Oral Treatment For Erectile Dysfunction Research Articles

(094) Synergy Between Orally Administered Phosphodiesterase-type-5-inhibitors and Topically Delivered Nitric-oxide in Eliciting Erectile Responses

Abstract Introduction Phosphodiesterase-type-5-inhibitors (PDE5i) represent first-line FDA-approved oral treatments for erectile dysfunction (ED). However, because their mode of action is dependent on the production of nitric oxide (NO) from nerve endings, patients that suffer neurogenic ED (for example, following the procedures for radical prostatectomy (RP) or resulting from diabetes) are commonly refractory to PDE5i treatment. We recently demonstrated proof-of-principle for increased efficacy of topically applied NO-releasing microparticles (NO-MP) in eliciting an erectile response when used in combination with the orally administered PDE5i, sildenafil. However, there are several other FDA approved PDE5i used to treat ED, which, although acting through the common mechanism of PDE5 inhibition, exhibit several characteristics that potentially could impact clinical and commercial translation of combination therapy. Objective The goal of the present studies was to determine if other commercially available PDE5i besides sildenafil (avanafil, tadalafil and vardenafil) also act cooperatively when used in combination with NO-MP to elicit an erectile response. Methods Sprague-Dawley rats underwent bi-lateral transection of the cavernous nerve (CN), as a model of RP, one-week prior to determining erectile response to treatment. We investigated the effect of oral administration of 0.05mg sildenafil/kg, 0.005mg tadalafil/kg, 0.01mg vardenafil/kg and 0.1mg avanafil/kg (approximately equivalent to clinical doses of 2.5mg, 0.25mg, 0.5mg and 5mg, respectively, administered to an 80 kg patient) 30 minutes prior to being anesthetized for the determination of erectile response by intracorporal pressure (ICP) and systemic blood pressure (BP). Baseline ICP and BP were recorded for 30 minutes, at which time 100 mg of NO-MP (or control, blank-MP) were applied to the rat penile shaft. The ICP and systemic BP were used to determine the time to the first erectile response, duration of the erectile responses, the maximal and average ICP/BP responses and the number of spontaneous erections per hour. Results Although oral treatment by PDE5i alone resulted in no observable erectile response, topical application of NO-MP resulted in spontaneous erectile responses. When NO-MP were applied in combination with oral PDE5i treatment, all PDE5i resulted in faster times to the first erectile response (on average 11 minutes compared to 22 minutes when NO-MP were used alone; P-value=0.041) and greater numbers of spontaneous erections (on average 4.6 erections per hour compared to 2.0 when NO-MP were used alone, P-value=0.043). Although there were no significant differences between any of the PDE5i when used in combination with NO-MP with respect to the average erectile responses per hour, duration of erectile response, and maximal ICP/BP, there was a trend in the vardenafil and avanafil treated animals for a more rapid onset of the erectile responses than observed with sildenafil and tadalafil. Conclusions Although knowledge of the molecular pathways that lead to an erection provide a rationale for a synergistic effect between PDE5i and NO in eliciting an erectile response, our results provide the first evidence of such synergy. Our results suggest a novel treatment strategy for patients with ED refractory to PDE5i, namely any of the FDA-approved oral PDE5 inhibitors used in combination with formulations that topically deliver NO to corporal tissue. Disclosure Yes, this is sponsored by industry/sponsor: Zylo Therapeutics, Inc Clarification Industry funding only - investigator initiated and executed study Any of the authors act as a consultant, employee or shareholder of an industry for: Zylo Therapeutics, Inc

A Comprehensive Review: Transdermal Drug Delivery System: A Tool For Novel Drug Delivery System

In the recent decade, skin delivery (topical and transdermal) has gained an unprecedented popularity, especially due to increased incidences of chronic skin diseases, demand for targeted and patient compliant delivery and interest in life cycle management strategies among pharmaceutical companies. Transdermal drug delivery system was presented to overcome the difficulties of drug delivery especially oral route. Transdermal drug delivery refers to a means of delivering drugs through the surface of the skin for local or systemic treatment. The drug functions after absorption through the skin into the systemic circulation via capillary action at a certain rate. Transdermal patches are now widely used as cosmetic, topical and transdermal delivery systems. These patches represent a key outcome from the growth in skin science, technology and expertise developed through trial and error, clinical observation and evidence-based studies that date back to the first existing human records. A transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through skin and into the bloodstream. An advantage of a transdermal drug delivery route over other types of delivery system such as oral, topical, intravenous (i.v.), intramuscular (i.m.), etc. is that the patch provides a controlled release of the medication into the patient, usually through either a porous membrane covering a reservoir of medication or through body heat melting thin layers of medication embedded in the adhesive. The main disadvantage to transdermal delivery systems stems from the fact that the skin composition offers very effective barrier that allow only small molecule based drugs to penetrate the skin and pass through the barrier. Sildenafil citrate (SLD) is a selective cyclic guanosine monophosphate-specific phosphodiesterase type 5 inhibitor used for the oral treatment of erectile dysfunction and more recently, it has been used for the treatment of pulmonary arterial hypertension and the enhancement of uteroplacental perfusion in case of fetal growth retardation. The challenges facing the oral administration of the drug include poor bioavailability and short duration of action that requires frequent administration. The main objective of transdermal drug delivery system is to deliver drugs into systemic circulation through skin at predetermined rate with minimal inter and intrapatient variations. Keyword: Skin delivery, Transdermal drug delivery, Oral rout, Sildenafil citrate, Pulmonary arterial hypertension

