da-8159 and Erectile-Dysfunction

Erectile dysfunction (ED) is the most frequently treated male sexual dysfunction worldwide. ED is a chronic condition that exerts a negative impact on male self-esteem and nearly all life domains including interpersonal, family, and business relationships.. The aim of this study is to provide an updated overview on currently used and available conservative treatment options for ED with a special focus on their efficacy, tolerability, safety, merits, and limitations including the role of combination therapies for monotherapy failures.. The methods used were PubMed and MEDLINE searches using the following keywords: ED, phosphodiesterase type 5 (PDE5) inhibitors, oral drug therapy, intracavernosal injection therapy, transurethral therapy, topical therapy, and vacuum-erection therapy/constriction devices. Additionally, expert opinions by the authors of this article are included.. Level 1 evidence exists that changes in sedentary lifestyle with weight loss and optimal treatment of concomitant diseases/risk factors (e.g., diabetes, hypertension, and dyslipidemia) can either improve ED or add to the efficacy of ED-specific therapies, e.g., PDE5 inhibitors. Level 1 evidence also exists that treatment of hypogonadism with total testosterone < 300 ng/dL (10.4 nmol/L) can either improve ED or add to the efficacy of PDE5 inhibitors. There is level 1 evidence regarding the efficacy and safety of the following monotherapies in a spectrum-wide range of ED populations: PDE5 inhibitors, intracavernosal injection therapy with prostaglandin E1 (PGE1, synonymous alprostadil) or vasoactive intestinal peptide (VIP)/phentolamine, and transurethral PGE1 therapy. There is level 2 evidence regarding the efficacy and safety of the following ED treatments: vacuum-erection therapy in a wide range of ED populations, oral L-arginine (3-5 g), topical PGE1 in special ED populations, intracavernosal injection therapy with papaverine/phentolamine (bimix), or papaverine/phentolamine/PGE1 (trimix) combination mixtures. There is level 3 evidence regarding the efficacy and safety of oral yohimbine in nonorganic ED. There is level 3 evidence that combination therapies of PDE5 inhibitors + either transurethral or intracavernosal injection therapy generate better efficacy rates than either monotherapy alone. There is level 4 evidence showing enhanced efficacy with the combination of vacuum-erection therapy + either PDE5 inhibitor or transurethral PGE1 or intracavernosal injection therapy. There is level 5 evidence (expert opinion) that combination therapy of PDE5 inhibitors + L-arginine or daily dosing of tadalafil + short-acting PDE5 inhibitors pro re nata may rescue PDE5 inhibitor monotherapy failures. There is level 5 evidence (expert opinion) that adding either PDE5 inhibitors or transurethral PGE1 may improve outcome of penile prosthetic surgery regarding soft (cold) glans syndrome. There is level 5 evidence (expert opinion) that the combination of PDE5 inhibitors and dapoxetine is effective and safe in patients suffering from both ED and premature ejaculation.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Alprostadil; Carbolines; Drug Therapy, Combination; Erectile Dysfunction; Humans; Hypogonadism; Imidazoles; Male; Middle Aged; Penile Erection; Phosphodiesterase 5 Inhibitors; Piperazines; Pyrimidines; Risk Factors; Sulfonamides; Sulfones; Tadalafil; Triazines; Vardenafil Dihydrochloride; Yohimbine

Several randomized controlled trials (RCTs) on phosphodiesterase type 5 inhibitors (PDE5-Is) have showed significant improvements in both lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) in men affected by one or both conditions, without a significant increase in adverse events. However, the results are inconsistent.. Perform a systematic review and meta-analysis of available prospective and cross-sectional studies on the use of PDE5-Is alone or in combination with α1-adrenergic blockers in patients with LUTS/benign prostatic hyperplasia (BPH).. A systematic search was performed using the Medline, Embase, and Cochrane Library databases through September 2011 including the combination of the following terms: LUTS, BPH, PDE5-Is, sildenafil, tadalafil, vardenafil, udenafil, α-blockers, and α1-adrenergic blocker. The meta-analysis was conducted according to the guidelines for observational studies in epidemiology.. Of 107 retrieved articles, 12 were included in the present meta-analysis: 7 on PDE5-Is versus placebo, with 3214 men, and 5 on the combination of PDE5-Is with α1-adrenergic blockers versus α1-adrenergic blockers alone, with 216 men. Median follow-up of all RCTs was 12 wk. Combining the results of those trials, the use of PDE5-Is alone was associated with a significant improvement of the International Index of Erectile Function (IIEF) score (+5.5; p<0.0001) and International Prostate Symptom Score (IPSS) (-2.8; p<0.0001) but not the maximum flow rate (Q(max)) (-0.00; p=not significant) at the end of the study as compared with placebo. The association of PDE5-Is and α1-adrenergic blockers improved the IIEF score (+3.6; p<0.0001), IPSS score (-1.8; p = 0.05), and Q(max) (+1.5; p<0.0001) at the end of the study as compared with α-blockers alone.. The meta-analysis of the available cross-sectional data suggests that PDE5-Is can significantly improve LUTS and erectile function in men with BPH. PDE5-Is seem to be a promising treatment option for patients with LUTS secondary to BPH with or without ED.

Topics: Adrenergic alpha-Antagonists; Carbolines; Drug Therapy, Combination; Erectile Dysfunction; Humans; Imidazoles; Lower Urinary Tract Symptoms; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Prostatic Hyperplasia; Purines; Pyrimidines; Sildenafil Citrate; Sulfonamides; Sulfones; Tadalafil; Treatment Outcome; Triazines; Vardenafil Dihydrochloride

To systematically review the evidence on the efficacy and safety of udenafil as treatment of erectile dysfunction from randomized controlled trials.. We searched PubMed, Embase, and the Cochrane Library database up to October 2011. The outcome measures assessed were the change from baseline for the International Index of Erectile Function erectile function domain score (primary), the change from baseline for Sexual Encounter Profile questions 2 and 3, the shift to normal rate (erectile function domain ≥ 26), the response to the Global Assessment Questionnaire and adverse effects (secondary). Two of us independently assessed the study quality and extracted data. All data were analyzed using Review Manager, version 5.0.2.. Five randomized controlled trials totaling 1109 patients were included. At the follow-up endpoints, udenafil was found to be more effective than placebo, and the tolerability was good. The pooled results showed that the udenafil group was significantly greater than the placebo group in the change from baseline for the International Index of Erectile Function erectile function domain score (mean difference 5.65, 95% confidence interval 4.41-6.89, P < .00001). All included studies indicated that most adverse events were mild or moderate in severity, and no serious adverse events were reported during the study period. The most common drug-related adverse events were flushing and headache (udenafil vs placebo, 5.6% vs 1.8% and 3.1% vs 0%, respectively).. The results from the current meta-analysis have suggested that udenafil is an effective and well-tolerated therapy for erectile dysfunction. The findings of the present review highlight the need for more efficient performance of higher quality, large-sample, various-race, long-term, randomized controlled trials to verify the efficacy and safety of udenafil.

Topics: Erectile Dysfunction; Humans; Male; Phosphodiesterase 5 Inhibitors; Pyrimidines; Randomized Controlled Trials as Topic; Sulfonamides

Erectile dysfunction (ED) is an important worldwide health issue that has a significant negative impact on the quality of life and life satisfaction of both the affected individual and his partner. Here we review the prevalence of ED in Asia, associated factors that may influence sexual attitudes and sexual behaviours, and randomized clinical trials (RCTs) of phosphodiesterase-5 (PDE-5) inhibitors to evaluate the clinical efficacy and safety of PDE-5 inhibitors in Asian men. We searched for English-language articles in MEDLINE and PubMed from January 2000 to September 2010. Our results showed that the overall reported prevalence rate of ED in Asia ranged widely, from 2% to 88%. This finding indicates that ED is a common and major health problem in this region. However, sociocultural and economic factors in Asia prevent people from seeking and obtaining appropriate medical care. We found reports on five kinds of PDE-5 inhibitors for the management of ED: sildenafil, vardenafil, tadalafil, udenafil and mirodenafil. The results of RCTs showed that these five PDE-5 inhibitors are more effective than placebo in improving erectile function in Asian men with ED and that these drugs have similar efficacy and safety profiles.

