Erectile Dysfunction Drug Use, Risk Behavior, and Sexually Transmitted Diseases

Thesis (Master's)--University of Washington, 2016-06

Comparison of clinical trials with sildenafil, vardenafil and tadalafil in erectile dysfunction

Erectile dysfunction (ED) affects up to 50% of men, between 40 and 70 years of age. In the first major trial of sildenafil in ED, at 24 weeks, improved erections were reported by 77 and 84% of men taking sildenafil 50 and 100 mg, respectively. Subsequently, sildenafil has been reported to be effective in men with ED associated with diabetes and prostate cancer, and in psychogenic ED. Sildenafil is safe in men with coronary artery disease, provided it is not used with the nitrates (a contraindication). The most commonly reported adverse effects with sildenafil are headache, flushing and dyspepsia. Vardenafil is more potent and more selective than sildenafil at inhibiting phosphodiesterase-5. Vardenafil is similarly effective to sildenafil in the treatment of ED. The only advantage that vardenafil has over sildenafil is that it does not inhibit phosphodiesterase-6 to alter colour perception, a rare side effect which sometimes occurs with sildenafil. Tadalafil has a longer duration of action than sildenafil and vardenafil. Tadalafil is similarly effective as sildenafil in the treatment of ED. In comparison studies, tadalafil is preferred to sildenafil (50/100 mg) by men with ED, possibly because of its longer duration of action. of the phosphodiesterase inhibitors, tadalafil may displace sildenafil as the drug of choice among men with ED.

Erectile dysfunction: prevalence, risk factors and involvement of antihypertensive drugs intervention

Purpose: To explore the literature regarding prevalance, risk factors and the involvement of antihypertensive drugs in erectile dysfunction (ED). Methods: Original research articles, reviews, editorials and case reports published in English language on the prevalence of sexual/erectile dysfunction in hypertensive men taking antihypertensive drugs and risk factors were identified through a search of four bibliographic databases, namely, PubMed, EMBASE, CINAHL and EBSCO Health. Results: Recent analyses suggest that hypertensive men of almost all age groups suffer from ED but it is more prevalent in elderly male patients. The involvement of β-blockers was found to be controversial. Nevertheless, some evidence had been found regarding the use of propranolol in high doses. Conclusion: The present review indicates the need for research to unravel the role of β-blockers in the manifestation of ED in hypertensive males, whom there are no contributory factors such as sedentary lifestyle, aging, stress and anxiety, etc.

How the prevalence rates of male sexual dysfunction vary using different criteria

Objectives: This study examined the prevalence of male sexual dysfunction (MSD) and how different criteria alter prevalence rates. Methods: Five hundred seventy-three Australian men completed an online survey. Results: Of these men, 42.2% were sexually functional and 57.8% reported 1 or more sexual dysfunctions. No matter which criteria were used, the most prevalent MSD was erectile dysfunction, followed by premature ejaculation, hypoactive sexual desire disorder, and delayed ejaculation. Frequencies varied according to different definitions and measures used to diagnose MSD. More than half of the men with MSD experienced only 1 sexual dysfunction. Conclusions: These results demonstrate the high prevalence of MSD and the relatively low level of comorbidity of MSDs. © 2014 Taylor & Francis Group, LLC.

Early postoperative pelvic-floor biofeedback improves erectile function in men undergoing radical prostatectomy: a prospective, randomized, controlled trial

Erectile dysfunction (ED) and urinary incontinence are common complications following radical prostatectomy (RP). Although pelvic-floor biofeedback training (PFBT) may improve urinary continence following RP, its effects on the recovery of potency are unknown. Fifty-two patients selected for RP were prospectively randomized for a treatment group (n=26) receiving PFBT once a week for 3 months and home exercises or a control group (n=26), in which patients received verbal instructions to contract the pelvic floor. Erectile function (EF) was evaluated with the International Index of Erectile Function-5 (IIEF-5) before surgery and 1, 3, 6 and 12 months postoperatively. Patients were considered potent when they had a total IIEF-5 score >20. Continence status was assessed and defined as the use of no pads. Groups were comparable in terms of age, body mass index, diabetes, pathological tumor stage and neurovascular bundle preservation. A significant reduction in IIEF-5 scores was observed after surgery in both groups. In the treatment group, 8 (47.1%) patients recovered potency 12 months postoperatively, as opposed to 2 (12.5%) in the control group (P=0.032). The absolute risk reduction was 34.6% (95% confidence interval (CI): 3.8-64%) and the number needed to treat was 3 (95% CI: 1.5-17.2). A strong association between recovery of potency and urinary continence was observed, with continent patients having a 5.4 higher chance of being potent (P=0.04). Early PFBT appears to have a significant impact on the recovery of EF after RP. Urinary continence status was a good indicator of EF recovery, with continent patients having a higher chance of being potent.

