Therapeutic effect of ozone and rutin on adriamycin-induced testicular toxicity in an experimental rat model.

To evaluate the cytoprotective effects of rutin, ozone and their combination on adriamycin (ADR)-induced testicular toxicity, 50 male albino rats were classified into five groups of ten animals each as follows: placebo group; ADR group; ADR + rutin group; ADR + ozone group and ADR + rutin + ozone group. Sperm functions, testosterone (T), luteinising hormone (LH), follicle stimulating hormone (FSH), testicular enzymes, oxidant/antioxidant status, C-reactive protein, monocyte chemoattractant proteins-1 and leukotriene B4 were determined. After ADR injection, a decline in sperm functions was observed. FSH and LH levels were increased, T level and testicular enzymes were decreased, significant enhancement in oxidative stress with subsequent depletion in antioxidants was detected and inflammatory markers were significantly elevated. Treatment with rutin and/or ozone, however, improved the aforementioned parameters. Ozone therapy alone almost completely reversed the toxic effects of ADR and restored all parameters to normal levels.

Characterisation of pomegranate juice effects on human corpus cavernosum.

Pomegranate (POM) juice may benefit the erectile process, but the scientific evidence is lacking. This study evaluates the molecular characterisation and confirmation of POM's action on human corpus cavernosum (HCC) obtained from patients (n = 16) undergoing penile prosthesis implantation. After phenylephrine contraction, the relaxant effects of POM with various inhibitors in the presence and absence of palmitic acid (PA)-induced acute oxidative stress were investigated. Electrical field stimulation (EFS)- and acetylcholine (ACh)-induced relaxation were performed using organ bath preparation. Expression of neuronal nitric oxide synthase (nNOS), endothelial (eNOS), phosphodiesterase (PDE)-5A and cGMP levels were assessed in cells from ex vivo organ cultures of HCC, using RT-PCR, ELISA and immunohistochemistry techniques. POM induced marked relaxation of HCC (maximum response: 97.0 ± 3.1%) and reversed the PA-induced decrease of EFS (20 Hz). nNOS transcription was increased by 7-fold in POM-treated cells without influencing eNOS and PDE5A expressions. We conclude that POM induced marked relaxation of HCC via: (i) nNOS stimulation, and (ii) downstream relaxation stimulated by nNOS and cGMP and bypassing the NO and PDE5. This action provides a rationale for the therapeutic or preventative use of POM in men with erectile dysfunction who do not respond well to PDE5 inhibitors.

Effect of avanafil on rat and human corpus cavernosum.

We compared the activity of a new phosphodiesterase-5 inhibitor (PDE5i) avanafil with sildenafil and tadalafil in human and rat corpus cavernosum (CC) tissues. The effect of avanafil with several inhibitors and electrical field stimulation (EFS) was evaluated on CC after pre-contraction with phenylephrine. With the PDE5i, sildenafil and tadalafil, concentration-response curves were obtained and cyclic guanosine monophosphate (cGMP) levels were measured in tissues. Avanafil induced relaxation with maximum response of 74 ± 5% in human CC. This response was attenuated by NOS inhibitor and soluble guanylate cyclase (sGC) inhibitor. Avanafil potentiated relaxation responses to acetylcholine and EFS in human CC and enhanced SNP-induced relaxation and showed 3-fold increase in cGMP levels. When compared with sildenafil, avanafil and tadalafil were effective at lower concentrations in human CC. In addition, Sprague-Dawley rats underwent in vivo intracavernosal pressure (ICP) and mean arterial pressure (MAP) measurements. Avanafil increased ICP/MAP that was enhanced by SNP and cavernous nerve (CN) stimulation in rat CC tissues. Also avanafil showed maximum relaxation response of 83 ± 7% in rat CC with 3-fold increase in cGMP concentration. Taken together, these results of our in vivo and in vitro studies in human and rat suggest that avanafil promotes the CC relaxation and penile erection via NO-cGMP pathway.

PDE5 inhibitors: considerations for preference and long-term adherence.

