (4.5 mg. in 100 ml. NaCl 0.45%) and an anode. Twelve paired experiments, "current 5 mA/no current", were conducted over 15 minutes. Oxybutynin tissue contents were measured and tissue viability, morphology and oxybutynin stability were assessed. RESULTS: Mean oxybutynin tissue concentrations were 3.84 micrograms./gm. in samples exposed to EMDA and 0.87 microgram./gm. in samples exposed to PD (p = 0.0006). The mean coefficients of variation were 57.85% in EMDA experiments and 89.78% in PD experiments. Tissues were viable and undamaged histologically and no oxybutynin structural modification was observed. CONCLUSIONS: EMDA enhances oxybutynin administration into viable bladder wall and reduces the variability in drug delivery rate.

Intermittent catheterization with a prelubricated catheter in spinal cord injured patients: a prospective randomized crossover study.

PURPOSE: We compared the safety and patient acceptance of a conventional Nélaton and a prelubricated nonhydrophilic catheter in 18 spinal cord injured patients on intermittent catheterization. MATERIALS AND METHODS: In a prospective crossover study each catheter was used for 7 weeks and the initial course was randomized. Urinalysis and urine culture were performed at 2, 4 and 7 weeks. Urethral trauma was evaluated by urethral cell count on the surface of each catheter used on the last day of each study period. Patient satisfaction was assessed at the end of the study by a questionnaire using multiple visual analog scales. RESULTS: Urinary tract infection was identified in 12 and 4 patients on a Nélaton and a prelubricated nonhydrophilic catheter (p = 0.03), while asymptomatic bacteruria was identified in 18 and 8 (p = 0.0244), respectively. The mean urethral cell count plus or minus standard deviation on the catheter surface was 6.7 +/- 2.8 x 10(4) and 15.1 +/- 8.9 x 10(4) for the prelubricated nonhydrophilic and the Néelaton catheter, respectively (p = 0.01). The prelubricated nonhydrophilic catheter resulted in a better mean satisfaction score than the Nélaton catheter (2.33 +/- 1.06 versus 4.72 +/- 2.13, p = 0.022). Urethral bleeding was reported in 2 patients during the study period while using the Nélaton catheter. CONCLUSIONS: The prelubricated nonhydrophilic catheter is a safe, effective and comfortable option in spinal cord injured patients on intermittent self-catheterization.

Successful management of retroperitoneal malignant fibrous histiocytoma involving both kidneys.

We report a rare case of a retroperitoneal inflammatory variant of malignant fibrous histiocytoma (MFH) involving both kidneys. The best treatment for MFHs is surgery with radical excision of the tumor. In this case the need to save at least one kidney meant tumorectomy was incomplete. The patient underwent adjuvant chemotherapy and 4 years later survives in a fairly good condition.

Intralesional alpha interferon therapy in papillary superficial transitional cell carcinoma of the bladder. A pilot study.

The tolerability, toxicity and therapeutic efficacy of recombinant interferon alpha-2a (rIFN alpha-2a), administered by intralesional injection, were evaluated in 15 patients with papillary superficial transitional cell carcinoma of the bladder, rIFN alpha-2a was delivered endoscopically in a single weekly dose of 3 x 10(6) IU for 4 weeks (total 12 x 10(6) IU). Transurethral resection of residual tumours was then performed. The response to treatment was assessed according to ultrasonographic, endoscopic and pathological findings. One patient achieved complete remission, 6 partial remission, 6 minor remission and 2 stabilisation of disease. All patients completed the course of treatment. A mild, transient, flu-like syndrome was documented after every injection. Immunological findings suggest that the antitumour effects of rIFN alpha 2a are not mediated through the immune system.

Diuretic ultrasound. A non-invasive technique for the assessment of upper tract obstruction.

A study was made of the diagnostic reliability of renal ultrasound with a diuretic in the evaluation of upper tract obstruction. The test comprised an initial renal ultrasound examination followed by the intravenous injection of 250 ml physiological saline with 40 mg frusemide; further ultrasound scans were carried out from 5 to 150 minutes later. A total of 67 patients was studied and the results were compared with those of diuretic intravenous urography, diuretic renography and, in some cases, the Whitaker test. Dynamic ultrasound with a diuretic showed a sensitivity of 94%, specificity of 94%, positive predictive value of 91% (obstructive), negative predictive value of 96% (non-obstruction) and a total diagnostic capacity of 94%.

Transdermal electromotive administration of verapamil and dexamethasone for Peyronie's disease.

