Efficacy and safety of an orodispersible vardenafil formulation for the treatment of erectile dysfunction in elderly men and those with underlying conditions: an integrated analysis of two pivotal trials.

INTRODUCTION: Men with erectile dysfunction (ED) are typically older and have one or more underlying cardiovascular conditions. AIM: To determine the efficacy and safety of a new orodispersible tablet (ODT) formulation of vardenafil for the treatment of ED, and whether age, or the presence of underlying conditions affects treatment outcomes. METHODS: This is an integrated analysis of data from two phase III, double-blind, multicenter, randomized, parallel-group, placebo-controlled studies that compared 10 mg on-demand vardenafil ODT with placebo in a general population of men with ED, stratified so that approximately 50% of patients were aged ≥ 65 years. Results were reported by age (<6 5 vs. ≥ 65 years) and presence/absence of diabetes, dyslipidemia, or hypertension. MAIN OUTCOME MEASURES: Primary measures were the erectile function domain of the International Index of Erectile Function (IIEF-EF) and Sexual Encounter Profile questions 2 (SEP2) and 3 (SEP3). RESULTS: Of the 701 men randomized (51% aged ≥ 65 years), 686 were included in the intent-to-treat population (placebo, n = 334; vardenafil ODT, n = 352). Vardenafil ODT was significantly superior to placebo for all primary efficacy measures, regardless of age, baseline ED severity, or underlying condition (P < 0.0001 for vardenafil vs. placebo for each endpoint). IIEF-EF scores and SEP2/3 success rates in older patients and men with underlying conditions were not significantly different to those of younger patients or men without underlying conditions. Adverse events (AEs) were mostly mild to moderate in severity, occurring with higher incidence in the vardenafil vs. placebo group. The most frequently reported drug-related AEs in the vardenafil group were headache, flushing, nasal congestion, dizziness, and dyspepsia, consistent with the known safety profile of phosphodiesterase type 5 inhibitors. CONCLUSIONS: Vardenafil ODT significantly improves erectile function in men with ED regardless of age, baseline ED severity, or underlying condition.

Time to onset of action of vardenafil: a retrospective analysis of the pivotal trials for the orodispersible and film-coated tablet formulations.

INTRODUCTION: Patients and physicians consider a rapid onset of action to be an important attribute of oral pharmacotherapy for erectile dysfunction. AIM: To investigate the time to onset of action of a new orodispersible tablet (ODT) formulation of vardenafil. METHODS: A post hoc integrated analysis was performed on data from two 12-week, double-blind, multicenter, randomized, parallel-group, placebo-controlled phase III trials of 10 mg vardenafil ODT. Data for the vardenafil film-coated tablet were generated from a retrospective integrated analysis at week 12 of four double-blind, multicenter, randomized, parallel-group, fixed-dose, placebo-controlled phase III trials. Time intervals (in 15-, 30-, and 60-minute increments, up to ≥6 hours after study medication intake) were determined for the period between dosing and start of sexual activity (with the intention of intercourse). MAIN OUTCOME MEASURES: The total number of sexual intercourse attempts and Sexual Encounter Profile question 3 (SEP3) success rates were calculated per time interval. RESULTS: Within 15 minutes postdosing, mean per-patient SEP3 success rates were 62.5% (vardenafil ODT) vs. 29.4% (placebo), with corresponding overall SEP3 success rates of 59.8% and 38.2%. In this time interval, 5.3% vs. 2.8% of all sexual activity attempts were initiated by subjects taking vardenafil ODT (n = 89) or placebo (n = 62), respectively. At 16-30 minutes postdosing, SEP3 success rates were 65.3% and 32.6% (mean per-patient) and 70.2% and 51.0% (overall) for vardenafil ODT vs. placebo, respectively, with a corresponding 10.4% and 8.7% of all sexual activity attempts being made by subjects taking vardenafil ODT (n = 170) or placebo (n = 118). Comparable results were observed for vardenafil 10 and 20 mg film-coated tablet at corresponding time intervals. CONCLUSIONS: Vardenafil ODT shows a rapid onset of action comparable with that of vardenafil film-coated tablet. In those men who begin sexual activity within 30 minutes after dosing, the majority of sexual attempts lead to successful intercourse.

The POTENT I randomized trial: efficacy and safety of an orodispersible vardenafil formulation for the treatment of erectile dysfunction.