Effects of a conventional aphrodisiac: a twenty eight day repeated administration of Sildenafil citrate graded doses on experimental rats

Sildenafil citrate (Viagra), a phosphodiesterase-5 inhibitor (PDE5I), has long been used as a first-line oral treatment for erectile dysfunction. While it has beneficial effects on the erectile organ, it also has some negative effects on other cells and/or tissues related to the reproductive system when exposed for an extended period of time. The purpose of this study was to study the long term effect of Viagra on sperm parameters in male Wistar albino rats. Twenty (20) albino male Wistar rats were selected into four groups (n=5) randomly. The control group was administered 1 mL/kg of distilled water while 50 mg/kg, 100 mg/kg, and 200 mg/kg body weight of Sildenafil citrate were administered once in a day for 28 days to three treatment groups of rats. Oral administration was done using oropharyngeal cannula once daily for 28 days. At the end of the trial period animals were sacrificed on the 29th day, and epididymal sperm and testes were collected subject to various analytical assays. Findings showed significant reduction in sperm count and sperm normality, with a significant incremental in sperm malformations/abnormality in 28 days Viagra exposed animal when compared to the control. The testicular assay depicted histopathological alterations in testes of male rats treated with Sildenafil citrate at all dose levels. The current study clearly demonstrated that long-term use of Viagra caused changes in sperm quality and quantity, resulting in a decrease in fertility rate. It also suggested that Viagra had an effect on spermatogenesis and epididymal function. Understanding the molecular downstream events involved in long-term PDE5 inhibitor exposure can be useful for supervising infertility related issues and suggesting corrective measures.

Synergy Between Sildenafil and Topically Delivered Nitric-oxide in Eliciting an Erectile Response in a Rat Model of Radical Prostatectomy

ABSTRACT Introduction Sildenafil belongs to a group of phosphodiesterase-type-5-inhibitors (PDE5i) which represent the only class of FDA-approved oral treatments for erectile dysfunction (ED). However, because their mode of action is dependent on the production of nitric oxide (NO) from nerve endings, patients that undergo radical prostatectomy (RP), which results in cavernous nerve (CN) injury, are commonly refractory to these pharmacologic agents. Objective Our goal was to investigate the ability of topically applied microparticles capable of transdermal delivery of NO (NO-MP) to act synergistically with sildenafil in eliciting an erectile response in an animal model of RP. Methods As a model of RP, Sprague-Dawley rats underwent bi-lateral transection of the CN one-week prior to determining erectile response to treatment. Rats were treated by oral gavage of 0.05 and 0.005 mg sildenafil/kg, 30 minutes before being anesthetized for the determination of intracorporal pressure (ICP) and systemic blood pressure (BP). Baseline ICP and BP were recorded for 30 min, at which time 250 or 100 mg NO-MP (or control, blank-MP) were applied to the rat penile shaft. The ICP and systemic BP were used to determine the time to the first erectile response, duration of the erectile responses, the maximal and average ICP/BP responses and the number of spontaneous erections per hour. Results Although oral treatment with sildenafil by itself resulted in no observable erectile response, topical application of NO-MP in combination with sildenafil resulted in both a faster time to the first erectile response and greater numbers of spontaneous erections compared to NO-MP used alone. Combination of orally administered 0.05 sildenafil/kg with topical application of 250mg NO-MP, compared to 250 mg NO-MP by itself, resulted in significantly more spontaneous erections (4.6 compared to 2 erections per hour, t-test; p-value = 0.043), with a significantly faster onset for the first erectile response (11 compared to 22 minutes; t-test, p-value = 0.041). Conclusions Although knowledge of the molecular pathways that lead to an erection provide a rationale for a synergistic effect between PDE5i and NO in eliciting an erectile response, our results provide the first evidence of such synergy. When combined with the NO-MP, this synergy in eliciting an erectile response was seen with 0.05 mg sildenafil/kg, which would be equivalent to a clinical dose of approximately 2.5 mg sildenafil for an 80 kg patient. Our results suggest a novel treatment strategy for patients with ED following RP whereby an oral PDE5i is used in combination with therapeutics that topically deliver NO to corporal tissue and also the potential to lower the therapeutic dose of oral PDE5i in all patients where it is used for the treatment of ED. Disclosure Yes, this is sponsored by industry/sponsor: ZyloTherapeutics, Inc. Clarification Industry funding only - investigator initiated and executed study Any of the authors act as a consultant, employee or shareholder of an industry for: ZyloTherapeutics, Inc

