Christopher P. Steidle

Efficacy and tolerability of dapoxetine in treatment of premature ejaculation: an integrated analysis of two double-blind, randomised controlled trials

BACKGROUNDnNo drugs are approved for treatment of premature ejaculation. Our aim was to determine the efficacy and tolerability of on-demand dapoxetine in patients with severe premature ejaculation.nnnMETHODSnWe determined the efficacy of dapoxetine in a prospectively predefined integrated analysis of two 12-week randomised, double-blind, placebo-controlled, phase III trials of identical design done independently, in parallel, at 121 sites in the USA. Men with moderate-to-severe premature ejaculation in stable, heterosexual relationships took placebo (n=870), 30 mg dapoxetine (874), or 60 mg dapoxetine (870) on-demand (as needed, 1-3 h before anticipated sexual activity). The primary endpoint was intravaginal ejaculatory latency time (IELT) measured by stopwatch. Safety and tolerability were assessed. All analyses were done on an intention-to-treat basis. The trials are registered at ClinicalTrials.gov, numbers NCT00211107 and NCT00211094.nnnFINDINGSn672, 676, and 610 patients completed in the placebo, 30 mg dapoxetine, and 60 mg dapoxetine groups, respectively. Dapoxetine significantly prolonged IELT (p<0.0001, all doses vs placebo). Mean IELT at baseline was 0.90 (SD 0.47) minute, 0.92 (0.50) minute, and 0.91 (0.48) minute, and at study endpoint (week 12 or final visit) was 1.75 (2.21) minutes for placebo, 2.78 (3.48) minutes for 30 mg dapoxetine, and 3.32 (3.68) minutes for 60 mg dapoxetine. Both dapoxetine doses were effective on the first dose. Common adverse events (30 mg and 60 mg dapoxetine, respectively) were nausea (8.7%, 20.1%), diarrhoea (3.9%, 6.8%), headache (5.9%, 6.8%), and dizziness (3.0%, 6.2%).nnnINTERPRETATIONnOn-demand dapoxetine is an effective and generally well tolerated treatment for men with moderate-to-severe premature ejaculation.

Phase 1/2 Dose-Escalation Study of a GM-CSF- Secreting, Allogeneic, Cellular Immunotherapy for Metastatic Hormone-Refractory Prostate Cancer

This open‐label, multicenter, dose‐escalation study evaluated multiple dose levels of immunotherapy in patients with metastatic hormone‐refractory prostate cancer (HRPC). The immunotherapy, based on the GVAX platform, consisted of 2 allogeneic prostate‐carcinoma cell lines modified to secrete granulocyte‐macrophage‐colony‐stimulating factor (GM‐CSF).

Correlation of computerized tomographic changes and histological findings in 80 patients having radical retroperitoneal lymph node dissection after chemotherapy for testis cancer

A total of 80 patients with stage B3 or B2/C germ cell testis tumors underwent computerized tomography before and after chemotherapy. The volume and computerized tomographic density of metastatic retroperitoneal tumor were measured on all scans. The patients then underwent full bilateral retroperitoneal lymphadenectomy. The change in volume and density of retroperitoneal disease was correlated with the histological type of the primary testis tumor and with the histological findings at retroperitoneal lymphadenectomy. In all 15 patients (100 per cent) without teratomatous elements in the original tumor and who had a greater than 90 per cent decrease in the volume of retroperitoneal masses as a response to systemic chemotherapy no teratoma or active cancer was found in the surgical specimen. In contrast, 7 of 9 patients (78 per cent) with teratomatous elements in the original specimen had either teratoma or carcinoma in the retroperitoneal lymphadenectomy specimens despite having a greater than 90 per cent decrease in tumor volume. This difference was significant (p less than 0.05). These data suggest that patients with no teratomatous elements in the original specimen and a greater than 90 per cent decrease in the volume of retroperitoneal masses in response to chemotherapy can be observed carefully for signs of recurrence rather than undergoing post-chemotherapy retroperitoneal lymphadenectomy.