Topics: Adult; Aged; Asia; Carbolines; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug-Related Side Effects and Adverse Reactions; Erectile Dysfunction; Humans; Imidazoles; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Prevalence; Purines; Pyrimidines; Pyrimidinones; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfonamides; Sulfones; Tadalafil; Triazines; Vardenafil Dihydrochloride

Udenafil is an oral PDE5 inhibitor that is currently available in South Korea for the treatment of erectile dysfunction (ED). Phase II clinical data presented at the 11th World Congress of the International Society for the Sexual and Impotence Research showed that in men with mild-to-severe ED, the drug produced a significant improvement in erectile function after 12 weeks of treatment. Udenafil has been reported as being well tolerated, although in August 2005, the Korean Food & Drug Administration had demanded further details regarding the presence of carcinogenic substances in the drug. A phase IIa clinical trial for ED is currently underway in the US, and phase III trials are planned for 2006.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Contraindications; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Evaluation, Preclinical; Erectile Dysfunction; Humans; Male; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Pyrimidines; Structure-Activity Relationship; Sulfonamides

Once-daily administration of phosphodiesterase type 5 inhibitors has been shown to correct erectile dysfunction (ED).. To evaluate the long-term efficacy and safety after once-daily oral administration of udenafil 75 mg in men with ED.. 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.. 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.. 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.. Once-daily dosing of udenafil 75 mg showed excellent efficacy and safety with long-term administration and allowed a more spontaneous sexual life.

Topics: Administration, Oral; Adult; Aged; Double-Blind Method; Drug Administration Schedule; Erectile Dysfunction; Headache Disorders; Humans; Long-Term Care; Male; Middle Aged; Penile Erection; Phosphodiesterase 5 Inhibitors; Pyrimidines; Sexual Behavior; Sulfonamides; Surveys and Questionnaires; Treatment Outcome

Nerve-preserving surgery has been provided for patients with rectal cancer; however, sexual dysfunction remains a common complication of rectal cancer surgery. This study explored the efficacy of udenafil to treat erectile dysfunction in male patients who underwent total mesorectal excision (TME) for rectal cancer.. We conducted a randomized, double-blind, placebo-controlled clinical trial involving 80 male patients who had decreased International Index of Erectile Function-5 (IIEF-5) scores after TME for rectal cancer. Patients received placebo (50 mg) or udenafil (50 mg) for 12 weeks. The primary outcome variable was the change in IIEF-5 scores. The secondary outcome variables were Sexual Encounter Profile (SEP) questions 2 (Q2) and 3 (Q3), and the Global Assessment Question (GAQ).. Baseline IIEF-5 scores, SEP Q2 and Q3 responses, and spontaneous erection rates were consistent in both groups. At the end of treatment, the change in IIEF-5 scores from the baseline was significantly higher in the udenafil group than it was in the placebo group (mean IIEF-5 score, 4.8 ± 4.0 vs 2.0 ± 1.7; P < .05). Responses to SEP Q2, SEP Q3, and GAQ were significantly higher in the udenafil group than they were in the placebo group (SEP Q2, P = .025; SEP Q3, P = .044; GAQ, P < .001). Treatment-related adverse events (n = 4) were all mild in severity.. Oral udenafil was deemed safe and effective for the treatment of erectile dysfunction in patients who underwent TME for rectal cancer.

Topics: Digestive System Surgical Procedures; Double-Blind Method; Erectile Dysfunction; Humans; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Postoperative Complications; Pyrimidines; Rectal Neoplasms; Rectum; Sulfonamides; Treatment Outcome

The method of administration of oral phosphodiesterase-5 inhibitors has been expanded to once-daily repeated administration with lower initial dosage than on-demand administration.. The aim of this study was to evaluate the efficacy and safety of once-daily udenafil as a treatment for erectile dysfunction (ED) for intermediate-term period.. This multicenter, randomized, double-blind clinical trial included 346 ED patients (placebo, udenafil 50 mg, udenafil 75 mg). Subjects were treated with each medication once daily for 24 weeks.. Subjects were asked to complete the International Index of Erectile Function (IIEF)-erectile function (EF) domain at baseline, 12 weeks, and 24 weeks and the development of adverse drug reactions (ADRs) was inspected.. Both dosages of udenafil induced a significant increase in IIEF-EF compared with placebo at both 12 and 24 weeks. When patients were divided according to the severity of baseline EF score, significant improvement was observed only with udenafil 75 mg regardless of the degree of ED. At 24 weeks, the proportions of patients who reported a return to normal EF (IIEF-EF over 26) were 39.1% for udenafil 50 mg and 47.0% for udenafil 75 mg. In terms of safety, ADRs were observed in 6.1%, 12.9%, and 17.9% for placebo, udenafil 50 mg, and 75 mg, respectively. Although a statistically higher rate of ADRs was observed in the udenafil 75 mg group (P = 0.024), the majority were mild and recovered without treatment.. Once-daily administration of udenafil 50 mg and 75 mg for 24 weeks resulted in improvement of EF. In particular, udenafil 75 mg improves EF regardless of the baseline degree of ED.

Topics: Double-Blind Method; Drug Administration Schedule; Erectile Dysfunction; Humans; Male; Middle Aged; Patient Satisfaction; Penile Erection; Phosphodiesterase 5 Inhibitors; Pyrimidines; Republic of Korea; Sexual Behavior; Sulfonamides; Surveys and Questionnaires; Time Factors; Treatment Outcome

The purpose of this study is to evaluate the hemodynamic interactions between udenafil and tamsulosin.. After a placebo lead-in period, 27 healthy volunteers received 200 mg udenafil + tamsulosin placebo, udenafil placebo +0.4 mg tamsulosin, or 200 mg udenafil +0.4 mg tamsulosin. Blood pressure and pulse rate (PR) were measured at 15 time points from 0 to 24 hours.. A single dose of udenafil, when administered with multiple tamsulosin doses, produced statistically significant increases in PR (mean: 10.7; 95% confidence interval: 5.3, 16.2 bpm; p < 0.001) compared with tamsulosin administered with an udenafil placebo. Systolic and diastolic blood pressure measurements remained unchanged. Two subjects who took udenafil with tamsulosin had a decrease in standing systolic blood pressure (SBP) greater than 30 mmHg in comparison to their baseline SBP; however, compared with the frequency of a decrease in standing SBP greater than 30 mmHg in comparison to the baseline, there was no significant difference in frequency among the four treatments (p = 0.243). There was no difference in the Cmax, AUClast, or AUCinf of udenafil and its active metabolite DA-8164 between the administration of udenafil and udenafil with tamsulosin.. The coadministration of udenafil and tamsulosin was not associated with clinically significant hemodynamic changes in healthy volunteers. Although this study was conducted on a small number of healthy young subjects, the use of udenafil for the treatment of erectile dysfunction in patients taking tamsulosin for the treatment of benign prostatic hyperplasia is not expected to cause significant safety problems.

Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Adult; Blood Pressure; Double-Blind Method; Drug Interactions; Erectile Dysfunction; Healthy Volunteers; Hemodynamics; Humans; Hypotension, Orthostatic; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Placebos; Prostatic Hyperplasia; Pyrimidines; Sulfonamides; Tamsulosin; Young Adult

Udenafil is a potent phosphodiesterase type-5 inhibitor (PDE5) previously shown in studies conducted in populations of Eastern-Asian ethnicity, to significantly improve sexual function, in addition to a favourable safety profile. The purpose of this study was to evaluate the efficacy and safety of udenafil for the treatment of erectile dysfunction (ED), for the first time in a non-Eastern-Asian population. In this multicentre, randomized, double-blind, parallel, placebo-controlled study conducted in five centres in Turkey, 118 eligible subjects were randomized to receive udenafil 100 mg taken as on-demand or matching placebo for an 8-week treatment period. The primary efficacy variable was the change from baseline of the International Index of Erectile Function Questionnaire-Erectile Function Domain (IIEF-EFD) score, secondary efficacy variables were changes from baseline in IIEF Questionnaire Domains' 2-5 scores (Intercourse Satisfaction, Orgasmic Function, Sexual Desire, Overall Sexual Satisfaction) and IIEF Questionnaire Grand Total score, changes from baseline in penetration success rates (SEP2) and intercourse completion rates (SEP3) and evaluation of responses to the global assessment question (GAQ). Patients treated with udenafil demonstrated significantly higher increase in the IIEF-EFD scores compared with placebo-treated subjects [4.0 (95% CI: 1.3-6.6; p = 0.003)]. Similarly, greater improvements were observed in the scores for SEP2 [0.65 (95% CI: 0.02-1.3, p = 0.043)], SEP3 [0.9 (95% CI: 0.3-1.5, p = 0.003)] and two other IIEF Questionnaire Domains (Domain 4: Sexual Desire, Domain 5: Overall Sexual Satisfaction). The proportion of positive responses to the GAQ was greater in the udenafil compared to the placebo group (72.2% vs. 49.1%, p = 0.014). The most frequent treatment-emergent adverse events were headache, flushing and rhinorrhea, all of mild or moderate severity. This is the first study to demonstrate in a non-Eastern-Asian population that udenafil 100 mg taken as on-demand can effectively improve erectile function and is well tolerated.