Vardenafil Oral Dispersible Films (ODFs) with Advanced Dissolution, Palatability, and Bioavailability

Oral, quick response, and on demand, also known as a spontaneous oral treatment for erectile dysfunction, is highly needed by both patients and physicians. Vardenafil is selective (fewer side effects) and more effective in difficult-to-treat conditions than sildenafil. This study aims at fostering the dual objectives of using biomolecules such as artificial sweetening agents to solubilize and mask the bitterness of vardenafil loaded on biodegradable polymeric materials (PVA, MC, SA, and PVP K30) to fabricate oral, fast-dissolving films (vardenafil ODFs) in the mouth without the need for water to ingest the dosage form. Furthermore, coprecipitated-dispersed mixtures of vardenafil and three sweeteners (sorbitol, acesulfame K, and sucralose) were prepared and characterized using FTIR, DSC, and solubility studies. Moreover, eight different vardenafil ODFs were prepared using the solvent-casting method. Modified gustatory sensation test, in vitro disintegration, and release studies were performed. In addition, the optimized ODF (F8) was compared with the commercial film-coated tablets pharmacokinetically (relative bioavailability, onset, and duration of actions were estimated). The results indicated that the three sweetening agents had comparable solubilizing capacity. However, both sucralose- and acesulfame K-based ODFs have a more enhanced sweet and palatable taste than sorbitol-sweetened ODF. The SA- and PVP K30-based ODFs showed significantly faster disintegration times and release rates than MC. In conclusion, PVA has good film-forming properties, but a higher ratio of PVA adversely affected the disintegration and release characteristics. The % relative bioavailability for ODF was 126.5%, with a superior absorption rate constant (Ka) of 1.2-fold. The Cmax and estimated Tmax were compared to conventional film-coated tablets.

Hybrid NiO nanostructured/sulfanilamide polymeric film for studying possible pharmacokinetic interaction between avanafil and nimodipine in real human serum by their simultaneous determination using square-wave voltammetry

Avanafil (AVN) is a new selective phosphodiesterase-5 (PDE-5) inhibitor, which is used as an oral treatment of erectile dysfunction. Coadministration of avanafil (AVN) with some antihypertensive drugs especially in elderly patients is a very common case. Nimodipine (NIM) is one of these hypotensive drugs that are commonly coadministered. Synergistic hypotension effect as a result of AVN and NIM coadministration is expected; therefore, it is mandatory to study the possible pharmacokinetic interaction between them. The main aim of the current work is to develop a simple, sensitive, and selective electrochemical method for simultaneous determination of AVN and NIM in human serum samples. Nickel oxide nanoparticles/poly(sulfanilamide) film was used as a new electrochemical modifier, which is electrodeposited on the surface of pencil graphite electrode (PGE) to improve its electrochemical properties. The best resolution between the two studied drugs was achieved by using Britton-Robinson buffer (BRB) at pH 3.0 producing two peaks at 1.45 V and 0.80 V for AVN and NIM, respectively. Furthermore, cyclic voltammetry was utilized for the first time to study the oxidation behavior of AVN and NIM and a plausible oxidation mechanism was suggested for both of them. The proposed square wave voltammetric method was successfully applied for trace quantification of AVN and NIM in real human serum samples with detection and quantitation limits of 0.037 and 0.10 μmol L−1 for AVN and 0.32 and 0.98 μmol L−1 for NIM, respectively. Moreover, the suggested approach was effectively implemented to investigate the possible pharmacokinetic interaction between AVN and NIM in serum samples of heathy human male volunteers. It was found from the pharmacokinetic parameters calculated for AVN when administered alone or in presence of NIM that there is a significant increase of serum concentration of AVN, when it is coadminstered with NIM, which stresses the importance of dose adjustment of AVN when coadministered with NIM.

Mirabegron improves erectile function in men with overactive bladder and erectile dysfunction: a 12-week pilot study.