INTRODUCTION: Orodispersible tablet (ODT) formulations offer improved convenience over film-coated formulations and are preferred by many patients. AIM: To investigate the efficacy and safety of an ODT formulation of 10 mg vardenafil administered on demand vs. placebo in a general population of men with erectile dysfunction (ED). METHODS: This was a 16-week, double-blind, multicenter, randomized, parallel-group, placebo-controlled study conducted at 40 centers across Europe and South Africa. Eligible participants were men aged > or = 18 years with ED for at least 6 months, in a stable heterosexual relationship for at least 6 months, highly motivated to obtain ED treatment, and making at least four attempts at sexual intercourse on four separate days, of which at least half were unsuccessful. Subjects were randomized to receive 12 weeks of treatment with either 10 mg vardenafil ODT on demand or placebo, and each treatment group was stratified such that approximately half of the subjects were aged > or = 65 years. MAIN OUTCOME MEASURES: Primary measures were the erectile function domain of the International Index of Erectile Function (IIEF-EF) and the Sexual Encounter Profile questions 2 and 3 (SEP2, SEP3). Secondary measures included SEP diary questions 1, 4, 5, and 6; the Treatment Satisfaction Scale; and the Global Assessment Question. RESULTS: Of the 409 men enrolled (54.8% aged > or = 65 years), 355 were included in the intent-to-treat population (vardenafil ODT, N = 183; placebo, N = 172). Vardenafil ODT therapy was statistically significantly superior to placebo for all primary (IIEF-EF, SEP2, SEP3) and secondary efficacy measures (all P < 0.0001). The incidence and type of treatment-related adverse events with vardenafil 10 mg ODT were comparable with those of the film-coated tablet formulation. CONCLUSIONS: Treatment with 10 mg vardenafil ODT, taken on demand, significantly improved erectile function and was well tolerated in a broad population of men with ED.

[Reconstructive possibilities for Peyronie's disease]. / Rekonstruktive Möglichkeiten bei der Induratio penis plastica.

The surgical treatment of Peyronie's disease involves a multistage procedure with increasing invasiveness. In addition to precise knowledge about the existing surgical treatment procedures, the indication and the informed consent process of the patient is extremely important. The dissatisfaction with the surgical results for many patients is due to false expectations and positivistic representations. If we can avoid this and make the right decisions during surgery, even these difficult-to-treat patients can be treated successfully.

Hematospermia-a Symptom With Many Possible Causes.

BACKGROUND: Hematospermia, or blood in the ejaculate, is a symptom with many possible causes that often gives rise to worry. Precise figures on its prevalence are unavailable. It is most common in men under 40, and its cause is usually benign; nonetheless, even a single episode of hematospermia calls for a basic diagnostic evaluation. METHODS: This review is based on pertinent articles re trieved by a search in PubMed with the key words "hemato spermia," "hemospermia," "ejaculation," "male semen," and "transrectal ultrasound." RESULTS: A diagnostic algorithm for hematospermia is described. The most common cause is iatrogenic trauma, in particular transrectal ultrasound-guided prostate biopsy to rule out prostate cancer. Urogenital infections are the second most common cause. Pathological changes of the prostate should be considered along with systemic causes, e.g., arterial hypertension or various hematologic disorders. A single event in men under 40 should be evaluated by precise history-taking, a meticulous physical examination including blood-pressure measurement, and urinalysis. Repeated episodes, or hematospermia in men over 40, calls for additional evaluation with further laboratory tests, imaging studies, and, in some cases, interventional diagnostic procedures. CONCLUSION: Further tests, preferably imaging studies, seem a reasonable way to detect or exclude potential causes of hematospermia, especially malignant ones. The treatment is directed at the underlying cause.

Impact of estrogen replacement therapy in a male with congenital aromatase deficiency caused by a novel mutation in the CYP19 gene.