INTRODUCTION: Erectile dysfunction (ED) is a highly prevalent condition affecting nearly one in five men worldwide. The advent of phosphodiesterase type 5 inhibitors (PDE5i) has revolutionised the ED treatment landscape and provided effective, minimally invasive therapies to restore male sexual function. MATERIALS AND METHODS: A pubmed search was performed of all English language articles from 1996 to present reviewing PDE5i, including pharmacokinetics, efficacy profiles and comparisons, where available. RESULTS: Currently available PDE5i in the United States include sildenafil, vardenafil, tadalafil and avanafil, each of which has unique side effect, pharmacokinetic and outcome profiles. Sildenafil is associated with increased rate of visual changes, vardenafil with QT prolongation and tadalafil with lower back pain. Avanafil and vardenafil orodispersible tablet rapidly achieve peak plasma concentration, which results in faster onset of action, whereas tadalafil exhibits the longest half-life. First time response to PDE5i is approximately 60-70%, with no significant differences in efficacy noted among therapies. The literature does not clearly demonstrate a preference for one drug. High-treatment success rates (89%) were reported when patients were prescribed all available PDE5i. Daily dosing with tadalafil is associated with improved erectile function (EF) over time. Finally, novel modes of patient-provider interaction, including internet-based education, communication and prescribing, may also improve long-term adherence. CONCLUSIONS: PDE5i represent first line therapy for ED with excellent overall efficacy and satisfactory side effect profiles. Enhanced communciation, coupled with increased knowledge of drug characteristics, comparative treatment regimens and optimal prescribing patterns, offer compelling tools to improve long-term treatment success.

Understanding the course of Peyronie's disease.

AIMS: To correct common misconceptions about Peyronie's disease (PD) that present obstacles to early recognition and treatment. METHODS: The prevalence, natural disease course, psychosocial effects and treatment considerations for patients with PD were reviewed. RESULTS: Studies over the past decade have shown that the prevalence of PD may be higher (up to 20%) than previously thought. PD can lead to emotional and relationship distress. Nearly 10% of men who present with PD are younger than 40. Both younger age and comorbid vascular disease have been associated with more severe and progressive PD. In the majority of patients, symptoms will either deteriorate or remain stable. PD is often associated with erectile dysfunction (ED). Effective, minimally invasive treatments used early in the disease course include unapproved and/or investigational intralesional injection therapy with verapamil, interferon (IFN) α-2b, or collagenase clostridium histolyticum (CCH). Surgical intervention is considered in patients with ED and/or penile deformity that impairs sexual functioning; however, preoperative discussion of appropriate expectations is important. DISCUSSION: The availability of effective minimally invasive and surgical therapies for PD suggests that active management should be considered over a 'wait-and-see' approach. CONCLUSION: Providing early intervention and improved education/awareness of PD as a chronic and progressive disorder may result in improved physical and psychosocial outcomes for PD patients. As general practitioners are often the first contact for men with PD, they are well positioned to recognise symptoms early and promptly refer patients for further evaluation and treatment.

Update on treatments for premature ejaculation.

Current and upcoming treatment options for premature ejaculation (PE) are of global clinical interest. In 2008, the International Society for Sexual Medicine published an evidence-based definition for PE. While there are no US Food and Drug Administration-approved therapies for PE, the American Urological Association 2004 guidelines state the serotonergic antidepressants paroxetine, sertraline, fluoxetine and clomipramine and the topical lidocaine-prilocaine cream are effective treatment options. However, there are limitations associated with their use, which may be overcome by PE-specific therapies currently in development. Two agents that are in advanced stages of clinical development include: (i) dapoxetine, an on-demand short-acting selective serotonin reuptake inhibitor, and (ii) PSD502, a metered-dose aerosol containing lidocaine and prilocaine, also for on-demand treatment. Another on-demand agent in development is tramadol, a weak opioid that is currently approved for treating pain. Coupled with efficient diagnosis, it is hoped that these newer agents will improve the quality of life for patients who suffer from PE.

Survey of patient and partner satisfaction following collagenase Clostridium histolyticum treatment for Peyronie's disease.