Phosphodiesterase type 5 inhibitors (PDE5i) is the only approved oral treatment for erectile dysfunction (ED) in the US, and alternative management remains necessary when this treatment fails or is contraindicated. Targeting other pathways than the NO-cGMP pathway and/or combining this approach with PDE5i may introduce new treatments for men who are unresponsive to PDE5i. This study aims to evaluate whether Mirabegron improves erectile function in men with concurrent overactive bladder and mild to moderate ED. Twenty subjects, 40-70 years old, registering International Index of Erectile Function (IIEF) score 11-25 and International Prostate Symptom Score 8-20, were treated with Mirabegron therapy for 12 weeks. Study participants were re-administered IIEF and OAB-q questionnaires on weeks 2, 4, 8, and 12 and assessed for adverse events. The primary and secondary endpoints were an increase in the IIEF-5 score of 4 units and a decrease in the Overactive Bladder questionnaire (OAB-q) symptom severity score of 10 units between study time points. Thirteen men completed the 12-week study. Mirabegron treatment improved the IIEF-5 scores in five patients (38.4%) by 4 points or more, whereas IIEF-5 scores were not affected by Mirabegron treatment in eight patients (61.5%). There were no clinically relevant decreases in the IIEF-5 score. Significant improvements were observed in intercourse satisfaction at week eight compared to baseline (p = 0.01). Orgasmic function and sexual desire were not affected by Mirabegron treatment. As expected, Mirabegron treatment reduced OAB symptoms based on OAB-q short form (p = 0.006) and OAB-q total health-related quality of life (HRQL) scores compared to baseline (p = 0.03). Residual bladder volumes were not affected by treatment. No serious side effects were reported during the study period. This study suggests that Mirabegron may improve both EF and OAB-related symptoms in some individuals without causing serious adverse events.

Development of an optimized avanafil-loaded invasomal transdermal film: Ex vivo skin permeation and in vivo evaluation.

Avanafil (AVA) is a recent FDA approved selective phosphodiesterase type 5 inhibitor used for oral treatment of erectile dysfunction. The oral bioavailability of the drug is challenged by its reduced water solubility, considerable presystemic metabolism, and altered absorption in the presence of food. Accordingly, this work aimed to surmount the aforementioned challenges through the development of optimized nanosized AVA invasomes with enhanced transdermal delivery. AVA invasomes were prepared according to a Box-Behnken experimental design to explore the impact of the following formulation factors: phospholipid % (X1), ethanol % (X2), terpene % (X3), and terpene type (X4) on vesicle size (Y1) and entrapment efficiency (Y2). The three numerical variables were used at three levels, while the categorical variable was used at two levels. The optimized formulation with vesicular size of 109.92 nm and entrapment efficiency of 96.98% was incorporated into a hydroxypropyl methyl cellulose-based transdermal film and characterized for its ex vivo permeation behavior and in vivo performance in rats. The optimized AVA invasomal film showed enhanced ex vivo permeation with an enhancement factor of 2.514 and a more than four-fold increase in relative bioavailability compared to the raw AVA film. These results provide insight into the capability of the optimized invasomal film to enhance the transdermal permeation and bioavailability of AVA.

Administration of sildenafil citrate not able to reduced hs-CRP on erectile dysfunction patient at Doctor Soetomo Hospital, Surabaya, Indonesia

Background: Phosphodiesterase type-5 (PDE5) inhibitors was the first choice for the oral treatment of erectile dysfunction because of its ability to prevent endothelial dysfunction and restored erectile function properly. However, the inflammatory parameter such as hs-CRP can be used to assess the performance of PDE5 inhibitors as well as clinical questionnaires, IIEF-5, and EHS. So that, this study aims to determine the effect of PDE5 inhibitors administration such as sildenafil citrate 50 mg per day can decrease the value of hs-CRP, as well as increased the IIEF-5 and EHS at Dr. Soetomo General Hospital.Methods: A true clinical experimental studies used pretest and posttest control group design were carried out among 20 patients during 4 weeks. In the next 2 weeks, the crossover was conducted among respondents for the washout period whereas divided into 2 groups, control (K1 and K2) and treatment (P1 and P2). Data were analyzed using Statistical Package for the Social Sciences (SPSS) version 16.0 software for Windows.Results: The average age of group K1 and P2 was 51 ± 12.07 years old whereas 48.60 ± 15.40 years old in group P1 and K2. The research was conducted in Andrology Clinic of Doctor Soetomo Hospital in Surabaya during June to November 2017. The research data were not normally distributed, then analyzed by two-tail T-group tests and Wilcoxon test at significance level α=0.05. The results showed that PDE5 inhibitors did not decrease the hs-CRP significantly (p>0.05), but increased EHS (p<0.05) and increased IIEF-5 (p<0.05) significantly.Conclusion: This study concluded that the administration of sildenafil citrate per day by oral increased the EHS and IIEF-5, but not able to reduced hs-CRP in patients with erectile dysfunction significantly.