Topics: Adult; Chi-Square Distribution; Double-Blind Method; Erectile Dysfunction; Humans; Male; Middle Aged; Patient Satisfaction; Penile Erection; Phosphodiesterase 5 Inhibitors; Pyrimidines; Recovery of Function; Sexual Behavior; Sulfonamides; Surveys and Questionnaires; Time Factors; Treatment Outcome; Turkey

A high-sensitivity LC/MS/MS method was developed and validated for the simultaneous determination of mirodenafil and its major metabolite, SK-3541, in human plasma. Mirodenafil, SK-3541, and udenafil as an internal standard were extracted from plasma samples with methyl tert-butyl ether. Chromatographic separation was performed on a Luna phenyl-hexyl column (100 × 2.0 mm) with an isocratic mobile phase consisting of 5 mM ammonium formate and ACN (23:77, v/v) at a flow rate of 0.35 mL/min. Detection and quantification were performed using a mass spectrometer in selected reaction monitoring mode with positive ESI at m/z 532.3 → 296.1 for mirodenafil, m/z 488.1 → 296.1 for SK-3541, and m/z 517.3 → 283.2 for udenafil. The calibration curves were linear over a concentration range of 2-500 pg/mL using 0.5 mL plasma for the microdose of mirodenafil (100 μg). Analytical method validation of the clinical dose (100 mg), with a calibration curve range of 2-500 ng/mL using 0.025-mL plasma, was also conducted. The other LC-MS/MS conditions were similar to those used for the microdosing. Each method was applied successfully to pharmacokinetic studies after a microdose or clinical dose of mirodenafil to six healthy Korean male volunteers.

Topics: Adult; Chromatography, High Pressure Liquid; Drug Dosage Calculations; Erectile Dysfunction; Humans; Male; Pyrimidines; Pyrimidinones; Sensitivity and Specificity; Sulfonamides; Tandem Mass Spectrometry; Young Adult

• To evaluate the impact and distribution of a single phosphodiesterase type 5 inhibitor (PDE5 I) dose (udenafil or tadalafil) in prostate tissue and plasma in patients with benign prostatic hyperplasia (BPH).. • Thirty BPH patients complaining of erectile dysfunction along with moderate-to-severe lower urinary tract symptoms (LUTS) who underwent transurethral resection of the prostate (TURP) were enrolled in the present study. • The patients were randomly divided into the three groups: group 1, TURP without PDE5 Is; group 2, 200 mg of udenafil given 1 h before TURP; and group 3, 20 mg of tadalafil given 1 h before TURP. • We evaluated the concentrations of PDE5-I, cAMP and cGMP in prostate tissues and plasma, and calculated the prostate tissue-to-plasma (T/P) ratio.. • The concentration of udenafil in prostate tissue and plasma was 2028.6 ± 360.8 ng/g and 463.7 ± 39.1 ng/mL, respectively, and the resulting T/P ratio was 4.4. The tadalafil concentration in prostate tissue and plasma was 385.7 ± 83.8 ng/g and 305.8 ± 41.1 ng/mL, respectively, and the T/P ratio was 1.3. • Udenafil and tadalafil significantly increased the cAMP and cGMP levels in plasma and prostate tissues.. • Udenafil and tadalafil significantly increased cAMP and cGMP levels and were more highly distributed in the prostate than plasma. The T/P ratio of udenafil was higher than tadalafil. • These findings may help in the assessment of the feasibility of using PDE5 Is to concurrently treat both LUTS and erectile dysfunction.

Topics: Aged; Carbolines; Erectile Dysfunction; Feasibility Studies; Humans; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Prostatic Hyperplasia; Prostatism; Pyrimidines; Sulfonamides; Tadalafil; Treatment Outcome

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.. To evaluate the efficacy and safety of once-daily dosing of udenafil in the treatment of ED.. 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.. 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.. 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.. 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.

Topics: Aged; Double-Blind Method; Drug Administration Schedule; Erectile Dysfunction; Humans; Male; Middle Aged; Patient Satisfaction; Penile Erection; Phosphodiesterase 5 Inhibitors; Placebo Effect; Pyrimidines; Republic of Korea; Severity of Illness Index; Sexual Behavior; Sulfonamides; Surveys and Questionnaires; Time Factors; Treatment Outcome

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.. 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.. 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.. 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.. 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.. 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.

Topics: Diabetes Complications; Double-Blind Method; Erectile Dysfunction; Humans; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Pyrimidines; Sulfonamides; Treatment Outcome

Udenafil is a phosphodiesterase 5 inhibitor used for the treatment of erectile dysfunction. It is metabolized to DA-8164, a major metabolite, by CYP3A4. This study was performed to investigate the effect of ketoconazole, a known CYP3A4 inhibitor, on the pharmacokinetics of udenafil.. An open-label, two-period, fixed-sequence crossover study was performed in 12 healthy male volunteers. They received a single 100-mg oral dose of udenafil. Following a 5-day interval, 400 mg of ketoconazole was administered once a day for three consecutive days. On day 3 of ketoconazole treatment, a second 100 mg of udenafil was dosed concomitantly. Blood samples were collected at time points up to 48 h without ketoconazole treatment and up to 72 h with ketoconazole co-administration. The plasma concentration of udenafil was determined using liquid chromatography-tandem mass spectrometry.. Following ketoconazole co-administration, the mean C(max) and AUC(last) of udenafil (95% confidence interval) increased 1.9-fold (1.60, 2.27) and 3.2-fold (2.82, 3.63), respectively. The median time to reach the C(max) was delayed in the co-administrated treatment, while the mean terminal elimination half-life (t(1/2)) remained relatively unchanged regardless of ketoconazole co-administration. The metabolic AUC ratio (AUC(last) of DA-8164/AUC(last) of udenafil) was 1.71 when udenafil was administered alone, and the value decreased to 0.19 when udenafil was dosed in the presence of ketoconazole. Regarding safety assessments, no clinically significant difference or serious adverse event was observed.. The systemic exposure of udenafil increased significantly when it was administered with ketoconazole. Dose adjustment may be required when these drugs are used together.

Topics: Access to Information; Administration, Oral; Adult; Asian People; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Interactions; Erectile Dysfunction; Half-Life; Humans; Ketoconazole; Male; Pyrimidines; Sulfonamides; Young Adult

Udenafil is a newly developed selective phosphodiesterase type 5 inhibitor for the treatment of men with erectile dysfunction (ED).. To evaluate the efficacy of udenafil in treating ED for up to 12 hours after dosing.. This was a randomized, double-blind, placebo-controlled, parallel-group, fixed dose design, multicenter study. Following a 4-week nondrug baseline period, 104 men with ED of broad etiology and severity were randomized to one of two treatment groups: udenafil 100 mg or placebo. Participants were requested to attempt sexual intercourse at 12 hours after udenafil or placebo dosing during a 4-week treatment period.. The primary efficacy variable was the response of patients to question 3 of the Sexual Encounter Profile (SEP Q3). The secondary efficacy measures were the response of patients to question 2 of the Sexual Encounter Profile (SEP Q2). Additional secondary efficacy measures included changes from baseline in the erectile function (EF) domain scores of the International Index of Erectile Function (IIEF) questionnaire.. Of the 104 patients, 103 (50 in the udenafil group, 53 in the placebo group) completed the study. Udenafil significantly enhanced the rate of maintenance of erection (SEP Q3; placebo, 28.3% vs. udenafil, 54.7%; P < 0.0001). Significant change from baseline in the IIEF-EF domain was observed in the udenafil group (placebo, -0.58 ± 0.67; udenafil, 4.40 ± 0.84; P < 0.0001). For SEP Q2, there was no difference from baseline and no difference between the two groups. The overall adverse events rate was 11.3%. Most adverse events were mild or moderate in severity, and no serious adverse events were reported during the study and the follow-up period.. Udenafil at 100 mg was effective for relieving ED for up to 12 hours after dosing. This duration of effectiveness could allow for flexibility and spontaneity in the sexual lives of patients.

