The first-generation phosphodiesterase 5 inhibitors and their pharmacokinetic issue.

BACKGROUND: Erectile dysfunction (ED) is a relatively frequent disease that negatively impacts the overall quality of life, well-being, and relationships. Although the use of phosphodiesterase 5 inhibitors (PDE5is) has revolutionized the treatment of ED, a high percentage of ED patients discontinue PDE5i treatment. OBJECTIVES: (i) To analyze the reasons for patient dissatisfaction leading to PDE5i discontinuation; (ii) analyze the pharmacokinetics of new formulations focusing on the time needed to reach an effective plasma concentration of PDE5is (Tonset ) following drug intake; and (iii) summarize the physicochemical properties of sildenafil to understand which excipients may increase the absorption rate. MATERIAL AND METHODS: An online PubMed literature search was conducted to identify English language publications from inception to January 2019. RESULTS: The main reasons for patient dissatisfaction when using PDE5is on demand are the relatively long Tonset after taking vardenafil and sildenafil, including formulations such as film-coated tablets, fine granules, orally disintegrating tablets (ODTs), and oral thin films (ODFs). The relatively long Tonset , further worsened when accompanied by eating, highlights the following: (i) the need for planning intercourse, determining partner-related issues; (ii) issues when having sex before the maximum effect of the drug; and (iii) lower drug-related placebo effects. Some data suggest that sildenafil is a 'difficult' molecule, but Tonset can be improved following absorption by buccal mucosa using appropriate excipients. CONCLUSIONS: We conclude that several ODT and ODF formulations can improve the 'discretion' issue because they are taken without water, but they have similar pharmacokinetics to corresponding film-coated tablet formulations. One ODF formulation of sildenafil was characterized by a shorter Tonset and could potentially increase patient satisfaction following treatment. However, more clinical studies are needed to confirm the findings. Surfactants and ascorbic acid appear to be crucial excipients for achieving a high absorption rate, but more studies are needed.

Trocar-guided trans-vaginal mesh surgery for pelvic organ prolapse: effects on urinary continence and anatomical and functional outcomes. A prospective observational study.

OBJECTIVE: Primary objective of this study was to assess the effects of trocar-guided transvaginal mesh surgery (TVM) on cure and prevention rates for incontinence, without concomitant surgery for Stress Urinary Incontinence (SUI). Our secondary objectives were anatomical outcomes, relief of symptoms and effect on quality of life (QoL). STUDY DESIGN: This prospective observational study evaluated women who underwent TVM for symptomatic stage >2 Pelvic Organ Prolapse (POP). SUI was evaluated objectively using the cough stress test with prolapse reduced. SUI and urge urinary incontinence (UUI) were subjectively evaluated using ICIQ-SF. Anatomical cure was defined as stage <2 at POP-Q. STATISTICAL ANALYSIS: McNemar chi-square test; paired t-test; Mann-Whitney test. RESULTS: Seventy-two patients reached final evaluation (mean follow-up 72 months). In the 40 pre-op continent patients, 34 (85%) remained continent postoperatively and 6 (15%) showed de novo SUI. Only 1 patient chose to undergo subsequent TVT. The number needed to treat was 6 to prevent 1 women developing de novo objective SUI and 39 to prevent 1 woman having to undergo SUI surgery. In the 32 pre-op incontinent patients, 18 (56.3%) became continent postoperatively. Only 1 patient chose to undergo subsequent TVT. UUI was present in 44 patients pre-operatively and 15 (20.8%) post-operatively (1 de novo). Forty-four patients (61.1%) were continent post-operatively for SUI and UUI. We observed a significant improvement in storage, voiding, post-micturition and prolapse-related symptoms. The anatomical cure rate was 87.5% for the anterior compartment and 90.3%.for the apical segment. The apical recurrence was 8.3% in the patients previously hysterectomised, 18.8% in the patients with uterus preservation and 0% in the patients with concomitant hysterectomy. QoL scores improved in all domains except sleep and personal relationships. We observed mesh exposure in 10 patients (13.9%), in 5 of whom it was associated with a concomitant hysterectomy CONCLUSIONS: TVM showed excellent results in terms of continence and can be performed without contemporary anti-incontinence surgery, for both continent and incontinent women. Patients should have pre-operative counselling before POP surgery. For severe uterine prolapse the Perigee™ System should be employed with concomitant hysterectomy because uterus preservation is associated with significantly higher apical recurrence rates.

Safety and efficacy of low intensity shockwave (LISW) treatment in patients with erectile dysfunction.

UNLABELLED: The primary goal in the management strategy of a patient with ED would be to determine its etiology and cure it when possible, and not just to treat the symptoms alone. One of the new therapeutic strategies is the use of low intensity extracorporeal shockwave (LISW) therapy. The mechanism of shockwave therapy is not completely clear. It is suggested that LISW induces neovascularization and improvement of cavernosal arterial flow which can lead to an improvement of erectile function by releasing NO, VEGF and PCNA. MATERIALS AND METHODS: 31 patients between February and June 2013 with mild to severe ED and non-Phosphodiesterase 5 inhibitors responders were enrolled. Patients underwent four weekly treatment sessions. During each session 3600 shocks at 0.09mJ/ mm2 were given, 900 shocks at each anatomical area (right and left corpus cavernosum, right and left crus). Improvement of the erectile function was evaluated using the International Index of Erectile Function (IIEF-EF), the Sexual Encounter Profile (SEP) diaries (SEP-Questions 2 and 3) and Global Assessment Questions (GAQ-Q1 and GAQ-Q2). RESULTS: At 3-month follow-up IIEF-EF scores improved from 16.54±6.35 at baseline to 21.03±6.38. Patients answering 'yes' to the SEP-Q2 elevated from 61% to 89% and from 32% to 62% in the SEP-Q3. A statistically significant improvement was reported to the Global Assessment Questions (GAQ-Q1 and GAQ-Q2). CONCLUSION: In conclusion, we can affirm that LISW is a confirmed therapeutic approach to erectile dysfunction that definitely needs more long-term trials to be clarified and further verified.