L-Cys/CSE/H2S pathway modulates mouse uterus motility and sildenafil effect

Sildenafil, a selective phosphodiesterase type 5 (PDE5) inhibitor, commonly used in the oral treatment for erectile dysfunction, relaxes smooth muscle of human bladder through the activation of hydrogen sulfide (H2S) signaling. H2S is an endogenous gaseous transmitter with myorelaxant properties predominantly formed from l-cysteine (l-Cys) by cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE). Sildenafil also relaxes rat and human myometrium during preterm labor but the underlying mechanism is still unclear. In the present study we investigated the possible involvement of H2S as a mediator of sildenafil-induced effect in uterine mouse contractility. We firstly demonstrated that both enzymes, CBS and CSE were expressed, and able to convert l-Cys into H2S in mouse uterus. Thereafter, sildenafil significantly increased H2S production in mouse uterus and this effect was abrogated by CBS or CSE inhibition. In parallel, l-Cys, sodium hydrogen sulfide or sildenafil but not d-Cys reduced spontaneous uterus contractility in a functional study. The blockage of CBS and CSE reduced this latter effect even if a major role for CSE than CBS was observed. This data was strongly confirmed by using CSE⿿/⿿ mice. Indeed, the increase in H2S production mediated by l-Cys or by sildenafil was not found in CSE⿿/⿿ mice. Besides, the effect of H2S or sildenafil on spontaneous contractility was reduced in CSE⿿/⿿ mice. A decisive proof for the involvement of H2S signaling in sildenafil effect in mice uterus was given by the measurement of cGMP. Sildenafil increased cGMP level that was significantly reduced by CSE inhibition. In conclusion, l-Cys/CSE/H2S signaling modulates the mouse uterus motility and the sildenafil effect. Therefore the study may open different therapeutical approaches for the management of the uterus abnormal contractility disorders.

Optimized nano-transfersomal films for enhanced sildenafil citrate transdermal delivery: ex vivo and in vivo evaluation.

Sildenafil citrate (SLD) is a selective cyclic guanosine monophosphate-specific phosphodiesterase type 5 inhibitor used for the oral treatment of erectile dysfunction and, more recently, for other indications, including pulmonary hypertension. The challenges facing the oral administration of the drug include poor bioavailability and short duration of action that requires frequent administration. Thus, the objective of this work is to formulate optimized SLD nano-transfersomal transdermal films with enhanced and controlled permeation aiming at surmounting the previously mentioned challenges and hence improving the drug bioavailability. SLD nano-transfersomes were prepared using modified lipid hydration technique. Central composite design was applied for the optimization of SLD nano-transfersomes with minimized vesicular size. The independent variables studied were drug-to-phospholipid molar ratio, surfactant hydrophilic lipophilic balance, and hydration medium pH. The optimized SLD nano-transfersomes were developed and evaluated for vesicular size and morphology and then incorporated into hydroxypropyl methyl cellulose transdermal films. The optimized transfersomes were unilamellar and spherical in shape with vesicular size of 130 nm. The optimized SLD nano-transfersomal films exhibited enhanced ex vivo permeation parameters with controlled profile compared to SLD control films. Furthermore, enhanced bioavailability and extended absorption were demonstrated by SLD nano-transfersomal films as reflected by their significantly higher maximum plasma concentration (Cmax) and area under the curve and longer time to maxi mum plasma concentration (Tmax) compared to control films. These results highlighted the potentiality of optimized SLD nano-transfersomal films to enhance the transdermal permeation and the bioavailability of the drug with the possible consequence of reducing the dose and administration frequency.

AB005. The role of serendipity in sexual medicine

The word “serendipity” is considered very difficult to define; it may be considered “A talent for making fortunate discoveries while searching for other things”. The history of sexual medicine teaches us the importance of serendipity along with research. Serendipity in the year 1988 was initiated by a slow elevator. Dr. Jacob Rajfer, Professor of Urology, had attended a meeting on the 2nd floor of the Univ. California LA and was waiting for an elevator to take him to his office on the 6th floor. The elevator was very slow to arrive, so Dr. Rajfer began looking around. There was a sign on a door across from the elevator that read: “Vascular smooth muscle lab”. Dr. Rajfer knew that an unknown substance, Endothelium-derived Relaxing Factor (EDRF) dilated blood vessels by relaxing smooth muscles. A penile erection resulted from vasodilation and the penis was full of vascular smooth muscle. The head of the vascular smooth muscle lab was Dr. Louis Ignarro who had just published that EDRF might be Nitric Oxide (NO). Drs. Rajfer and Ignarro began collaborating, and in 1990 published that ‘NO’ mediates erections: a discovery started by a slow elevator and leading to Dr. Ignarro receiving a Nobel Prize in 1998 and Pfizer scientists developing Viagra! Viagra, which was able to dilate smooth muscle, was being developed by Pfizer researchers to treat angina when increased nocturnal and spontaneous erections were noted. The FDA approved Viagra as the first oral treatment for erectile dysfunction in 1998. Serendipity, research and Viagra impacted how we look at aging and intimacy. The language of sexual medicine changed as well: the old term, ‘impotence’ (lacking in power) was changed to ‘erectile dysfunction’ or ED. Serendipity has played a role in the discovery of more than 24% of all drugs on the market. We would all do well to heed the wise words of Louis Pasteur: “Chance Favors the Prepared Mind”.

