Safety of autologous bone marrow-derived mesenchymal stem cells in erectile dysfunction: an open-label phase 1 clinical trial.

BACKGROUND AIMS: The efficacy of phosphodiesterase type 5 inhibitors (PDE5Is), which are commonly used to treat erectile dysfunction (ED), is not satisfactory in patients with denervation of the cavernous nerve due to pelvic surgeries and diabetes mellitus (DM). Pre-clinical studies using bone marrow-derived mesenchymal stem cells (BMSCs) to treat ED have shown promising results. The authors conducted a phase 1 clinical trial with autologous BMSCs in patients with ED due to radical prostatectomy or DM. METHODS: Ten patients (five with post-prostatectomy ED and five with DM-associated ED) who could not perform sexual activity despite taking the maximum dose of a PDE5I were enrolled. The brief clinical trial protocol was registered with the US National Institutes of Health on ClinicalTrials.gov (NCT02344849). The primary outcome was the safety of stem cell therapy, and the secondary outcome was the improvement of erectile function. RESULTS: Of the 13 patients screened, 10 were registered in the clinical trial and received autologous BMSCs and nine completed the clinical trial. One patient with post-prostatectomy ED experienced two treatment-emergent adverse events (TEAEs) (pyrexia and back pain), and two patients with DM-associated ED experienced a total of five TEAEs (one case each of viral upper respiratory tract infection, prostatitis and pruritus and two cases of hyperglycemia). Of these patients, one with DM-associated ED experienced two serious TEAEs (two instances of hyperglycemia). All TEAEs were considered not to be related to autologous BMSC therapy. In addition, no clinical significance was identified related to other safety measures, such as laboratory tests and vital signs. The mean International Index of Erectile Function score increased significantly at 1 month versus baseline (24.9 versus 18.1, P = 0.0222). CONCLUSIONS: This phase 1 clinical trial confirmed the safety and potential efficacy of autologous BMSC therapy in patients with ED. The authors' results need to be confirmed by a phase 2 clinical trial.

Establishment of NOAEL for intracavernous injections of human bone marrow-derived mesenchymal stem cells in rats.

Purpose: To assess the possible negative health effects of human bone marrow-derived mesenchymal stem cells (hBMSCs) on fertility and early embryonic development following intracavernous injections in rats. Materials and Methods: A total of 88 Crl:CD(SD) male and female rats were equally divided into 4 groups in a random manner: control group (normal saline), low-dose group (2×105 hBMSCs), moderate-dose group (1×106 hBMSCs), and high-dose group (2×106 hBMSCs). hBMSCs or normal saline was injected into the penis of the rats 3 times at 2-week-intervals prior to mating. We compared each group with respect to parameters of reproduction and histopathology. Results: For male rats, various degrees of flushing and swelling were observed at the penile injection site in all the groups, although the severity increased in a dose-dependent manner in the hBMSC injection groups. There were no statistically significant differences in mean body weights and food consumption among all the groups of both sexes. There were no statistically significant differences in reproductive parameters among all the groups of both sexes. The absolute and relative organ weights did not significantly differ among the groups. At the time of necropsy, no remarkable findings were observed in gross examinations in all groups. On histopathological analysis, minimal mononuclear cell infiltration was observed in the right epididymis of each rat in the moderate- and high-dose groups. Conclusions: The non-toxic amount of hBMSCs for male fertility and early embryogenesis in rats under the test conditions was determined to be 2×106 cells/head.

Cross-Sectional Association of Metabolic Syndrome and Its Components with Serum Testosterone Levels in a Korean-Screened Population.

PURPOSE: We evaluated the associations of metabolic syndrome (MetS) and its components with testosterone levels in the Korean population. MATERIALS AND METHODS: This cross-sectional study was performed among 6,967 adult (age≥20 years) men who attended health screening during 2006 to 2015. MetS was defined using the National Cholesterol Education Program Adult Treatment Panel III criteria. Associations were evaluated using unconditional logistic regression. RESULTS: The estimated age-adjusted prevalence of MetS in adult and middle-aged (≥40 years) Korean men was 27.5% and 30.6%, respectively. Quartile analysis showed that high serum testosterone levels were significantly associated with a low risk of MetS (highest vs. lowest quartile, odds ratio=0.528; ptrend<0.001), with an approximately 13% reduction in MetS risk per 1 ng/mL increment of serum testosterone levels. After considering covariates such as age and body mass index (BMI), the reduction in MetS risk was attenuated but remained significant (7% reduced risk per 1 ng/mL). Testosterone levels were inversely correlated with all MetS components, including hyperglycemia (r=-0.041), increased body size (r=-0.093), increased triglyceride levels (r=-0.090), decreased high-density lipoprotein cholesterol levels (r=-0.030), and elevated blood pressure (r=-0.071, all p<0.05). Among them, elevated triglyceride levels and blood pressure were independently associated with low serum testosterone levels, even after adjustment for age and BMI. CONCLUSIONS: Serum testosterone levels were inversely associated with MetS in Korean men. This association was attenuated after adjustment for age and BMI but remained significant. Among MetS components, increased triglyceride levels and elevated blood pressure were independently associated with testosterone levels, regardless of obesity.