Intralesional injection of collagenase Clostridium histolyticum (CCH) is a minimally invasive, Food and Drug Administration-approved, effective treatment for Peyronie's disease (PD). To assess the satisfaction of patients and their female sexual partners (FSP) following CCH therapy for PD, we conducted a retrospective review of the records of all patients treated with CCH for PD between 04/2014 and 03/2016. Collected variables included demographics, pre- and post-treatment sexual function, penile curvature, penile vascular findings, and treatment outcomes. Patients and their FSPs were subsequently contacted by telephone and queried regarding their ability to have intercourse and their satisfaction with treatment. A total of 24 couples responded to our questionnaire and constitute the subjects of this analysis. Patient and FSP satisfaction with treatment were 67% and 71%, respectively. Significant predictors of FSP satisfaction with treatment included recall of penile trauma during prior sexual intercourse, improved ability to have sexual intercourse following treatment, and absence of post-procedural glans hypoesthesia. In conclusion, CCH imparts a significant benefit on a couple's sexual health. Partner satisfaction with treatment is correlated with improved ability to have sexual intercourse and absence of patient glans hypoesthesia.

Pharmacotherapy for erectile dysfunction.

Erectile dysfunction (ED) is defined as the consistent inability to obtain or maintain an erection for satisfactory sexual relations. An estimated 20-30 million men suffer from some degree of sexual dysfunction. The past 20 years of research on erectile physiology have increased our understanding of the biochemical factors and intracellular mechanisms responsible for corpus cavernosal smooth muscle contraction and relaxation, and revealed that ED is predominantly a disease of vascular origin. Since the advent of sildenafil (Viagra), there has been a resurgence of interest in ED, and an increase in patients presenting with this disease. A thorough knowledge of the physiology of erection is essential for future pharmacological innovations in the field of male ED.

Gene and stem cell therapy for erectile dysfunction.

Erectile dysfunction (ED) is defined as the inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance. ED is a highly prevalent health problem with considerable impact on the quality of life of men and their partners. Although the treatment of ED with oral phosphodiesterase type V (PDE5) inhibitors is effective in a wide range of individuals, it is not efficacious in all patients. The failure of PDE5 inhibitors happens mainly in men with diabetes, non-nerve sparing radical prostatectomy, and high disease severity. Therefore, improved therapies based on a better understanding of the fundamental issues in erectile physiology and pathophysiology have recently been proposed. Here, we summarize studies on ED treatment using gene and stem cell therapies. Adenoviral-mediated intracavernosal transfer of therapeutic genes, such as endothelial nitric oxide synthase (eNOS), calcitonin gene-related peptide (CGRP), superoxide dismutase (SOD), and RhoA/Rho kinase and mesenchymal stem cell-based cell and gene therapy strategy for the treatment of age- and diabetes-related ED are the focus of this review.

Erectile dysfunction in urethral stricture and pelvic fracture urethral injury patients: diagnosis, treatment, and outcomes.

Urethral stricture disease, pelvic fracture urethral injury (PFUI), and their various treatment options are associated with erectile dysfunction (ED). The etiology of urethral stricture disease is multifactorial and includes trauma, inflammatory, and iatrogenic causes. Posterior urethral injuries are commonly associated with pelvic fractures. There is a spectrum in the severity of both conditions and this directly impacts the treatment options offered by the surgeon. Many published studies focus on the treatment outcomes and the relatively high recurrence rates after surgical repair. This communication reviews the current knowledge of the association between ED and urethral stricture disease, as well as PFUI. The incidence, pathophysiology, and clinical ramifications of both conditions on sexual function are discussed. The treatment options for ED in those patients are reviewed and summarized.

Comparison of infrapubic versus transcrotal approaches for inflatable penile prosthesis placement: a multi-institution report.

