pyrimidinones and Erectile-Dysfunction

To systematically review evidence on the efficacy and safety of mirodenafil treatment in erectile dysfunction (ED) from randomised controlled trials.. We searched PubMed, Embase and the Cochrane Library database up to March 2013. Two authors independently assessed study quality and extracted data. All data were analyzed using RevMan 5.0. Outcome measures assessed were the International Index of Erectile Function (IIEF), erectile function domain (EFD) score (primary), the Sexual Encounter Profile questions 2 and 3, and the response to the Global Assessment Questionnaire and adverse effects (secondary).. A total of 374 participants from three randomized controlled trials were identified in this meta-analysis. After 12 weeks treatment, mirodenafil was found to be more effective than placebo, and tolerability was good. The pooled results showed that the IIEF EFD score for 100 mg mirodenafil group was higher than placebo group (MD = 8.13, 95%CI: 6.64-9.61, p < 0.00001) and the mirodenafil group was also higher than placebo group in the changes from baseline for the IIEF EFD score (MD = 7.32, 95%CI: 5.56-9.07, p < 0.00001), respectively. The most common drug-related adverse events were flushing and headache (mirodenafil versus placebo: 15.8% versus 3.2%, 3.1% versus 0%; respectively).. This meta-analysis suggested that mirodenafil is effective and well-tolerated therapy for ED.

Topics: Double-Blind Method; Erectile Dysfunction; Humans; Male; Multicenter Studies as Topic; Penile Erection; Phosphodiesterase 5 Inhibitors; Pyrimidinones; Randomized Controlled Trials as Topic; Severity of Illness Index; Sulfonamides; Treatment Outcome

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

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Erectile Dysfunction; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Pyrimidinones; Structure-Activity Relationship

We aimed to evaluate whether changes in urinary and sexual function can influence health-related quality of life.. Out of 54 recruited patients, 36 were enrolled, and data for 30 participants with erectile dysfunction were available. At baseline and after 1 and 2 months, each participant completed the International Index of Erectile Function (IIEF-15), the International Prostate Symptom Score (IPSS) and the Medical Outcomes Study Short-Form 36-Item Health Survey (SF-36). Uroflowmetry, post-voiding residual volume and the nocturnal penile tumescence (NPT) test were performed at baseline and at the study's conclusion.. Compared with baseline, the IPSS, IIEF-15, peak urinary flow rate, NPT parameters and mental component of the SF-36 exhibited significant improvement at the study's conclusion. Among the symptomatic parameters, the changes in the storage and erectile function parameters contributed significantly to the change in the mental component score on the SF-36 (p = 0.007, R(2) = 0.502).. The daily administration of low-dose mirodenafil (50 mg) produced improvements in urinary and erectile function with or without sexual stimulation. Furthermore, this therapy enhanced the mental component of health-related quality of life by improving storage and erectile symptoms.

Topics: Adult; Erectile Dysfunction; Humans; Lower Urinary Tract Symptoms; Male; Middle Aged; Penile Erection; Phosphodiesterase 5 Inhibitors; Prospective Studies; Prostate; Pyrimidinones; Quality of Life; Sulfonamides; Surveys and Questionnaires; Treatment Outcome; Urinary Tract; Urodynamics

We evaluated the improvement in erectile dysfunction and lower urinary tract symptoms as well as the safety of once daily administration of 50 mg mirodenafil in men with erectile dysfunction.. A total of 226 patients visited for treatment of erectile dysfunction and were recruited for the study. Of these men 180 met the study inclusion criteria after completing a 2-week screening period (visit [V]1). The patients were randomly allocated into 2 groups. Group 1 (90 patients) received 50 mg mirodenafil once daily and group 2 (90 patients) received a placebo daily. Blood pressure, heart rate, IIEF-5 (5-item version of the International Index of Erectile Function), and SEP (Sexual Encounter Profile) questions 2 and 3 were assessed at 4 (V2), 8 (V3) and 12 weeks after the start of treatment (V4). I-PSS (International Prostate Symptom Score), maximal flow rate and post-void residual volume were also assessed for the evaluation of lower urinary tract symptoms.. Of the 180 patients 71 in group 1 and 63 in group 2 completed the 12-week clinical trial. IIEF-5 and I-PSS significantly improved in group 1 (p <0.001 for both). Facial flushing was the most common adverse effect, followed by headaches. Notably there were no statistically significant differences in either of the variables related to the cardiovascular system.. Once daily administration of 50 mg mirodenafil was efficacious and safe for the treatment of erectile dysfunction and lower urinary tract symptoms.