Topics: Adult; Aged; Double-Blind Method; Drug Administration Schedule; Erectile Dysfunction; Humans; Male; Middle Aged; Penile Erection; Phosphodiesterase 5 Inhibitors; Pyrimidines; Sulfonamides; Time Factors; Young Adult

Udenafil is a cyclic guanosine 3',5'-monophosphate-specific phosphodiesterase type 5 (PDE5) inhibitor developed for the treatment of erectile dysfunction. The aim was to evaluate the effect of food on the pharmacokinetics of udenafil.. An open, randomized, three-way crossover study was conducted. Fifteen healthy male volunteers received a single 200-mg oral dose of udenafil while fasting, after a low-fat meal, and after a high-fat meal separated by 7-day washout periods. Serial blood samples were taken up to 48 h after oral administration.. Under fasting conditions, udenafil was rapidly absorbed and t(max) was observed typically 1.5 h after administration. The mean t(max) values after a low-fat meal and a high-fat meal were 2.6 and 2.1 h, respectively. The ratios (90% confidence intervals) of the geometric means compared with the fasting condition for C(max) and AUC(last) were 0.79 (0.70, 0.90) and 0.96 (0.89, 1.03) in the low fat-fed condition, respectively, and 1.01 (0.89, 1.15) and 1.03 (0.96, 1.11), respectively, in the high fat-fed condition.. The t(max) of udenafil was delayed under the fed conditions. However, although the C(max) was reduced by approximately 21% in the low fat-fed state, overall bioavailability was not affected when taken with food.

Topics: Adult; Aged; Area Under Curve; Cross-Over Studies; Erectile Dysfunction; Food-Drug Interactions; Humans; Male; Middle Aged; Phosphodiesterase Inhibitors; Pyrimidines; Sulfonamides; Young Adult

Udenafil is a potent selective phosphodiesterase type 5 (PDE5) inhibitor newly developed for the treatment of erectile dysfunction (ED).. This study was performed to evaluate the efficacy and safety of udenafil therapy in patients with ED.. In this multicenter, double-blind, placebo-controlled, fixed-dose, parallel-group phase III trial, 167 patients with ED of diverse origin and severity were randomized to take placebo or udenafil at fixed doses of 100 or 200 mg as needed for 12 weeks.. Primary efficacy variable was change from baseline in erectile function (EF) domain scores of the International Index of Erectile Dysfunction (IIEF) questionnaire. Secondary efficacy variables include change from baseline in scores on the IIEF Questions 3 and 4 (IIEF Q3 and Q4), change from baseline in all domain scores of the IIEF, patients' responses to questions 2 and 3 of the Sexual Encounter Profile (SEP2 and SEP3), and patients' responses to the Global Assessment Question (GAQ). Any adverse events were also recorded during the trial.. After 12 weeks of treatment, the patients treated with udenafil showed significantly greater change from baseline in the IIEF-EF domain score compared with placebo (placebo, 0.20; 100-mg udenafil, 7.52; and 200-mg udenafil, 9.93, respectively) (P < 0.0001). Compared with placebo, udenafil significantly enhanced the rates of successful penetration (SEP Q2) and maintenance of erection (SEP Q3) (P < 0.0001). Furthermore, significantly greater proportions of udenafil treatment groups responded positively to the GAQ compared with the placebo group (GAQ: placebo, 25.9%; 100-mg udenafil, 81.5%; and 200-mg udenafil, 88.5%, respectively) (P < 0.0001). Treatment-related adverse events were generally mild to moderate with facial flushing and headache being the most common.. Udenafil is an effective and well-tolerated therapy for ED of broad-spectrum etiology and severity.

Topics: Adult; Aged; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Erectile Dysfunction; Humans; Male; Middle Aged; Patient Satisfaction; Penile Erection; Phosphodiesterase Inhibitors; Pyrimidines; Quality of Life; Research Design; Severity of Illness Index; Sexual Behavior; Sulfonamides; Treatment Outcome

The phosphodiesterase (PDE) type 5 inhibitor is a widely used agent that facilitates penile erection. Udenafil is newly developed as a PDE-5 inhibitor.. This is the first study to determine the safety, tolerability and pharmacokinetics of udenafil in healthy subjects. Udenafil was safe and well tolerated in healthy Korean subjects. The AUC and C(max) of udenafil increased supraproportionally with increasing dose upon single administration, but there was no significant drug accumulation upon multiple administrations.. To evaluate the safety, tolerability and pharmacokinetics (PK) of udenafil, a novel phosphodiesterase type 5 inhibitor.. A double-blind, randomized, placebo-controlled, dose-rising, parallel-group, single- and multiple-dose study was conducted in healthy Korean subjects. The subjects were allocated to single-dose groups of 25, 50, 100, 200 or 300 mg (eight subjects in each dose group, including two placebos), or to multiple-dose groups of 100 or 200 mg (once-daily dosing for 7 days; nine subjects in each dose group, including three placebos). Serial samples of blood and urine were collected after oral administration and the drug concentrations in plasma and urine were determined by high-performance liquid chromatography. Safety and tolerability were evaluated by monitoring clinical laboratory parameters and adverse events.. Udenafil reached peak plasma concentrations at 0.8-1.3 h, and then declined mono-exponentially with a terminal half-life of 7.3-12.1 h in the single-dose study. The area under the time-concentration curves (AUC) and maximum plasma concentrations (C(max)) increased supraproportionally with increasing dose in the single-dose study. During multiple dosing, a steady state was reached at 5 days and little accumulation occurred after repeated dosing for 7 days. Udenafil was generally well tolerated in these healthy subjects, and no serious adverse events occurred.. Udenafil was safe and well tolerated in healthy volunteers. The AUC and C(max) of udenafil increased supraproportionally with increasing dose upon single administration, but there was no significant drug accumulation upon multiple administrations.

Topics: Administration, Oral; Adult; Area Under Curve; Dose-Response Relationship, Drug; Double-Blind Method; Erectile Dysfunction; Humans; Korea; Male; Penile Erection; Phosphodiesterase Inhibitors; Pyrimidines; Sulfonamides

The efficacy of statins is related to the 'common soil' hypothesis, which proposes oxidative stress and inflammation as main pathophysiologic processes in the disease group of diabetes and endothelial dysfunction. This study evaluated the recovery of erectile function after administration of chronic statin alone in streptozotocin (STZ)-induced diabetes mellitus (DM) rats, focusing on the anti-oxidative effects and consequentially recuperated endothelial function. A total of 45 male Sprague-Dawley rats (8 weeks old) were divided into three groups (n = 15 each): an age-matched normal control group (Control group), an uncontrolled DM group (DM group), and a statin-treated group (Statin group). The rats in the DM and Statin group received an injection of STZ (60 mg/kg). Beginning 10 weeks after the establishment of DM, the Statin group received daily treatment with atorvastatin (10 mg/kg) via oral gavage for four weeks. After 14 weeks, the results of the experiment were evaluated. The ratios of intracavernosal pressure (ICP) to mean arterial pressure (MAP) were recorded with cavernosometry (20 Hz, 3 V, 0.2 msec for 30 seconds) before and after the intravenous administration of udenafil (1 mg/kg). Expression of alpha-smooth muscle actin (α-SMA) was evaluated using cavernosal tissue. In addition, changes in RhoA translocation ratio and myosin phosphatase target subunit 1 (MYPT1) phosphorylation were evaluated with western blot. Superoxide dismutase (SOD) and malondialdehyde (MDA) levels were also analyzed as measurements of oxidative stress levels. The ICP/MAP and area under the curve (AUC)/MAP ratios of the Statin group were obviously superior to the DM group, but were not comparable to the Control group (P<0.001). The level of oxidative stress, namely SOD activity, was also significantly lower in the Statin group than in the DM group (P = 0.015), and was comparable to the Control group. In contrast, MDA levels were not considerably different among the groups (P = 0.217). The RhoA translocation ratio was not significantly different among the groups (P = 0.668), whereas MYPT1 phosphorylation in the Statin group was significantly lower than in the DM group (P = 0.030), and similar to the Control group. Expression of α-SMA in the Statin group was higher than in the DM group (P<0.001), and comparable to the Control group. Chronic statin treatment alone showed anti-oxidative effects and helped to restore the erectile mechanism, but did not lead to the full recovery

Topics: Administration, Intravenous; Animals; Arterial Pressure; Atorvastatin; Diabetes Mellitus, Experimental; Erectile Dysfunction; Male; Malondialdehyde; Penile Erection; Pyrimidines; Rats; Rats, Sprague-Dawley; Sulfonamides; Superoxide Dismutase

Erectile dysfunction (ED) is frequently observed in end-stage renal disease (ESRD) patients on hemodialysis (HD) compared to non-uremic patients. This situation causes severe psychogenic problems in patients and disrupts the quality of life. Different phosphodiesterase type 5 (PDE-5) inhibitors have been used, and efficacies revealed, for the treatment of ED in HD patients; however, there are no studies related to udenafil use or results for HD patients. This study retrospectively evaluated the efficacy and reliability of udenafil for HD patients.. The laboratory findings, side effects after treatment, and International Index of Erectile Function (IIEF) scores before and after treatment were compared and evaluated for HD patients who applied to our urology clinic with ED complaints and were treated with udenafil.. The results showed that in the HD patient group with ED, apart from ED, there were severe rates of other sexual dysfunction. In our patient group, there was a statistically significant improvement in all scores for erectile function (p = 0.033), orgasmic function (p < 0.001), sexual desire (p < 0.001), relationship satisfaction (p < 0.001), and general satisfaction (p < 0.001) after treatment. The reported side effects were headache in one patient and dyspepsia in one patient.. We concluded that udenafil is an effective and reliable treatment approach for HD patients; however, our results require support from prospective randomized crossover studies with sildenafil.