OBJECTIVE: To evaluate the effects of the transdermal electromotive administration of verapamil and dexamethasone on plaque size, penile deviation, pain, erectile function and capacity for vaginal penetration in patients with Peyronie's disease. PATIENTS AND METHODS: Forty-nine patients were treated four times weekly for six consecutive weeks. During each session the drug mixture was administered from a receptacle fixed to the skin overlying the plaques, using 2.4 mA pulsed current for 20 min. Plaque size and penile deviation were evaluated by dynamic penile duplex ultrasonography, X-ray and photographs; pain, erectile function and capacity for vaginal penetration were assessed using a questionnaire. Vital signs and side-effects were recorded. Differences before and after treatment were assessed. RESULTS: The plaque disappeared in 8% of patients, with a measurable reduction in volume in 74% and no change in 18% (P < 0.001). Penile deviation resolved in 10% of the men, decreased in 74% and remained unchanged in 16% (P < 0.001). The plaque volume was halved in two-thirds of the men, to a mean (sd) of 515 (301) mm3, and the penile deviation halved in 45% of patients, to 24 (5) degrees; pain was completely eliminated in 88% (P < 0.001). Erectile function was completely restored in 42% of patients with initial erectile dysfunction and improved in 17% (P < 0.001); vaginal penetration improved in 73%. No toxicity was noted, except for a transient skin erythema at the site of the penile and dispersive electrodes. CONCLUSION: The transdermal electromotive administration of verapamil and dexamethasone is clinically safe and appears to be an effective treatment in patients with Peyronie's disease.

Autonomic dysreflexia during urodynamics.

UNLABELLED: Autonomic dysreflexia (AD) is an acute syndrome characterised by inappropriate and massive autonomic response that occurs in patients with spinal cord injury above the T6 level. AIMS: to evaluate the incidence of AD during cystometry and the relationships with clinical and urodynamic features. PATIENTS AND METHODS: Forty-eight spinal cord injury patients were studied by neurological and urological examination and urodynamic evaluation with concurrent recording of blood pressure, heart rate and symptoms and signs of AD. Patients were considered to have AD if blood pressure reached values higher than 150/100 mmHg. RESULTS: All the patients showed a significant increase of both systolic and diastolic blood pressure, although only 20 showed pressure values higher than 150/100 mmHg (in seven of them without AD symptoms). AD was more frequent in cervical patients (P = 0.034), but did not correlate with any other clinical features: sex ratio, age, disease duration, completeness of lesion, incidence of detrusor hyperreflexia/areflexia and detrusor-sphincter dyssynergia, voiding modalities, usage of anticholinergic drugs. In three patients blood pressure increase began when uninhibited contraction started, in 11 it was coincident with uninhibited contraction peak and in the other six it appeared at maximum bladder capacity. CONCLUSIONS: (1) during urodynamic evaluation all the patients with lesion level above T6 showed signs of sympathetic stimulation, although only some showed dangerous blood pressure values; (2) the relationship between urodynamic data and dysreflexia crisis shows that both the presence of detrusor uninhibited contractions and bladder distension are able to stimulate the crisis; (3) treatment with anticholinergic drugs is not sufficient to prevent autonomic dysreflexia starting from the bladder, unless it induces detrusor areflexia. These patients are at risk of developing autonomic dysreflexia following bladder distension.

Intravesical electromotive administration of oxybutynin in patients with detrusor hyperreflexia unresponsive to standard anticholinergic regimens.

PURPOSE: About 15% to 20% of patients with detrusor hyperreflexia do not benefit from oral oxybutynin regimens, frequently because of unpleasant side effects. Several reports indicate that intravesical oxybutynin is effective in many of these patients but there are some who still fail to respond. MATERIALS AND METHODS: A select group of 10 adults with detrusor hyperreflexia unresponsive to standard oral and intravesical oxybutynin regimens were treated at weekly intervals with 5 mg. oxybutynin orally, or 5 mg. oxybutynin in 100 ml. intravesically for 60 minutes of passive diffusion and for 30 minutes with 5 mA. electrical current. Each treatment (plus oral placebo and 2 intravesical controls) was associated with an 8-hour, full urodynamic monitoring session, and periodic blood and bladder content sampling. RESULTS: There was no significant objective improvement with oral or intravesical passive diffusion oxybutynin. Conversely there was significant improvement in 5 of 6 objective urodynamic measurements with intravesical electromotive oxybutynin. Plasma profiles were a single peak and decay following oral oxybutynin and 2 distinct peaks with intravesical passive diffusion and electromotive oxybutynin. Area under the curve for intravesical passive diffusion were 709 ng. per 8 hours versus oral 1,485 (p <0.05) versus intravesical electromotive 2,781 (p <0.001). Bladder content samples confirmed oxybutynin absorption. Oral oxybutynin caused anticholinergic side effects in 7 of 10 patients. There were no side effects with intravesical passive diffusion or electromotive administrations. CONCLUSIONS: Accelerated intravesical administration results in greater bioavailability and increased objective benefits without side effects in previously unresponsive patients compared with oral and intravesical passive diffusion oxybutynin administration.

Urodynamics in spinal cord injured patients walking with reciprocating gait orthosis.

PURPOSE: We evaluated the effects of walking with reciprocating gait orthosis on bladder function and upper urinary tract status in spinal cord injured patients. MATERIALS AND METHODS: Seven patients using reciprocating gait orthosis underwent urodynamics before and during walking. Abdominal ultrasound was performed before and after urodynamics. RESULTS: Baseline urodynamics showed detrusor areflexia in 3 patients and hyperreflexia in 4. During walking urodynamics revealed hyperreflexia in 6 patients with worse uninhibited detrusor contraction amplitude (38.2 +/- 41.2 versus 73.7 +/- 44.4 cm. water, p = 0.006) and duration (2.1 +/- 2.1 versus 6.8 +/- 5.3 minutes, p = 0.023). After walking ultrasound demonstrated bilateral pyelectasia in 2 patients. CONCLUSIONS: Spinal cord injured patients using reciprocating gait orthosis have worse urodynamic measurements and upper urinary tract disorders during walking. They require close urological followup.