Inflatable penile prostheses (IPP) are associated with excellent long-term outcomes. To date, no study has evaluated the significance of surgical approach on IPP intraoperative variables. High-volume surgeons placing the Titan 0-degree prosthesis from March-July 2012 completed questionnaires including pre-/intraoperative variables. Intraoperative data were compared between surgeons performing an infrapubic versus transcrotal approach for total length of prosthesis, proximal and distal measurements, rear-tip extender (RTE) length, reservoir size and fill volume and ability to place the reservoir in the space of Retzius. Forty-six surgeons placed 256 IPPs, with a median of 5 (range 1-10) inserted. Transcrotal placement was performed most commonly (80%). Revision procedures accounted for 13% of cases, with 19% previously undergoing robotic-assisted prostatectomy. Compared with infrapubic, transcrotal placement resulted in a longer total prosthesis (22.3 cm vs 20.6 cm, P < 0.0001), increased proximal dilation (10.1 cm vs 8.6 cm, P < 0.0001), longer RTEs (1.9 cm vs 1.2 cm, P < 0.0001) and larger reservoir fill volume (79 cc vs 71 cc, P = 0.0003). No differences were noted in distal measurements or ability to place the reservoir in the space of Retzius. Compared with the infrapubic approach, high-volume surgeons placing the Titan 0-degree IPP transcrotally achieved increased proximal dilation with an ~1-2-cm-longer prosthesis inserted.

Collagenase Clostridium histolyticum for the pharmacological management of Peyronie's disease.

Peyronie's disease (PD) is defined as the abnormal accumulation of connective tissue in the tunica albuginea of the penis, and is an ongoing physical and psychological challenge for thousands of Americans. In vitro studies in the 1950s uncovered the potential of collagenase Clostridium histolyticum (CCH) to disrupt the collagen-containing plaques in PD, and opened the door to more in-depth clinical trials. Results indicated that with multiple dosage cycles followed by plaque modeling, penile curvature can be corrected, on average, in up to 35% of cases, with the majority of patients achieving ≥ 25% improvement in penile curvature. Most studies also indicated an improvement in patient-reported symptoms from the Peyronie's Disease Questionnaire. Adverse events from treatment with CCH included penile bruising, pain and edema, but most were mild to moderate in severity and usually resolved without intervention, suggesting that CCH is an effective and safe treatment for PD.

Therapeutic advances in the treatment of Peyronie's disease.

Peyronie's disease (PD) is an under-diagnosed condition with prevalence in the male population as high as 9%. It is a localized connective tissue disorder of the penis characterized by scarring of the tunica albuginea. Its pathophysiology, however, remains incompletely elucidated. For the management of the acute phase of PD, there are currently numerous available oral drugs, but the scientific evidence for their use is weak. In terms of intralesional injections, collagenase clostridium histolyticum is currently the only Food and Drug Administration-approved drug for the management of patients with PD and a palpable plaque with dorsal or dorsolateral curvature >30°. Other available intralesional injectable drugs include verapamil and interferon-alpha-2B, however, their use is considered off-label. Iontophoresis, shockwave therapy, and radiation therapy have also been described with unconvincing results, and as such, their use is currently not recommended. Traction therapy, as part of a multimodal approach, is an underused additional tool for the prevention of PD-associated loss of penile length, but its efficacy is dependent on patient compliance. Surgical therapy remains the gold standard for patients in the chronic phase of the disease. In patients with adequate erectile function, tunical plication and/or incision/partial excision and grafting can be offered, depending on degree of curvature and/or presence of destabilizing deformity. In patients with erectile dysfunction non-responsive to oral therapy, insertion of an inflatable penile prosthesis with or without straightening procedures should be offered.

The direction and severity of penile curvature does not have an impact on concomitant vasculogenic erectile dysfunction in patients with Peyronie's disease.

Although the association between Peyronie's disease (PD) and erectile dysfunction (ED) is well established, limited data are available correlating penile curvature and penile hemodynamic parameters. We sought to examine this association in a cohort of PD men undergoing penile duplex Doppler ultrasound (PDDU). PD patients were retrospectively evaluated to correlate the extent and direction of penile curvature with measured vascular parameters. Demographic variables, disease characteristics and PDDU parameters were tabulated and statistically compared based on extent (≤ 45° and >45°) and direction (dorsal, ventral, lateral, ventrolateral, dorsolateral) of curvature. A total of 220 PD patients (mean age of 55.0 ± 9.2 years) underwent PDDU at one institution from January 2008 to December 2010. Overall, 69.5% of patients were found to have vasculogenic ED (arterial insufficiency (AI): 10%; veno-occlusive dysfunction (VOD): 43.2%; AI + VOD: 16.4%). Mean curvature was similar among all PDDU groups (AI: 41.7 ± 5.2°; VOD: 41.3 ± 2.5°; AI+VOD: 37 ± 4.1°; no-ED: 37.3 ± 3°; P > 0.85). No significant differences were noted in the presence or type of ED among various directions of curvature (P = 0.34) or when curvatures were stratified by ≤ 45° and >45°. The direction and extent of penile curvature are not associated with altered rates of vasculogenic ED on PDDU in PD patients.