Topics: Erectile Dysfunction; Humans; Kidney Failure, Chronic; Male; Middle Aged; Penile Erection; Phosphodiesterase 5 Inhibitors; Pyrimidines; Quality of Life; Renal Dialysis; Reproducibility of Results; Retrospective Studies; Sulfonamides; Treatment Outcome

Chronic treatment with phosphodiesterase type 5 inhibitors (PDE5) is effective in an animal model of diabetes-induced erectile dysfunction (DMED). In addition, recent research indicates that glycemic control can restore DMED.. We evaluated the effect of chronic administration of PDE5 combined with glycemic control on DMED.. Sprague-Dawley rats (8 weeks old) were divided into five groups (n = 10 each): normal control (C), diabetes (DM), DM treated with insulin (DM-I), DM treated with PDE5 (DM-P), and DM treated with insulin and PDE5 (DM-I + P). Rats in the diabetic groups received an injection of streptozotocin (45 mg/kg). After 10 weeks of induced diabetes, the DM-I group was treated with a daily injection of neutral protamine Hagedorn, and the DM-P group was treated with a daily dosage of 20 mg/kg PDE5 (DA-8159) for 4 weeks. The DM-I + P group was treated with both treatments simultaneously. After 14 weeks of induced diabetes, an evaluation of erectile function and histological and biochemical markers of corporal tissue was performed.. Erectile function and histological and biochemical markers in corporal tissue.. Rats in the DM group showed markedly lower erectile parameters than those in the C group, whereas rats in the DM-I and DM-P groups showed intermediate erectile function between the DM and C groups. Rats in the DM-I + P group showed restored erectile function, comparable with group C. A comparison of apoptotic index, expression of the endothelial marker, and phosphorylation of endothelial nitric oxide synthase and Akt displayed a similar pattern with the results from cavernosometry (DM < DM-I = DM-P < DM-I + P = C, P < 0.05). The distribution of phosphorylated myosin phosphatase target subunit 1 was in the reverse order.. Chronic administration of PDE5 or glycemic control with insulin resulted in restoration of overt DMED. The combination of both treatments was superior to monotherapy with insulin or PDE5.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Drug Therapy, Combination; Erectile Dysfunction; Hypoglycemic Agents; Insulin; Male; Nitric Oxide Synthase Type III; Penile Erection; Phosphodiesterase 5 Inhibitors; Pyrimidines; Random Allocation; Rats; Rats, Sprague-Dawley; Streptozocin; Sulfonamides

To investigate the pathogenesis of hyperlipidemia-related erectile dysfunction and the effects of DA-8159, a new phosphodiesterase-5 inhibitor, on protein expression, we performed a proteomic analysis of differentially expressed proteins in the corpus cavernosum of hyperlipidemic rats by two-dimensional electrophoresis-mass spectrometry. Rats were fed high-cholesterol diet and treated with 5 mg·kg(-1)·day(-1) DA-8159 concurrently. After 5 months apparent hyperlipidemia and significantly decreased maximal intra-cavernous pressure were observed in the control group with the alteration of 8 proteins, which were restored by DA-8159 treatment. The proteins whose levels decreased >2-fold and attenuated by DA-8159 were determined alcohol dehydrogenase, aldolase A, annexin 1, and tropomyosin-rat, whereas proteins increased>2-fold and recovered by DA-8159 were found to be aldehyde dehydrogenase complex, guanine deaminase, creatine kinase-B, and phosphoglycerate mutase type B subunit.

Topics: Animals; Biomarkers; Disease Models, Animal; Electrophoresis, Gel, Two-Dimensional; Erectile Dysfunction; Hyperlipidemias; Male; Penile Erection; Penis; Phosphodiesterase 5 Inhibitors; Proteins; Proteomics; Pyrimidines; Rats, Sprague-Dawley; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Sulfonamides; Time Factors

To prevent cavernous nerve injury and corpus cavernosum apoptosis-induced erectile dysfunction (ED) after prostatectomy surgery, we investigated whether oral administration of udenafil combination with covering adipose-derived stem cells (ADSCs) and brain-derived neurotrophic factor (BDNF) immobilized poly-lactic-co-glycolic (PLGA) membrane on the injured cavernous nerve could further improve erectile dysfunction.. Adult Sprague-Dawley rats were divided into 5 groups: normal group (sham-operated group), bilateral cavernous nerve injury (BCNI) group (BCNI group), udenafil group (oral administration of udenafil 20 mg/kg daily), AB group (BCNI group with ADSCs covered with BDNF membrane on cavernous nerve), AB/udenafil group (AB group with udenafil group). After 4 weeks, erectile function was examined before tissue harvest. Penile tissues were evaluated in terms of the expression of smooth muscle actin (SMA), neuronal nitric oxide synthase (nNOS), and vascular endothelial growth factor (VEGF). The cyclic guanosine monophosphate (cGMP) level of the corpus cavernosum was quantified by cGMP assay.. AB/udenafil treatment markedly improved erectile function and prevented the architecture damage of the corpus cavernosum, compared with other treated groups. Udenafil had no statistical significance on increasing nNOS expression, but enhanced VEGF expression. On the contrary, the AB group had no statistical significance on enhancing VEGF expression, but increased nNOS expression. AB/udenafil treatment significantly increased nNOS expression, VEGF expression, and elevated cGMP level, compared with the udenafil group and AB group.. The orally administered udenafil combination with ADSC/BDNF-membrane system protected cavernous nerve and improved angiogenesis in the corpus cavernosum, which further maintained erectile function in a rat model of postprostatectomy erectile dysfunction.

Topics: Adult; Animals; Brain-Derived Neurotrophic Factor; Erectile Dysfunction; Humans; Male; Penile Erection; Penis; Phosphodiesterase 5 Inhibitors; Pyrimidines; Rats; Rats, Sprague-Dawley; Stem Cell Transplantation; Sulfonamides; Treatment Outcome

It has been suggested that risk of erectile dysfunction (ED) increases with duration of diabetes and phosphodiesterase type 5 inhibitors (PDE5I) are not as effective in treatment of diabetes-associated ED. However, few studies have investigated time-dependent change in erectile function during the course of diabetes.. To investigate time-dependent change in erectile function and responsiveness to PDE5I in streptozotocin-induced diabetic rats and to understand the pathophysiology of diabetic ED.. At 6, 8, 10, 12, and 14 weeks after diabetic induction, erectile function was assessed by cavernous nerve stimulation before and after administration of DA-8159, a novel PDE5I. Penile tissue was assessed for apoptosis with immunohistochemistry. Protein expression of Rho-kinase 2 (ROCK2), myosin phosphatase targeting subunit 1 (MYPT1), and endothelial nitric oxide synthase (eNOS) was evaluated by Western blot.. Streptozotocin was injected into 50 8-week-old male Sprague-Dawley rats, which were then classified into five diabetic groups according to the observation period.. Diabetic rats maintained normal erectile responses until 6 weeks of diabetes. Following 8 weeks, the rats showed lower erectile responses at higher frequencies of nerve stimulation, which were normalized to control by administration of DA-8159. In contrast, erectile responses were significantly decreased in 10-week diabetic rats, and administration of DA-8159 resulted in partial recovery of normal responses. At more than 12 weeks, rats demonstrated severe deterioration of erectile function, which did not fully respond to PDE5I. Corporal apoptosis was significantly increased after 10 weeks. Upregulation of ROCK2 was found at 6 weeks, and was followed by an increase of MYPT1 phosphorylation. Phosphorylation of eNOS showed marked suppression at 6 weeks and remained lower during the experimental period.. Impairment of erectile function was followed by decreased responsiveness to PDE5I during the course of diabetes. The RhoA/ROCK pathway played an important role in diabetes-associated ED.