Efficacy and Safety of a Fixed-Dose Combination Therapy of Tamsulosin and Tadalafil for Patients With Lower Urinary Tract Symptoms and Erectile Dysfunction: Results of a Randomized, Double-Blinded, Active-Controlled Trial.

BACKGROUND: Phosphodiesterase type 5 inhibitors and α-adrenergic blocking agents (α-blockers) are widely used for the treatment of erectile dysfunction (ED) and lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). AIMS: To assess the efficacy and safety of fixed-dose combinations (FDCs) of tamsulosin and tadalafil compared with tadalafil monotherapy in patients with comorbid BPH-associated LUTS and ED. METHODS: A randomized, double-blinded, active-controlled trial was conducted of 510 men with BPH-associated LUTS and ED. Patients were treated with FDCs of tamsulosin 0.4 mg plus tadalafil 5 mg (FDC 0.4/5 mg), tamsulosin 0.2 mg plus tadalafil 5 mg (FDC 0.2/5 mg), or tadalafil 5 mg for a 12-week treatment period. For a subsequent 12-week extension period, the patients were administered FDC 0.4/5 mg. OUTCOMES: The primary outcomes were changes from baseline in total International Prostate Symptom Score (IPSS) and International Index of Erectile Function erectile function domain (IIEF-EF) score at week 12 to prove superiority and non-inferiority of FDCs compared with tadalafil 5 mg. The safety assessments were adverse reactions, laboratory test results, and vital signs at week 24. RESULTS: The mean changes in total IPSS and IIEF-EF scores were -9.46 and 9.17 for FDC 0.4/5 mg and -8.14 and 9.49 for tadalafil 5 mg, respectively, which indicated superiority in LUTS improvement (P = .0320) and non-inferiority in ED treatment with FDC 0.4/5 mg compared with tadalafil 5 mg. However, the results from FDC 0.2/5 mg failed to demonstrate superiority in LUTS improvement. No clinically significant adverse events regarding the investigational products were observed during the 24-week period. CLINICAL IMPLICATIONS: The FDC 0.4/5 mg is the first combined formulation of an α-blocker and a phosphodiesterase type 5 inhibitor that offers benefits in patient compliance and as add-on therapy in patients with comorbid BPH-associated LUTS and ED. STRENGTHS AND LIMITATIONS: The study clearly demonstrated the advantage of FDC 0.4/5 mg. The main advantage of FDC 0.4/5 mg was the enhanced efficacy on BPH-associated LUTS comorbidity with ED, the lower incidence of side effects, and the simplification and convenience of therapy, which led to better overall patient compliance. However, the lack of a tamsulosin monotherapy control group was a limitation of this study. CONCLUSION: The FDC 0.4/5 mg therapy was safe, well tolerated, and efficacious, indicating that combination therapy could provide clinical benefits for patients with BPH-associated LUTS complaints and ameliorate the comorbidity of ED. Kim SW, Park NC, Lee SW, et al. Efficacy and Safety of a Fixed-Dose Combination Therapy of Tamsulosin and Tadalafil for Patients With Lower Urinary Tract Symptoms and Erectile Dysfunction: Results of a Randomized, Double-Blinded, Active-Controlled Trial. J Sex Med 2017;14:1018-1027.

A Phase 3 Study to Evaluate the 1-Year Efficacy and Safety of Udenafil 75 mg Once Daily in Patients With Erectile Dysfunction.

