Biomedical subjects
Publications and source records attributed to F Montorsi.
We present the case of a 44-year old man, presenting with acute left flank pain and gross haematuria, affected by bilateral renal mass and massive para-aortic and mediastinic lymphadenopathy, highly suspicious for metastatic renal cancer.
OBJECTIVE: To assess the efficacy and tolerability of vardenafil in men with erectile dysfunction (ED) due to traumatic spinal cord injury (SCI). METHODS: In this multicenter, double-blind, placebo-controlled, parallel-group 12-week study, 418 men aged 18 years and older with ED for more than 6 months consequent to SCI were randomized to vardenafil (n = 207) or placebo (n = 211) (10 mg for 4 weeks, then maintained or titrated to 5 or 20 mg at weeks 4 and 8). Efficacy assessments included the erectile function (EF) domain score of the International Index of Erectile Function questionnaire and diary questions regarding penetration, maintenance of erection to completion of intercourse, and ejaculation. RESULTS: Baseline patient characteristics were similar in the vardenafil (mean age 40 years) and placebo (mean age 39 years) groups. Mean baseline EF domain scores were 11.6 in the vardenafil group and 12.1 (moderate ED) in the placebo group. EF domain score in the vardenafil group improved to 22.0 (mild ED) at last observation carried forward vs 13.5 in the placebo group (p < 0.001). Over 12 weeks of treatment, mean per-patient penetration (76% vs 41%), maintenance (59% vs 22%), and ejaculation (19% vs 10%) success rates were significantly greater vs placebo (all p < 0.001). The most frequently reported drug-related adverse events were headache (vardenafil 15%, placebo 4%), flushing (vardenafil 6%, placebo 0%), nasal congestion (vardenafil 5%, placebo 0%), and dyspepsia (vardenafil 4%, placebo 0%). CONCLUSION: Vardenafil significantly improved erectile and ejaculatory function and was generally well tolerated in men with erectile dysfunction due to spinal cord injury.
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First-dose success of phosphodiesterase type 5 (PDE5) inhibitors may be adversely affected in patients with comorbidities. This article reports first-dose success rates for vardenafil 10 mg in men with erectile dysfunction (ED) and associated comorbidities who participated in the challenge phase of the Reliability--Vardenafil for Erectile Dysfunction I study. This study involved an open-label, single-dose, 1-week challenge period where patients who achieved SEP-2 (penetration) success were randomised to vardenafil 10 mg or placebo for 12 weeks in a double-blind manner. The first-dose success rates for SEP-2 and SEP-3 (maintenance of erection to completion of intercourse) were stratified according to comorbidities. Safety was assessed using adverse events (AEs). Of 600 men who received a single 10 mg dose of vardenafil, 32% had hypertension, 16% had diabetes and 19% had dyslipidaemia. Vardenafil demonstrated overall effectiveness, including first-dose SEP-2 and SEP-3 success rates in patients with and without specific comorbidities. Initial overall success rates for SEP-2 and SEP-3 during the challenge phase were 87% and 74% respectively. First-dose SEP-2 and SEP-3 success rates were 84% and 66% in men with hypertension (n = 191); 84% and 72% in men with dyslipidaemia (n = 116); and 75% and 58% in men with diabetes (n = 95). Vardenafil was well tolerated and most AEs, including the most frequently reported flushing (3.5%), were mild to moderate in intensity. Vardenafil 10 mg is generally well tolerated and efficacious, providing first-dose success with a consistently high rate of reliability of penetration and maintenance of erection in men with ED and associated comorbidities.
The molecular mechanisms underlying the regulation of vas deferens (VD) motility and semen emission are still poorly understood. We now report evidence on VD expression of phosphodiesterase type 5 (PDE5), which regulates nitric oxide (NO)-induced relaxation and cGMP breakdown in smooth muscle cells. In human VD, the PDE5 abundance was relatively high (>3 x 10(6) molecules/microg total RNA), although 10-fold lower than in corpora cavernosa (CC). Also cGMP metabolising activity was higher in CC than in VD. However, both tissues share the same sensitivity to a broad panel of cGMP-related PDE inhibitors: sildenafil, tadalafil, dipyridamole, zaprinast, vinpocetine, EHNA and cilostamide. Based on the rank order of potency of these PDE inhibitors, we found that the cGMP metabolizing activity in human VD mostly corresponds to PDE5. PDE5 was immunolocalized in all the muscular layers of human and rabbit VD and was found to be negatively involved in regulating NO-induced relaxation. In addition, by using a rabbit model of hypogonadotropic hypogonadism, we found that PDE5 gene expression and activity are androgen-dependent in VD, as previously demonstrated in CC. In fact, the sensitivity to a NO-donor (NCX4040), its enhancement by PDE5 inhibitors and the PDE5-related cGMP breakdown were all affected by androgen manipulation. Our results provide a hypothesis explaining the beneficial effects of PDE inhibitors in patients with rapid ejaculation.