Sexual dysfunction in multiple sclerosis

Multiple sclerosis is a chronic disease that commonly affects young adults who may be sexually active. Sexual dysfunction is a significant, but often underestimated, symptom of multiple sclerosis, affecting 50-90% of men and 40-80% of women. The types of sexual dysfunction can be categorized in terms of the normal sexual response cycle: sexual interest/desire dysfunction (reduced libido), sexual arousal dysfunction (including erectile dysfunction) and ejaculatory and orgasmic dysfunction. Sexual dysfunction may not only be due to lesions affecting the neural pathways involved in physiological function (primary dysfunction), but also result from general physical disabilities (secondary dysfunction) or psychological and emotional issues (tertiary dysfunction). Comprehensive management should address all these possible contributing problems. Specific pharmacotherapy is only currently available for erectile dysfunction. This review summarizes the available information about sexual dysfunction in men and women with multiple sclerosis.

Excess adenosine in murine penile erectile tissues contributes to priapism via A2B adenosine receptor signaling.

Priapism, abnormally prolonged penile erection in the absence of sexual excitation, is associated with ischemia-mediated erectile tissue damage and subsequent erectile dysfunction. It is common among males with sickle cell disease (SCD), and SCD transgenic mice are an accepted model of the disorder. Current strategies to manage priapism suffer from a poor fundamental understanding of the molecular mechanisms underlying the disorder. Here we report that mice lacking adenosine deaminase (ADA), an enzyme necessary for the breakdown of adenosine, displayed unexpected priapic activity. ADA enzyme therapy successfully corrected the priapic activity both in vivo and in vitro, suggesting that it was dependent on elevated adenosine levels. Further genetic and pharmacologic evidence demonstrated that A2B adenosine receptor-mediated (A2BR-mediated) cAMP and cGMP induction was required for elevated adenosine-induced prolonged penile erection. Finally, priapic activity in SCD transgenic mice was also caused by elevated adenosine levels and A2BR activation. Thus, we have shown that excessive adenosine accumulation in the penis contributes to priapism through increased A2BR signaling in both Ada -/- and SCD transgenic mice. These findings provide insight regarding the molecular basis of priapism and suggest that strategies to either reduce adenosine or block A2BR activation may prove beneficial in the treatment of this disorder.

Role of adenosine signaling in penile erection and erectile disorders.

INTRODUCTION: Penile erection is a hemodynamic process, which results from increased flow and retention of blood in the penile organ due to the relaxation of smooth muscle cells. Adenosine, a physiological vasorelaxant, has been shown to be a modulator of penile erection. AIM: To summarize the research on the role of adenosine signaling in normal penile erection and erectile disorders. MAIN OUTCOME MEASURES: Evidence in the literature on the association between adenosine signaling and normal and abnormal penile erection, i.e., erectile dysfunction (ED) and priapism. METHODS: The article reviews the literature on the role of endogenous and exogenous adenosine in normal penile erection, as well as in erectile disorders namely, ED and priapism. RESULTS: Adenosine has been shown to relax corpus cavernosum from various species including human in both in vivo and in vitro studies. Neuromodulatory role of adenosine in corpus cavernosum has also been demonstrated. Impaired adenosine signaling through A(2B) receptor causes partial resistance of corpus cavernosum, from men with organic ED, to adenosine-mediated relaxation. Increased level of adenosine has been shown to be a causative factor for priapism. CONCLUSION: Overall, the research reviewed here suggests a general role of exogenous and endogenous adenosine signaling in normal penile erection. From this perspective, it is not surprising that impaired adenosine signaling is associated with ED, and excessive adenosine signaling is associated with priapism. Adenosine signaling represents a potentially important diagnostic and therapeutic target for the treatment of ED and priapism.