INTRODUCTION: Once-daily administration of phosphodiesterase type 5 inhibitors has been shown to correct erectile dysfunction (ED). AIM: To evaluate the long-term efficacy and safety after once-daily oral administration of udenafil 75 mg in men with ED. METHODS: This clinical trial was an open-label, fixed-dose, 24-week extension study (DA8159_EDDL_III) of a 24-week double-blinded efficacy and safety study of once-daily udenafil (parent study: DA8159_EDD_III). Subjects received udenafil 75 mg once daily for 24 weeks during this extension study, and the follow-up visit occurred during the 4-week ED treatment-free period. MAIN OUTCOME MEASURES: Subjects were asked to complete the International Index of Erectile Function questionnaire and the Global Assessment Questionnaire at the 24-week extension and after the 4-week ED treatment-free period, and the development of adverse drug reactions was investigated. RESULTS: In total, 302 subjects were enrolled in this extension study. Improvement was shown with an increased erectile function (EF) domain score compared with baseline (14.60 ± 4.57) at extension week 48 (23.98 ± 5.44) and a slight increase in EF domain score compared with the last time point (week 24) of the parent study (P < .001). The Global Assessment Questionnaire showed a high improvement rate of 95.4% at the extension 48-week time point. For shift to normal, almost half the subjects (45.1%) recovered "normal" EF, and 14.2% of subjects reported normal erections after the 4-week ED treatment-free period. The occurrence rate of adverse drug reactions was 8%, which consisted mainly of flushing and headache. CONCLUSION: Once-daily dosing of udenafil 75 mg showed excellent efficacy and safety with long-term administration and allowed a more spontaneous sexual life.

Bone marrow-derived mesenchymal stromal cell therapy in a rat model of cavernous nerve injury: Preclinical study for approval.

BACKGROUND AIMS: Although clinical studies using stem cells to treat erectile dysfunction have been performed or are ongoing, there is little consensus on the optimal protocol. We aimed to develop a protocol optimizing human bone marrow-derived mesenchymal stromal cell (hBMSC) therapy in a rat model of cavernous nerve injury. METHODS: We performed, in order, a dose-finding study, a toxicokinetic study of hBMSCs, and a study to determine the timing and number of cell injections. RESULTS: From the dose-finding study, 1 × 10(6) cells were selected as the dose per hBMSC injection. From the toxicokinetic study, 14 days was selected as the interval between repeat treatments. In the final study, the ratio of maximal intracavernous pressure to mean arterial pressure was significantly lower in the control group than in the sham group (23.4% vs. 55.1%, P <0.001). An immediate single injection of hBMSCs significantly improved erectile function compared with the control group (39.8%, P = 0.035), whereas a delayed single injection showed improvement with a marginal trend (38.1%, P = 0.079). All histomorphometric changes were significantly more improved in the immediate or delayed single injection groups than in the control group. Repeat treatments did not provide any benefit for the recovery of erectile function and histomorphometric changes. CONCLUSIONS: Intracavernous injection of 1 × 10(6) hBMSCs results in a recovery of penile erection and histomorphometric changes in a rat model of cavernous nerve injury, even when treatment was delayed until 4 weeks after cavernous nerve injury.

Prospective investigation of change in the prostate-specific antigens after various urologic procedures.

PURPOSE: Prostate-specific antigen (PSA) is the most important marker in the diagnosis and follow-up of patients with prostate cancer. The primary objective of this study was to evaluate the effect of various urologic procedures in prostatic area on serum free and total PSA levels. SUBJECTS AND METHODS: A series of 62 patients (8 after digital rectal examination [DRE], 12 after transrectal ultrasonography [TRUS], 11 after rigid cystoscopy, 13 after prostatic massage, 8 after TRUS-guided prostate biopsy, and 10 after transurethral resection of prostate [TURP]) were enrolled in the study. Blood samples were taken from each patient before procedure and at 10, 30, 60, and 120 minutes after procedures. RESULTS: Prostate massage, rigid cystoscopy, TURP, and TRUS-guided prostate biopsy caused statistically significant rise in total and free PSA levels in the serum. There was no significant increase in total and free PSA levels in the serum after DRE and TRUS. The mean differences were greater for free PSA level in the serum for TURP, TRUS-guided prostate biopsy, prostate massage, and rigid cystoscopy. CONCLUSION: Total and free PSA levels in the serum are altered by prostate massage, rigid cystoscopy, TRUS-guided prostate biopsy, and TURP. The PSA rises were related to the stimulation strength of the procedures. The total and free PSA levels were increased significantly from 10 minutes after procedures, except DRE and TRUS, and were increased to maximal level at 60 minutes after procedures.

Kidney Laterality and the Safety of Hand-assisted Live Donor Nephrectomy: Review of 1000 Consecutive Cases at a Single Center.