Topics: Administration, Oral; Adult; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Erectile Dysfunction; Humans; Male; Middle Aged; Penile Erection; Phosphodiesterase 5 Inhibitors; Pyrimidinones; Sulfonamides; Treatment Outcome; Young Adult

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 efficacy and safety of the phosphodiesterase type 5 inhibitor, UK-369,003 modified release (MR), for the treatment of storage lower urinary tract symptoms (LUTS) in men with and without erectile dysfunction (ED).. This was a multicentre, double-blind, placebo-controlled, parallel-group study conducted across 50 centres in North and South America, Europe and Australia. In all, 310 men aged ≥ 18 years with a clinical diagnosis of overactive bladder (OAB; voiding frequency ≥ 8 times/24 h, urgency episode frequency once or more per 24 h and a mean voided volume of <300 mL) and maximum urinary flow rate of >5 mL/s in a voided volume of >150 mL were stratified into two groups (with or without ED) and randomized to one of five treatment groups (10, 25, 50 or 100 mg UK-369,003; or placebo once a day) for 12 weeks. The primary study endpoints were those derived from the bladder diary that recorded the number of voluntary urinary voids, volume of urine per void, leaks and urgency episodes over a 72-h period, before baseline and again at 2, 4 and 12 weeks. Secondary efficacy measures included the International Prostate Symptom Score (total and storage and voiding subscores), International Index of Erectile Function-Erectile Function domain (IIEF-EF), questions 5 and 6 of the Quality of Erection Questionnaire (QEQ), the Overactive Bladder Questionnaire Short Form, the Patient Perception of Bladder Condition, the International Consultation on Incontinence Questionnaire-Male LUTS, and the patient-reported treatment impact questionnaire.. Overall, there were no clinically relevant treatment differences in voiding frequency, mean voided volume, urgency episode frequency, or nocturia frequency for any dose of UK-369,003 MR compared with placebo. In the subset of patients with ED there were improvements in the IIEF-EF and QEQ scores in all UK-369,003 treatment groups compared with placebo.. These data provide no evidence of efficacy for UK-369,003 in the treatment of storage LUTS in men (based on classic OAB eligibility criteria). However, although the endpoints on these classic OAB efficacy variables were negative, there is evidence to suggest a greater preference, satisfaction and willingness to use UK-369,003 again for all treatment groups compared with placebo.

Topics: Epidemiologic Methods; Erectile Dysfunction; Humans; Male; Middle Aged; Phosphodiesterase Inhibitors; Prostatism; Pyrimidinones; Quality of Life; Sulfonamides; Treatment Outcome; Urinary Bladder, Overactive