Management of benign prostatic hyperplasia: role of phosphodiesterase-5 inhibitors.

Several studies have highlighted a strong association between benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS) and erectile dysfunction (ED), particularly in elderly men. Many epidemiological trials, such as in vitro and in vivo studies, have reported the emerging role of metabolic syndrome, including abdominal obesity, impaired glucose metabolism, hypertriglyceridemia, low high-density lipoprotein cholesterol, and hypertension, in the development and progression of urinary and sexual symptoms. Moreover, many authors have focused their studies on the identification of all the shared pathogenetic mechanisms of LUTS/BPH and ED, including alteration of cyclic guanosine monophosphate and RhoA-ROCK pathways or vascular and neurogenic dysfunction. All these are potential targets for proposed phosphodiesterase type 5 inhibitors (PDE5-Is). Therefore, several trials have recently been designed to evaluate the role of PDE5-Is alone or in combination with conventional treatment for BPH, such as α-adrenergic blockers, in men affected by LUTS/BPH, with or without ED. Different PDE5-Is are in clinical use worldwide and currently six of them are licensed for the oral treatment of ED. All these compounds differ in pharmacokinetic factors, with influence on drug action, and subsequently in the overall safety and efficacy profile.

Impact of a First Treatment with Phosphodiesterase Inhibitors on Men and Partners’ Quality of Sexual Life: Results of a Prospective Study in Primary Care

Phosphodiesterase type 5 inhibitors (PDE5is) as oral treatment for erectile dysfunction (ED) facilitate the management of ED in primary care. Still, compliance is low and general practitioners (GPs) do not always feel confident with this pathology. AIM.: The aim of this paper is to evaluate the impact of a first treatment with PDE5i on the patient and his partner and the management of ED by GPs. The Evaluation après traitement de la dyfonction erectile, du bien-êtré émotionnel d'un patient en fonction de la rigidité de son érection survey was a longitudinal, observational French study with prospective collection of data from the GP, the patient, and his partner at baseline and after 3 months of treatment. GPs benefited from a short educational session before starting the survey. The main outcome measures are the Erection Hardness Score (EHS), Self-Esteem and Relationship (SEAR) questionnaire, Index of Sexual Life (ISL), and Erectile Dysfunction Inventory of Treatment Satisfaction. A total of 478 men aged 19-80 years (mean 57 years) were included in the survey by 229 GPs. Before treatment, EHS was mostly grade 1 (28%) or 2 (44%). At the end of the survey, an improvement was reported for 88% of the patients and 58% achieved maximum score EHS 4 (penis completely hard and fully rigid). Mean SEAR scores significantly increased after 3 months for self-esteem, overall and sexual relationship, and more notably with greater improvement in EHS (P < 0.001). Improvement in partners' ISL scores was significantly higher with greater improvement in EHS (P < 0.001) and in SEAR score for self-esteem. The safety profile of PDE5i was good with few adverse events, mostly headaches. More than 80% of the participating GPs considered that the survey had changed their management of ED. After 3 months of treatment with PDE5i, a significant improvement in self-esteem was observed in patients with ED, associated with improvement in erection.