OBJECTIVE: To determine the feasibility of performing right-sided, hand-assisted, laparoscopic donor nephrectomy (HALDN) and compare with the results of left-sided surgeries in both donors and recipients. METHODS: Between September 2006 and September 2013, 1000 consecutive patients underwent HALDN at our institution. Patient characteristics and the intraoperative or postoperative parameters of the donors and recipients were retrospectively evaluated. Preoperative data, including relative renal function, vascular anatomy, and parenchymal abnormalities, were evaluated to determine the reasons for harvesting the right kidney. Intraoperative and postoperative data, including pneumoperitoneum time, warm ischemia time, complications, chronic kidney disease stage, and graft function, were compared between donors and recipients who underwent right- and left-sided procurement. RESULTS: Mean follow-up period was 21 months in donor and 42 months in recipient. Right-sided HALDN was performed on 421 patients (42.1%). The most common reasons for selecting the right kidney was reduced right kidney function (53.4%) followed by multiple left renal arteries (34.2%). None of 1000 patients required conversion to open surgery or developed major complications. Serum creatinine concentrations and chronic kidney disease stage at the last follow-up examinations were similar in donors. There were no significant differences in graft function and ureter-related complications between right- and left-sided kidneys at the last follow-up examination. CONCLUSION: Right-side HALDN is a safe procedure. The donor side can be freely selected using HALDN to benefit both donors and recipients.

Antibiotic prophylaxis with intravenous ceftriaxone and fluoroquinolone reduces infectious complications after transrectal ultrasound-guided prostatic biopsy.

PURPOSE: To assess the rates of infectious complications before and after the change of prophylactic antibiotic regimens in prostate needle biopsy. MATERIALS AND METHODS: The records of 5,577 patients who underwent prostate needle biopsy at Asan Medical Center between August 2005 and July 2012 were retrospectively reviewed. Group 1 (n=1,743) included patients treated between 2005 and 2009 with fluoroquinolone for 3 days, group 2 (n=2,723) included those treated between 2009 and 2012 with ceftriaxone once before the biopsy and fluoroquinolone before biopsy and continue therapy for 3 days, and group 3 (n=1,111) received the same treatment for more than 7 days after the biopsy. Univariable and multivariable logistic regression models addressed risk factors associated with infectious complication after prostate needle biopsy. RESULTS: Infectious complication after prostate needle biopsy developed in 18 (group 1), seven (group 2), and two patients (group 3) (p=0.001). In group 1, seven patients with infectious complication had positive blood cultures and harbored fluoroquinolone-resistant Escherichia coli, four had ceftriaxone susceptible isolates, and three had extended spectrum beta-lactamase-positive E. coli. Two patients in group 1 required intensive care because of septic shock. In multivariable analysis, the patients with combination of fluoroquinolone and ceftriaxone had significantly lower infectious complication rate than the fluoroquinolon alone (p=0.003). CONCLUSIONS: Antibiotic prophylaxis with ceftriaxone and fluoroquinolone before prostate needle biopsy decreased the risk of potentially serious infectious complications.

Is intravesical Bacillus Calmette-Guérin therapy superior to chemotherapy for intermediate-risk non-muscle-invasive bladder cancer? An ongoing debate.

The objective of this study was to evaluate the risk of recurrence in patients with intermediate-risk non-muscle-invasive bladder cancer (NMIBC) after intravesical instillation with chemotherapeutic agents or Bacillus Calmette-Guérin (BCG) therapy. A cohort of 746 patients with intermediate-risk NMIBC comprised the study group. The primary outcome was time to first recurrence. The recurrence rates of the transurethral resection (TUR) alone, chemotherapy, and BCG groups were determined using Kaplan-Meier analysis. Risk factors for recurrence were identified using Cox regression analysis. In total, 507 patients (68.1%), 78 patients (10.5%), and 160 (21.4%) underwent TUR, TUR+BCG, or TUR+chemotherapy, respectively. After a median follow-up period of 51.7 months (interquartile range=33.1-77.8 months), 286 patients (38.5%) developed tumor recurrence. The 5-yr recurrence rates for the TUR, chemotherapy, and BCG groups were 53.6%±2.7%, 30.8%±5.7%, and 33.6%±4.7%, respectively (P<0.001). Chemotherapy and BCG treatment were found to be predictors of reduced recurrence. Cox-regression analysis showed that TUR+BCG did not differ from TUR+chemotherapy in terms of recurrence risk. Adjuvant intravesical instillation is an effective prophylactic that prevents tumor recurrence in intermediate-risk NMIBC patients following TUR. In addition, both chemotherapeutic agents and BCG demonstrate comparable efficacies for preventing recurrence.

Comparative study of autologous stromal vascular fraction and adipose-derived stem cells for erectile function recovery in a rat model of cavernous nerve injury.