Safety and efficacy of low intensity shockwave (LISW) treatment in patients with erectile dysfunction

ABSTRACT The primary goal in the management strategy of a patient with ED would be to determine its etiology and cure it when possible, and not just to treat the symptoms alone. One of the new therapeutic strategies is the use of low intensity extracorporeal shockwave (LISW) therapy. The mechanism of shockwave therapy is not completely clear. It is suggested that LISW induces neovascularization and improvement of cavernosal arterial flow which can lead to an improvement of erectile function by releasing NO, VEGF and PCNA. Materials and Methods: 31 patients between February and June 2013 with mild to severe ED and non-Phosphodiesterase 5 inhibitors responders were enrolled. Patients underwent four weekly treatment sessions. During each session 3600 shocks at 0.09mJ/ mm2 were given, 900 shocks at each anatomical area (right and left corpus cavernosum, right and left crus). Improvement of the erectile function was evaluated using the International Index of Erectile Function (IIEF-EF), the Sexual Encounter Profile (SEP) diaries (SEP-Questions 2 and 3) and Global Assessment Questions (GAQ-Q1 and GAQ-Q2). Results: At 3-month follow-up IIEF-EF scores improved from 16.54±6.35 at baseline to 21.03±6.38. Patients answering ‘yes’ to the SEP-Q2 elevated from 61% to 89% and from 32% to 62% in the SEP-Q3. A statistically significant improvement was reported to the Global Assessment Questions (GAQ-Q1 and GAQ-Q2). Conclusion: In conclusion, we can affirm that LISW is a confirmed therapeutic approach to erectile dysfunction that definitely needs more long-term trials to be clarified and further verified.

Treatment of bilateral varicocele and other scrotal comorbidities using a single scrotal access: our experience on 34 patients.

INTRODUCTION: Varicocele is the main cause of infertility in male and the most correctable cause of it too. In this study, we present our experience on 34 patients affected by bilateral varicocele and other scrotal comorbidities treated underwent surgery with a scrotal access. MATERIALS AND METHODS: 34 patients were enrolled with clinical palpable and infraclinical (ultrasonic doppler scanning) bilateral varicocele and other comorbidities like right hydrocele, left hydrocele, bilateral hydrocele, and epididymal cyst. They all underwent scrotal bilateral varicocelectomy under local anesthesia. RESULTS AND DISCUSSION: At 6 months, no other complications were reported. No case of testicular atrophy was observed. None had recurrence of varicocele. All scrotal comorbidities were treated as well. CONCLUSION: Scrotal access with local anesthesia is a safe and useful technique to treat patients with bilateral varicocele and other scrotal comorbidities.

Immunomodulatory activity of a plant extract containing human papillomavirus 16-E7 protein in human monocyte-derived dendritic cells.

This study reports the immunomodulatory activity on human monocyte derived dendritic cells (MDDCs) of a vaccine preparation shown to be effective against an HPV16-related tumour in an animal model. The vaccine is composed of extract from Nicotiana benthamiana leaves containing HPV16 E7 protein expressed by a potato virus X-derived vector (NbPVX-E7). The effect of the extract was evaluated on MDDC differentiation and maturation by monitoring the phenotypic expression of specific markers. The results show that NbPVX-E7 does not induce monocyte differentiation to dendritic cells, but does induce MDDC maturation. Plant extract does not influence MDDC-uptake of E7-FITC while it significantly improves the Ovalbumin-FITC uptake, considered as a model antigen. Importantly, NbPVX-E7-pulsed MDDCs/PBMCs are able to prime human blood-derived lymphocytes from healthy individuals to induce HPV16 E7-specific cytotoxic activity. This is a propaedeutic study for a possible use of E7-containing plant extract in human immunotherapy of HPV-related lesions.

Exploiting the plant secretory pathway to improve the anticancer activity of a plant-derived HPV16 E7 vaccine.

The human papillomavirus 16 (HPV16) E7 oncoprotein can be considered a "tumor-specific antigen", and therefore it represents a promising target for a therapeutic vaccine against HPV-associated tumors. Efficient production of E7 protein with a plant-based transient expression system has been already described and it was demonstrated that E7-containing crude plant extracts confer partial protection against tumor challenge in a mouse model system. Before adopting the plant-based system as a cost-effective method for the production of an E7-based anti-cancer vaccine, some aspects, such as the oncoprotein yield, need further investigation. In the present study, we report the transient expression, mediated by a potato virus X (PVX)-derived vector, of the E7 protein targeted to the secretory system of Nicotiana benthamiana plants by using a plant-derived signal sequence. Targeting the antigen to the secretory pathway enhanced the E7 protein expression levels about five-fold. Mice immunized by s.c. administration with crude foliar extracts containing E7 showed strong stimulation of cell-mediated immune response after five boosters, as detected by ELISPOT. After challenging with the E7-expressing C3 tumor cells, tumor growth was completely inhibited in 80% of the vaccinated animals and a drastic reduction of tumor burden was observed in the remaining tumor-affected mice. These data demonstrate that, by enhancing E7 yield, it is possible to improve the anti-cancer activity of the plant-based experimental vaccine and open the way for a large-scale production of the E7 protein which could be purified or used as in planta formulation, also suitable for oral therapeutic vaccination.