Challenges in Translating Academic Research into Therapeutic Advancement

Challenges in Translating Academic Research into Therapeutic Advancement

810 SILODOSIN (KMD-3213) IS A LONG-ACTING α-1A ADRENOCEPTOR ANTAGONIST WITH ACTIVITY IN THE HUMAN CORPUS CAVERNOSUM

INTRODUCTION AND OBJECTIVES: Silodosin (KMD-3213, RapafloTM, Watson Pharmaceuticals, Inc. USA) is a new and highly selective 1A-adrenoreceptor (AR) antagonist for the treatment of lower urinary tract symptoms (LUTS) in men with BPH, a condition associated with erectile dysfunction (ED). Silodosin treats both irritative and obstructive symptoms. Silodosin induced responses on the human corpus cavernosum (HCC) needs further clarification. METHODS: HCC samples were obtained from patients (patient age: 50 66 yr) undergoing penile prosthesis surgery. Using the organ bath technique, drug effects were investigated with phenylephrine (PE, 10 M)-induced tension and electrically induced (0-40 Hz, 3 ms, 10 seconds, 60V) relaxation as well as on the acetylcholine (10 nM1000 nM) and sodium nitroprusside (SNP, 1 nM) induced relaxations of HCC strips (n 12). Direct EFS and KCl (100 mM) induced contractile responses were also generated in the presence of silodosin (0.01 M). RESULTS: Silodosin (0.01 M to 100 mM) induced relaxation (84.68 13.8 % and 37.62 10%) on PE and KCl precontracted strips. EFS-induced relaxant nitrergic responses (43.66 4.44% and 57.05 6.80%, p 0.1178) and contractile adrenergic (11.03 5.98%) neurogenic responses were not significantly affected by incubation with silodosin. ACh (40.01 1.41%, at 100 mM) and SNP (37.46 7.98, at 1 nM) induced relaxations were significantly enhanced (84.68 13.8%, 85.47 3.30%, p 0.0001, respectively) by silodosin. CONCLUSIONS: Inhibition of 1A-AR induces marked penile smooth muscle relaxation. The enhanced relaxation responses to ACh and SNP indicates the involvement of nitric oxide-cGMP pathways. However, silodosin does not target afferent nitrergic and adrenergic nerves in the HCC, and thereby does not act on the neurogenic erectile responses. Our results provide a rationale for the future use of silodosin as an oral treatment for ED. If approved for the human CC, silodosin may contribute to improved erectile function in patients treated for BPH-linked LUTS. Further clinical investigations of silodosin are necessary to evaluate the beneficial effect in ED patients who are not responding sufficiently to PDE5 inhibitors. It is still unknown whether the combination of silodosin and PDE-5 inhibitors is more effective than either mono-treatment.

Analyzing the efficacy of a new natural compound made of the alga Ecklonia bicyclis, Tribulus terrestris and BIOVIS ® in order to improve male sexual function

Background We investigated the therapeutic efficacy of a new composite natural drug based on Tribulus terrestris, BIOVIS ® and the alga Ecklonia bicyclis in order to improve male sexual function, selecting patients using the International Index of Erectile Function (IIEF), Nocturnal Penile Tumescence and Rigidity Testing (NPTR) using the RigiScan ® device and hormonal levels. Materials and methods A total of 164 patients with erectile dysfunction (ED) were enrolled between September 2009 and January 2010. Patients were classified as having mild ( n = 64), moderate ( n = 62) or severe (I = 38) ED. Mean age was 53.1 years. A new compound (150 mg of the alga Ecklonia bicyclis, 396 mg of Tribulus terrestris and 144 mg of BIOVIS ®) was administered to all patients twice a day for 60 days. The IIEF questionnaire was administered and NPTR testing was carried out using the Rigiscan ® device both pre and post-treatment with all patients. Results 150 patients were evaluable, and their IIEF scores were all significantly improved, with an increase of 78% in the mild ED group, an 80% improvement in the moderate ED group, and an improvement of 108% in the severe ED group compared with the baseline. The mean IIEF scores for all the patients showed significant improvement after 8 weeks of treatment with this new composite drug (baseline 14.3 ± 1.5 to 26.2 ± 3.2; P = 0.01). Among other parameters penile rigidity and tumescence, as tested using the RigiScan ® showed significant improvement for treated patients. Furthermore, no significant side effects were claimed. Conclusion The active components of these three natural compounds (namely protodioscin, a steroidal saponin, contained in Tribulus terrestris; the polyphenols, dieckol, florofucofuroeckol and bieckol, contained in the alga Ecklonia bicyclis; and the polymers of d-glucosamine and n-acetyl- d-glucosamine contained in BIOVIS ®) when combined, seem to work in synergy not only improving erectile function but also stimulating testosterone-dependent sexual desire. Protodioscin is able to stimulate testosterone production and it also has an androgen-mimetic action, binding and activating the testosterone receptors. Polyphenols play an anti-nflammatory role, modulating the cytokines (lipopolisaccarids, TNF-alpha, IFN-gamma) with a potent antioxidant and antifibrotic effect. BIOVIS ® acts on both the non-adrenergic and non-cholinergic system (NANC) and on the endothelial cell system as a strong nitric oxide synthetase (NOS) stimulator. Our study demonstrated that this new composite drug was effective in the oral treatment of ED.

The Management of Erectile Dysfunction with Placebo Only: Does it Work?