The abilities of intracavernous injection of autologous stromal vascular fraction (SVF) and adipose-derived stem cells (ADSCs) to facilitate recovery of erectile function in a rat model of cavernous nerve (CN) injury were compared. Forty male Sprague-Dawley rats were randomly divided into four groups: sham and control groups (intracavernous injection of phosphate-buffered saline), SVF group (intracavernous injection of SVF), and ADSC group (intracavernous injection of ADSCs). Rats in the latter three groups underwent bilateral CN injury prior to injection. The evaluation of erectile function and histomorphometric studies were performed 4 weeks after injection. The ratio of maximal intracavernous pressure to mean arterial pressure was significantly lower in the control group than in the sham group (0.18 vs. 0.56, p < .001). Intracavernous injection of SVF (0.36, p = .035) significantly improved erectile function compared with that in the control group, whereas the ADSC group (0.35, p = .052) showed marginally significant improvement. The smooth muscle/collagen ratio, smooth muscle content, number of neuronal nitric-oxide synthase-positive nerve fibers, and expression of von Willebrand factor were significantly higher in the SVF and ADSC groups than in the control group. Expression of endothelial nitric-oxide synthase was significantly increased in the SVF group. The increases in the smooth muscle/collagen ratio and von Willebrand factor expression were larger in the SVF group than in the ADSC group. Intracavernous injection of SVF or ADSCs was equally effective in recovering penile erection in a rat model of CN injury.

Efficacy and Safety of the Selective α1A-Adrenoceptor Blocker Silodosin for Severe Lower Urinary Tract Symptoms Associated With Benign Prostatic Hyperplasia: A Prospective, Single-Open-Label, Multicenter Study in Korea.

PURPOSE: To evaluate the efficacy and safety of silodosin 8 mg once daily in a 12-week treatment of subjects with severe lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: A total of 100 subjects from 10 urology centers in Korea were included in this study. The inclusion criteria were as follows: age ≥50 years, International Prostate Symptom Score (IPSS) ≥20, quality of life (QoL) score ≥3, urine volume ≥120 mL and maximal urinary flow rate (Qmax) <15 mL/s, and postvoid residual volume (PVR) <100 mL. We assessed the improvement of LUTS with change in IPSS, QoL score, Qmax, PVR, and adverse events at baseline and 4 and 12 weeks after treatment with silodosin 8 mg once daily. RESULTS: The IPSS values were 23.27±3.34, 15.89±6.26, and 13.80±6.31 at baseline, 4, and 12 weeks, respectively, with significant improvements (p<0.0001, p=0.0214, respectively). QoL scores were 4.44±0.85, 3.38±1.20, and 3.04±1.20 at baseline, 4, and 12 weeks, respectively, and the differences were statistically significant (p<0.0001). There was a significant difference in Qmax between baseline and 12 weeks (p<0.0001) but not in PVR (p=0.9404) during the clinical trial. The most frequent adverse event in this study was ejaculation failure with 13 cases. However, no subject dropped out because of ejaculation failure, and in 12 of the 13 cases it was fully resolved without further treatment. CONCLUSIONS: Silodosin 8 mg once daily may be effective and safe in Korean patients with severe LUTS associated with BPH.

Evaluation of sperm deoxyribonucleic acid (DNA) damage and effects on embryo development using a mouse cryptorchidism model.

OBJECTIVE: To investigate the effects of sperm deoxyribonucleic acid (DNA) damage on fertilization and embryo development using a mouse cryptorchidism model of sperm DNA damage induction. MATERIALS AND METHODS: Male ICR mice (aged 5-6 weeks) underwent cryptorchidism on their left testicles and sham operations on their right testicles. Spermatogenesis and sperm DNA fragmentation were assessed after 1, 2, and 4 weeks using hematoxylin-eosin staining, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling assays. Intracytoplasmic sperm injection into the oocytes of BDF1 females (aged 4-6 weeks) was performed using DNA-damaged sperm and normal sperm, and the fertilization rates and embryonic development were compared. RESULTS: The testicular weight and size gradually decreased after induction of cryptorchidism, with progressive reduction of spermatogenesis and increased DNA damage after 1, 2, and 4 weeks. After intracytoplasmic sperm injection, the fertilization and blastocyst development rates were significantly lower in the cryptorchidism group; however, about one quarter of the embryos arising from DNA-damaged sperm continued to develop. CONCLUSION: This was an in vivo animal study to evaluate the effects of sperm DNA damage using a cryptorchidism model. Sperm DNA damage increased significantly over time after cryptorchidism. This model could be useful in investigating male factor infertility and evaluating the biologic effects of paternal DNA damage on fertilization and future embryonic development.