Drugs and local chemical mediators

10.1 Histamine and cytokines 10.1.1 Actions of histamine 10.1.2 Drugs that modify the actions of histamine 10.1.3 Cytokines 10.2 Eicosanoids 10.2.1 Cyclooxygenase (COX) and lipooxygenase system 10.2.2 Actions of eicosanoids 10.2.3 Drugs that modify the actions of eicosanoids 10.2.3.1 Inhibit phospholipase A2 10.2.3.2 Non-selective cyclooxygenase inhibitors 10.2.3.3 Selective COX-2 inhibitors 10.2.3.4 Agonists at prostaglandin receptors 10.2.3.5 Leukotriene receptor antagonists 10.3. 5-Hydroxtryptamine (serotonin), nitric oxide, and endothelin 10.3.1 5-HT and migraine 10.3.2 5-HT and the gastrointestinal tract 10.3.3 Nitric oxide and angina 10.3.4 Nitric oxide and erectile dysfunction 10.3.5 Endothelin and pulmonary hypertension

Male reproductive health disorders among Aboriginal and Torres Strait Islander men : a hidden problem?

OBJECTIVE: To better understand help-seeking behaviours and reproductive health disorders among Aboriginal and Torres Strait Islander men. DESIGN, SETTING AND PARTICIPANTS: A cross-sectional mixed-methods study conducted from 1 May 2004 to 30 April 2005 of 293 Aboriginal and Torres Strait Islander men aged 18 years and over from urban, rural and remote communities in the Northern Territory and Queensland. MAIN OUTCOME MEASURES: Subscale of the International Index of Erectile Function, self-reported help-seeking behaviours for erectile dysfunction (ED) and prostate disease, thematic analysis of semi-structured interviews and focus groups. RESULTS: The prevalence of moderate-to-severe ED increased across age groups, from about 10% in younger men (under 35 years) to 28% in men aged 55-74 years. Moderate-to-severe ED was strongly associated with reporting a chronic condition (odds ratio [OR], 3.67) and residing in a remote area (OR, 2.94). Aboriginal and Torres Strait Islander men aged 40-59 years showed similar low levels of help-seeking behaviours compared with non-Indigenous men from a comparable population-based study. About half of the men with ED saw a doctor or received treatment for ED in each population. While prostate cancer rates were low in both studies, testing for prostate problems was less frequent in Aboriginal and Torres Strait Islander men (11.4%) than in non-Indigenous men (34.1%, P < 0.001), despite similar levels of concern about prostate cancer. Barriers to help-seeking included shame, culturally inappropriate services and lack of awareness. CONCLUSION: This study, the first to investigate reproductive health of Aboriginal and Torres Strait Islander men, found low levels of help-seeking behaviours for reproductive health disorders, with implications for missing a predictor of chronic disease and late diagnosis of prostate disease.

Distinct Allostery Induced in the Cyclic GMP-binding, Cyclic GMP-specific Phosphodiesterase (PDE5) by Cyclic GMP, Sildenafil, and Metal Ions

The activity of many proteins orchestrating different biological processes is regulated by allostery, where ligand binding at one site alters the function of another site. Allosteric changes can be brought about by either a change in the dynamics of a protein, or alteration in its mean structure. We have investigated the mechanisms of allostery induced by chemically distinct ligands in the cGMP-binding, cGMP-specific phosphodiesterase, PDE5. PDE5 is the target for catalytic site inhibitors, such as sildenafil, that are used for the treatment of erectile dysfunction and pulmonary hypertension. PDE5 is a multidomain protein and contains two N-terminal cGMP-specific phosphodiesterase, bacterial adenylyl cyclase, FhLA transcriptional regulator (GAF) domains, and a C-terminal catalytic domain. Cyclic GMP binding to the GAFa domain and sildenafil binding to the catalytic domain result in conformational changes, which to date have been studied either with individual domains or with purified enzyme. Employing intramolecular bioluminescence resonance energy transfer, which can monitor conformational changes both in vitro and in intact cells, we show that binding of cGMP and sildenafil to PDE5 results in distinct conformations of the protein. Metal ions bound to the catalytic site also allosterically modulated cGMP- and sildenafil-induced conformational changes. The sildenafil-induced conformational change was temperature-sensitive, whereas cGMP-induced conformational change was independent of temperature. This indicates that different allosteric ligands can regulate the conformation of a multidomain protein by distinct mechanisms. Importantly, this novel PDE5 sensor has general physiological and clinical relevance because it allows the identification of regulators that can modulate PDE5 conformation in vivo.