Recent reports of the impact of estrogen receptor alpha and aromatase deficiency have shed new light on the importance of estrogen for bone formation in man. We describe a novel mutation of the CYP19 gene in a 27-yr-old homozygous male of consanguinous parents. A C to A substitution in intron V, at position -3 of the splicing acceptor site before exon VI of the CYP19 gene, is the likely cause of loss of aromatase activity. The mRNA of the patient leads to a frameshift and a premature stop codon 8 nucleotides downstream the end of exon V. Both parents were shown to be heterozygous for the same mutation. Apart from genua valga, kyphoscoliosis, and pectus carniatus, the physical examination was normal including secondary male characteristics with normal testicular size. To substitute for the deficiency, the patient was treated with 50 micro g transdermal estradiol twice weekly for 3 months, followed by 25 micro g twice weekly. After 6 months estrogen levels (<20 at baseline and 45 pg/ml at 6 months; normal range, 10-50) and estrone levels (17 and 34 ng/ml; normal range, 30-85) had normalized. Bone maturation progressed and the initially unfused carpal and phalangeal epiphyses began to close within 3 months and were almost completely closed after 6 months. The bone age, assessed by roentgenographic standards for bone development by Gruelich and Pyle, was 16.5 at baseline and 18-18.5 yr after 6 months of treatment. Bone density of the distal radius (left), assessed by quantitative computed tomography, increased from 52 to 83 mg/cm(3) (normal range, 120-160) and bone mineral density of the lumbar spine, assessed by dual-energy x-ray-absorptiometry, increased from 0.971 to 1.043 g/cm(2) (normal range, >1.150). Osteocalcin as a bone formation parameter increased from 13 to 52 micro g/l (normal range, 24-70) and aminoterminal collagen type I telopeptide as a bone resorption parameter increased from 62.9 to 92.4 nmol/mmol creatinine (normal range, 5-54). Semen analysis revealed oligoazoospermia (17.4 million/ml; normal >20) at baseline. After 3 months of treatment, the sperm count increased (23.1 million/ml) and decreased rapidly (1.1 million/ml) during the following 3 months. The sperm motility was reduced at baseline and decreased further during treatment. Area under the curve of insulin, C-peptide, and blood glucose levels during oral glucose tolerance test decreased after 6 months (insulin: 277 vs. 139 micro U/ml.h; C-peptide 52 vs. 15 ng/m.h; area under the curve glucose: 17316 vs. 12780 mg/d.min). Triglycerides (268 vs. 261 mmol/liter) and total cholesterol levels (176 vs. 198 mmol/liter) did not change significantly, but the low-density lipoprotein/high-density lipoprotein ratio decreased from 5.37 to 3.56 and lipoprotein (a) increased from 19.9 to 60.0 mg/dl (normal range, <30). In this rare incidence of estrogen deficiency, estrogen replacement demonstrated its importance for bone mineralization and maturation and glucose metabolism in a male carrying a novel mutation in the CYP19 gene.

The treatment of stress incontinence in men: part 2 of a series of articles on incontinence.

BACKGROUND: Stress incontinence in men is a rare, usually iatrogenic condition. Its prevalence can be expected to rise in the future because of the increasingly common performance of radical prostatectomy. Most men who have undergone prostatectomy experience a transient disturbance of urinary continence. Such disturbances are only rarely due to structural damage to the sphincter apparatus and therefore have a good prognosis for spontaneous recovery. METHOD: Selective literature review. RESULTS: Pelvic floor training and/or pharmacotherapy can be used for more rapid restoration of subjectively satisfactory urinary continence. If the sphincter is intact, continence can also be regained in the early postoperative period through the submucosal injection of bulking agents. Incontinent patients whose urinary sphincter is dysfunctional because of denervation or direct injury to striated muscle can now be treated with a variety of surgical techniques. The implantation of an artificial sphincter is the gold standard of therapy. Properly selected and informed patients can also be treated with minimally invasive procedures, such as the creation of a male suburethral sling, although the experience with such procedures to date has not been extensive. CONCLUSION: Post-prostatectomy incontinence has a good prognosis and should thus be treated conservatively at first. If it nonetheless persists, surgical treatment is indicated for patients who choose it after being fully informed about their options.

The undescended testis: diagnosis, treatment and long-term consequences.

BACKGROUND: The late descent of a testicle into the scrotum may impair its development. Reduced fertility is the main risk of primary cryptorchidism even after timely treatment, as histopathological changes (Leydig cell hypoplasia) already become apparent in the first few months of life. There is evidence, however, that treatment is often delayed. Hormonal and surgical treatments complement each other and should be provided before the child's first birthday. METHODS: Selective literature search in PubMed (January 2008) based on the following keywords: "cryptorchidism", "maldescensus testis", "etiology", "therapy", "semen quality", "testicular cancer". Particular attention was paid to the current S2 guidelines on cryptorchidism. RESULTS/DISCUSSION: Hormone therapy is the best initial treatment in most cases, with a few exceptions. If this is unsuccessful, surgery should be performed without delay. The success of treatment depends on the initial position of the testicle. Treatment does not lessen the risk of malignancy. Parents must be informed about this risk. The undescended testicle is the most common genital malformation in boys. When diagnosed, it should be treated hormonally and/or surgically before the child's first birthday to minimize the risk of impaired fertility. Successful treatment before age 13 appears not to lessen the risk of testicular cancer, but it does facilitate early detection by enabling physical examination of the testicle.