Intravesical oxybutynin: mode of action assessed by passive diffusion and electromotive administration with pharmacokinetics of oxybutynin and N-desethyl oxybutynin.

PURPOSE: A proportion of patients with detrusor hyperreflexia who are unresponsive to oral oxybutynin often benefit from intravesical oxybutynin instillation. To our knowledge the precise mode of action of this method is obscure. MATERIALS AND METHODS: In 12 patients with detrusor hyperreflexia who were previously unresponsive to oral and intravesical passive diffusion of 5 mg. oxybutynin we administered 5 mg. oxybutynin orally as well as increased doses of 15 mg. oxybutynin intravesically with passive diffusion and with 15 mA. associated electric current. Each administration mode per patient was associated with an 8-hour urodynamic monitoring session during which oxybutynin and N-desethyl oxybutynin plasma levels, and intravesical oxybutynin uptake were measured. RESULTS: A dose of 5 mg. oxybutynin orally induced no urodynamic improvement with an area under the plasma concentration time curve of combined N-desethyl oxybutynin plus oxybutynin of 16,297 ng./8 hours and an area under the curve ratio of N-desethyl oxybutynin-to-oxybutynin of 11:1. Passive diffusion oxybutynin resulted in 12 mg. oxybutynin intravesical uptake and significant improvement in 3 of 8 urodynamic measurements, although the area under the curve of combined N-desethyl oxybutynin plus oxybutynin was only 2,123 ng./8 hours and the N-desethyl oxybutynin-to-oxybutynin ratio was 1.1:1.0. Electromotive administration of oxybutynin resulted in almost complete intravesical uptake of the 15 mg. dose, significant improvement in all 8 urodynamic measurements and an increased oxybutynin level versus oral and passive diffusion, although the area under the curve of combined N-desethyl oxybutynin plus oxybutynin was 4,574 ng./8 hours and the N-desethyl oxybutynin-to-oxybutynin ratio was inverted at 1.0:1.4. The oral dose of 5 mg. oxybutynin caused anticholinergic side effects in 8 of the 12 patients. Neither intravesical passive diffusion nor electromotive administration caused side effects with an uptake of 12 and 15 mg., respectively. CONCLUSIONS: A large proportion of intravesical oxybutynin is sequestered, probably in the urothelium. Intravesical oxybutynin administration confers therapeutic benefits via localized direct action within the bladder wall.

Prevalence of chronic prostatitis in men with premature ejaculation.

OBJECTIVES: To investigate the prevalence of chronic prostatitis in men with premature ejaculation. The etiology of premature ejaculation is currently considered psychological in nature. However, the possibility that urologic, hormonal, or neurologic factors may contribute to this condition should be considered in its management. METHODS: We evaluated segmented urine specimens before and after prostatic massage and expressed prostatic secretion specimens from 46 patients with premature ejaculation and 30 controls by bacteriologic localization studies. The incidence of premature ejaculation in the subjects with chronic prostatitis was also evaluated. RESULTS: Prostatic inflammation was found in 56.5% and chronic bacterial prostatitis in 47.8% of the subjects with premature ejaculation, respectively. When compared with the controls, these novel findings were statistically significant (P <0.05). CONCLUSIONS: Considering the role of the prostate gland in the mechanism of ejaculation, we suggest a role for chronic prostate inflammation in the pathogenesis of some cases of premature ejaculation. Since chronic prostatitis has been found with a high frequency in men with premature ejaculation, we stress the importance of a careful examination of the prostate before any pharmacologic or psychosexual therapy for premature ejaculation.

Clean intermittent catheterization and prevention of renal disease in spinal cord injury patients.

Upper urinary tract complications have been reported in about 20-30% of spinal cord injury patients. Their pathogenesis is linked to the presence of high-pressure uninhibited detrusor contractions, high leak point pressure and low bladder compliance. The aim of this study was to evaluate the incidence of upper urinary tract complications in two homogeneous groups of spinal cord injury patients with different bladder emptying modalities (intermittent catheterization vs. tapping, abdominal straining, Crede's manoeuvre) and the relationship with clinic and urodynamic features. A total of 17 patients (22%) had upper urinary tract complications. The incidence of both urinary tract dilatation and vesicoureteral reflux was significantly lower in patients having intermittent catheterization (P = 0.03 and 0.04 respectively). Intermittent catheterization thus seems to be effective in preventing upper urinary tract disease in spinal cord injury patients requiring mechanical bladder emptying modalities. The finding of upper urinary tract complications also in patients having intermittent catheterization showing high intravesical pressures stresses the need of adding anticholinergic medications to the rehabilitation regimen of these patients.