A Phase 3, Multicenter, Open Label, Randomized Study Of Abarelix Versus Leuprolide Plus Daily Antiandrogen In Men With Prostate Cancer

PURPOSEnWe compared the endocrinological and biochemical efficacy of abarelix depot, a gonadotropin-releasing hormone antagonist, with that of a widely used combination of luteinizing hormone releasing hormone agonist and a nonsteroidal antiandrogen.nnnMATERIALS AND METHODSnA total of 255 patients were randomized to receive open label 100 mg. abarelix depot or 7.5 mg. leuprolide acetate intramuscularly injection on days 1, 29, 57, 85, 113 and 141 for 24 weeks. Patients in the abarelix group received an additional injection on day 15 and those in the leuprolide acetate group received 50 mg. bicalutamide daily. Patients could continue treatment with study drug for an additional 28 weeks. The efficacy end points were the comparative rates of avoidance of testosterone surge (greater than 10% increase) within 7 days of the first injection and the rapidity of achieving reduction of serum testosterone to castrate levels (50 ng./dl. or less) on day 8. Patients were monitored for adverse events and laboratory abnormalities.nnnRESULTSnAbarelix was more effective in avoidance of testosterone surge (p <0.001) and the rapidity of reduction of testosterone to castrate levels on day 8 (p <0.001) than combination therapy. No significant difference was seen between the groups in the initial rate of decline of serum prostate specific antigen or the ability to achieve and maintain castrate levels of testosterone. No unusual or unexpected adverse events were reported.nnnCONCLUSIONSnAbarelix as monotherapy achieves medical castration significantly more rapidly than combination therapy and avoids the testosterone surge characteristic of agonist therapy. Both treatments were equally effective in reducing serum prostate specific antigen, and achieving and maintaining castrate levels of testosterone.

The Roles of Extracorporeal Shock Wave Lithotripsy and Percutaneous Nephrostolithotomy in the Management of Pyelocaliceal Diverticula

Various combinations of extracorporeal shock wave lithotripsy (ESWL*) and percutaneous nephrostolithotomy were used in the treatment of 40 stone-containing caliceal diverticula in 39 patients (16 men and 23 women). Only 1 of 26 patients (4%) treated with ESWL as a single modality became stone-free, although 9 (36%) became asymptomatic. Ten patients undergoing ESWL primarily eventually required percutaneous nephrostolithotomy due to persistence of symptoms and all became stone-free. A total of 14 patients underwent a percutaneous approach as a single modality, and the diverticula in 13 of these patients became stone-free, although 2 patients did have residual parenchymal fragments. Therefore, 21 of 24 patients (87.5%) became completely free of stones using the percutaneous approach. All patients managed with percutaneous nephrostolithotomy became free of symptoms. The complex nature of access during percutaneous nephrostolithotomy favors a 1-stage approach with direct puncture into the stone-containing diverticulum. Simultaneous fulguration of the diverticulum at percutaneous nephrostolithotomy is favored, since all 17 patients in whom this technique was used had complete obliteration of the diverticulum on followup contrast studies. These data suggest that caliceal diverticula should be managed with percutaneous nephrostolithotomy, since ESWL monotherapy is unlikely to produce a stone-free or symptom-free status.

Randomized, double-blind, crossover trial of sildenafil in men with mild to moderate erectile dysfunction: efficacy at 8 and 12 hours postdose.

OBJECTIVESnTo clarify the period of responsiveness to sildenafil.nnnMETHODSnUnder a double-blind protocol, men with mild to moderate erectile dysfunction (International Index of Erectile Function [IIEF] Erectile Function domain score, 11 to 25) were randomized to sildenafil (100 mg) or placebo and attempted intercourse 8 hours (range, 7 to 9 hours) postdose (first 4-week phase) and 12 hours (11 to 13 hours) postdose (second 4-week phase after treatment crossover). The primary outcome was the per-patient proportion (PPP; least squares means [95% confidence interval]) of affirmative responses to the Sexual Encounter Profile question 3 (SEP3: Did your erection last long enough for you to have successful intercourse?).nnnRESULTSnFor sildenafil (n = 174) versus placebo (n = 177), baseline values were similar but the PPP of successful intercourse attempts increased to 76% (69% to 82%) versus 50% (43% to 57%) in phase 1 (odds ratio [OR] = 3.2) and 79% (72% to 85%) versus 52% (44% to 60%) in phase 2 (OR = 3.5), and the PPP of Erection Hardness Score 4 erections (completely hard and fully rigid) was 41% (34% to 48%) versus 10% (7% to 15%) in phase 1 (OR = 6.2) and 44% (37% to 51%) versus 17% (12% to 23%) in phase 2 (OR = 4.0). Thus, at 12 hours, the odds of successful intercourse tripled and of a completely hard erection quadrupled. The sildenafil group achieved greater (P <0.001) PPP of successful penetration (SEP2), satisfaction with erection hardness (SEP4), and satisfaction with the sexual experience (SEP5); improvement in IIEF domain scores; and treatment satisfaction on the Erectile Dysfunction Inventory of Treatment Satisfaction.nnnCONCLUSIONSnIn men with mild to moderate ED, responsiveness to sildenafil may persist much longer than 4 hours.