To evaluate the efficacy and safety of the phosphodiesterase type 5 inhibitor UK-369,003 for the treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) in men with and without erectile dysfunction (ED).. This was a multicentre, double-blind, placebo- and active-controlled, parallel-group study conducted across 45 centres in North and South America, Europe, and Australia. In all, 418 men aged ≥ 40 years with a clinical diagnosis of BPH, an International Prostate Symptom Score (IPSS) of ≥ 13, and maximum urinary flow rate (Q(max) ) of 5-15 mL/s for a voided volume of > 150 mL were stratified into two groups (with and without ED) and randomized to one of seven treatment groups, i.e. UK-369,003 at 10, 25, 50 or 100 mg modified release (MR), UK-369,003 40 mg immediate release (IR), tamsulosin 0.4 mg prolonged release, or placebo, for 12 weeks. The primary study endpoint was the change in total IPSS after 12 weeks of treatment. Secondary efficacy measures were IPSS storage and voiding subscores, Q(max) , International Index of Erectile Function-Erectile Function domain, questions 5 and 6 of the Quality of Erection Questionnaire, the International Consultation on Incontinence Questionnaire-Male LUTS, the patient-reported treatment-impact questionnaire, and a bladder diary in which patients recorded the number of voluntary urinary voids, volume of urine voided per micturition, leaks, and urgency episodes.. The mean change in the IPSS from baseline at week 12 for UK-369,003 100 mg MR and 40 mg IR was -2.91 and -2.50 better than placebo, respectively. There was increasing efficacy with increasing dose of the MR formulation. For UK-369,003 100 mg MR, Q(max) improved by 2.10 mL/s compared with 0.84 mL/s in the placebo group.. UK-369,003 had clinically meaningful efficacy and was well tolerated in men with LUTS associated with BPH. The Bayesian statistical analysis gave high posterior probabilities for true differences between UK-369,003 100 mg MR and placebo. There was greater preference, satisfaction and willingness to use UK-369,003 again for all treatment groups compared with placebo.

Topics: Adult; Aged; Epidemiologic Methods; Erectile Dysfunction; Humans; Male; Middle Aged; Patient Satisfaction; Phosphodiesterase Inhibitors; Prostatic Hyperplasia; Prostatism; Pyrimidinones; Quality of Life; Sulfonamides; Treatment Outcome

Mirodenafil is a recently developed oral phosphodiesterase type 5 inhibitor, which was observed to significantly improve erectile function and was well tolerated in men with broad-spectrum erectile dysfunction (ED).. To investigate the efficacy and safety of mirodenafil treatment compared with placebo in men taking at least one antihypertensive medication.. A multicenter, double-blind, placebo-controlled, parallel group, fixed-dose study was conducted with 109 subjects who were randomized to placebo or mirodenafil 100 mg for 12 weeks on an "as needed" basis.. The primary efficacy measures were the changes from baseline in sum of scores on International Index of Erectile Function-erectile function domain (IIEF-EF) questions 1 to 5 and 15 with treatment. The secondary efficacy measures included scores on IIEF question 3 and 4 (Q3 and Q4), all domain scores of IIEF, and Sexual Encounter Profile Question 2 and 3 (SEP2 and SEP3) along with responses to Global Assessment Question (GAQ) and Life Satisfaction Checklist (LSC). The safety assessments included laboratory tests, vital signs, 12-lead electrocardiogram recordings, and patients' reporting of adverse events.. The mirodenafil group showed significantly greater increase in IIEF-EF scores at 12 weeks compared with the placebo group (9.35 ± 6.86 vs. 2.66 ± 6.44, P<0.001). The mirodenafil group also demonstrated significantly greater improvement in scores of IIEF Q3 and Q4, other four domains of IIEF, SEP2, SEP3, and LSC along with percentages of patients responding positively to GAQ compared with the placebo group. During the study, no clinically significant changes were observed regarding blood pressure, heart rate, electrocardiographic findings, or laboratory values. Facial flushing and headache were the most common treatment-associated adverse events, which were mild or moderate in severity, resolving spontaneously.. Mirodenafil was effective and safe in men with ED concomitantly taking antihypertensive medications.

Topics: Antihypertensive Agents; Blood Pressure; Double-Blind Method; Electrocardiography; Erectile Dysfunction; Flushing; Headache; Heart Rate; Humans; Hypertension; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Pyrimidinones; Sulfonamides