Topics: Animals; Apoptosis; Blotting, Western; Diabetes Mellitus, Experimental; Disease Progression; Erectile Dysfunction; Male; Nitric Oxide Synthase Type III; Penile Erection; Penis; Phosphodiesterase 5 Inhibitors; Protein Phosphatase 1; Pyrimidines; Rats; Rats, Sprague-Dawley; rho-Associated Kinases; Sulfonamides

Preservation of the cavernous nerves (CNs) during radical prostatectomy is crucial for the patient's erectile function. Despite advances in operative technique, the majority of men report compromised erectile function postprostatectomy or complete loss of potency due to CN trauma even with nerve-sparing modifications..   This study was designed to investigate whether repeated dosing of udenafil, a phosphodiesterase type 5 inhibitor, helps to improve erectile function after CN injury.. Using the CN crush injury model, 8-week-old male Sprague Dawley rats were divided into the following groups; sham-operated group, bilateral CN crush injury exposed to either no udenafil (vehicle) or udenafil (5, 20 mg/kg) daily for two different durations (4 and 8 weeks, p.o.).. At both time points, CN electrical stimulation was used to assess erectile function by measuring the intracavernous pressure. The expressions of hypoxia-inducible factor 1-alpha (HIF-1α), transforming growth factor-beta (TGF-β1), nerve growth factor (NGF), endothelin B receptor (ET(B) ), endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS), and sonic hedgehog homolog (SHH) in penile tissue were examined. Immunohistochemical antibody staining was performed for NGF, eNOS, nNOS, CD31, and alpha-smooth muscle actin (α-SMA). Additionally, terminal deoxynucleotidyl transferase-mediated nick-end labeling assay was performed to quantify apoptosis and the tissue slides were stained for Masson's trichrome to assess the smooth muscle/collagen ratio.. Udenafil improved erectile function in a dose- and time-dependent manner with the maximum erectile function recovery achieved by 20 mg/kg udenafil at an 8-week time point. CN injury increased the expression of HIF-1α, TGF-β1, NGF, and ET(B) , however, decreased the expression of eNOS, nNOS, and SHH. Udenafil significantly suppressed these alterations. The results from the histological analyses show that udenafil markedly reduces apoptosis induced by CN injury and augments the smooth muscle/collagen ratio.. CN injury induces significantly impaired erectile function and altered gene/protein expression. Chronic administration of udenafil preserves erectile function and has a beneficial role against the pathophysiological consequences of CN injury.

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Erectile Dysfunction; Hedgehog Proteins; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Nerve Growth Factor; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; Penile Erection; Penis; Phosphodiesterase 5 Inhibitors; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin B; Sulfonamides; Transforming Growth Factor beta1

Erectile dysfunction (ED) is a major complication of diabetes mellitus (DM). This study investigates the relationship between ED and the downregulation of constitutive nitric oxide synthase (cNOS) in the corpus cavernosum (CC) of diabetic rats. It also examines the effects of udenafil, a phosphodiesterase type 5 (PDE5) inhibitor, on ED and cNOS expression levels. After 16 weeks of daily oral treatment with udenafil in diabetic rats, the intracavernous pressure/mean arterial pressure (ICP/MAP) ratio was recorded to measure erectile function, and cNOS expression was measured using reverse transcriptase (RT)-PCR and immunoblots. Although the ICP/MAP ratio and the expression levels of endothelial NOS (eNOS) and neuronal NOS (nNOS) in the CC were markedly decreased in diabetic rats, long-term udenafil treatment improved the erectile function and increased cNOS expression compared with diabetic controls. These findings suggest that ED in DM is closely related to decreased cNOS expression in the CC and that udenafil has the ability to compensate for this pathological change by modulating cNOS expression. Udenafil also has an inhibitory role in cGMP (cyclic guanosine monophosphate) degradation.

Topics: Animals; Base Sequence; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Disease Models, Animal; DNA Primers; Electric Stimulation; Erectile Dysfunction; Gene Expression Regulation, Enzymologic; Male; Nitric Oxide Synthase Type I; Penis; Phosphodiesterase Inhibitors; Polymerase Chain Reaction; Pyrimidines; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sulfonamides

Erectile dysfunction is highly prevalent in diabetic patients and PDE V inhibitors are effective and safe for the treatment of erectile dysfunction in men with diabetes. Therefore, in this study we investigated whether a pharmacokinetic interaction occurs between DA-8159 and metformin, as both drugs are metabolized via hepatic CYP3A1/2 in rats.. DA-8159 (30 mg kg(-1)) and metformin (100 mg kg(-1)), both separately and together, were administered to rats either intravenously or orally. The V (max), K (m), CL(int), apparent inhibition constants (K (i)), [I]/K (i) and concentrations of each drug in the liver and intestine were then measured.. After i.v. administration of both drugs simultaneously, the AUC of DA-8159 and metformin was significantly greater (21.2 and 33.9% increase for DA-8159 and metformin, respectively) than that of each drug alone. After p.o. administration of the drugs, the AUC of metformin was also significantly greater (20.7% increase) in the presence of DA-8159 than in its absence. However, the AUC of DA-8159 was similar in the absence and presence of metformin.. The significantly greater AUC of metformin and DA-8159 after i.v. administration of both drugs and of metformin after p.o. administration of both drugs is probably due to competitive inhibition for the metabolism of these drugs via hepatic CYP3A1/2. However, the similar AUCs of DA-8159 in the absence and presence of metformin, after p.o. administration, indicates that the dose of metformin used was insufficient to inhibit the hepatic and intestinal metabolism of DA-8159.

Topics: Administration, Oral; Animals; Area Under Curve; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP3A; Drug Interactions; Erectile Dysfunction; Hypoglycemic Agents; Infusions, Intravenous; Intestines; Liver; Male; Membrane Proteins; Metformin; Phosphodiesterase Inhibitors; Pyrimidines; Rats; Rats, Sprague-Dawley; Sulfonamides; Tissue Distribution

Gene expression changes in the corpus cavernosum of hypercholesterolemic rats were not fully assessed, which were not previously known to be associated with hypercholesterolemia-related erectile dysfunction (ED). To provide molecular insight into pathophysiology of hypercholesterolemia-related ED and to investigate the effects of Udenafil, a phosphodiesterase type 5 (PDE5) inhibitor, on gene expression, we performed microarray gene expression analysis via gene discovery methods using GenoCheck platinum cDNA chip (Ansan, S. Korea). Sixteen male Sprague-Dawley rats were fed 2% cholesterol diet for 5 months. Half of them were orally treated with Udenafil (20 mg/kg/day) simultaneously. Eight age-matched rats fed normal diet were served as normal control. RNA was extracted from corpus cavernosum and microarray analysis was performed. Decreased erectile responses and hypercholesterolemia were observed in hypercholesterolemic control group. In microarray analysis, 122 candidate genes were noted to be altered based on the magnitude of expression changes, which includes 44 down-regulated and 78 up-regulated genes compared with the age-matched normal controls. These changes were, however, significantly attenuated by treatment with Udenafil. Out of the 78 up-regulated genes, 8 genes were significantly decreased by the chronic treatment with Udenafil. The altered genes were cytochrome oxidase biogenesis protein OXA1, skeletal muscle myosin heavy chain, lipophilin, fast skeletal muscle isoforms beta/alpha, myosin light chain 3, cytochrome c oxidase, adipocyte fatty acid binding protein and one EST gene. In contrast, among the 44 down-regulated genes, Kruppel-like factor 5 and cyclin D1 genes were increased after the Udenafil treatment. These results provide the molecular basis for understanding the pathogenesis of hypercholesterolemia-related ED and offer clues on determining the underlying action mechanism of a PDE5 inhibitor.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Cholesterol, Dietary; Cyclic Nucleotide Phosphodiesterases, Type 5; Erectile Dysfunction; Gene Expression Profiling; Gene Expression Regulation; Hypercholesterolemia; Male; Oligonucleotide Array Sequence Analysis; Penis; Phosphodiesterase Inhibitors; Pyrimidines; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sulfonamides

P-glycoprotein, an ATP-dependent efflux pump, is a membrane transporter that influences the absorption and excretion of drugs. There is a striking overlap between the substrates for CYP3A4 and P-glycoprotein. This study was designed to assess whether udenafil, a substrate of CYP3A4, is also a P-glycoprotein substrate. Udenafil stimulated P-glycoprotein ATPase activity, a putative measure of P-glycoprotein affinity, although with lower affinity than a proven substrate, verapamil. Bidirectional transport studies of udenafil using Caco-2 cell monolayers showed that its efflux (15.9-22.8 x 10(-6) cm/s) was significantly higher than its influx (3.7-9.1 x 10(-6) cm/s). P-glycoprotein inhibitors such as cyclosporine, tariquidar and verapamil significantly increased the influx of udenafil and decreased the efflux of udenafil. These results indicate that udenafil is a substrate for P-glycoprotein. The low bioavailability, variable absorption and drug-drug interactions of udenafil may be related to the variability of CYP3A4 and P-glycoprotein expression and to possible CYP3A4 and P-glycoprotein interactions.