[New treatment options for erectile dysfunction. Pharmacologic and nonpharmacologic options]. / Neue Therapieoptionen zur Behandlung der erektilen Dysfunktion. Medikamentöse und nichtmedikamentöse Möglichkeiten.

Erectile dysfunction is a medical condition that influences the sexual life of millions of men and women worldwide. Due to a large number of currently available drugs, the therapy of erectile dysfunction has changed profoundly during the last decades. The pharmacologic options are divided into initiators versus conditioners and central- or peripheral-acting drugs. Besides intraurethral and intracavernous application of prostaglandin E(1) (PGE(1), peripheral initiator)--a transdermal application is still in clinical testing--there are drugs for oral application. PGE(1), the vasoactive drug mainly used, was replaced by sildenafil in first-line-therapy. PGE(1), administered intracavernosally or intraurethrally, is highly effective with success rates up to 90%, but the attrition rate due to personal inconvenience remains significant. Yohimbine is known as a central amplifier of erection and is useful in psychogenic and mild organic erectile dysfunction. Apomorphine, a central initiator of erection, amplifies erectile response as a central dopamine agonist in mild and moderate erectile dysfunction and starts acting 15-20 min after sublingual application. The phosphodiesterase type 5 (PDE-5) inhibitors sildenafil, vardenafil, and taldalafil are peripheral conditioners. Sildenafil, the most distributed oral agent worldwide, should be taken orally 60 min before sexual intercourse in combination with sexual stimulation. Sildenafil shows a high efficacy-safety profile with success rates for all etiologies between 50-80%. Paralleling nitrate-containing medication is an absolute contraindication. Vardenafil, another selective PDE-5 inhibitor with potentially higher selectivity and efficacy compared to sildenafil was just approved. The data from the clinical trials show the same adverse events and success rates as sildenafil. Tadalafil, just launched as well, amplifies erectile function for up to 24 h, allowing the patient to engage in sexual activity for this period. Adverse events and success rates resemble those of the other two substances. If medical treatment fails, there are nonpharmacologic options such as the vacuum constriction device and penile implants. The vacuum device is a safe and effective option for well-selected patients. Penile implants, especially the inflatable ones, completely imitate the physiologic erection. Due to recent research, infection rates and mechanical failures were minimized. Therefore penile implant surgery is well accepted by the patients and their partners. Despite this wide variety of options, therapy of erectile dysfunction should be performed in an individually adapted way. The patient's exact history, physical examination, collaboration of medical disciplines and choice of therapy will offer all patients the possibility to achieve or regain a satisfying sexual life.

An extract from the bark of Aspidosperma quebracho blanco binds to human penile alpha-adrenoceptors.

PURPOSE: We determined whether an extract from the bark of the tree Aspidosperma quebracho blanco, which is used as a prescription drug to treat erectile dysfunction in some countries, can bind to human penile alpha1 and alpha2-adrenoceptors, and cloned human alpha-adrenoceptor subtypes. MATERIALS AND METHODS: Competition binding studies were performed with alpha1 and alpha2-adrenoceptors with the extract and 4 subfractions prepared from it using [3H]prazosin (New England Nuclear, Dreieich, Germany) and [3H]RX 821002 (2-methoxy-idazoxam) (Amersham, Braunschweig, Germany) as the radioligands, respectively. RESULTS: In a concentration dependent manner the extract inhibited 2-methoxy-idazoxam binding to human penile alpha2-adrenoceptors. Somewhat less potently it inhibited [3H] prazosin binding to penile alpha1-adrenoceptors. The extract also inhibited binding to cloned alpha2-adrenoceptors more potently than to alpha1-adrenoceptors but did not discriminate among subtypes. Subfraction B was more potent than the others for all cloned alpha1-adrenoceptor subtypes and much more potent at all penile and all cloned alpha2-adrenoceptor subtypes. This fraction largely contained yohimbine, whereas the other fractions were devoid of yohimbine. Based on yohimbine competition binding experiments with penile and cloned alpha1 and alpha2-adrenoceptors, it appears that the inhibitory effects of the abstract and its subfractions can largely be explained by its yohimbine content. CONCLUSIONS: An alpha-adrenoceptor mediated component of the pro-erectile effects of Aspidosperma quebracho blanco bark extract may predominantly be caused by its yohimbine content. The alpha-adrenoceptor independent, pro-erectile effects of the extract could not be determined from this study.