Failure to attain stretched penile length after intracavernosal injection of a vasodilator agent is predictive of veno-occlusive dysfunction on penile duplex Doppler ultrasonography.

Penile duplex Doppler ultrasound (PDDU) assesses the etiology of erectile dysfunction. Peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistive index (RI) are common PDDU parameters. We assessed whether stretched penile length (SPL) in the flaccid state and measured penile length at peak erection after intracavernosal injection (ICI) of a vasodilator during PDDU correlated with the etiology of erectile dysfunction. We performed a retrospective review of 93 patients who underwent PDDU for erectile dysfunction. Normal and stretched penile length were measured, both at a flaccid state prior to ICI and at peak erection during PDDU. Collected data included patient demographics, vascular, and anatomic parameters. The mean age was 52 years. SPL was equivalent to peak penile length after ICI in 60 patients (65%, group 1) and did not match in 33 (35%, group 2). There were no significant differences between the two groups in terms of flaccid, stretched, and post-ICI erect penile lengths, IIEF score, PSV, percent rigidity or tumescence, and vasodilator dose used. Patients in group 2 had less of a change in penile length from flaccid to erect state (36% vs. 44%, p = 0.02), higher EDV (12.0 vs. 8.5, p = 0.041), lower RI (0.6 vs. 1.0, p = 0.046), and more veno-occlusive dysfunction (82% vs. 53%, p = 0.001). On multivariate analysis, failure to reach maximum SPL at peak ICI erection (OR 2.255, CI 1.191-4.271, p = 0.0126), EDV (OR 1.281, CI 1.115-1.471, p < 0.001) and RI (OR 0.694, CI 0.573-0.723, p = 0.009) predicted veno-occlusive dysfunction. Failure to reach maximal SPL during PDDU using ICI with a vasodilator agent predicted veno-occlusive dysfunction, which is independent of both penile rigidity and tumescence. This measurement could serve as another diagnostic tool for predicting veno-occlusive dysfunction when PDDU is not readily available. Limitations include the subjective nature of penile measurements and different PGE1 doses used.

Differential expression of novel biomarkers (TLR-2, TLR-4, COX-2, and Nrf-2) of inflammation and oxidative stress in semen of leukocytospermia patients.

Chronic genitourinary inflammation results in Leukocytospermia (LCS), an elevated number of white blood cells (WBCs) in semen, which, in association with oxidative stress, may suppress sperm function, and manifest as male factor infertility. The current clinical diagnosis of LCS employs manual enumeration of WBCs and requires complex staining and laboratory skills or measurement of inflammatory cytokines and chemokines levels. Many patients with idiopathic infertility are asymptomatic. In search of better inflammatory markers for LCS, we evaluated expression of toll-like receptors 2 and 4 (TLR-2/4), cyclooxygenase-2 (COX-2), and nuclear factor (erythroid-derived 2)-like 2 (Nrf-2) in semen samples of age-matched infertile patients with and without LCS. We employed the usage of specific Western blot evaluation, cytokine array; immunofluorescence microscopy (IFM) followed by computer-based analysis, and other molecular approaches. As compared with non-LCS patients (n = 38), semen samples from LCS patients (n = 47) displayed significantly lower total sperm count (p < 0.01), motility (p < 0.0001), normal head count (p < 0.0001), and a significantly higher white blood cell count (p < 0.0001). Differential cytokine profiling of seminal plasma by antibody array revealed up-regulation of several pro-inflammatory chemokines in LCS samples. Western blot analysis of LCS seminal plasma (n = 15) also showed a significant increase in expression of TLR-2 (p < 0.001) and 4 (p < 0.01), COX-2 (p < 0.001), and Nrf-2 (p < 0.001) as compared with semen samples from non-LCS patients (n = 15). Computer-based objective IFM analysis of spermatozoa from LCS patients showed increased expression of TLR-4 (p < 0.001), Cox-2 (p < 0.01), and (Nrf-2) (p < 0.01). Significant differences in the subcellular localization of these proteins were evident in the sperm head and tail segments of LCS samples. Altogether, these observations suggest that TLR-2/4, COX-2, and Nrf-2 can serve as novel biomarkers of inflammation and oxidative stress. Therefore, developing a rapid assay for these biomarkers may facilitate early diagnosis and management of LCS especially in idiopathic and asymptomatic male infertility patients.