Topics: Adenosine Triphosphatases; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Caco-2 Cells; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Erectile Dysfunction; Humans; Male; Phosphodiesterase Inhibitors; Pyrimidines; Sulfonamides

To examine the changes in the erectile function in diet-induced obese rats and investigate the oral efficacy of DA-8159, a new phosphodiesterase type 5 (PDE5) inhibitor, on penile erection in obese rats.. The rats were fed a high-energy diet for 12 weeks and divided into three groups: an obesity-resistant (OR) control group, an obesity-prone (OP) control group, and an OP-DA-8159 treatment (DA-8159) group. The electrostimulation-induced erectile responses were measured in all groups. The body weight, plasma cholesterol, triglyceride and glucose levels were also measured.. In the OP control group, the maximum intracavernous pressure (ICP) and ICP/blood pressure (ICP/BP) ratio after electric stimulation were significantly lower than those in OR control group. The corresponding area under the curve (AUC) of the ICP/BP ratio, the detumescence time and the baseline cavernous pressure were also lower than those in the OR control group, but this difference was not significant. The body weight gain, plasma cholesterol and triglyceride level in the OP group were significantly higher than those in the OR group. After administering the DA-8159, a significant increase in the maximum ICP and the ICP/BP ratio were observed. The corresponding AUCs in the DA-8159 group were also higher than those in the two control groups. Furthermore, the detumescence time was significantly prolonged after treatment with DA-8159.. These results demonstrate that diet-induced obesity affects the erectile function in rats and these erectile dysfunction (ED) can be improved by the treatment with DA-8159, indicating DA-8159 might be a treatment option for ED associated with obesity.

Topics: Animal Feed; Animals; Diet; Erectile Dysfunction; Male; Obesity; Penile Erection; Phosphodiesterase Inhibitors; Pyrimidines; Rats; Sulfonamides

To assess the efficacy of the phosphodiesterase 5 inhibitor, DA-8159, in selective serotonin reuptake inhibitor (SSRI)-induced rat erectile dysfunction model by measuring intracavernous pressure (ICP).. Erectile dysfunction was induced by oral administration of either paroxetine or fluoxetine in rats. The changes in ICP and mean arterial pressure (MAP) were simultaneously recorded throughout electrostimulation of the cavernous nerve with 2 or 10 Hz after intravenous injection of DA-8159 (1 mg/kg). Statistical analysis was performed on the ICP/MAP ratio and the area under the curve of the ICP/MAP ratio.. Although the reduction in the ICP responses after acute paroxetine or fluoxetine administration was statistically significant, the electrical stimulation of the cavernous nerve induced a statistically significant, frequency-dependent increase in the ICP/MAP ratio after DA-8159 administration. The differences in the ICP/MAP ratio and corresponding area under the curve values from the SSRI-treated group were statistically significant.. The results of the present study have demonstrated that DA-8159 reverses the decrease in ICP induced by SSRI treatment, suggesting that DA-8159 may be a potential therapeutic agent for the treatment of erectile dysfunction associated with the use of SSRIs.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Area Under Curve; Blood Pressure; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Evaluation, Preclinical; Electric Stimulation; Erectile Dysfunction; Fluoxetine; Injections, Intravenous; Male; Nitric Oxide; Nitric Oxide Synthase; Paroxetine; Penile Erection; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Pressure; Pyrimidines; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Sulfonamides

Pharmacokinetic parameters of DA-8159 and one of its metabolites, DA-8164, were compared after intravenous and oral administration of DA-8159 at a dose of 30 mg/kg to control rats and rats pretreated with Klebsiella pneumoniae lipopolysaccharide (KPLPS). After intravenous and oral administration of DA-8159, most of the pharmacokinetic parameters of DA-8159 and DA-8164 were not significantly different between two groups of rats. This suggested that the pharmacokinetic parameters of DA-8159 and DA-8164 were not affected considerably by KPLPS.

Topics: Administration, Oral; Animals; Area Under Curve; Chromatography, High Pressure Liquid; Erectile Dysfunction; Half-Life; Infusions, Intravenous; Injections, Intravenous; Klebsiella pneumoniae; Lipopolysaccharides; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Pyrimidines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

The pharmacokinetic parameters of DA-8159, a new erectogenic, were compared after intravenous and oral administration of the drug at a dose of 30 mg/kg to control rats and rats with acute renal failure induced by uranyl nitrate (U-ARF). After intravenous administration to rats with U-ARF, the plasma concentrations of DA-8159 were higher than those in control rats. This resulted in a significantly greater area under the plasma concentration-time curve from time zero to time infinity (AUC) of DA-8159 in rats with U-ARF (304 compared with 365 microg min/ml for control rats and rats with U-ARF). The significantly greater AUC in rats with U-ARF was due to significantly slower total body clearance (Cl) of DA-8159 (98.6 compared with 82.2 ml/min/kg). The significantly slower Cl in rats with U-ARF was due to slower renal clearance (1.07 ml/min/kg compared with not calculable, due to impaired kidney function) and nonrenal clearance (97.5 compared with 82.2 ml/min/kg due to slower metabolism) than those in control rats. After oral administration of DA-8159 to rats with U-ARF, the AUC (122 compared with 172 microg min/ml) was significantly greater and Cl(R) was slower (3.47 ml/min/kg compared with not calculable) than those in control rats. The significantly greater AUC in rats with U-ARF could be due to slower Cl of DA-8159 in the rats.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Acute Kidney Injury; Administration, Oral; Animals; Area Under Curve; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Stability; Erectile Dysfunction; Injections, Intravenous; Male; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Pyrimidines; Rats; Rats, Sprague-Dawley; Sulfonamides; Time Factors; Uranyl Nitrate

DA-8159 (5-[2-propyloxy-5-(1-methyl-2-pyrrolidinylethylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidine-7-one, CAS 268203-93-6) is a new pyrazolopyrimidinone derivative for the treatment of erectile dysfunction. The test agent was administered by gavage at dose levels of 0, 17.5, 70, and 280 mg/kg to Sprague-Dawley male rats from 28 days before mating to the end of the mating period, and to females from 14 days before mating to day 6 of gestation. Effects of the test agent on general findings and reproductive performance of parent animals and on early embryonic development were examined. At 280 mg/kg, salivation and hair loss were observed at a high incidence in males and females, respectively. One female out of 24 died during the treatment period. A decrease in food consumption and a decrease in body weight were observed in both sexes. No treatment-related gross findings and histopathological findings were seen, except that the dead animal exhibited atrophy of the thymus. A decrease of prostate weight and an increase of liver, lung and spleen weights were seen. An increase in the period and irregularity of sexual cycle was observed. A decrease in fertility and pregnancy index was also seen. A decrease in the number of corpora lutea, implantations, and litter size was observed. There were no treatment-related changes in precoital time, mating index, sperm parameters, and serum testosterone concentration. At 17.5 mg/kg and 70 mg/kg, there were no adverse effects on all the parameters examined. Based on these results, DA-8159 induces suppressed body weight, decreased food consumption, irregularity in sexual cycle, reduced fertility, and decreased number of corpora lutea, implantations, and litter size at 280 mg/kg and no observed adverse effect levels (NOAELs) of DA-8159 are considered to be 70 mg/kg for general toxicity and reproductive capability of parent animals and for early embryonic development, respectively.