Randomized clinical trials (RCT) remain the gold standard in providing scientific evidence in medical practice in spite of the significant placebo effect in the treatment of several disorders. Although the first-line therapy for erectile dysfunction (ED) is oral phosphodiesterase type-5 inhibitor (iPDE5), the placebo effect in RCT of iPDE5 for ED occurs at a rate as high as 50%. To evaluate the role of therapeutic illusion in the oral treatment for ED. A prospective, controlled, single-blind, parallel-group study was performed at single-center. One hundred and twenty-three patients with ED were randomly assigned into three groups and received different letters: Group 1 (G1) was informed to be receiving a substance for ED treatment; Group 2 (G2) was informed that they could be receiving an active drug or placebo; Group 3 (G3) was conscious to be using placebo. Starch capsules were dispensed to all patients. Median follow up was 12 weeks. ED improvement was assessed after 8 weeks of the intervention by the erectile function domain of the International Index of Erectile Function (IIEF) and the Quality of Erection Questionnaire. ED severity was classified by the IIEF erectile function (IIEF-EF) domain score into five categories: no ED (score of 26-30), mild (22-25), mild to moderate (17-21), moderate (11-16), and severe (6-10). Improvement in IIEF-EF domain was considered as a change in category of severity. ED severity improved in all three groups (G1 = 31.7%, P = 0.039; G2 = 36.8%, P = 0.028; G3 = 36.8%, P = 0.002) and no difference was found among groups (P = 0.857). Improvement of quality of erection score was only significant in G2 (P = 0.005) and G3 (P < 0.001). Written-suggested therapeutic illusion for patients with ED has no major influence in the outcomes. However, treatment of ED with oral placebo capsules demonstrates clinical effects, improving erectile function and quality of erection.

Phosphodiesterase inhibitors and the eye

Phosphodiesterase type 5 (PDE5) inhibitors are effective oral treatments for erectile dysfunction and have become one of the most widely prescribed medications worldwide. The mechanism of action is to reduce the degradation of cyclic GMP (cGMP) potentiating the effect of nitric oxide in the corpus cavernosum and allowing erectile function to occur by consequent relaxation of penile smooth muscle. Because of the presence of PDE5 in choroidal and retinal vessels these medications increase choroidal blood flow and cause vasodilation of the retinal vasculature. The most common symptoms are a blue tinge to vision and an increased sensitivity to light. There have been reports of non-arteritic anterior ischaemic optic neuropathy and serous macular detachment in users of PDE5 inhibitors, although a causal relationship has not been conclusively shown. Despite the role of cGMP in the production and drainage of aqueous humour these medications do not appear to alter intraocular pressure and are safe in patients with glaucoma. All PDE5 inhibitors weakly inhibit PDE6 located in rod and cone photoreceptors resulting in mild and transient visual symptoms that correlate with plasma concentrations. Psychophysical tests reveal no effect on visual acuity, visual fields or contrast sensitivity; however, some studies show a mild and reversible impairment of blue-green colour discrimination. PDE5 inhibitors transiently alter retinal function on electroretinogram testing but do not appear to be retinotoxic. Despite the role of cyclic nucleotides in tear production there is no detrimental effect on tear film quality. Based on the available evidence PDE5 inhibitors have a good ocular safety profile.

EFFICACY AND SAFETY OF ORAL MIRODENAFIL IN THE TREATMENT OF ERECTILE DYSFUNCTION IN MEN WITH DIABETES : A MULTI-CENTER, RANDOMIZED, DOUBLE BLIND, PLACEBO-CONTROLLED, FIXED DOSE, PARALLEL GROUP CLINICAL TRIAL

INTRODUCTION AND OBJECTIVES: Despite the placebo effect has been reported in several disorders, randomized clinical trials (RCT) remain the gold standard to provide scientific evidence in medical practice. Although the first-line therapy for erectile dysfunction (ED) is oral phosphodiesterase type-5 inhibitor (iPDE5), the placebo effect in RCT of iPDE5 for ED occurred at a rate as high as 50%. We aimed to evaluate the patients’ therapeutic illusion in the oral treatment for ED. METHODS: A prospective, controlled, single-blind, parallel-group study was performed at single-center in Brazil. One-hundred and twentythree patients with ED were randomly assigned into 3 groups according to a letter with different written information: Group 1 was informed to be receiving a substance for ED treatment; Group 2 that could be receiving an active drug or placebo; Group 3 was conscious to be using placebo. Investigators were blinded to informative letters and white starch capsules for on-demand use were dispensed to all patients. The main outcome at 8 weeks was improvement of ED, which was assessed by the International Index of Erectile Function (IIEF) erection function domain and the Quality of Erection Questionnaire (QEQ). Analyses were done by intention to treat. RESULTS: Erectile function domain score significantly improved in all three groups (G1= 38.2%, p=0.039; G2= 43.7%, p=0.028; G3= 42.4%, p<0.002) and no statistically difference was found among groups (p=0.68). While quality of erection score improved in all groups, it was statistically significant in G2 (p=0.005) and G3 (p<0.001). Although intercourse satisfaction domain improved in all groups (G1 p= 0.002; G2 p< 0.001; G3 p< 0.001), the orgasmic function domain showed no significant changes (G1 p= 0.540; G2 p= 0.523; G3 p= 0.550). CONCLUSIONS: Written-suggested therapeutic illusion for patients with ED has no major influence in the outcomes. However, treatment of ED with oral placebo capsules demonstrates clinical effects, improving erectile function and intercourse satisfaction.