Salt and cocrystals of sildenafil with dicarboxylic acids: solubility and pharmacokinetic advantage of the glutarate salt

Sildenafil is a drug used to treat erectile dysfunction and pulmonary arterial hypertension. Because of poor aqueous solubility of the drug, the citrate salt, with improved solubility and pharmacokinetics, has been marketed. However, the citrate salt requires an hour to reach its peak plasma concentration. Thus, to improve solubility and bioavailability characteristics, cocrystals and salts of the drug have been prepared by treating aliphatic dicarboxylic acids with sildenafil; the N-methylated piperazine of the drug molecule interacts with the carboxyl group of the acid to form a heterosynthon. Salts are formed with oxalic and fumaric acid; salt monoanions are formed with succinic and glutaric acid. Sildenafil forms cocrystals with longer chain dicarboxylic acids such as adipic, pimelic, suberic, and sebacic acids. Auxiliary stabilization via C-H center dot center dot center dot O interactions is also present in these cocrystals and salts. Solubility experiments of sildenafil cocrystal/salts were carried out in 0.1N HCl aqueous medium and compared with the solubility of the citrate salt. The glutarate salt and pimelic acid cocrystal dissolve faster than the citrate salt in a two hour dissolution experiment. The glutarate salt exhibits improved solubility (3.2-fold) compared to the citrate salt in water. Solubilities of the binary salts follow an inverse correlation with their melting points, while the solubilities of the cocrystals follow solubilities of the coformer. Pharmacokinetic studies on rats showed that the glutarate salt exhibits doubled plasma AUC values in a single dose within an hour compared to the citrate salt. The high solubility of glutaric acid, in part originating from the strained conformation of the molecule and its high permeability, may be the reason for higher plasma levels of the drug.

As disfunções sexuais femininas no periódico Archives of Sexual Behavior.

Após o sucesso de vendas do Viagra, medicamento indicado para o tratamento da disfunção erétil, lançado em 1998, houve uma rápida proliferação de artigos, livros e encontros sobre as disfunções sexuais femininas. Desde 2000, um intenso debate sobre o envolvimento da indústria farmacêutica na produção biomédica sobre as disfunções sexuais femininas e a concomitante busca por um medicamento similar ao Viagra destinado às mulheres tem envolvido profissionais de diferentes disciplinas. Esta dissertação teve como objetivo investigar os discursos científicos sobre as disfunções sexuais femininas, através do exame dos artigos publicados no periódico Archives of Sexual Behavior, desde sua fundação, em 1971, até 2007. O periódico foi escolhido por sua legitimidade neste campo de saberes, por abranger um amplo período (36 anos) e seu caráter multidisciplinar. Pretendeu-se investigar quando, como e por quais grupos profissionais as disfunções sexuais femininas foram descritas e abordadas no periódico. No caso das chamadas disfunções sexuais, as descrições científicas, que vêm aumentando significativamente nos últimos anos, dão origem a prescrições de terapias, medicamentos, intervenções cirúrgicas, programas de educação sexual e políticas públicas. Ou seja, subjacente a esse discurso, que afirma ser empírico e imparcial, estão processos que se encontram muito além dos limites de um laboratório ou das atividades de um pesquisador. Buscou-se, assim, pensar a produção científica como produto de articulações e negociações que se desenrolam em esferas diversas, envolvendo processos culturais, sociais, econômicos e também cognitivos ou científicos, em contraposição às concepções que caracterizam a ciência como um projeto que apenas revela verdades. Para tanto, foi apresentado o contexto do surgimento de uma ciência da sexualidade, no decorrer do século XIX e, em seguida, o contexto no qual emergiram os discursos sobre as disfunções sexuais femininas, o que propiciou sua emergência naquele dado momento, o modo como foram definidas e por quem, como se articularam a processos sociais, econômicos e culturais e que transformações sofreram ao longo dos anos.