OBJECTIVE: To assess the long-term safety and tolerability of tadalafil for patients with erectile dysfunction (ED). PATIENTS AND METHODS: This was a multicentre, open-label, 24-month extension trial involving 1173 men with ED. The mean age was 57 (range 23-83) years and 74.8% of patients were taking concomitant medications for comorbid conditions, including diabetes mellitus in 30.5% of men and hypertension in 29.5%. These patients had participated in 1 of 5 previous 8-week or 12-week randomised, double-blind, placebo-controlled tadalafil studies. In the present trial, the starting 10mg dose of tadalafil could be increased to 20mg if the patient could not achieve satisfactory intercourse or reduced to 5mg for an adverse event that was persistent, intolerable and judged by the investigator to be related to tadalafil. RESULTS: Four hundred ninety-three (42.0%) men completed 24 months of treatment. In addition, a further 234 (19.9%) completed 18 months of treatment due to a sponsor decision to reduce the study duration. The total tadalafil exposure was 1676.0 patient-years. Tadalafil was safe and well tolerated. Headache (15.8%), dyspepsia (11.8%), nasopharyngitis (11.4%), and back pain (8.2%) were the most common treatment-emergent adverse events. The rate of discontinuations due to adverse events for this 18-24-month study was 6.3% and the rate for any individual event was <1%. Serious adverse events occurred in 8.6% of patients. No consistent pattern of serious adverse events assessed as causally associated with tadalafil administration was observed. None of the four deaths that occurred during the study was assessed as tadalafil related. There were no clinically significant laboratory or electrocardiographic findings or changes in vital signs in mean baseline-to-endpoint analysis attributable to tadalafil. Tadalafil administration was not causally associated with drug-induced hepatotoxicity, neutropenia, thrombocytopenia, or renal dysfunction. CONCLUSION: Tadalafil at doses of 5, 10, or 20mg taken as needed up to once daily for 18 to 24 months was safe and well tolerated. These findings support the long-term use of tadalafil in the clinical management of erectile dysfunction.
Despite availability of outcome measures and scales for assessing erectile dysfunction (ED) treatment efficacy, guidelines are not available for assessing broader therapeutic outcomes or defining treatment failure in ED. An International Consensus Advisory Panel was convened to develop guidelines, definitions and a new algorithm for evaluating treatment effectiveness in ED. These new guidelines are recommended for use in both research and clinical practice. A multidisciplinary, international panel, consisting of 11 senior researchers and clinicians, was convened to address pertinent issues concerning therapeutic outcome assessment for ED. The panel utilized a modified Delphi method of consensus development and proposed a new model for outcomes assessment. This model is inherently testable, using existing instruments and current methods of assessment. Following a comprehensive literature review and discussion, the Panel recommended adoption of a new treatment effectiveness conceptual framework or theoretical model for assessing therapeutic outcomes in ED. Treatment effectiveness is presumed to be a combined function of two other factors, treatment response and treatment satisfaction. Treatment response is based on the combined assessment of efficacy and tolerability, and treatment satisfaction on the combined assessment of patient and partner satisfaction. Taken together, these two domains define an overall domain of treatment effectiveness. This therapeutic index would be derived by independently assessing treatment efficacy and satisfaction by means of event logs, questionnaires or the more typical patient interview methods. In conclusion, the Ad Hoc Advisory Consensus Panel recommends adoption of a new framework or conceptual model for conducting ED outcome trials or clinical research. The concept of 'treatment effectiveness' is proposed as a new 'umbrella concept' or distal outcome to be evaluated.