Characterization of reactive oxygen species induced effects on human spermatozoa movement and energy metabolism.

Reactive oxygen species (ROS) inhibit sperm movement and have been implicated in male infertility. In this study, we determined the effects of specific ROS produced by activated leukocytes on human spermatozoa and investigated their metabolic site of action. We used chemiluminescence and electron paramagnetic resonance (EPR) to characterize the ROS generated by both blood and seminal leukocytes. We also determined the effects of these ROS on sperm energy metabolism using biochemical analyses and flow cytometry. Both blood and seminal leukocytes produced the same characteristic ROS which were determined to be hydrogen peroxide (H2O2) and superoxide radicals (O2*-). EPR using the spin trapping technique indicated that superoxide radical-dependent hydroxyl radicals (HO.) were also generated. ROS generated by PMA-stimulated blood leukocytes (2-5 x 10(6)/ml) caused inhibition of sperm movement in 2 h (p < .01). Using the hypoxanthine/ xanthine oxidase (0.5 U/ml) system to generate ROS, we determined that spermatozoa ATP levels, after ROS treatment, were reduced approximately eight-fold in 30 min (0.10 x 10(10) moles/10(6) sperm cells) compared to control (0.84 X 10(-10) moles/10(6) sperm cells) (p < .01). Sperm ATP reduction paralleled the inhibition of sperm forward progression. Neither superoxide dismutase (100 U/ml) nor dimethyl sulfoxide (100 mM) reversed these effects; however, protection was observed with catalase (4 X 10(3) U/ml). Flow cytometric analyses of sperm treated with various doses of H2O2 (0.3 mM-20.0 mM) showed a dose-dependent decrease in sperm mitochondrial membrane potential (MMP); however, at low concentrations of H2O2, sperm MMP was not significantly inhibited. Also, sperm MMP uncoupling with CCClP had no effect on either sperm ATP levels or forward progression. These results indicate that H2O2 is the toxic ROS produced by activated leukocytes causing the inhibition of both sperm movement and ATP production. O2*- and HO. do not play a significant role in these processes. Low concentrations of H2O2 causing complete inhibition of sperm movement and ATP levels inhibit sperm energy metabolism at a site independent of mitochondrial oxidative phosphorylation.

Selective inhibition of the A form of monoamine oxidase by 4-dimethylamino-alpha-methylphenylalkylamine derivatives in the rat.

The inhibitory effects on monoamine oxidase (MAO) of some dimethylamino-alpha-phenylalkylamine derivatives were examined in a rat brain mitochondrial preparation in vitro and in rat brain slices following oral administration. In the in vitro assay the compounds were shown to be selective inhibitors of the A form of MAO, being 100-600 times more potent in inhibiting the deamination of [14C]5-hydroxytryptamine than that of [14C]phenetylamine. Using an ex vivo brain slice technique it was found that the new compounds were reversible and very selective inhibitors of type A MAO in the rat brain and the most potent compounds (FLA 405, 314, 336 and 558) were equipotent with clorgyline. The compounds increased the monoamine concentrations in whole rat brain, particularly that of 5-hydroxytryptamine, in the same dose range which produced MAO inhibition. Some of the new compounds, e.g. FLA 336 and FLA 717, caused only weak potentiation of the vaso-pressor effect of orally administered tyramine.