An open-label study of abarelix in men with symptomatic prostate cancer at risk of treatment with LHRH agonists

OBJECTIVESnTo evaluate the ability of abarelix, a gonadotropin-releasing hormone antagonist, to provide an alternative treatment to bilateral orchiectomy in men with advanced prostate cancer symptoms and to evaluate its safety, clinical and biochemical efficacy, and effects on prostate-specific antigen and serum hormone levels.nnnMETHODSnFor 168 days, 81 patients from 17 centers received monthly intramuscular injections of open-label abarelix 100 mg (at least one dose). Patients were evaluated for the avoidance of bilateral orchiectomy, efficacy, disease response, percentage of change in prostate-specific antigen level, change in the intensity of pain, neurologic compromise, and other efficacy variables. Safety was evaluated through reports of adverse events and abnormal laboratory values.nnnRESULTSnNo patients required bilateral orchiectomy, but 2 patients were withdrawn from the study because of treatment-related events and were considered as failures to avoid orchiectomy. Treatment produced an 88% (38 of 43) objective response rate on day 85. Sixty-five (90%) of 72 patients experienced improvement in the pain score and/or analgesic use, urinary obstruction, urinary catheter removal, hydronephrosis, and/or azotemia. No patient with impending neurologic compromise at study entry developed spinal cord compression. The median reduction from the baseline prostate-specific antigen value was 75% on day 15 and greater than 95% from day 57 onward. Abarelix was well tolerated, and adverse events were the sequelae of advanced prostate cancer, comorbid medical disorders, or medical castration.nnnCONCLUSIONSnThese results suggest that abarelix provides a safe and effective medical alternative to surgical castration in symptomatic patients with advanced prostate cancer without the risk of the clinical flare associated with luteinizing hormone-releasing hormone agonists.

Long-term, Multicenter Study of the Safety and Efficacy of Topical Alprostadil Cream in Male Patients with Erectile Dysfunction

INTRODUCTIONnAlprostadil is approved for treatment of male erectile dysfunction (ED) by injection or urethral insertion. Topical delivery of alprostadil offers an improved alternative.nnnAIMnTo evaluate the long-term safety and efficacy of topical alprostadil cream.nnnMETHODSnThis was a multicenter, open-label, long-term study in 1,161 patients (998 double-blind rollover; 163 naïve) with ED. For the first 4 weeks, patients could administer eight doses of 200 mcg alprostadil to the penis meatus before intercourse (up to 2 per/week). Patients then self-selected to administer 300 or 100 mcg doses if hypo-responsive or hyper-responsive, respectively, or 200 mcg if no change, for up to 9 months (2 doses/week).nnnMAIN OUTCOME MEASURESnSafety evaluated patient/partner adverse events (AEs), changes in vital signs, clinical laboratory tests, physical examinations, and electrocardiograms. Efficacy assessed International Index of Erectile Function, Sexual Encounter Profile, Patient Self Assessment of Erection, and Global Assessment Questionnaire.nnnRESULTSnApproximately 12% of patients discontinued due to hypo-/hyper-responsiveness, 16% withdrew consent for a variety of reasons, and less than 5% discontinued because of AEs. The majority of patients (73%) selected 300 mcg alprostadil as the final dose. The most common AEs involved application site burning or erythema (12.2%), meatal or glans pain (4.4%), and prolonged or painful erection (1.3%). Only 5 (0.4%) patients reported a prolonged erection of >or=4 hours (priapism). Vaginal burning or itching (2.1%) was reported most frequently by partners. The majority of patients (74%) demonstrated an overall improvement in erectile function on most end-points, especially after adjusting dose strength to their individual responsiveness.nnnCONCLUSIONSnTopical alprostadil cream was considered effective and safe by most patients and their partners, with most AEs limited to the application site. Dose adjustment to 300 mcg alprostadil facilitated the greatest improvement in erectile function in the majority of patients. A separate report will integrate patient data from the open-label extension and prior double-blind studies.