Influence of pertussis toxin on superficial bladder carcinoma in rats.

The proliferation and migration of cells is a fundamental process for the metastasis of malignant tumour cells. In several in vitro studies, pertussis toxin (PTX) inhibited cell proliferation and cell motility in the human transitional cell carcinoma cell line J82. The present study investigated the effect of the intravesical application of PTX on the development of superficial bladder cancer in rats. We used the model of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN, 0.05% via drinking water x10 weeks) to induce superficial bladder carcinomas in 40 female rats. After 16 weeks the rats were treated in two groups with 0.4 ml PTX (1 microg/ml) or 0.4 ml phosphate buffered saline (PBS) by intravesical application (once a week for 10 weeks). In the 25th week urine cytology was determined and all rats were killed at week 26 followed by histological evaluation. In the control group, the urine cytology was positive for G2/G3 cells in ten of 17 rats. In the PTX group G2/G3 cells were determined in five of 20 rats ( P two tailed <0.05). Histopathologically 12 rats (71%) of the control group and 11 rats (55%) of the PTX group developed T1-T2 transitional-cell carcinomas. No local or systemic side effects were disclosed. PTX treatment reduces the development of G3 transitional cell carcinomas in rats and may represent a new approach for local therapy in superficial bladder cancer.

ACE gene I/D and NOS3 G894T polymorphisms and response to sildenafil in men with erectile dysfunction.

OBJECTIVES: To examine a potential association between the response to the phosphodiesterase-5 inhibitor sildenafil and angiotensin-converting enzyme (ACE), as well as NOS3 G894T genotypes in patients with erectile dysfunction (ED). An insertion/deletion (I/D) polymorphism in the gene encoding the ACE and a single nucleotide exchange polymorphism (G894T) in the gene NOS3 encoding endothelial nitric oxide synthase have been associated with cardiovascular disorders. METHODS: The response to sildenafil in 113 men with ED was monitored according to the patients' diaries. ACE and NOS3 genotypes were determined in patients with ED and in 108 healthy male blood donors. RESULTS: Genotype distributions of ACE and NOS3 polymorphisms in the patient group were similar to those of the healthy control group. Analysis of the response to sildenafil revealed that 15 of 20 individuals homozygous for the ACE II genotype showed a positive erectile response after sildenafil use and only 46 of 93 D allele (combined DD and DI genotypes) carriers had a positive response (positive erectile response, odds ratio 3.07, 95% confidence interval 1.03 to 9.13, P = 0.04; chi-square test). Analysis of NOS3 genotypes revealed that 30 of 52 individuals homozygous for the G894 allele had a sufficient response to sildenafil and only 4 of 12 patients homozygous for the 894T allele had a sufficient erection. CONCLUSIONS: It appears that patients with elevated ACE serum concentrations, as associated with the D allele of the ACE I/D polymorphism, are less likely to respond to sildenafil.

Sildenafil response is influenced by the G protein beta 3 subunit GNB3 C825T polymorphism: a pilot study.

PURPOSE: Sildenafil is the oral phosphodiesterase-5 inhibitor that revolutionized treatment for erectile dysfunction. We investigated a potential association of the G protein beta 3 subunit (GNB3) C825T polymorphism, a determinant of intracellular signal transduction, with the drug response to sildenafil in patients with erectile dysfunction. MATERIALS AND METHODS: In 113 men with erectile dysfunction and 111 healthy male controls genotype status of the GNB3 C825T polymorphism was determined by polymerase chain reaction and restriction analysis. Patients with erectile dysfunction received sildenafil at a dose of 25 to 100 mg. according to the individual erectile response. Drug response was measured by interviewing the patient according to the erection scale of 0 to 5. RESULTS: The GNB3 genotype distribution of patients with erectile dysfunction exactly matched that of healthy controls. Analysis of the response to sildenafil revealed a significant association of C825T allele status with the erectile response to sildenafil. In the group with TT genotype we observed a 90.9% response but only a 50.9% and 48.9% response in patients with the CC and TC genotype, respectively. The odds ratio for a positive erectile response was 10.0 (95% CI 1.2 to 81.1) for patients with the TT versus the TC/CC genotype (p = 0.01). CONCLUSIONS: The response to sildenafil is significantly associated with GNB3 C825T genotype status in patients with erectile dysfunction.