Mirodenafil is a newly developed oral phosphodiesterase type 5 inhibitor, currently under investigation as a treatment for erectile dysfunction (ED).. We investigated the efficacy and safety of on demand mirodenafil therapy at fixed doses (50 and 100 mg) in Korean men with a broad range of ED.. A multicenter, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study was conducted with 223 subjects who were randomized to placebo or mirodenafil at fixed doses of 50 or 100 mg for 12 weeks on an "as needed" basis.. Primary efficacy measures were scores on the International Index of Erectile Function (IIEF) Question 3 (Q3) and Question 4 (Q4). Secondary efficacy measures included all domain scores of the IIEF, Sexual Encounter Profile Question 2 (SEP2), Sexual Encounter Profile Question 3 (SEP3), the Global Assessment Question (GAQ), and the Life Satisfaction Checklist (LSC). Safety assessments included laboratory tests, vital signs, physical examination, 12-lead electrocardiogram recordings, and patients' reporting of adverse events.. Mirodenafil 50 and 100 mg groups showed a significantly greater increase in IIEF Q3 (P = 0.0001, P < 0.0001, respectively) and Q4 scores (both P < 0.0001) at the end point compared with the placebo group. And mirodenafil in both doses significantly improved the scores of all five domains of the IIEF, SEP2, and SEP3 as well as the percentages of patients responding positively to the GAQ compared with the placebo group. As for LSC scores, the two mirodenafil groups showed significantly greater improvements in items regarding life as a whole, sexual life, and partner relationship than the placebo group. Most treatment-associated adverse events were of mild intensity, resolving spontaneously.. Mirodenafil, in doses of 50 or 100 mg, significantly improved erectile function and were well tolerated in a representative population of Korean men with broad-spectrum ED of various etiologies and severities.

Topics: Administration, Oral; Adult; Aged; Dose-Response Relationship, Drug; Double-Blind Method; Erectile Dysfunction; Humans; Korea; Male; Middle Aged; Patient Satisfaction; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Pyrimidinones; Sulfonamides; Treatment Outcome; Young Adult

To evaluate the efficacy and safety of SK3530, a newly developed type 5 phosphodiesterase inhibitor (PDE5I), in Korean men with erectile dysfunction (ED).. A total of 119 patients were randomized at 10 centers in Korea to receive either SK3530 (50, 100, or 150 mg; n = 89) or placebo (n = 30) taken l h before anticipated sexual activity for an 8-week period. The patients were evaluated at baseline and 4 and 8 weeks after beginning therapy. Efficacy was assessed using the International Index of Erectile Function (IIEF), Sexual Encounter Profile (SEP), and the Global Assessment Question (GAQ). Safety was analyzed by adverse events, laboratory values and vital signs.. At the end of the study, all the primary and secondary efficacy end-points were statistically significantly improved by SK3530 compared with placebo (P<0.05). Of the 89 patients in the treatment arm, 36 (42.3%) achieved normal erectile function after treatment, including six patients with severe ED. Treatment-related adverse events occurred in 32 patients. The most common adverse events were flushing, headache, dizziness and eye redness (10.9%, 7.6%, 2.5% and 2.5%, respectively), and most were mild. Only two patients discontinued treatment during the study period because of adverse events.. The results of our phase II study have confirmed the efficacy and safety of SK3530 in a broad population of men with ED of various etiologies and severity. The optimal doses in terms of efficacy and safety were determined to be 50 mg and 100 mg, respectively.

Topics: Double-Blind Method; Erectile Dysfunction; Humans; Korea; Male; Middle Aged; Patient Satisfaction; Phosphodiesterase Inhibitors; Placebos; Pyrimidinones; Sulfones; Treatment Outcome

5-Ethyl-2-{5-[4-(2-hydroxyethyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-7-propyl-3,5-dihydropyrrolo[3,2-d]pyrimidin-4-one (SK3530) is a new phosphodiesterase type-5 inhibitor currently undergoing a Phase III investigation for the treatment of male erectile dysfunction. This study first describes a rapid and sensitive LC/MS/MS assay method for the quantification of SK3530 and its major metabolite, SK3541, in human plasma. The assay was validated to demonstrate the specificity, linearity, recovery, lower limit of quantification (LLOQ), accuracy, and precision. The multiple reaction monitoring was based on the transition of m/z=532.5-->99.1 for SK3530, 488.6-->295.5 for SK3541, and 520.3-->99.1 for SK3304 (internal standard). The assay utilized a single liquid-liquid extraction and isocratic elution, and the LLOQ was 1 ng/ml using 0.2 ml human plasma. The assay was linear over a range from 1 to 1000 ng/ml for both SK3530 and SK3541, with correlation coefficients >0.9999. The mean intra- and inter-day assay accuracy ranged from 94.7 to 101.6% and 96.8 to 101.1% for SK3530 and 92.6-105.7% and 97.4-107.8% for SK3541, respectively. The mean intra- and inter-day precision was between 7.2-12.1% and 5.7-7.4% for SK3530 and 4.6-13.2% and 5.0-14.1% for SK3541, respectively. The developed assay was applied to a clinical pharmacokinetic study after oral administration of SK3530 in healthy male volunteers (dose 100 mg).