Comparative analysis of periprostatic implantation and intracavernosal injection of human adipose tissue-derived stem cells for erectile function recovery in a rat model of cavernous nerve injury.

BACKGROUND: We compared periprostatic implantation (PPI) and intracavernosal injection (ICI) of human adipose tissue-derived stem cell (ADSC) to facilitate recovery of erectile function in a rat model of cavernous nerve (CN) injury. METHODS: Bilateral CN dissection (BCND) was induced in Sprague-Dawley rats. After BCND 10 rats each were treated with PPI and/or ICI of ADSCs. After 4 weeks erectile responses to electric pelvic ganglion stimulation were studied. Each penis was evaluated in terms of the expression of neuronal nitric oxide synthase and smooth muscle content. RESULTS: The ratio of maximal intracavernosal pressure to mean arterial pressure was significantly decreased in the BCND group (24.5%) compared to the sham group (64.2%). PPI and ICI significantly improved erectile function (46.7% and 47.9%, respectively) compared to the BCND group. A combination of PPI and ICI (42.5%) did not afford any incremental effect on erectile function. After stem cell therapy, the expression of neuronal nitric oxide synthase increased slightly in the ICI group without statistical relevance, whereas the PPI and combination groups showed marginally significant increases (P = 0.08). In both the PPI and ICI groups, the smooth muscle content was similar to the sham group. The combination group showed remarkable increase in smooth muscle content to an extent greater than that seen when either treatment was given alone, although statistically not significant. CONCLUSION: PPI or ICI of ADSCs in a rat model of CN injury were equally effective in recovering penile erection, but may address different types of pathophysiology.

Efficacy and safety of avanafil for treating erectile dysfunction: results of a multicentre, randomized, double-blind, placebo-controlled trial.

UNLABELLED: Study Type--Therapy (RCT) Level of Evidence 1b. What's known on the subject? and What does the study add? Avanafil is a potent selective phosphodiesterase type 5 (PDE5) inhibitor newly developed for treating erectile dysfunction (ED). Preclinical and clinical phase I studies showed that avanafil had enhanced selectivity, faster onset of action and a favourable side-effect profile relative to currently available PDE5 inhibitors. As the result of phase III clinical trial for the efficacy and safety of avanafil treatment (100 and 200 mg), taken as needed over a period of 12 weeks, in Korean patients with ED, avanafil is an effective and well-tolerated therapy for ED of broad-spectrum aetiology and severity. OBJECTIVE: • To evaluate the efficacy and safety of avanafil, a new potent selective phosphodiesterase type 5 (PDE5) inhibitor, in patients with erectile dysfunction (ED). PATIENTS AND METHODS: • The present study was a multicentre, randomized, double-blind, placebo-controlled, fix-dosed phase three clinical trial involving 200 patients with ED. • The subjects were treated with placebo or avanafil (100 or 200 mg) for 12 weeks and were asked to complete the International Index of Erectile Function (IIEF), the Sexual Encounter Profile (SEP) diary, and the Global Assessment Questionnaire (GAQ). • The primary outcome variable was the change from baseline for IIEF erectile function domain (EFD) score. • The secondary outcome variables were SEP Q2 and Q3, the shift to normal rate (EFD ≥ 26), and response to the GAQ. RESULTS: • Compared with placebo, patients who took 100 or 200 mg of avanafil had significantly improved IIEF-EFD score. • There were similar results when comparing Q2 and Q3 in the SEP diary and the GAQ. • Flushing was the most common treatment-related adverse event. • Most adverse events were transient and mild or moderate in severity. CONCLUSION: • Avanafil is an effective and well-tolerated therapy for ED of broad-spectrum aetiology and severity.

A therapeutic confirmatory study to assess the safety and efficacy of Zydena (udenafil) for the treatment of erectile dysfunction in male patients with diabetes mellitus.