In the long-term there is biochemical evidence of recurrent prostate carcinoma in approximately 40% of patients after radical prostatectomy (RP). Detecting the site of recurrence (local vs distant) is critical for defining the optimum treatment. Pathological and clinical variables, e.g. Gleason score, involvement of seminal vesicles or lymph nodes, margin status at surgery, and especially the timing and pattern of prostate-specific antigen (PSA) recurrence, may help to predict the site of relapse. Transrectal ultrasonography (TRUS) of the prostatic fossa in association with TRUS-guided needle biopsy is considered more sensitive than a digital rectal examination for detecting local recurrence, especially if PSA levels are low. Although it cannot detect minimal tumour mass at very low PSA levels (< 1 ng/mL) TRUS biopsy is presently the most sensitive method for detecting local recurrence. Nevertheless, the conclusive role of biopsy of the vesico-urethral anastomosis remains unclear. However, 111In-capromab pendetide scintigraphy and [11C]-choline tomography (which are better than conventional imaging for detecting metastatic tumour), have low detection rates for local disease and are considered complementary to TRUS in this setting. Patients with a high PSA after RP may be managed with external beam salvage radiotherapy. An initial PSA of < 1 ng/mL, Gleason score < 8 and radiation dose of 66-70 Gy seem to be key factors in determining success. Although a positive TRUS anastomotic biopsy may predict a better outcome after radiation therapy, the need to take a biopsy in the event of PSA failure remains under investigation. The value of salvage radiation to the prostatic bed for PSA-only progression after RP remains in question.
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Since it was initially described in 1992 laparoscopic adrenalectomy (LA) has been gaining popularity amongst urologists and its range of applications has progressively widened. Ten years after the first report of LA this type of operation is presently considered to be the 'standard of care' for most adrenal diseases requiring surgery. We define the current role of laparoscopy in the management of surgical adrenal diseases, using a Medline search (1997-2002) to assess reports of LA, focusing on indications, approaches (transperitoneal and retroperitoneoscopic) and comparative analyses, taking particular care to evaluate operative duration, rate of conversion and transfusion, complications and hospital stay. With both approaches LA is safe and effective and, when compared with open surgery, offers the same functional results with all the advantages of minimally invasive surgery. We conclude that LA based on either approach should be considered the treatment of choice for benign adrenal lesions. Although very promising, conservative surgery and LA should still be evaluated in cases of malignancy.
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The widespread acceptance of prostate-specific antigen (PSA) measurement as an early detection method for prostate cancer (Pca), coupled with the recent heightened public awareness of Pca as a common disease, has led to an increase in the detection of Pca. It has been established that digital rectal examination (DRE) and PSA are the most useful front-line methods for assessing an individual's risk of Pca. In addition to an elevated PSA above 4 ng/mL and an abnormal DRE, the decision to proceed with TRUS-guided biopsy may also be supported by other factors. Determining the presence of a significant rise in PSA between tests, whether the degree of PSA is concordant with the size of the prostate, and age appropriate PSA may aid in the interpretation of this risk. Grayscale transrectal ultrasound (TRUS) has been established as the first choice imaging technique making it possible to take biopsies, measure the volume and obtain a general overview of the prostate. To improve, however, the TRUS detection rate of Pca, many ultrasonographic technique improvements have been introduced and continuously evaluated. As for prostate biopsy, in the prostate with visible lesions, lesion-guided biopsies only play a role in combination with systematic biopsies, while the systematic prostate biopsy scheme should at the present time include 10 or 12 cores according to prostatic weight. The other imaging techniques actually play a marginal role in Pca detection, but may be useful for staging newly diagnosed Pca or in patient re-staging in case of biochemical failure after radical treatment.
Apomorphine SL (Ixense (TM) ) (apo SL) is a dopamine receptor agonist that can enhance sexual function in patients with erectile dysfunction (ED). For a patient, the ability to achieve a physiological erection, tolerability, efficacy and the speed of onset of the therapy are of considerable importance when considering ED treatment. Recent studies have focused on determining the patient's tolerability to apo SL as a therapy for ED. In addition, the cardiovascular profile of those patients that would be likely to receive apo SL in the clinic has been assessed. These studies have shown that apo SL is safe and effective in the treatment of ED and offers a new therapeutic option for the first-line treatment of patients with different concomitant diseases including cardiovascular disease and diabetes. The most frequently reported adverse events were nausea and dizziness, but no major adverse events have been noted in any of the clinical trials.