Topics: Abnormalities, Drug-Induced; Animals; Body Weight; Embryo Implantation; Erectile Dysfunction; Estrous Cycle; Female; Fertility; Litter Size; Male; Organ Size; Pregnancy; Pyrimidines; Rats; Rats, Sprague-Dawley; Reproduction; Sex Characteristics; Sexual Behavior, Animal; Spermatozoa; Sulfonamides; Testosterone

DA-8159 is a pyrazolopyrimidinone derivative which is a potent and selective phosphodiesterase type 5 inhibitor. The efficacy of oral DA-8159 has been demonstrated in conscious and spinalized rabbits by its enhancement of nitric oxide-induced erections. The aim of this study was to investigate the time dependency of this efficacy on its plasma concentration in rabbits. DA-8159 was given orally to normal rabbits at a dose of 10 or 30 mg/kg in order to determine its pharmacokinetic parameters. After then, to investigate the relationship between penile erectile activity and plasma half-life, a dose of 10 mg/kg DA-8159 was administered and the erectile response was examined in a time-course manner by measuring the length of the uncovered penile mucosa after the intravenous administration of sodium nitroprusside, which was administered 1, 3, 6, 8, 24 hours after administering DA-8159. DA-8159 was absorbed rapidly with a Tmax of 0.6 hours in 30 mg/kg and 1.0 hour in the 10 mg/kg group, and T1/2 of 1.23 hours in 30 mg/kg and 1.17 hours in 10 mg/kg, respectively. DA-8159 was not detected in the blood plasma 3 hours (10 mg/kg) or 6 hours (30 mg/kg) after administration. In an erection test, DA-8159 alone (10 mg/kg) induced a penile erection for approximately 2 hours but there was no significant erection thereafter. Although the DA-8159-induced penile erection disappeared, an intravenous injection of sodium nitroprusside significantly induced a penile erection for 6 hours, when the plasma drug concentration was below the detection limit and a no longer visible erection was noted. These results demonstrate that DA-8159 is absorbed and rapidly cleared in rabbits. In addition, it can enhance a sodium nitroprusside-induced penile erection even after 6 hours, which is approximately five times longer than the plasma half-life in the rabbits. These results suggest that DA-8159 may have an erectile potential for much longer than its measured half-life.

Topics: Administration, Oral; Analysis of Variance; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Erectile Dysfunction; Half-Life; Male; Nitroprusside; Penile Erection; Phosphodiesterase Inhibitors; Pyrimidines; Rabbits; Sulfonamides; Time Factors

Intravenous administration of DA-8159, 30 mg/kg, to rats with diabetes mellitus induced by streptozotocin (DMIS), AUC of DA-8164 (a metabolite) was significantly smaller in rats with DMIS (57.9 compared with 81.8 microg x min/mL). This may be due to more contribution of significantly faster clearance of DA-8164 than that of significantly greater formation of DA-8164 in the rats. For example, the CL of DA-8164 was significantly faster (9.68 compared with 6.29 mL/min/kg) after intravenous administration of DA-8164, 10 mg/kg, to rats with DMIS and in vitro intrinsic clearance for the formation of DA-8164 was significantly faster (1.92 compared with 1.59 microL/min/mg protein) in hepatic microsomal fraction of rats with DMIS due to significant increase in expression of CYP3A1(23) in the rats. DA-8164 was formed mainly via CYP3A1/2 in rats. After intravenous administration of DA-8159, renal clearance was significantly faster in rats with DMIS (5.79 compared with 2.80 mL/min/kg) due to urine flow-dependent renal clearance of DA-8159 in rats. After oral administration of DA-8159, the AUC values of both DA-8159 and DA-8164 were not significantly different between two groups of rats. Although the exact reason is not known it may be due to changes in first-pass effect of DA-8159 in rats with DMIS.

Topics: Administration, Oral; Animals; Diabetes Mellitus, Experimental; Erectile Dysfunction; Infusions, Intravenous; Male; Pyrimidines; Rats; Rats, Sprague-Dawley; Sulfonamides

Influence of dietary protein deficiency on the pharmacokinetics of DA-8159 and one of its metabolites, DA-8164, was investigated after intravenous and oral administration of DA-8159 at a dose of 30 mg kg(-1) to male Sprague-Dawley rats allowed free access to a 23% (control) or 5% (protein-calorie malnutrition, PCM) casein diet for 4 weeks. The total area under the plasma concentration-time curve from time zero to time infinity (AUC) values of DA-8164 were significantly smaller after both intravenous (87.0 vs 162 microg min mL(-1)) and oral (144 vs 319 microg min mL(-1)) administration of DA-8159 to PCM rats. This could be due to the decrease in CYP3A1/2 (50-60%) in the rats because DA-8164 was mainly formed via CYP3A1/2 in rats. This could be supported by significantly slower in-vitro CL(int) (2.04+/-0.646 vs 3.15+/-0.693 microL min(-1) (mg protein)(-1)) for the formation of DA-8164 in hepatic microsomal fraction of PCM rats. After intravenous administration of DA-8159, the AUC values of DA-8159 were not significantly different between the two groups of rats although the AUC of DA-8164 was significantly smaller in PCM rats, and this may be due to the minor metabolic pathway of DA-8164 in rats. However, after oral administration of DA-8159, the AUC of DA-8159 was significantly greater in PCM rats (194 vs 122 microg min mL(-1)). This was not due to enhanced absorption of DA-8159 from the gastrointestinal tract in the rats but may be due to a decreased intestinal first-pass effect of DA-8159 in the rats.

Topics: Administration, Oral; Animals; Erectile Dysfunction; Infusions, Intravenous; Male; Protein-Energy Malnutrition; Pyrimidines; Rats; Rats, Sprague-Dawley; Sulfonamides

DA-8159 is a pyrazolopyrimidinone derivative which exhibits potent and selective phosphodiesterase type 5 (PDE5) inhibition. The aim of this study was to investigate the effects of DA-8159 on inducing a penile erection in rabbits with an acute spinal cord injury (ASCI). DA-8159 was given either orally (1, 3, or 10 mg/kg) or intravenously (0.1 or 0.3 mg/kg) to conscious male albino rabbits with a surgical transection of the spinal cord at the L2-L4 lumbar vertebra or ischemic-reperfusion SCI rabbits. Erection was evaluated in a time-course manner by measuring the length of the uncovered penile mucosa. DA-8159 induced a dose-dependent erection in both transection and ischemic-reperfusion ASCI rabbits. The efficacy of DA-8159 was potentiated by an intravenous injection of sodium nitroprusside, a nitric oxide donor. Potentiation of the effect by nitric oxide donor implies that DA-8159 can enhance the erectile activity during sexual arousal. These results suggest that DA-8159 may be useful for treating erectile dysfunction in patients with an SCI.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Acute Disease; Animals; Area Under Curve; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Erectile Dysfunction; Male; Penile Erection; Pyrimidines; Rabbits; Reperfusion Injury; Spinal Cord; Spinal Cord Injuries; Sulfonamides

The subacute toxicities and toxicokinetics of a new erectogenic, DA-8159, were evaluated after single (at the 1st day) and 4-week (at the 28th day) oral administration of the drug, in doses of 0 (to serve as a control), 12.5, 50 and 200 mg/kg/day, to male and female dogs (n=3 for male and female dogs for each dose). DA-8159 had an effect on the immune-related organs (or tissues), circulatory systems, liver, adrenal glands, ovaries and pancreas. The toxic dose was 200 mg/kg and no observed adverse effect level was less than 50 mg/kg for male and female dogs. There were no significant gender differences in the pharmacokinetic parameters of DA-8159 for each dose after both single and 4-week oral administration. The pharmacokinetic parameters of DA-8159 were dose-independent after single oral administration; the time to reach a peak plasma concentration (T(max)) and the dose-normalized area under the plasma concentration-time curve from time zero to 24 h in plasma (AUC(0-24 h)) were not significantly different among three doses. However, accumulation of DA-8159 after 4-week oral administration was considerable at toxic dose, 200 mg/kg/day. For example, after 4-week administration, the dose-normalized AUC(0-24 h) value at 200 mg/kg/day (4.71 and 15.3 microg h/ml) was significantly greater than that at 12.5 mg/kg/day. After 4-week oral administration, the dose-normalized C(max) and AUC(0-24 h) at 200 mg/kg/day were significantly higher and greater, respectively, than those after a single oral administration.

Topics: Administration, Oral; Animals; Body Weight; Dogs; Erectile Dysfunction; Female; Kinetics; Male; Motor Activity; Phosphodiesterase Inhibitors; Pyrimidines; Sulfonamides