INTRODUCTION: Patients with diabetes mellitus (DM) are reported to experience more severe erectile dysfunction (ED) symptoms and respond less to ED treatments compared with patients with ED of other etiologies. AIM: This study was undertaken to evaluate the safety and efficacy of udenafil for the treatment of ED in a larger number of patients with DM. METHODS: A placebo-controlled, randomized, double-blind, double-dummy, parallel-group design multicenter study, fixed-dose trial was conducted. The trial involved seven study sites in Korea, with 174 ED patients with DM. The subjects, treated with placebo, 100 mg, or 200 mg of udenafil for 12 weeks, were asked to complete the International Index of Erectile Function (IIEF), the Sexual Encounter Profile (SEP) diary, and the Global Assessment Question (GAQ) during the study period. MAIN OUTCOME MEASURES: The primary efficacy parameter was the change in the erectile function domain (EFD) score of IIEF from baseline. Secondary parameters were IIEF questions 3 (Q3) and Q4, SEP Q2 and Q3, rate of achieving normal erectile function (EFD ≥ 26), and the response to GAQ. RESULTS: Compared with the placebo, patients receiving both doses of udenafil showed statistically significant improvements in the IIEF-EFD score, respectively. However, statistically significant difference was not observed between the udenafil 100 mg and the udenafil 200 mg groups. Similar results were observed in the comparison of Q3 and Q4 of IIEF, SEP diary, and GAQ. The percentages of subjects experiencing at least one adverse event related to the study drugs were 3.6%, 15.8%, and 22.4% for the placebo, udenafil 100 mg, and udenafil 200 mg groups, respectively. However, these events were all mild in severity. Major adverse events were flushing, headache, nausea, and conjunctival hyperemia. CONCLUSION: Udenafil was significantly effective for the treatment of ED, demonstrating statistically significant improvement in erectile function in patients with DM. The incidence of adverse events was relatively low and well tolerated in patients with DM.

Efficacy and safety of once-daily dosing of udenafil in the treatment of erectile dysfunction: results of a multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND: A once-daily dosing regimen with a phosphodiesterase type 5 inhibitor is needed for the treatment of erectile dysfunction (ED), in part because of the behavioral complexities associated with sexual intimacy. Many patients prefer spontaneous rather than scheduled sexual activities or they anticipate frequent sexual encounters. The pharmacokinetic profiles of udenafil with a time of maximal concentration of 1.0-1.5h and a terminal half-life of 11-13 h make udenafil a good candidate for once-daily dosing. OBJECTIVE: To evaluate the efficacy and safety of once-daily dosing of udenafil in the treatment of ED. DESIGN, SETTING, AND PARTICIPANTS: This multicenter randomized double-blind, placebo-controlled, fix-dosed clinical trial involved 237 patients with ED. The subjects, who were treated with placebo or udenafil (25mg, 50mg, or 75 mg) once daily for 12 wk, were asked to complete the International Index of Erectile Function (IIEF), the Sexual Encounter Profile (SEP) diary, and the Global Assessment Questionnaire (GAQ) during the study. MEASUREMENTS: The primary outcome parameter was the change from baseline for the IIEF erectile function domain (EFD) score. The secondary outcome parameters were SEP questions 2 and 3, the shift to normal rate (EFD ≥ 26), and the response to the GAQ. RESULTS AND LIMITATIONS: Compared with placebo, patients who took 50mg or 75 mg of udenafil had a significantly improved IIEF-EFD score. Similar results were observed in comparing questions 2 and 3 in the SEP diary and the GAQ. Flushing was the most common treatment-related adverse event, which was transient and mild to moderate in severity. CONCLUSIONS: Udenafil significantly improved erectile function among ED patients when administered in doses of 50mg or 75 mg once daily for 12 wk. Daily administration of udenafil (50mg) may be another treatment option for ED.

Tadalafil Administered Once Daily for Treatment of Lower Urinary Tract Symptoms in Korean men with Benign Prostatic Hyperplasia: Results from a Placebo-Controlled Pilot Study Using Tamsulosin as an Active Control.

OBJECTIVES: Assess the efficacy and safety of once-daily tadalafil or tamsulosin versus placebo during 12 weeks on lower urinary tract symptoms (LUTS) in Korean men with benign prostatic hyperplasia (BPH). METHODS: Following a 4-week placebo run-in period, 151 Korean men were randomly assigned to receive once-daily tadalafil 5 mg, tamsulosin 0.2 mg, or placebo for 12 weeks. RESULTS: The International Prostate Symptom Score (IPSS) least squares mean changes from baseline to endpoint were numerically but not significantly improved in the tadalafil (-5.8) and tamsulosin (-5.4) groups compared with placebo (-4.2, P > 0.05). Decreases in IPSS obstructive and irritative subscores, IPSS Quality of Life score, and BPH Impact Index from baseline to endpoint were largest in the tadalafil group followed by tamsulosin, though none separated significantly from placebo. Increases in maximum urinary flow rate were small and not significantly different than placebo; the increase was largest in the tadalafil group (2.5 mL/sec), followed by the placebo (2.3 mL/sec) and tamsulosin (2.1 mL/sec) groups. The percentage of subjects reporting at least one treatment-emergent adverse event was 26.5, 13.7 and 3.9% in the tamsulosin, tadalafil and placebo groups, respectively. CONCLUSIONS: In this pilot study in Korean men, those with BPH and treated with tadalafil 5 mg or tamsulosin 0.2 mg once daily experienced a reduction in LUTS, which was numerically (but not statistically) significant compared with the placebo. Tadalafil was well tolerated and few subjects discontinued the study due to treatment-emergent adverse events. Larger studies in Asian men with BPH and LUTS treated with phosphodiesterase type 5 inhibitors are needed.