Bradykinin-Induced Contractions of Canine Prostate and Bladder: Effect of Angiotensin-Converting Enzyme Inhibition

Alpha-adrenergic, cholinergic, and serotonergic receptor-mediated contractile responses have been well characterized in the genitourinary tissues of several mammalian species. The present study characterizes the in vitro contractile responsiveness of canine bladder and prostate to the peptides, bradykinin, angiotensin I, and angiotensin II. All preparations contracted to 0.15 M KCl. Bradykinin elicited contractile responses in both prostate (10(-10) to 10(-7) M) and bladder (10(-10) to 10(-6) M). In both tissues, angiotensin II produced minimal responses and angiotensin I failed to elicit contractions. The potent angiotensin converting enzyme (ACE) inhibitor, enalaprilic acid [MK-422] (10(-6) M) increased the contractile response to the prostate to bradykinin two-fold while having no effect on bradykinin-induced contractions in the bladder. Enalaprilic acid did not affect the contractile responses of the two tissues to angiotensin I or angiotensin II. The canine urogenital tissue contractile responses to bradykinin, angiotensin I, and angiotensin II may have relevance to human physiology. Previous studies have demonstrated that human prostatic tissue, specifically benign prostatic hyperplasia (BPH), has the highest concentration of ACE activity of tissues evaluated. Bradykinin is a potent peptidergic contractile agent in canine bladder and prostate. The activity of enalaprilic acid to amplify the bradykinin-induced contractions in the canine prostate is consistent with high levels of ACE in the tissue. These data confirm the sensitivity of the canine prostate to bradykinin and report for the first time, the ability of bradykinin to induce contractions in the prostate. These studies support the possibility that bradykinin may be involved in mediating micturition under normal and pathological states such as infravesical obstruction secondary to BPH. Furthermore, the results from these investigations in canine urogenital tissues, if applicable to humans, suggest that urinary function be closely monitored in patients receiving ACE inhibitor therapy.

Characterization of type I 5α-reductase activity in DU145 human prostatic adenocarcinoma cells

Abstract The conversion of testosterone (T) to dihydrotestosterone (DHT) has been demonstrated to be catalysed by at least two isoforms of human steroid 5α-reductase, designated types I and II. Type II 5α-reductase expression predominates in human accessory sex tissues, localized to the fibromuscular stromal compartment. The type I isoform predominates in skin, prostatic epithelia and, to a lesser extent, in prostatic fibromuscular stroma. The significance of the type I isoform to prostatic cellular growth and function remains undefined. In cultured DU145 cells, we evaluated the metabolism of [ 14 C]-T and demonstrated the time-dependent formation of [ 14 C]-DHT. Oxidative metabolism (conversion of [ 14 C]-T to [ 14 C]-androstenedione) and the formation of conjugated androgen metabolites occurred at a relatively low rate in the DU145 cells. Using human type I 5α-reductase cDNA, Northern blot analysis of DU145 cell mRNA revealed high levels of type I isoform expression. Analogous probing of the DU145 cells with a human 5α-reductase II cDNA failed to reveal expression of the type II isoform. The expression of functional type I activity has been confirmed pharmacologically using isoformselective 5α-reductase inhibitors. Reductive metabolism of [ 3 H]-T in the DU145 cells was inhibited in a concentration-dependent manner by LY306089, a potent non-steroidal type I-selective inhibitor (IC 50 = 10.0 nM). SKF105657, a steroidal type II-specific inhibitor was distinctly less active at inhibiting [ 3 H]-DHT formation. LY306089 was a non-competitive inhibitor of type I 5α-reductase in DU145 cellular homogenates with an apparent K i value of 4.0 nM. These studies have identified and pharmacologically defined type I 5α-reductase activity in an androgen-insensitive prostatic cancer cell line and provide the basis for additional investigations into the significance of type I 5α-reductase to human prostatic pathophysiology.