It is well recognized that sexual stimulation leading to penile erection is controlled by different areas in the brain. Animal erection studies have shown that apomorphine (a D2>D1 dopamine receptors nonselective agonist) seems to act on neurons located within the paraventricular nucleus and the medial preoptic area of the hypothalamus. Yet, only recently, was a centrally acting agent, apomorphine sublingual, approved for the treatment of erectile dysfunction. The present functional magnetic resonance imaging placebo-controlled study presents the first in vivo demonstration of the apomorphine-induced modulation of cortical and subcortical brain structures in patients with psychogenic erectile dysfunction. Noteworthy, patients in comparison with potent controls, showed an increased activity in frontal limbic areas that was downregulated by apomorphine. This suggests that psychogenic impotence may be associated with previously unrecognized underlying functional abnormalities of the brain.
Sildenafil is one of two oral drugs approved for first-line treatment of erectile dysfunction (ED). Anecdotally, some young healthy men who wish to enhance their sexual performance are requesting or abusing sildenafil. In this randomized double-blind, placebo-controlled clinical study, we investigated the effect of sildenafil in young men without ED. A total of 60 young healthy men age 20-40 y with no reported ED were enrolled for this single-dose home-use study. Subjects had used no medication in the 6 months prior to the study. All had been engaged in a stable relationship for at least 3 months. After completing the IIEF-5 questionnaire, patients were randomized in a double-blind fashion to receive either one 25 mg tablet of sildenafil (group 1) taken prior to intercourse, or an identical placebo tablet (group 2). All subjects completed a questionnaire relating to their erectile quality. There were no differences between the two groups in the reported improvement of erection quality, 12/30 sildenafil vs 10/30 placebo (Fisher's test, P=0.79). Sildenafil caused a significant reduction of the postejaculatory refractory time (12/30 vs 4/30) (chi(2) test, P=0.04). Sildenafil does not improve erections in young healthy men. Sildenafil should not be given to young healthy men to improve their erections and patients should be advised against recreational abuse of the drug. In this limited single-dose home study, sildenafil appears to reduce the postorgasmic refractory time. Although controlled studies are needed to evaluate the efficacy of erection-enhancing drugs in premature ejaculation, it is possible that sildenafil might be useful for this indication.
Treatment satisfaction, subanalysed by demographic variables, was evaluated in patients switching from successful intracavernosal prostaglandin E(1) (PGE(1)) therapy to oral sildenafil citrate. The validated Erectile Dysfunction Inventory of Treatment Satisfaction questionnaire was administered at the end of PGE(1) therapy and after 12 weeks of sildenafil treatment in a multicentre, open-label study. Men with erectile dysfunction (n=176) who were switched from stable PGE(1) therapy to sildenafil (25-100 mg) were equally satisfied with onset of action, duration of action, and confidence in ability to engage in sexual activity, but expressed greater overall treatment satisfaction with sildenafil (P<0.01), better ease of use (P<0.001), naturalness of erectile process (P<0.001), and intention to continue treatment (P<0.001). Partners (n=32) were overall more satisfied with sildenafil (P<0.05), and their responses correlated with patient satisfaction (r=0.68). Compared with PGE(1) injection, these data suggest that patients may be less likely to discontinue taking sildenafil treatment for their erectile dysfunction.
Although the ureter is functionally simply a tube to transport urine, ureteric surgery requires detailed anatomical knowledge and advanced surgical skills, because the ureter has a delicate blood supply. Therefore, the urological surgeon must have distinct strategies available to bridge ureteric defects of various sites and lengths. Furthermore, handling during and after surgery should be individualized to the patient's pre- and intraoperative situation. In this review, the indications for reconstruction of a specific ureteric defect, the required techniques and postoperative recommendations are discussed.
Erectile dysfunction (ED) is a common medical condition that affects the sexual life of millions of men worldwide. Many drugs are now available for treating ED; oral pharmacotherapy represents the first-line option for most patients with ED. Sildenafil, an inhibitor of the enzyme phosphodiesterase type 5, is currently the most widely prescribed oral agent and has a very satisfactory efficacy-safety profile in all patient categories. Apomorphine SL is a dopamine D1- and D2-receptor agonist which has recently been approved for marketing in Europe. It is best selected for treating patients with mild to moderate ED. Vardenafil and tadalafil are new phosphodiesterase type 5 inhibitors which are expected to be approved this year. Both of them have significant positive efficacy-safety profiles. Patients who do not respond to oral pharmacotherapy or who cannot use it are good candidates for intracavernosal and intraurethral therapy. Alprostadil is the most widely used drug, both for injection therapy and for the intraurethral route. The efficacy of second-line treatment is high but the attrition rate remains significant.