Efficacy and safety of oral mirodenafil in the treatment of erectile dysfunction in diabetic men in Korea: a multicenter, randomized, double-blind, placebo-controlled clinical trial.

INTRODUCTION: Mirodenafil is a newly developed selective phosphodiesterase type 5 (PDE5) inhibitor for the treatment of erectile dysfunction (ED). AIM: To evaluate the efficacy, safety and tolerability of mirodenafil in the treatment of ED in Korean men with diabetes. METHODS: A multicenter, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study was conducted with 112 subjects who were randomized to either placebo or mirodenafil 100 mg on demand for 12 weeks. MAIN OUTCOME MEASURES: Primary efficacy variable was the erectile function (EF) domain scores of the International Index of Erectile Dysfunction (IIEF) questionnaire. Secondary efficacy variables included change in the scores of IIEF question 3 and 4 (IIEF Q3 and Q4) from baseline, change in all domain scores in the IIEF from baseline, Sexual Encounter Profile questions 2 and 3 (SEP2 and SEP3), the Global Assessment Question (GAQ) and the Life Satisfaction Checklist (LSC). RESULTS: After 12 weeks of treatment, mirodenafil group showed significantly greater change in the IIEF-EF domain score from baseline compared with the placebo group (9.3 vs. 1.4, P < 0.0001). The changes from baseline in the mirodenafil group in IIEF Q3 (1.7 vs. 0.4, P < 0.0001) and Q4 (1.7 vs. 0.3, P < 0.0001) were higher compared with the placebo group. Differences between the mirodenafil and placebo groups were significant in the SEP2 (82.0% vs. 55.2%, P = 0.0003), SEP3 (68.9% vs. 22.3%, P < 0.0001). Difference in GAQ "YES" responses was also significant (76.9% vs. 19.1%, P < 0.0001). Normal EF domain scores (≥ 26) at study end were achieved by 32.7% and 9.4% in the mirodeniafl and placebo groups, respectively (P = 0.0031). As for the LSC scores, the mirodenafil group showed significantly greater improvements in sexual life and partner relationship than the placebo group. Most treatment-associated AEs were mild that resolved spontaneously. CONCLUSIONS: Mirodenafil is an effective and well-tolerated agent for the treatment of diabetic patients with ED in Korea.

Disorders of orgasm and ejaculation in men.

INTRODUCTION: Ejaculatory/orgasmic disorders are common male sexual dysfunctions, and include premature ejaculation (PE), inhibited ejaculation, anejaculation, retrograde ejaculation, and anorgasmia. AIM: To provide recommendations and guidelines concerning current state-of-the-art knowledge for management of ejaculation/orgasmic disorders in men. METHODS: An international consultation in collaboration with the major urology and sexual medicine associations assembled over 200 multidisciplinary experts from 60 countries into 25 committees. Committee members established specific objectives and scopes for various male and female sexual medicine topics. The recommendations concerning state-of-the-art knowledge of disorders of orgasm and ejaculation represent the opinion of seven experts from seven countries developed in a process over a 2-year period. MAIN OUTCOME MEASURE: Expert opinion was based on grading of evidence-based medical literature, widespread internal committee discussion, public presentation and debate. RESULTS: Premature ejaculation management is largely dependent upon etiology. Lifelong PE is best managed with PE pharmacotherapy (selective serotonin re-uptake inhibitor [SSRI] and/or topical anesthetics). The management of acquired PE is etiology specific and may include erectile dysfunction (ED) pharmacotherapy in men with comorbid ED. Behavioral therapy is indicated when psychogenic or relationship factors are present and is often best combined with PE pharmacotherapy in an integrated treatment program. Retrograde ejaculation is managed by education, patient reassurance, pharmacotherapy, or bladder neck reconstruction. Delayed ejaculation, anejaculation, and/or anorgasmia may have a biogenic and/or psychogenic atiology. Men with age-related penile hypoanesthesia should be educated, reassured, and instructed in revised sexual techniques which maximize arousal. CONCLUSIONS: Additional research is required to further the understanding of the disorders of ejaculation and orgasm.