Correlação da resposta clínica à vardenafila em dois regimes terapêuticos com parâmetros vasculares e escore de risco cardiovascular em hipertensos com disfunção erétil vasculogênica

A disfunção erétil (DE) tem alta prevalência entre hipertensos e tem sido considerada marcador precoce de risco cardiovascular. A presença e gravidade da DE bem como a resposta clínica aos inibidores da fosfodiesterase tipo 5 (PDE5) parecem depender da biodisponibilidade do óxido nítrico (NO) endotelial e da extensão da doença aterosclerótica. O objetivo deste estudo foi avaliar a resposta clínica da vardenafila usada em dois regimes terapêuticos em hipertensos com DE vasculogênica e sem doença cardiovascular maior, correlacionando a gravidade da DE e a eficácia da vardenafila com dados antropométricos, laboratoriais, escore de risco cardiovascular e parâmetros vasculares funcionais e estruturais. A resposta clínica à vardenafila nos dois regimes foi avaliada conforme o percentual de respostas positivas à questão 3 do Perfil do Encontro Sexual (PES3). Os parâmetros vasculares considerados foram a espessura médio-intimal (EMI) da carótida comum, a dilatação mediada pelo fluxo (DMF) da artéria braquial e a dilatação nitrato-mediada (DNM). Foram incluídos 100 homens hipertensos com idade entre 50 e 70 anos, sendo 74 portadores de DE vasculogênica e 26 com função erétil normal que serviram de grupo controle. Nos pacientes com DE, o índice de massa corporal, relação cintura-quadril, EMI da carótida, níveis séricos de triglicerídeos, colesterol total e LDL foram significativamente maiores que no grupo controle. Após o uso de vardenafila on demand (fase 1), os pacientes com mais de 50% de respostas positivas ao PES3 ou 50% de respostas afirmativas e um incremento de 6 pontos ou mais em relação ao Índice Internacional de Função Erétil (IIEF-FE) basal e/ou resposta positiva a Questão de Avaliação Global (QAG), foram considerados respondedores. O escore do IIEF-FE basal se correlacionou negativamente com a EMI da carótida (r=-0,48, P<0,001) e com o escore de Framingham (r= -0,41, P<0,001) no grupo com DE. Houve forte correlação positiva entre a resposta clínica à vardenafila com a DMF (r= 0,70, P<0,001), que não se observou entre o sub-grupo de diabéticos. Os 35 pacientes considerados não-respondedores na fase 1 foram randomizados e, em desenho duplo-cego, receberam vardenafila ou placebo diariamente durante cinco semanas, podendo usar 10 mg de vardenafila uma hora antes da atividade sexual (fase2). Houve resposta clínica positiva em 38,8% dos que receberam a vardenafila na fase 2 e esta resposta se correlacionou com a frequência sexual (r= 0,68, P<0,01) e com o escore de Framingham (r= -0,65, P<0,01), com a EMI da carótida (r= -0,61, P=0,01) e com o LDL-colesterol (r= -0,64, P<0,01). A vardenafila foi bem tolerada em ambos os regimes terapêuticos. Concluímos que nessa amostra de hipertensos, a gravidade da DE foi relacionada a parâmetros vasculares estruturais (EMI), enquanto a resposta clínica à vardenafila on demand foi mais diretamente dependente da função vascular momentânea (DMF). Houve benefício na utilização de vardenafila diariamente com o objetivo de resgatar a eficácia do inibidor quanto à melhora do desempenho sexual. A falta de eficácia clínica ao inibidor da PDE5 em ambos os regimes terapêuticos pode servir como marcador clínico que identifica homens hipertensos com um risco cardiovascular aumentado.