Topics: Administration, Oral; Adult; Calibration; Chromatography, High Pressure Liquid; Erectile Dysfunction; Humans; Male; Molecular Structure; Pharmacology, Clinical; Pyrimidinones; Quality Control; Reference Standards; Reproducibility of Results; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization; Sulfones; Tandem Mass Spectrometry

Topics: Erectile Dysfunction; Humans; Male; Penile Erection; Phosphodiesterase 5 Inhibitors; Pyrimidinones; Sulfonamides

Topics: Erectile Dysfunction; Humans; Male; Penile Erection; Pyrimidinones; Sulfonamides

Enhanced RhoA/Rho-kinase pathway plays anti-erectile role and is associated with reduced response to type 5 phosphodiesterase inhibitor (PDE5I) in diabetic animals. We tested whether adjunctive simvastatin to conventional insulin treatment would restore PDE5I-induced as well as basal erectile response in diabetic rat model of erectile dysfunction. Forty 8-week-old male Sprague-Dawley rats were equally divided into four groups, (n=10) i.e. the diabetic group (D), age-matched control (C), conventional insulin treatment (I) and adjunctive simvastatin to conventional insulin treatment (S). Following 10weeks of intraperitoneal injection of streptozotocin (STZ, 35mg/kg), the group I and S received insulin (10U NPH/day) for 4weeks. Concurrently, group S received simvastatin (20mg/kg/day). Following 14weeks of diabetes induction, basal and PDE5I (intravenous mirodenafil 1mg/kg)-elicited erectile response were assessed during cavernous nerve electrostimulation. Then, penile tissues were processed for molecular assessment. Although group I failed to restore basal and PDE5I-induced erectile response, group S showed normalized erectile responses. Furthermore, group I showed improvement of only eNOS-related pathway, whereas group S effectively controlled both eNOS-related and RhoA/Rho-kinase pathway. Conclusively, adjunctive use of simvastatin to conventional insulin treatment showed more effectiveness in restoring erectile responses of diabetic rats by controlling the RhoA/Rho-kinase pathway than conventional insulin treatment alone.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Erectile Dysfunction; Insulin; Male; Nitric Oxide Synthase Type III; Penile Erection; Phosphodiesterase 5 Inhibitors; Pyrimidinones; Rats; Rats, Sprague-Dawley; rho-Associated Kinases; rhoA GTP-Binding Protein; Simvastatin; Sulfonamides

The area under the curve (AUC) of mirodenafil after intravenous administration in diabetes mellitus induced by streptozotocin (DMIS) rats was significantly smaller (by 28.0 %) than the control value, and the AUC(SK3541)/AUC(mirodenafil) ratio was significantly greater (by 130 %) in DMIS rats. This may be explained by the significantly faster hepatic CL(int) of mirodenafil, owing to increased hepatic CYP1A, CYP2B1/2, CYP2D, and CYP3A expression, and a faster hepatic blood flow rate, compared with control values. The AUC of mirodenafil after oral administration was comparable between DMIS and control rats, possibly because of the comparable intestinal CL(int), which may be attributable to increased CYP1A2 expression and decreased CYP2D expression in the intestines of DMIS rats.

Topics: Administration, Oral; Animals; Area Under Curve; Diabetes Complications; Diabetes Mellitus, Experimental; Erectile Dysfunction; Infusions, Intravenous; Male; Pyrimidinones; Rats; Rats, Sprague-Dawley; Streptozocin; Sulfonamides

Mirodenafil (SK3530) is a new potent and selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5). Recent clinical trials have demonstrated that mirodenafil is an effective treatment for erectile dysfunction. Its mechanism of action is enhancement of nitric oxide (NO) induced cGMP formation resulting in significant relaxation of the corpus cavernosum (CC). The aim of this study was to investigate the oral efficacy of mirodenafil in an acute spinal cord-injured rabbit model. Mirodenafil or sildenafil citrate was given orally to male rabbits with a surgical transection of the spinal cord at the L2-L4 lumbar vertebra or ischemic-reperfusion spinal cord injury (SCI). Erections were evaluated in a time-course manner by measuring the length of the uncovered penile mucosa. In the transection SCI model, penile erections were induced at 0.3, 1 and 3 mg/kg of mirodenafil but sildenafil only showed an erectile response at 3 mg/kg. The effects of 1 and 3 mg/kg of mirodenafil were significantly increased by intravenous injection of sodium nitroprusside (SNP), a nitric oxide donor. In the ischemic-reperfusion injury model, 3 mg/kg of either mirodenafil or sildenafil produced a penile erection response. After injection of SNP, the lengths of immediate penile erections were significantly increased in the 1 and 3 mg/kg mirodenafil and 3 mg/kg sildenafil groups. The onset of erectile activity was faster with mirodenafil than with sildenafil citrate. These results demonstrate that mirodenafil may be useful for treating erectile dysfunction in patients with a spinal cord injury.

Topics: Administration, Oral; Animals; Erectile Dysfunction; Male; Mucous Membrane; Penile Erection; Phosphodiesterase 5 Inhibitors; Pyrimidinones; Rabbits; Spinal Cord Injuries; Sulfonamides

The purpose of this paper is to characterize the cytochrome P450 (CYP) enzymes involved in the metabolism of a new oral erectogenic, mirodenafil, to a major circulating active metabolite, N-dehydroxyethyl-mirodenafil, and to investigate the inhibitory potential of mirodenafil on seven CYP enzymes in human liver microsomes. CYP3A4 was identified as the major enzyme and CYP2C8 as a minor enzyme responsible for mirodenafil N-dealkylation based on correlation analysis, inhibition studies, and cDNA-expressed CYP enzyme activities. Plasma concentrations of mirodenafil and its N-dealkylated metabolite could therefore change with co-administration of known CYP3A4 inducers or inhibitors. Mirodenafil inhibited CYP3A4, CYP2C19 and CYP2D6 activities with IC50 values of 15.6, 38.2 and 77.0 microM, respectively, in human liver microsomes. However, it is very unlikely that mirodenafil will significantly alter the clearance of other compounds metabolized by CYPs 1A2, 2A6, 2C8, 2C9, 2C19, 2D6 and 3A4 because the maximum plasma concentration of mirodenafil is 0.55 microM after oral dosing of mirodenafil (100 mg) in male volunteers.

Topics: Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dealkylation; Dose-Response Relationship, Drug; Enzyme Inhibitors; Erectile Dysfunction; Humans; Kinetics; Male; Microsomes, Liver; Pyrimidinones; Substrate Specificity; Sulfonamides

To examine whether chronic treatment with a type 5 phosphodiesterase inhibitor (PDE5I) could suppress corporal apoptosis via potentiation of Akt signalling in diabetic erectile dysfunction.. Sprague-Dawley rats (12 wk old) were divided into three groups (n=12 in each): normal control, diabetes (DM), and diabetes treated with PDE5I (DM+PDE5I). The rats in the diabetic groups received a single injection of streptozotocin (50mg/kg), and from 8 wk after establishment of diabetes, DM and DM+PDE5I were treated with vehicle and PDE5I (SK-3530, 10mg/kg), respectively, for 4 wk. After 12 wk of streptozotocin injections, six rats in each group underwent cavernosometry with cavernous nerve electrostimulation (2V, 0.2 ms, 50s, 2.5-20 Hz). The penile tissues from the remaining six rats were used for immunohistochemical evaluation of apoptosis, immunoblotting for the phosphorylation of Akt and its downstream molecule Bad, and a colorimetric assay of caspase activity.. Rats in the DM group showed markedly lower erectile parameters than those in the control group, whereas rats in the DM+PDE5I group showed normalized results. Despite persistent hyperglycaemia, PDE5I treatment significantly reduced the mean apoptotic index (39.6+/-4.6 vs. 21.3+/-1.7, p<0.05). Densitometry revealed significantly higher levels of Akt and Bad phosphorylation, implying inhibition of pro-apoptotic stimuli. PDE5I treatment also significantly inhibited the activities of cavernosal caspase 3 and caspase 9, the main effectors of apoptosis.. Chronic treatment with PDE5I activated Akt signalling, which suppressed pro-apoptotic stimuli and maintained erectile function in rat model of diabetic erectile dysfunction.

Topics: Animals; Apoptosis; Diabetes Complications; Disease Models, Animal; Erectile Dysfunction; Male; Muscle, Smooth; Penis; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrimidinones; Rats; Rats, Sprague-Dawley; Signal Transduction; Sulfones

Topics: Animals; Apoptosis; Diabetes Complications; Disease Models, Animal; Erectile Dysfunction; Male; Muscle, Smooth; Penis; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrimidinones; Rats; Rats, Sprague-Dawley; Signal Transduction; Sulfones

To investigate the problem of drug analogue adulteration in male erectile dysfunction health products.. Survey of over-the-counter male erectile dysfunction health products available in convenience stores and pharmacies in Hong Kong.. Tertiary referral centre for clinical toxicology analysis in Hong Kong.. The pattern and extent of adulteration of male erectile dysfunction health products with sildenafil, tadalafil, and vardenafil as well as their structurally modified analogues.. Of 26 products studied, one (4%) was found to contain undeclared sildenafil, while 14 (54%) contained drug analogues of different kinds. The latter included acetildenafil, hydroxyacetildenafil, hydroxyhomosildenafil, and piperidenafil. The first three were analogues of sildenafil and the last was an analogue of vardenafil. One young patient presented with ataxia after taking an acetildenafil-containing product.. The positive rate of concealed drug analogues in male erectile dysfunction health products is alarmingly high. Such analogues are difficult to detect by ordinary laboratory methods, and might be used in an attempt to evade regulatory inspection. Without going through the stringent drug testing process, the adverse effects of these chemicals remain largely unknown and unpredictable. Effective surveillance system and control measures are needed urgently. The medical profession and the public should be alerted to this under-recognised threat.

Topics: Adult; Ataxia; Carbolines; Data Collection; Drug Contamination; Erectile Dysfunction; Hong Kong; Humans; Imidazoles; Male; Nonprescription Drugs; Phosphodiesterase Inhibitors; Piperazines; Plant Preparations; Purines; Pyrimidinones; Sildenafil Citrate; Sulfones; Tadalafil; Triazines; Vardenafil Dihydrochloride

Sildenafil (5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one), a potent and selective phosphodiesterase type 5 (PDE5) inhibitor, provided the first oral treatment for male erectile dysfunction. The objective of the work reported in this paper was to combine high levels of PDE5 potency and selectivity with high and dose-independent oral bioavailability, to minimize the impact on the C(max) of any interactions with coadministered drugs in the clinic. This goal was achieved through identification of a lower clearance series with a high absorption profile, by replacing the 5'-piperazine sulfonamide in the sildenafil template with a 5'-methyl ketone. This novel series provided compounds with low metabolism in human hepatocytes, excellent caco-2 flux, and the potential for good aqueous solubility. The in vivo oral and iv pharmacokinetic profiles of example compounds confirmed the high oral bioavailability predicted from these in vitro screens. 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (2) was selected for progression into the clinic.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Administration, Oral; Animals; Azetidines; Biological Availability; Caco-2 Cells; Crystallography, X-Ray; Cyclic Nucleotide Phosphodiesterases, Type 5; Dogs; Dose-Response Relationship, Drug; Erectile Dysfunction; Humans; Ketones; Male; Models, Molecular; Molecular Structure; Pyrimidines; Pyrimidinones; Structure-Activity Relationship